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PHCL 412/512: introduction to pharmacology -Midterm Study Guide

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Lecture I

Introduction and History of Pharmacology Lecturer: Dr. Qin Chen, Ph. D. List of Terms:

Term Definition Pharmacology Science of drugs, from the Greek: Pharmakos = “medicine or drug” and

Logos = “Study” Pharmacy Uses of Drugs

Pharmaceutics The process of turning a new chemical entity into a medication. Pharmaceutical

Drug Chemical substance for medical diagnosis, treatment, or prevention of

disease. Pharmacopoeia A book containing directions for identification of samples and

preparation of compound medicines, published by the authority. = Textbook or Computer Database

Pharmacognosy Study of drugs from natural sources. A Brief History of Pharmacology: Pharmacology has studied and developed all over the word, particularly in China, the Islamic World, Egypt, and Greece, and utilized various natural sources, such as animal parts, plants, minerals. More recently, more synthetic compounds have be used in pharmacology. Shen Nong (or “Divine Farmer”) was one of the first predecessors of pharmacology, originating in 2000 B.C. He mainly specialized in Chinese herbal medicine, and wrote the Herb-Root Classic (Bencoao Jing, compilated by 300 B.C. – 200 A.D.). He discovered the effects of certain

herbs by testing them on himself. However, according to legend, he also passed away pursuing such research. Thoth was considered the Egyptian goddess of knowledge, and the Medical Book of Thoth (1550-1292 B.C.E.), the religious scroll, contain cures for diseases from plant and animal mixtures. The Ebers Papyrus (dating from 1552 B.C.E.) contained 700 “drugs”, such as beer, turpentine,

beries, poppy, lead, salt, minerals). This is the world’s oldest preserved medical and pharmacological record. It had 700 recipes for treatment of different medical conditions. Hippocrates (460-377 B.C.) was an Ancient Greek Physician from the Greek Island of Kos. He is considered the Father of Western Medicine, and separated medicine from religion and superstition. He discovered the pharmacological properties of the bark and leaves of the willow tree. The legend is that if an individual had a fever or was in pain, they could chew or consume the bark and leaves

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of the willow tree and such illness would subside. He attributed illness and sickness to an imbalance of certain entities in your body known as humors. Diocles of Carystus was another Greek physician who was considered a Younger Hippocrates. He studied a wide range of medicine, particularly anatomy, and wrote on pharmacotherapeutic treatises in 400 B.C.E. He emphasized also the use of diet, nutrition, and medicinal uses of plants. Pedanius Dioscorides (40-90 A.D.) was a third Greek physician who wrote the De Materia Medica, which was a 5-volume book containing Medical materials, and is still widely used for more than 1500 years. Aulus Cornelius Celsus was a Roman encyclopedist who wrote De Medicine, which was a compendium of eight books, in which books 5 and 6 consisted of pharmacology, which later contributed to diet and pharmacy. Galen (129-200 A.D.) was a Roman physician, surgeon, and philosopher who promoted Hippocratic teaching. He wrote 600 treatises totaling 10 million words. He researched on anatomy, physiology, pathology, pharmacology, and neurology based on dissections of monkeys and pigs. He discovered that the larynx is the main generator of voice. He also discussed the use of stimulants (agonists) and inhibitors (antagonists) in the circulatory system, nervous system, and respiratory system. The Islamic Golden Age (750-1257) was a series of efforts in the Islamic World to discuss pharmacology. Al-Kindi (801-873) was an Arab physician who wrote De Gradibus, a book on the mathematical calculations quantifying drug strength. Muhammad Ibn Zakariya Razi (865-915) promoted medical uses of chemical compounds. Sabur bin Sahl was an Arabic physician who developed the first pharmacopoedia as well as formulas preparation (869 A.D.) in the form of powsders, tablets, ointments, and syrups. Abu al-Qasim Al-Zahrawi (936-1013) was involved in liber servitoris as well as preparation of medicine by sublimation and distillation. Al-Biruni wrote the Kitab al-Saydalah (The Book of Drugs, 973-1050) which described the properties of drugs as well as the role of the pharmacy and pharmacist. Ibn Sinna (Avicenna) wrote the Canon of Medicine (the Law of Medicine, 1025) which described over 700 preparations, their properties, mode of action, as well as their indication. Al-Muwaffaq developed the foundations of the true properties of remedies, such as arsenious oxide, silicic acid, sodium carbonate vs. potassium carbonate, and discussed the poisonous nature of copper and lead compounds and the distillation of seawater for drinking.

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Phillippus Aureolus Theophrastus Bombastus von Hohenheim (1493-1541) took on the name Paracelsus (“equal or greater than Celsus”) and was a German-Swiss Renaissance physician, botanist, alchemist, and astrologer. He was involved in the use of chemical and minerals (zinc) in medicine. He is deemed by some as the father of toxicology, with his statement, “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.”

William Withering (1741-1799) was an English botanist, geologist, chemist, and physician. He was able to utilize an extract of the foxglove plant to treat dropsy (congestive heart failure), which allowed him to discover digitalis. Meriwether Lewis and William Clark led the Lewis and Clark

Expedition based with the Corps of Discovery (1804-1806) which was commissioned by President Thomas Jefferson. They studied plants, animal life, and geography in the Ohio Valley, and further supported the use of willow bark tea to treat fever and pains. Friedrich Serturner (1783-1841) was a German who isolated alkaloid from opium. He later overdosed himself and three friends from this alkaloid. This alkaloid was named Morphine, after the Greek god of dreams, Morpheus. He overdosed himself and his three friends on this same substance. Modern pharmacology arose from Friedrich Wohler (1800-1882), a German chemist who synthesized organic compounds, such as urea. He was also the co-discoverer of beryllium, silicon, aluminum, and isolated yttrium, beryllium, and titanium. Rudolph Buchheim (1820-1879) was a German pharmacologist who engaged in experimental science and modern pharmacology (since 1847). He was a professor at the University of Dorpat in Estonia, and established the first pharmacological institute. He developed his first pharmacology laboratory in the basement of his home, and developed the bioassay. He was also professor of pharmacology and toxicology at the University of Giessen. Oswald Schmiedeberg (1838-1921) was a medical doctor from the University of Dorpat, an 1866 recipient. He was the Professor of Pharmacology at the University of Strasbourg (since 1872) and developed the “Outline of Pharmacology” in 1878. He discovered the use of glucuronic acid as a conjugate in xenobiotic

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metabolism, an its relation in cartilage, collagen, and amyloid. He also discovered the muscarine effect on the heart, and is considered the founder of modern pharmacology. He trained most of the men who became professors at German universities and elsewhere. John Jacob Abel (1857-1938) received his M.D. in 1888 at the University of Strsbourg. He was the First chain in pharmacology at the University of Michigan (1891) and chaired the pharmacology department at Johns Hopkins University from 1893). He studied the isolation of epinephrine from adrenal gland extracts (1897-1898), as well as isolated amino acids from the blood (1914) and isolated histamine from pituitary extract (1919). He was able to prepare pure crystalline insulin (1926) and co-founded the Journal of Biological Chemistry in 1905 and the Journal of Pharmacology and Experimental Therapeutics (1909). Claude Bernard (1813-1878) was a French physiologist who experimented in medicine. He discovered the mechanism of curare (which was used as arrow poison) as it acts at the neuromuscular junction to interrupt the stimulation of muscle by nerve impulses (1842). He discovered the uses of pancreatic secretions in the digestion of fats (1848), and the secretions of glucose into the blood by the liver (1848), and discovered that the liver was the major producer of sugar (1855). He isolated glycogen (1857), and discovered the concept of homeostasis. Pharmacologists who have won the Nobel Prize (per ASPET)

Recipient Year Research Paul Greengard 2000 Signal Transduction in Nervous System

Robert F. Furchgott, Ferid Murad 1998 Nitric Oxide Alfred G. Gilman 1994 G-Protein Edwin G. Krebs 1992 Protein phosphorylation as a regulatory mechanism

Sir James W. Black, Gertrude B. Elion

1988 Chemotherapy

Earl W. Sutherland, Jr. 1971 Action of Hormones Julius Axelrod 1970 Humoral transmitters in nerve terminals

Linus Carl Pauling 1954 Chemical bonds in structure of complex substances Herbert Spencer Gasser 1944 Action potential of nerve fibers Corneille J.F. Heymans 1938 Brain control of blood pressure and oxygen content Sir Henry Hallett Dale 1936 Acetylcholine as neurotransmitter

Frederick Grant Banting 1923 Discovery of Insulin Nobel Prizes Closely Related to Pharmacology

Recipient Year Research Emil Adolf Von Behring 1901 Serum therapy against diphtheria

Frederick Grant Banting and John James Rickard Macleod

1923 Discovery of Insulin

Sir Henry Hallett Dale and Otto Loewi

1936 Acetylcholine as a neurotransmitter

Gerhard Domagk 1939 Sulfonamidochrysoidine (Prontosil) as antibiotics Sir Alexander Fleming, Ernst Boris

Chain, Sir Howard Walter Florey 1945 Discovery of Penicillin

Edward Calvin Kendall, Tadeus Reichstein, Philip Showalter Hench

1950 Adrenal Cortex Hormones

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Selman Abraham Waksman 1952 Discovery of streptomycin Daniel Bovet 1957 Drugs block neurotransmitters, antihistamines

Konrad Bock, Feodor Lynen 1964 Cholesterol and fatty acid metabolism Sir Bernard Katz, Ulf von Euler,

Julius Axelrod 1970 Synaptic neurotransmitters (catecholamines)

Earl W. Sutherland 1971 cAMP as second messengers for epinephrine Roger Guillernin, Andrew V.

Schally, Rosalyn Yalow 1977 Peptide hormones (TRH, GnRH)

Sun K. Bergstrom, Bengt I, Samuelsson, John R. Vane

1982 Discovery of prostaglandins

Michael S. Brown and Joseph L. Goldstein

1985 Regulation of cholesterol metabolism

Stanley Cohen, Rita Levi-Montalcini

1986 Discovery of growth factors

Sir James w. Black, Gertrude B. Elion, George H. Hitchings

1988 Antimetabolites for chemotherapy

Edmond H. Fischer, Edwin G. Krebs 1992 Reversible protein phosphorylation Alfred G. Gilman, Martin Rodbell 1994 G-proteins

Robert F. Furchgott, Louis J. Ignarro, Ferid Murad

1998 Nitric Oxide

Arvid Carlsson, Paul Greengard, Eric R. Kandel

2000 Signal transduction of nervous system

Major Pharmaceutical Companies Rank Country Company

1 U.S.A. Pfizer 2 Switzerland Novartis 3 U.S.A. Merck and Company 4 Germany Bayer 5 United

Kingdom GlaxoSmithKline

6 U.S.A. Johnson and Johnson 7 France Sanofi 8 Switzerland Hoffman-La Roche 9 United

Kingdom AstraZeneca

10 U.S.A. Abbott Laboratories 11 U.S.A. Bristol-Myers Squib 12 U.S.A. Eli Lilly and Company 13 U.S.A. Amgen 14 Germany Boehringer Ingelheim 15 U.S.A. Schering-Plough 16 U.S.A. Baxter International 17 Japan Takedo Pharmaceutical Company 18 U.S.A. Genentech 19 U.S.A. Procter and Gamble

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Lecture II

Pharmacodynamics and Pharmacokinetics Lecturer: Dr. Patrick Ronaldson, Ph. D. Pharmacokinetics is defined as how the body deals with drugs, from the Greek word pharmakon (meaning drug) and the word kinetic (meaning movement). It studies the quantitative analysis of the relationship between the dose of a drug and the ensuing changes in drug concentration in the blood and other tissues. There are many pharmacological and chemical events involved when an individual takes a pill, including absorption, metabolism, and clearance. Pharmacokinetics, or how the drugs are handled by the body, is organized into four distinct phases, giving the acronym ADME:

1. Absorption 2. Distribution 3. Metabolism 4. Elimination

The illustration provides an extremely detailed overview of ADME. As the drug is broken down, facilitating the chemical’s liberation from the tablet form. It must then be absorbed into the bloodstream, and possibly bound to plasma proteins, namely albumin. Drugs are not always administered orally. This complex system can involve enteral methods of drug delivery (sublingual, oral, rectal), parenteral (subcutaneous, intramuscular, intravenous, spinal, and intraosseal), or even topical (skin and inhalation). Pharmacokinetics is an attempt to explain with physiologically, anatomically, and chemically the drug and its action. However, it is important to understand drug movement across the membrane. How does a drug move across these cellular barriers? Drugs do need to be absorbed and also need to cross a barrier. There are really only four discussed forms of movement across cellular barriers:

1. Paracellular Transport: Movement of hydrophilic compounds across with the assistance of channels.

2. Diffusion: Movement of compounds

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across the membrane with 3. Facilitated Diffusion: Use of membrane carriers to move

hydrophilic compounds. 4. Drug Transporters: Transmembrane proteins that utilize the

energy of ATP hydrolysis to carry biological processes. However, there are many considerations in the part of the drug as well as on the part of the tissue that can affect the drug’s absorption. On the part of the drug, absorption can be affected by the following:

1. Lipid Solubility: More hydrophobic compounds may move more readily than more hydrophilic compounds. However, it is important for the compound to not have 100% lipophilicity because it can impede the passage of drugs.

2. Molecular Size and Weight: Large bulky drugs cannot cross well. For example, proteins cannot cross the membrane of the gut for this reason.

3. pKa-value: This value can help up determine the ratio of unionized and ionized forms of the compound, and can affect the ability to cross the gastrointestinal (GI) tract.

Absorption can be affected by membrane permeability by the following:

1. Membrane Permeability: The lipid composition plays a role. 2. pH: pH of the tissue can affect the absorption rate. 3. Local Blood Flow: Well-perfused organs can allow higher rates of

drug absorption in comparison to poorly-perfused organs.

4. Local Anatomy: The small intestine tends to provide a better absorptive environment in comparison to the stomach because of the intestinal villi.

5. Transport Mechanisms: Different mechanisms have different rates.

We can examine the movement of drugs in the body through permeation and Fick’s law. Movement is affected by three things: (1) Permeation, (2) Fick’s Law of Diffusion, and (3) Water and Lipid Solubility. The following is a table summary of the membrane permeation.

Mechanism Active/Passive? Governed by Fick’s Law? Aqueous Diffusion Passive Yes

Lipid Diffusion Passive Yes Transport by Special Carriers Active (but is capacity limted) No

Endocytosis, Pinocytosis Active No But what is Fick’s law of diffusion? Fick’s Law of Diffusion predicts the rate of movement of molecules across a barrier, and states that most drugs move down their concentration gradient in passive diffusion. It is calculated as the following:

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𝑅𝑎𝑡𝑒  𝑜𝑓  𝑁𝑒𝑡  𝐹𝑙𝑢𝑥   𝐽 = !"#$%#&'(&)"#  !"#$%&'( ×!"#$"%&'(')*  !"#$$%&%#'(  ×  !"#$!"#$%&'"  !!!"#$%&&

or   𝐽 = !×!×∆!

∆!.

Water and lipid solubility is the third factor in the movement of drugs in the body. Aqueous diffusion depends on the degree of ionization, as water likes charges. Lipid Diffusion is pH dependent, as many drugs are weak acids or weak bases. Thus, the ionization of weak acids and bases can be determined by the Henderson-Hasselbach equation which is simply described as the following equation: 𝑝𝐻 = 𝑝𝐾! + log

[!"#$%&%"'&()][!"#$#%&$'(]

. For weak

acids, it can be calculated as: 𝑝𝐻 = 𝑝𝐾! + log!!

!". For weak bases, it can be

calculated as: 𝑝𝐻 = 𝑝𝐾! + log[!]

[!"!]. Most drugs are either weak acids, weak

bases or amphoteric. A drug’s pKa value represents the pH at which 50% of the molecules in solution are ionized, where there is an equal ratio of ionized and non-ionized compounds. Acids are increasingly ionized in a basic environment. Bases are increasingly ionized in an acid environment. For example, aspirin is a weak acid, and is readily absorbed across the stomach lining. Differences in the pH of body fluids can lead to drug “trapping” in certain compartments, which can lead to changes in absorption and/or elimination.

Body Fluid Range of pH Stomach 1.9-2.6 Intestine 6.4-7.6

Urine 5.0-8.0 Breast Milk 6.4-7.6

It is important to remember that drugs will not diffusion in its ionized form, but only in its non-ionized form. Such elements of the Bronsted-Lowry acids and bases can facilitate ion “trapping” by the kidney. Pyrimethamine is a weak base of pKa = 7.0. The urine pH can be adjusted from 5.5 to 8.0. To acidify urine, one can utilize NH4Cl, while making urine more alkaline requires the addition of NaHCO3. This is because the ionized for is not reabsorbed, and can be rapidly excreted. In an overdose of a weak base, you can acidify urine with NH4Cl, while overdose of a weak acid typically requires alkalinzing urine with NaHCO3. Essentially, we can manipulate the urine to allow non-ionized compounds to be excreted out of the body. Drug formulations are important because they can help determine the rate of absorption. They can be given as liquids, tablets,

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enteric-coated tablets, etc. The rate of absorption for various preparations is as follows (from fastest to slowest):

1. Liquids 2. Suspension Solutions 3. Powders 4. Capsules 5. Tablets 6. Coated Tablets 7. Enteric-Coated Tablets

A secondary part of drug absorption is complexation. The drug can be liberated or inhibited in the presence of other compounds in the stomach. As seen with tetracycline, an empty stomach optimizes tetracycline absorption over time. However, the presence of divalent and trivalent cations can promote chelation with tetracycline. A third part of drug absorption is the alteration in GI motility. It can determine whether a compound sits in the GI tract longer or shorter and can consequently affect absorption. Propantheline decreases the GI transit, causing more absorption of digoxin. Metoclopramide increases GI transit, and spur less absorption of digoxin. The point is that you can speed up or slow down transit, and can possibly affect absorption. The final consideration is interference with drug absorption. Charcoaid interferes with drug absorption because it is a terrific binding agent. Essentially, it binds with the drug in question and then allows the drug to be passed through the stool. Now, we are in the D in ADME, or Distribution. The distribution of drugs can be affected by four factors:

1. Size of Organ: The skeletal muscle is a large organ that is difficult to fill, while the brain is a smaller organ that fills quickly. Larger organs are much more harder to fill, while smaller organs can fill up quickly.

2. Blood Flow: Well-perfused organis will achieve high tissue concentrations. Poor organs will yield low tissue concentrations.

3. Solubility: Highly lipid soluble drugs like organs and tissue with high lipid content, such as in the brain.

4. Binding: Particularly plasma protein binding. When drugs are bound to plasma proteins, you can increase the free concentration of a drug by introduction with another drug.

In protein binding, the major plasma protein is albumin. If you have a drug, such as D1, that

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has is bound at a certain percentage. With the introduction of another drug that has higher binding (D2), you can increase the concentration of free D1 in the system. Placental transfer is another mechanism in the alteration of drug distribution. Pregnancy is a very big thing because the placental membrane is not only a membrane but has a lot of efflux transporters. Drugs that are introduced to the mother can cross to the fetus. However, there are some drugs that are charged, and consequently cannot cross the placenta, while other drugs are noncharged and can cross the placenta, as seen in the comparison between thiopental and tubocurarine. The blood-brain barrier is a series of tight-junctions consisting of astrocytes and capillaries. Tight-junctions are ideal because they limit paracellular diffusion and provide high trans-endothelial resistance (approximately 6,000 Ohms per square centimeter). It is extremely tight. Tight junctions are dynamic protein complexes. The brain acts to maintain homeostasis. There are a variety of transporters at the luminal (blood) and abluminal (brain) side of the endothelial cell:

1. ATP-Binding Cassette (ABC) a. P-Glycoprotein: They are considered the “gorillas” of the

transpoters. They limit drug absorption at the brain. They protein tissues from toxins and exogenous chemicals. The better question to ask is what drugs are NOT substrates for the transport.

b. Multidrug Resistance Proteins c. Breast Cancer

Resistance Protein 2. Solute Carriers (SLC)

a. Organic Anion Transporting Polypeptides

The blood-brain barrier helps maintain homeostasis and restricts access to toxic xenobiotics/metabolites. Orally observed drugs undergo a first-pass effect, which is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches systemic circulation. Basically, a fraction of drug

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is lost during the process of absorption. It is generally related to the liver and gut wall. The drug is swallowed and it is absorbed by the digestive system and consequently enters the hepatic portal system. It is carried through the portal vein into the liver before reaching the body, metabolizing many drugs to the point of metabolizing little that enters into the circulatory system. This creates a reduction in the bioavailability of the drug. The primary systems affected are (1) the gastrointestinal lumen, (2) gut wall enzymes, (3) bacterial enzymes, and (4) hepatic enzymes. There are significant differences between oral and intravenous administration. The onset involves the drug reaching the liver and getting metabolized. In intravenous administration, the duration of a drug is shorter in comparison to the same drug administered orally. Bioavailbility (F) is the fraction of drug absorbed into the systemic circulation. Bioavailibility is calculated as:

!"#$  !"#$%  !!!  !"#$%  (!"#$%)!"#$  !"#$%  !!!  !"#$%  (!"#$!"#$%&')

×100 . The bioavailability (F) can change with different modes, and with such changes in bioavailability, there are changes in half-lives. What happened to the drug? It got metabolized. We can discuss another factor, namely the apparent volume of distribution (Vd). It is pharmacological/theoretical volume that a drug would have to occupy if it were uniformly distributed to provide the same concentration in blood plasma. Drugs move between compartments. When the drug is absorbed in blood, it can move to the site of action and to peripheral tissues. The Volume of distribution is the volume that relates the amount of drug given to the body to the plasma concentration. It is calculated as: 𝑉! =

!"#$%&  !"  !"#$  !"  !!!  !"#!  (!")!"#$%#  !"#$  !"#!$#%&'%("#  (!"

! ). If the

therapeutic serum concentration of a drug is known, you can calculate the dose to give based on the apparent volume of distribution. The dose is calculated as: 𝐷𝑜𝑠𝑒 = 𝑉!×𝐶! , where Cp is the plasma concentration in milligrams per Liter. Remember that the apparent volume of distribution is the volume of fluid which the drug would occupy if it were evenly distributed through that volume at the concentration measured in the plasma (central compartment). It is largely an abstract or theoretical concept since it does not represent an actual physical volume inside the animal. The Vd relates the dose of drug administered to the resulting concentration in the plasma. It is utilized because of convenience and because the ratio of the dose administered to the plasma concentration has units of volume. The volume of distribution rarely corresponds to an actual physical volume. The ranges of volumes of distribution are as follows:

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However, we can notice several trends. A lipophilic drug will tend to have a larger volume of distribution. However, a drug with a high affinity for plasma proteins will have a small volume of distribution. The key points are that (1) drugs with a large Vd mean that a typically larger dose of drug will be needed to achieve a target drug concentration in the plasma and ultimately the desired response and (2) lipid-soluble drugs have a larger Vd than water-soluble drugs. Drugs are distributed in multiple phases. First phase drugs are distributed to high flow areas such as the heart, liver, kidneys, and brain). Later phases drugs are distributed to “low flow” areas such as bones, fat, and skin. Metabolism and Excretion are the M and E of ADME. Metabolism will be covered in the next lectures. However, the movement of drugs are between compartments, and there are alteration of drug excretion, such as (1) GI & Biliary (minor), (2) Kidneys (major), Lungs (minor), and Skin (minor). Kidneys are the major route of excretion. The enterohepatic circulation is the major circulation involved in biliary excretion and GI elimination. The kidneys are the more major contributor to excretion. The kidneys contain a multitude of transporters, which allow the kidneys to handle a multitude of drugs. What is the major determinant of kidney function is renal clearance. When blood goes to the kidney, the drugs get filtered out, and is consequently processed and eliminated. In renal epithelial, there is a diversity of transporters. We can know how fast a drug is metabolized or eliminated from the body by biological half-life, and we also need to understand the concept of clearance. Clearance relates the rate of elimination to the plasma

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concentration. It is essentially the amount removed per unit time.

Clearance is calculated by the following: 𝐶𝐿 =!"#$  !"  !"#$#%&'#(%  !"  !"#$  (!"

!! )

!"#$!"  !"#$  !"#!$#%&'%("#  (!"! )

.

Most drugs are cleared by the kidneys and relate to renal clearance, which is defined as the volume of plasma that is totally cleared of a drug in one minute during passage through the kidneys. In order to understand clearance, we need to understand kinetics. There are two types of kinetics discussed in pharmacology:

1. Zero-Order Kinetics: The rate of elimination is constant regardless of concentration. There is a fixed amount of drug that can be handled at any time.

2. First-Order Kinetics: The rate of elimination is proportionate to the concentration, where the higher the concentration, the greater the amount of the drug eliminated per unit time. A constant fraction of the drug is metabolized per unit time. Note that for many drugs that are cleared by the kidneys, the clearance rate is dependent on the blood flow through that organ.

It can be summarized in the following table Rate Order Description Visual Zero-Order Constant rate of elimination

First-Order Rate of elimination if proportional to concentration

This introduces the concept of half-life. The half-life (t1/2) is the derived parameter, completely determined by volume of distribution (Vd) and clearance (CL). It is calculated by: 𝑡!/! =

!.!"#×!!!!

. There is also a concept of multicompartment distribution, where after absorption, many drugs undergo an early distribution phase followed by a slower elimination phase. There is a back and forth between blood and tissues. Half-life determines the rate at which blood concentration rises during constant infusion.

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As a physician or practitioner, it is important to achieve the desired drug levels. The amount of drug delivered is equal to the amount metabolized

and eliminated (steady state, Cpss). Steady state is attained after approximately four half times. The time to steady state is independent of dosage. Steady-state concentrations are proportional to dose/dosage interval and are proportional to the ratio of bioavailability to clearance. The fluctuations are proportional to dose interval/half-time. It is blunted by slow absorption. The multiple dosing regimen is given at each half-life. It takes 5 half-lives to reach steady state. The half-life is important because it determines the rate at which blood concentration rises during constant infusion. What will increase the plasma half-life? It can be increased by (1) an increased volume of distribution and (2) decreased clearance. However, the dosage often needs to be adjusted when elimination is altered by disease. In renal disease or reduced cardiac output, there is a reduction in the clearance of drugs. We can correct the dose by the following calculation: 𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑  𝐷𝑜𝑠𝑒 =  !"#$%&#  !"#$  ×!"#$%&!

!!  !"#$%!"!"#  !"#$%$&'#!""  !"/!"#

. Normal creatinine clearance is around 100 mL/min or 6 L/hr. In males it is between 97-137 mL/min. In females, it is 88-128 mL/min. Males tend to have a higher creatinine clearance because they have a higher degree of skeletal mass. However, creatinine clearance is affected by age. Each decade corresponds to a decrease of about 6.5 mL/min. Now another question arises. How do I maintain a constant blood level of a drug? This can be done with dose regimens, and even giving a loading dose. Dose Regimens is a plan for drug administration over a period of time. It is important to achieve therapeutic levels of the drug in the blood, without exceeding the minimum toxic concentration. If the therapeutic dose must be achieved rapidly and the Vd is large, then a large loading dose may be needed to onset the therapy. The loading dose is calculated as the following equation: 𝐿𝑜𝑎𝑑𝑖𝑛𝑔  𝐷𝑜𝑠𝑒 =  !"#$%&  !"  !"#$%"&'$"()  ×!"#$%"&  !"#!"#  !"#$%#&'(&)"#

!"#$%$"&$'"&"(). This is roughly translated as

𝐿𝐷 =!!(!)×!!""(

!"! )

!. Dose regimens are a plan for drug administration over a

period of time. It is necessary to achieve therapeutic levels of the drug in the blood, without exceeding the minimum toxic concentration. The maintenance rate (maintenance dose) of drug administration is equal to the rate of elimination at steady state. The maintenance dose is a function of clearance. It can be calculated as:

𝑀𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒  𝐷𝑜𝑠𝑒 =   !"#$%$&'#  ×!"#$%"&  !"#$%#  !"#$%#&'(&)"#!"#$%$"&$'"&"()

or 𝑀𝐷 =!"( !!!)×!!""(

!"! )

!.

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Lecture III

Drug Metabolism and Pharmacodynamics Lecturer: Dr. Patrick Ronaldson, Ph. D. Metabolism is the M in the ADME, and alteration of drug metabolism is impotant when it comes to drugs and drug products. It consists of three major concepts:

1. Lipophilic to Hydrophilic: If we are to ultimately eliminate drugs via the kidneys, we need to make from a lipophilic compound to a hydrophilic compound.

2. First Pass Effect (in oral administration): It can affect a lot of things.

3. Cytochrome P450 However, in order to understand metabolism, we need to understand biotransformation. Biotransformation is the process in which drugs are modified by the organism. Usually, any sort of biotransformation process involves enzymes. It happens with respect to drug metabolism. Enzymes are there to metabolize endogenous substrates, vitamins, steroids, hormones, etc. The biotransformation of metabolism focuses on decreasing the lipid solubility, eventually making the drug more water-soluble. Drug metabolism decreases lipophilicity, and makes it water soluble for elimination through the kidneys. Once again, the purpose of biotransformation is to allow a chemical transition from lipophilic to hydrophilic. It involves taking the active drug and converting it to a metabolite. Metabolites can act as an active drug, active toxicant, or become inactive. There are even compounds known as pro-drugs that readily convert to the active compounds. How do we relate the concentrations to the effect? If we look at the curve, as the drug concentration increases in serum, we have a delay in effect. When the drug reaches its peak, the effect is delayed, but the drug’s concentration begins to fall. Therefore, drug concentration is proportional to drug effect. Where can we see biotransformation? We can see it in many chemicals, such as ethanol and thiopental. Ethanol, without the aid of biotransformation, can remain in the body for approximately four weeks. With the effects of biotransformation, it can last in a much shorter period (approximately 20 mg/dL/h). Thiopental would remain in the body for years without biotransformation, but fortunately it can be cleared from the body in 3-8 hours with such chemical processes. With oral administration, we do need to take into account the First Pass Effect. When you take a drug that is absorbed across the wall, the drug can hit many things in the liver. The liver then can metabolize out the drug.

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The concentration gets thinner. The liver is not the only tissue that can metabolize the drug. There can be metabolism in other tissues as well. The drug is taken into the GI tract and is absorbed into the GI wall. Then the drug is placed into the hepatic vein and pumped into the aorta. Some of the drugs can get back into the hepatic artery and go into the liver and be cycled to clearance. The drugs travel through the celiac artery and superior and inferior mesenteric arteries and go back into the GI tract. This provides an efficient means of filtering a drug out through recirculation. The concentration of drug in plasma can drop quickly after administration. Biotransformation can be dictated by two types of reactions: (1) Phase I and (2) Phase II. Phase I reactions include (1) oxidation (with Cytochrome P450), (2) reduction, (3) deamination, and (4) hydrolysis. Phase II reactions involve addition (i.e., conjugation) of subgroups to –OH, NH2, and –SH function groups on a drug molecule. This is not saying that they’re sequential. Some compounds may only need to be metabolized by Phase I reactions while other compounds may go directly to Phase II reactions. But the biotransformation can give a lot more pharmacological knowledge. It determines the therapeutic half-life. It may produce the active metabolite, and also allows a site of “drug-drug interaction”. The results of biotransformation can be the halting of the pharmacological effect, with an exception, where there is production of an active metabolite. It restricts distribution, and facilitates excretion, making the drug much more hydrophilic. The major organs involved in biotransformation include:

1. The Liver (High Capacity) 2. Intestines, Lung, Kidney (Medium Capacity) 3. Skin, Testis, Placenta, Adrenals (Low Capacity) 4. Brain? à It is starting to be more appreciated as an organ that

metabolizes drugs, mainly because the substrate specificity is greatly restricted in brain.

So, we see biotransformation with a simple chemical, such as benzene. Benzene is a notably hydrophobic compound, with an aromatic ring and no function groups. It has an extremely low solubility (1/1,430). When benzene undergoes the Phase I reaction, it is converted to phenol (a hydroxyl group replaces one of the protons), bringing its solubility to 1/15. However, with a pKa in physiological conditions at 10, it is much difficult to deprotonate the hydroxyl group in phenol. When phenol undergoes a Phase II reaction, then it is converted to glucuronide, bringing its solubility to 1/3 and the pKa to 3.4, allowing deprotonation and secretion out into the urine.

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We can also see a Phase I biotransformation, occurring with a variety of substrates, a variety of reactions (especially those with oxidation or hydroxylation). It can allow reactive oxidation, or even add or expose a functional group. One key part of the Phase I biotransformation involves the Cytochrome P450 Family. The Cytochrome P450 Family consists of eighteen groups of enzymes, with 54 subfamilies that are classified according to biochemical characteristics. The predominant one in humans is the CYP3A4/5, which performs approximately 36% of Phase I metabolism. It can also be noted that 50% of all drugs utilize CYP 3A4/5. One kind of Phase I reaction is hydrolysis. It involves esterases and amidases. It essentially adds water across a covalent bond, and exposes the function group(s). This occurs in most tissues and in plasma. Other reactions can include aromatic hydroxylation and hydrolysis with amidase, with the example in Mepivicaine. Phase II Biotransformation may involve coupling of a new function group to a drug or metabolite (through conjugation). The purpose is to increase water solubility and ionization. The result is to enhance renal or biliary excretion. Phase II biotransformations help yield pharmacologically inactive compounds. Particular molecules can undergo several Phase II reactions. Major Conjugation Reactions are listed:

Conjugation Conjugate Chemical Group

Reactions

Glucuroni-dation

Acidic sugar -OH, -COOH, -NH2, -SH

Sulfation Sulfate -OH, -NH2 Methylation CH3+ -OH, -NH2 Acetylation CH3COO- -NH2 Amino Acid Amino Acid -COOH

Glutathione GSH Electrophiles

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One example of a glutathione conjugation is the conjugation of Tylenol to mercapturic acid, a cysteine conjugate. Mercapturic acids are extremely hydrophilic and can consequently be eliminated easily.

There are two types of agents that can affect the rate of

biotransformation: inductors and inhibitors. Inductors increase the rate of biotransformation, and

can spur increased expression of

biotransformation enzymes. Inductors can ultimately decrease the plasma concentration of a

drug due to metabolism of the drug. Ultimately, this results in a decreased half-life. Some of the major players Inhibition leads to a decreased rate of biotransformation. It is involved in drug-drug interactions, and results in an increased half-life. For instance, grapefruit juice inhibits CYP3A4. Another example is that cimetidine inhibits many cytochrome p450s. The following is a list of inducers and inhibitors:  

Inducers Inhibitors St. John’s Wort Grape Fruit Juice Phenobarbital Cimetidine Pentobarbital Valproic Acid

Carbamezapine Verapamil Phenytoin Ketoconazole Rifampin Haloperidol Modafinil

Now it is important to discuss pharmacogenetics, mainly to introduce the human variation in biotransformation. Humans are physiologically and physically different. Different races utilize different

CYP450 enzymes. There are two types of outliers, namely rapid metabolizers and poor metabolizers. Rapid metabolizers have lower than normal serum concentrations, while poor metabolizers have higher than normal serum concentrations. Some drugs can affect poor metabolizers and drug-drug interactions at some CYP450 enzymes, such as Serzone (Nefazodone HCL) with CYP3A4. Other variables affecting drug metabolism include:

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§ Enzyme Induction § Enzyme Inhibition § Diet § GI Flora § Age § Disease § Genes § Sex

The following table describes the statistical differences in the various demographics and metabolic pathways:

Metabolic System CYP 2C19 CYP 2D6 CYP 1A2 Drugs Metabolized via

Pathway S-mephenytoin,

Omeprazole, Others Codeine, Dextromethorphan,

Tricyclic Antidepressants, Captopril, Flecainide, Many Others

Caffeine, Theophylline, Acetaminophen,

Propranolol, Others % of Caucasians

(decreased or low activity)

3-5 3-10 12-13

% of Blacks (decreased or low activity)

3-5 0-2 12-13

% of Asians (decreased or low

activity)

18-23 0-2 12-13

Men and women have different drug metabolism. For instance, men metabolize drugs such as chlordiazepoxide and diazepam faster than women. This is because such drugs can distribute into fat, increase the half-life and decrease clearance rates of the drug. Aging can also increase the half-life of drugs. Diseases can affect biotransformation also, mainly because CYP450 enzymes are also affect and the liver is the site of biotransformation. Bioactivation is actually where the metabolite can lead to a reactive intermediate. Some reactive intermediates are toxic and can bind to nucleic acids or proteins. For instance, acetaminophen transformation and bioactivation can produce reactive intermediates that can cause necrosis, brain edema, and death. However, it is easily cleared out of the system. However, with use of alcohol, the reactive intermediate of acetaminophen is often not cleared as fast, and can dwell in the liver and bloodstream. Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorgnisms or parasites within or on the body and the mechanisms of drug action and the relationship between concentration and effect. Essentially, it studies the mechanism of drug action. Receptors are specific molecules in a biological system that drugs

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interact with. The interaction between a drug and a receptor produces a change in the function of the system. Most receptors are proteins, having high affinity but low capacity. Effectors are molecules that translate the drug-receptor interaction into a change in cellular activity. When we get drug receptor-effector response, the drug binds, something happens in the cell, and an effect occurs. In order for drugs to interact to receptors, they should have (1) shape, (2) size, (3) charge, and (4) atomic composition. This ultimately leads to the “lock and key theory” of drug-receptor interaction. The drug acts like a key and the receptor acts like a lock. When it interacts correctly, it can create a drug-receptor complex. The binding of a drug to its particular receptor can be dynamic. How well a drug binds to a receptor is dictated by the affinity of the drug for the receptor. This can be shown by the following reaction:

Essentially, this illustrates that if the rate of the reverse reaction is much more favorable than the rate of the forward reaction, then the scenario would provide a low dissociation constant (Kd). A low dissociation constant allows for high affinity. When concentration of a drug is equal to Kd, then the drug will occupy 50% of its receptors. This formula demonstrates that as affinity decreases, the receptor occupancy will also decrease: 𝑓 = !"#$!!"#"$%&!  !"#$%&'&(

!"!#$  !"#"$%&!'= !"

! ! !"= !

! !!!.

The majority of all receptors are proteins, and receptors bind with drugs and bring about a change in cell function. The evidence is in (1) the extreme potency/efficacy of drugs, (2) chemical selectivity (i.e., similar molecules producing similar effects), and (3) molecular cloning and reconstitution. Sometimes a change in one carbon will still allow some difference in shape, while enantiomers may yield one desired effect in one enantiomer over another. From a structural point of view, one enantiomer may fully occupy the receptor binding pocket, while the other enantiomer only provides a partial match. This shows the stereo-selectivity of the receptors. Drug receptors consist of three interrelated components, with (1) recognition, (2) transduction, and (3) amplification. Recognition is mainly the interaction between the drug and receptor. Transduction is the recognition of the signal to cause activation or inhibition, and amplification is mainly the exponential expression for a desired effect. There are several types of receptors and their effectors, as shown:

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Dose-response curves are considered the cornerstone of pharmacology. The EC50 is the effective concentration for 50% response. Another curve is the log-dose response curve. You can tell two things from dose-response curves:

1. Potency: amount of drug required to produce a response. It can cause a left/right shift of the dose-response curve.

2. Efficacy: Ability of a drug to induce a maximal response. This can be determined by the height of the dose-response curve.

There are two types of drugs: agonists and antagonists. Agonists bind to a receptor and elicit a pharmacological effect. Antagonists bind to a receptor but do not elicit a pharmacological effect. Antagonists can prevent/inhibit the ability of an agonist to bind and elicit an effect. There are several types of agonist:

1. Full Agonists: They bind and activate a receptor, displaying the full efficacy of the receptor.

2. Partial Agonist: Receptor elicits a biological effect or a balance of activated and inactivated receptors’ affinity for active form. There is no full biological effect.

3. Inactive Compound (Antagonist): Have equal preference for the activated and inactivated receptors.

4. Inverse Agonist: Opposite effect of what the agonist would do due to affinity for the inactivated receptor.

There are also three types of antagonists:

1. Competitive Antagonist: Competition for the same binding site 2. Noncompetitive Antagonism: Binds but the affinity is so much

greater to allow competition by the drug.

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3. Allosteric Inhibition: Binding to a site away from the binding site to block the action of the binding site.

We can see the effects of a competitive antagonist in a dose-response curve, particularly in acetylcholine to induce smooth muscle contraction. A partial agonist produces an effect if no full agonist is present, but acts as an antagonist in the presence of a full agonist. Drugs can also produce more than one effect as the dose increases. One example is morphine. As the dosage increases, the effects can range from constipation and antitussive effects to respiratory depression and death. Now it often goes into the question the therapeutic index. It is a comparison of the amount of the therapeutic agent that causes the

therapeutic effect to the amount that causes death or toxicity. Succinctly, it is how selective is a drug in producing its desired effects versus its adverse effects. It can be calculated by the following formula: 𝑇𝐼 = !"!"

!"!", where LD50 is the lethal dose

while the ED50 is the effective dose. With drug safety, there must be understanding of the therapeutic window. The therapeutic window of a drug is the range of drug dosages, which can treat disease effectively while staying within the safety range. It is,

succinctly, the range of steady-state concentrations that provides therapeutic efficacy with minimal toxicity. It is calculated by: 𝑇𝑊 =!"#$%&$  !""#$%

!!!"#$!%&'(  !""#$%= !"#"$%&  !"#$%  !""#$%

!!!"#$!%&'(  !""#$%. However, there are several factors

influencing dose-response relationships:

In review, agonists retain affinity, selectivity, potency, and efficacy. Antagonists retain affinity, selectivity, and potency. Competitive antagonists decrease potency, and non-competitive antagonists decrease both potency and efficacy. The drugs often produce more than one effect. Drug response depends on the tissue it acts on.

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Lecture IV

Drug Receptor and Targets Lecturer: Dr. Qin Chen, Ph. D. In previous lectures, pharmacology was discussed in terms of drug action in two fronts, the molecular level and the systemic (whole organism) level. At the molecular level, we can observe that the drug’s mechanism can yield a biological effect. For example, aspirin will bind to cyclooxygenase. At the whole organism level, we can see the therapeutic effect of a drug and its unwanted, adverse, or side effect. Drugs can affect a patient therapeutically or adversely. They result from drug interaction with specific molecules in our body. It is important to understand what drugs interact with which receptor. All drugs have a biological effect. It not only has the desired effect, but also has undesirable effects. There are many biological effects of drugs:

§ Killing harmful invading organisms, such as bacteria and viruses (as in antibiotics and antiviral drugs).

§ Killing cancer cells (chemotherapeutic agents) § Neutralizing acid (antacids). § Modifying underactive physiological process (e.g. insulin) § Modifying overactive physiological processes (e.g. enzyme

inhibitors) The mechanism of the biological effects of drugs is in the interaction between an exogenous chemical (drug) and the endogenous biochemical target (receptor). The drug is essentially interacting with the target molecule. Knowing which receptor is involved in which disease is important in the development of drugs. Drug-receptor interaction is important for therapeutic decisions in clinical practice. Why should we understand the drug receptor concept? It is important for three reasons:

1. Receptors largely determine the quantitative relations between dose or concentration of a drug and its pharmacological effects.

2. Receptors are responsible for the selectivity of drug action. 3. Receptors mediate the actions of pharmacologic agonists and

antagonists. Ultimately the receptors are the agents that give off the response.

The drug receptor is a drug target. The receptors consist mostly of protein. However, there are some drugs that do not target a protein, such as

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antacids (Calcium carbonate or magnesium hydroxide) and charcoal. Some drug receptor proteins can include (but are not limited to):

§ Enzymes § Endocrine factor receptors, such as G-protein coupled receptors,

tyrosine kinase receptors, and nuclear hormone receptors. § Signaling molecules § Ion channels § Cell structure proteins

There are two locations of receptor:

1. Cell surface, such as those receptors for growth factor, endocrine factor, G-protein coupled receptors, and ion channels. Classic receptor proteins are plasma membrane proteins to pharmacologists and microbiologists.

2. Intracellular Receptors, such as those for enzymes and nuclear receptors.

However, another question arises. Does one ligand code for only one receptor? The answer is no. A single ligand can code for multiple receptors, depending on:

§ Pharmacologically distinct types that are coded by different genes. The amino acid sequences can be very different.

§ Subtypes, which allows relation in terms of amino acid sequences. § Structure of the receptor: One receptor can be made of different

subunits. § Post translational modifications § Downstream signaling pathways § Tissue distributions: Can be dependent on the receptor as well as

the associated vasculature. § Abundance and Ratio § Factors affecting receptor expression

There are several examples of such drugs. One of them is the Dopamine Receptor. There are several different subtypes of dopamine, and are different in terms of distribution, amino acid sequence and/or post-translational modifications, and in downstream signaling. The table describes these dopamine receptor subtypes:

Dopamine Receptor Subtype

Organs Expressed Downstream Signaling Molecules

D1 Widely expressed throughout the brain, pulmonary artery

Gαs and activation of adenylate cyclase

D2 Pulmonary Artery Gαi and inhibit adenylate cyclase D3 Brain (Islands of Calleja and Nucleus

Accumbens) Gαi and inhibit adenylate cyclase

D4 Pulmonary Artery, Atria, Polymorphisms associated with ADD

Gαi and inhibit adenylate cyclase

D5 Pulmonary Artery Gαs and activation of adenylate cyclase

Another example involves the catecholamine receptor (adrenoceptor) subtypes. There are pharmacologically distinct types, α and β. They are

26

different in amino acid sequences due to different genes, and are different in downstream signaling molecules. A table describes the following: Type Subtype Downstream Signaling Molecule α 1 Gq coupled receptor

2 Gi coupled receptor β 1 Gs coupled receptor

2 Gs coupled receptor, Gi coupled receptor 3 Gs coupled receptor

A common feature of ligand binding to membrane receptor is signal transduction. When a extracellular ligand binds to a receptor at the membrane, it spurs signal transduction to yield a biological effect. What the binding essentially does is spur an intracellular effect to produce that biological effect. What triggers signal transduction is another field of study. There are several types of receptors, which can be described in the following table: Receptor Diagram Description Examples G-Protein Coupled Receptor

Large protein family of transmembrane receptors

that sense molecules outside the cell and

activate inside signal transduction pathways, and ultimately cellular

responses.

Dopamine, Muscarinic

Acetylcholin, Opioid,

Angiotensin, Oxytocin,

Rhodopsin, Prostanoids,

Melatonin

Receptor Tyrosine Kinase

High-affinity cell surface receptors for many

polypeptide growth factors, cytokines, and hormones.

They are not only key regulators of normal

cellular processes but also have a critical role in the

development and progression of many types

of cancer.

EGF, Insulin, IGF, PDGF, FGF, VEGF

Cytokine Receptor

Receptors that bind cytokines. They play a role

in the inflammatory response.

Interferon, Interleukins

Nuclear Receptor

Class of proteins found within cells that are

responsible for sensing steroid and thyroid

hormones and certain other molecules. They

work with other proteins to regulate the expression of specific genes, controlling

the development, homeostasis, and metabolism of the

organism.

Gluco-corticoids, Estrogen,

Progesterone, Testosterone,

Thyroid Hormone, Retinoids, Vitamin D

G-protein Coupled Receptors

Fig 1-15

Examples: Dopamine, Muscarinic Acetylcholine, Opioid, Angiotensin, Oxytocin, Rhodopsin, Prostanoids, Melantonin How many GPCRs? >662, 950 Database: www.gpcr.org

7 transmembrane domains

Receptor Tyrosine Kinase

Examples: EGF, Insulin, IGF, PDGF, FGF, VEGF

Cytokine Receptor

Examples: interferon, interleukins,

Nuclear Receptor

Fig 1-17

Examples: glucocorticoids, estrogen, progesterone, testosterone, thyroid hormone, retinoids, vitamin D,

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Ion Channels

Pore-forming proteins that help establish and control

the voltage gradient across the plasma membrane of cells by alloing a flow of

ions down their electrochemical gradient.

Digitalis, Verapamil

The following are the most studied signaling pathways:

§ G-proteins § Phosphoinositide 3-Kinase § Protein Kinase A § Mitogen Activated Protein Kinases (MAPKs) § Protein Kinase C § Calcium Calmodulin-dependent protein kinase (CaM kinase)

One example of cytokine receptors is tumor necrosis factor-α. TNF-α is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. When extrinsic activating ligands bind to TNF, the death domain and TRADD/FADD adaptors catalyze the activation of Caspase 8, which further catalyzes/activates Caspase 3 and further catalyzes activation of Caspases 6 and 7. They ultimately will permit apoptosis, with DNA fragmentation, membrane blebbing, protein degradation, and cell shrinkage. This is apoptosis via the external pathway. The G-protein is a guanine nucleotide-binding protein. It hydrolyzes GTP to GDP. There are two classes of G-proteins, the (1) monomeric small GTPase such as those in the Ras family of small GTPase, and the (2) heterotrimeric G-protein complex, consisting of Gα, Gβ, and Gγ subunits. There are also several subclasses per function:

§ Gsα – stimulatory of cAMP production § Giα – inhibitory of cAMP production § Goα – G other § Gαq – Activates phospholipase C

Ion Channel

Fig 1-14

a lipid kinase adds phosphate to the 3-position of inositol ring of phosphatidylinositol (PtdIns) and phosphoinositides

Phosphoinositide 3-Kinase (PI3K):

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§ Gαt – transducin regulation

There are also different downstream signals:

§ Adenylyl cyclase § Phospholipase C § Phospholipase A2 § Phosphodiesterase

The main kinase is phosphoinositide 3-kinase (PI3K). They are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking, which in turn are often involved in cancer. A lipid kinase adds phosphate to the 3-position of the inositol ring of phosphatidylinositol (PtdIns) and phosphoinositides. What is interesting is that it is phosphorylating lipids. This is one of the main kinases to tyrosine kinase and GPCRs. Protein Kinase A is another family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). It is involved in regulation of glycogen, sugar, and lipid metabolism. Anchoring proteins have designated specificity of substrate phosphorylation. The MAPK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. It consists of an activator protein binding, membrane translocation, oligomerization, and phosphorylation activating MAP3K, which then activates MEK, which consequently activates MAPK. The biological response can be proliferation, apoptosis, developmental morphogenesis, cell cycle arrest, innate and acquired immunity, cell repair, etc. Protein Kinase C is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in urn are activated by

Anchoring proteins: designated specificity of substrate phosphorylation

Protein Kinase A

MAPK pathway

Protein Kinase C

Autophosphorylate Subcellular distribution of PKCs and their substrates Binding of a ligand or substrate activates PKCs Translocate to membrane fraction

Substrates: Ser or Thr in a variety of Arg-rich sequences

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signals such as increases in the concentration of diacylglycerol or calcium ions. They autophoshorylate and have maintain a subcellular distribution of PKCs and their substrates. The binding of a ligand or substrate activates PKCs. They translocate to the membrane fraction. The substrates are serine or threonine in a variety of arginine-rich sequences. As you can tell on the chart from the Human Genome Project, there are 1,543 genes (5% of the total) coding for receptors. There are 376 genes coding for signaling molecules (approximately 1.2% of the total), and 500 coding for signaling kinases. Together they interact to yield the biological effect. We can provide a summary with the following diagram. With drug research and development, there are also regulatory, bureaucratic factors involved in producing a single drug. There is the basic research, which involves synthesis, examination, and screening. Next, there are preclinical tests on animals, than clinical trials (Phase I, Phase II, and Phase III), and then Phase IV (post-marketing surveillance) with introduction and registration into the market. The success of drug development is dependent on:

§ Most desirable effect (e.g. specific receptor targeting) § Least undesirable effect § Well-absorption § Distribution to target tissues § Metabolism does not generate toxic products § Metabolites are eliminated in reasonable time frames.

Review of Pharmacokinetics Pharmacodynamics is the mechanisms of drug action, including molecular, biochemical, and physiological effects of drugs. Pharmacokinetics is the process of drug molecules moves from one physiological compartment to another, therefore the effect of such on the usefulness of drugs. This includes drug absorption, distribution, metabolism, and elimination (ADME). It is important to remember that there are many drug and protein interactions from a structural point of view. One enantiomer may fully occupy the receptor-binding pocket, while the other enantiomer is only a partial match. Consequently, these partial mismatches can contribute to side as well as adverse effects. We can measure the drug activity with the dose-response curve. The dose-response curve describes the change in effect on an organism caused by differing levels of exposure to a stressor after a certain exposure time. It is also important to remember that there are several types of inhibitors, which are described in the following table:

Drugs and Protein Interaction: Structural Point of View

Fig 1-10

Dose Response Curve

EC50 = effective concentration for 50% response

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Type of Inhibitor

Description Diagram

Competitive Binding of the inhibitor to the active site on the enzyme prevents binding of the substrate, and vice versa.

Pseudo-

Irreversible Slowly dissociate from their receptor, and does not completely halt binding.

Allosteric Regulation of enzyme or other protein by binding an effector molecule at the

allosteric site, or the site other than the protein’s active site.

Drugs can also fall into two categories, described in this table:

Type of Drug

Description Diagram

Agonist Chemical that binds to a receptor of a cell and triggers a response by that

cell.

Antagonist Receptor ligand or drug that does

not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist- mediated

responses.

Agonists

Fig 1-8

Antagonists

Fig 1-9

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We can measure the drug’s effectiveness in terms of potency and efficacy, which will be elaborated in this table:

Term Description Diagram Potency Amount of drug required producing a

response.

Efficacy Ability of a drug to induce a maximal

response.

It is also important to remember that the complexity of most diseases can be due to:

§ Single Genes § Multiple Genes § Interaciton between Genes § Epigenetic Regulation § Overlapping Signaling Pathways of Normal vs. Disease States

Case Study A 51-year old man presents to his medical clinic due to difficulty breathing. The patient is afebrile and normotensive, but tachypneic. Auscultation of the chest reveals diffuse wheeze. The physician provisionally makes the diagnosis of bronchial asthma and administers epinephrine by intramuscular injection, improving the patient’s breathing over several minutes. A normal chest X-ray is subsequently obtained, and the medical history is remarkable only for mild hypertension that was recentlytreated with propranolol. The physician instructs the patient to discontinue use of propranolol, and changes the patient’s anti-hypertensive medication to verapamil. Why is the physician correct to discontinue propranolol? Why is verapamil a better choice for managing hypertension in this patient?

Answer Propranolol, a non-selective beta-adrenoceptor block, is a useful antihypertensive agent because it reduces cardiac output and probably vascular resistance as well. However, it also prevents beta-2-receptor-induced bronchodilation and may participate bronchoconstriction in susceptible individuals. Calcium channel blockers such as verapamil also reduce blood pressure but do not cause bronchoconstriction or prevent bronchodilation. Selection of the most appropriate drug or drug group for one condition requires awareness of the other conditions of a patient may have and receptor selectivity of the drug groups available.

Potency: amount of drug required to produce a response

Efficacy: ability of a drug to induce a maximal response

Potency: amount of drug required to produce a response

Efficacy: ability of a drug to induce a maximal response

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Lecture V

Autonomic Drugs: Autonomic Physiology Review Lecturer: Dr. Meredith Hay, Ph.D.

Learning Objectives Anatomy

1. Explain how various regions of the central nervous system regulate autonomic nervous system function.

2. Describe how the neuroeffector junction in the autonomic nervous system differs from that of a neuron-to-neuron and the somatic system synapses.

3. Compare and contrast the anatomical features of the sympathetic and parasympathetic systems.

Neurochemistry 1. For each neurotransmitter in the autonomic nervous system, list the

neurons that release them and the type and location of receptors that bind with them.

2. Describe the mechanism by which neurotransmitters are removed. 3. Distinguish between cholinergic and adrenergic receptors.

Physiology 1. Explain how autonomic reflexes contribute to homeostasis. 2. Describe the overall and specific functions of the sympathetic

system. 3. Describe the overall and specific functions of the parasympathetic

system. 4. Describe and understand the role and function of the arterial

baroreflex. Because so many drugs exert the therapeutic and side effects by altering the function of the autonomic nervous system, a thorough understanding of autonomic anatomy and physiology is a critical prerequisite for understanding cardiovascular pharmacology. The pharmacological response to a class of autonomic drugs can be predicted if the organ innervation and receptor classification are known. Most of the time, the sympathetic and parasympathetic nervous systems act in concert with each other, but usually as opposites. We can think about the sympathetic nervous system as a “fight or flight” response and the parasympathetic nervous system as a “rest and digest”. There is

33

competition between these two systems. One will have dominance in either the sympathetic or the parasympathetic nervous systems. The sympathetic nervous system is very diffuse in its anatomy. You want all its organ activated at once to ensure survival. The parasympathetic nervous system is extremely discrete, specific to different organs. With the parasympathetic, you can activate one organ. The sympathetic preganglionic cell bodies are in the spinal cord, while the sympathetic postganglionic neurons are in the sympathetic chain. The parasympathetic preganglionic neurons are in the brain stem, while the parasympathetic postganglionic neurons are in the organs themselves. It allows the parasympathetic nervous system to activate a specific organ, giving its ability to be discrete. (LO – Anatomy, Question 1) We know about the somatic nervous system (brain and spinal cord), which controls different functions. They get afferent and efferent information. The somatic nervous system is involved in conscious function. The postganglionic neurons are in the sympathetic chain. The sympathetic nervous system is illustrated in green. Almost every organ is dually innervated. The pink is in the parasympathetic nervous system and the postganglionic neurons are in the organs themselves. (LO – Anatomy, Question 2) One of the fundamental differences between the somatic nervous system and the autonomic nervous system is that in the somatic, there is one neuron that goes out and innervates a muscle. Whereas in the autonomic nervous system, either parasympathetic or sympathetic, there is almost always two neurons involved (with the exception of the adrenal gland). Individuals don’t think about breathing or pumping their heart. Once again, the somatic nervous system only contains one neuron, while the autonomic nervous system motor pathway is a two-neuron pathway. (LO – Anatomy, Question 3) The autonomic nervous system is a part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, controlling visceral functions. The autonomic nervous system is involved in the regulation of heart rate, digestion, respiratory ate, salivation, perspiration, pupillary dilation, micturition, and sexual arousal. The responses to sympathetic and parasympathetic nerve stimulation are frequently antagonistic, as exemplified by their opposing effects on heart rate and gut motility. It is important to remember that the autonomic nervous system’s purpose is to maintain homeostasis. The second most important function is to get the body for fighting, reaction, or survival. If it’s normally performing homeostasis, it is getting ready to react. It is important to note the dual innervation by the autonomic

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system (essentially by both divisions of the autonomic nervous system). Most organs are dually innervated by both the sympathetic and parasympathetic nervous system. Usually, one system predominates in controlling the activity of a given organ. For example, in the heart, the vagus (Cranial Nerve X) is the predominant controlling factor for rate. The pharmacological response to a class of autonomic drugs can be predicted if the organ innervation and receptor classification are known. If a drug inhibits the activity of one limb of the autonomic nervous system, it may activate the other limb of the autonomic nervous system. In a dually innervated organ, the side effects associated with that drug will be caused by the unopposed activity of the other limb of the autonomic nervous system in that organ. (LO – Physiology, Question 1) The following diagram can illustrate this:

One particular organ that is known for its innervation is the heart. The heart is well innervated by both branches of the autonomic nervous system. For the most part, when the heart rate is under discussion, the vagus controls most of the heart rate. When people get scared, their sympathetic activity not only increases, but the parasympathetic nervous activity goes down. The SA node is innervated by the parasympathetic nervous system to place the brakes on the heart rate. The sympathetic nerves control the heart rate as well

as the strength of the contraction. Remember that it is a “fight or flight”, and involves a series of noticeable and hidden effects:

Noticeable Effects Hidden Effects § Pupil dilation § Mouth goes dry § Tension of neck and shoulder muscles § Heart pumps faster § Chest pains

§ Brain gets body ready for action. § Adrenaline released for fight/flight. (Surge of

norepinephrine and epinephrine). § Rise in blood pressure § Liver releases glucose to provide energy for

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§ Palpitations § Sweating § Muscle tension for action § Breathing fast and shallow –

Hyperventilation (Bronchodilation) § Oxygen needed for muscles

muscles. § Digestion slows or ceases. § Sphincters close, then relax § Cortisol released (depression of the immune

system)

There are many diagram of the sympathetic nervous system. This is for the pre-ganglionic body in the thoracolumbar spinal cord. Spinal injury can have changes in organ function depending on the level of the injury. If you have higher injury, you can have decreased organ function or death. This is why to think about the anatomy and the sympathetic nervous system.

This is with the anteromedial lateral horn of the spinal cord, where the preganglionic cell body is. They actually have more than one choice. There is redundancy in the anatomy. It is not just one neuron comes out, visits the ganglia, goes into the heart. There is actually the neuron is at this level. Sometimes they’ll come into this chain, but not synapse, but might move one or two nodes up, and then go to the organ. Or it will synapse to the horn and then move down. There is redundancy in the organ. It also facilitates rapid response to the organs. The adrenal gland is one of the exceptions. Innervation to the adrenal gland itself goes all the way though the sympathetic chain until it reaches the adrenal medulla. This means that the synapse is in the gland. It can cause body-wide release of epinephrine (a.k.a. adrenaline and norepinephrine) in an extreme emergency, known as an adrenalin “rush” or surge. When we talk about sympathetic drugs, we need to know what happens to each of these drugs when you give an agonist or an antagonist. The sympathetic division discharges as a unit in emergency situations. The effects of this discharge are of considerable value in preparing to cope with the emergency. For example, sympathetic activity accelerates the heart rate and raises blood pressure (providing better perfusion of the vital organs and muscles) and constricts the blood vessels of the skin (which limits bleeding from wounds). Increasing sympathetic activity causes:

16

Adrenal gland is exception

• Synapse in gland • Can cause body-wide release of

epinephrine aka adrenaline and norepinephrine in an extreme emergency

(adrenaline  “rush”  or  surge)

36

1. Increases in heart rate and contractility: Rate and force of contraction go up.

2. Increase in Blood Pressure, due to vasoconstriction of the blood vessels.

3. Renal and cutaneous blood flows are decreased, to reduce necessity or urination and having to vasodilate.

4. Splanchnic blood flow is decreased, as blood does not ned to go to the spleen.

5. Blood flow to the liver and muscles is increased due to the increase in synthesis and use of energy and increase transport of energy sources.

6. Increased blood glucose due to glycogenolysis and gluconeogenesis, due to sympathetic innervation to the beta cells of the pancreas.

7. Visceral activity is decreased. 8. Bronchioles are dilated to facilitate ventilation. 9. Pupils are dilated.

(LO – Physiology, Question 2) The preganglionic cell body for the parasympathetic nervous system is particularly in the midbrain and pons or in the sacral region. The neuron leaves the midbrain and travels all the way down to its organs and consequently innervates the organ, whether it is in the gut or the heart, and in that organ is where you find that postganglionic neuron. With the parasympathetic nervous system comes a parasympathetic discharge. In a general way, the functions promoted by activity in the parasympathetic division of the autonomic nervous system are those concerned with the less physical aspects of day-to-day living. For example, parasympathetic activity favors digestion and absorption of food by increasing the activity of the intestinal musculature, increasing gastric secretion, and relaxing of the pyloric sphincter. Increasing parasympathetic activity involves thinking about “rest and digest”:

1. Heart rate decreases, due to activation of the parasympathetic nervous system and the heart rate going down.

2. Gastrointestinal secretions are increased to essentially promote digestion.

3. Contraction of the gall bladder. 4. Increased glucose storage in the liver. 5. Retina is protected from light. 6. Urinary bladder and rectum are emptied.

(LO – Physiology, Question 3)

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Central control of the Autonomic NS

Amygdala: main limbic region for emotions

-Stimulates sympathetic activity, -Can be voluntary when decide to

recall frightful experience - cerebral cortex acts through amygdala

Hypothalamus: main integration

center, peptide action, PVN Reticular formation-Brain Stem:

most direct influence over autonomic function RVLM,

NTS

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The best way to remember this is with the acronym SLUDD: § S – Salivation § L – Lacrimation § U – Urination § D – Digestion § D – Defecation

On top of the autonomic nervous system, there is an overlay of the rest of the brain on the autonomic nervous system. And that is obvious because you have an autonomic response. The amygdala is the main limbic region for emotions. It stimulates sympathetic activity, and can be voluntary when individuals decide to recall a frightful experience. This is because the cerebral cortex acts through the amygdala. The hypothalamus is the main integration center, utilizing peptide action and the paraventricular nuclei. The reticular formation, a part of the brain stem, has the most direct influence over autonomic function RVLM, NTS. Essentially, higher order functions do impact the nervous system. What is included here is a summary thus far:

When we start discussing drugs, we start talking about modulation of neurotransmitter receptors. Drugs that block that process will affect something to do with neurotransmission. Remember that the somatic nervous system is needed to move your foot, brain, etc., and the autonomic is involved in unconscious movements. Preganglionic neurons both release acetylcholine. It is important to remember. Post-ganglionic neurons are where things get a little different. The postganglionic neurons in sympathetic components release catecholamines, norepinephrine and epinephrine. The parasympathetic components secrete

Summary  thus  far….

ACh

Para

sym

path

etic

Com

pone

nt

ACh

Sym

path

etic

Com

pone

nt

ACh

NE

Adrenal Medulla

ACh

Epi,NE

Som

atic

Com

pone

nt

ACh

Skeletal Muscle

Preganglionic

Postganglionic

Effector Organs

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acetylcholine. It can be also noted in the following diagram also. The top nervous system, the somatic nervous system, releases acetylcholine, acts on nicotinic Type II receptors. In the middle, the sympathetic preganglionic fiber releases acetylcholine to Nicotinic Type I receptors and activates the chain. It releases

norepinephrine and activates either alpha-receptors or beta-receptors. Now what happens with sympathetic activation to the heart is a consequent increase in heart rate. The parasympathetic preganglionic fiber goes to the end organ, activates the neuron, and releases acetylcholine in the gut, but acts on the muscarinic receptor. (LO – Neurochemistry, Question 1) With different receptors there are different classifications. Let’s talk about cholinergic receptors. Nicotinic receptors are ligand-gated ion channels. They let sodium cations pass to produce action potentials. Nicotinic Type I receptors are in the sympathetic and parasympathetic ganglia. They are also in the adrenal medulla and almost every receptor will be in the central nervous system. Type II receptors are involved in the somatic nervous system. They are in skeletal muscle, and also in the brain.

There is also another way to think about it. The illustration above is a parasympathetic ganglionic synapse. The action potential fires, and goes through the ganglia. Calcium enters the presynaptic end. The transmitter (acetylcholine) is released, and acetylcholine binds to the nicotinic receptor to allow sodium cations to move and excite the postganglionic neuron. There are three ways by which neurotransmitters are removed from the synaptic cleft: (1) enzymatic degradation, (2) re-uptake, and (3) diffusion. There are drugs that will inhibit or act on acetylcholinesterase.

ACh N2

Nicotinic 2

receptors

Smooth muscle Cardiac muscle

gland

ganglion

Postganglionic fiber

Preganglionic fiber

Sympathetic Adrenal Medulla

Epi NE

ACh ACh

Parasympathetic

Somatic Nervous system

Central Nervous System

Peripheral Nervous System

Effector Organ

Autonomic Nervous system

muscarinic receptors

N1

Nicotinic 1

receptors

Alpha/beta receptors

N1

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There is overstimulation of the receptors because of blockers. (LO – Neurochemistry, Question 2) There are cholinergic (acetylcholine receptors) and the muscarinic receptors (IP3 and decrease cAMP, activation of potassium channel). There are three types:

Receptor Type Action Location M1 IP3 CNS, Autonomic Ganglia M2 Increase IK, decrease

cAMP via Gi Heart, Sinoatrial Node, Atrioventricular Nodes Atria

Muscle, Ventricles M3 IP3, Ca2+ via Gq Exocrine Glands, Smooth Muscle, Endothelial Cells

Often G-protein coupled receptors make heavy use of second messenger systems. The action potential goes down, releasing acetylcholine, binds to the receptor, and has its effect on the receptor organ. This can be shown in another parasympathetic organ synapse. There are specific drugs that block adenylyl cyclase and the side effects will be dependent upon using which receptors.

Where these receptors are expressed can allow information as to what they do. We have two major categories of transmitter systems. The postganglionic nervous system releases epinephrine and norepinephrine. The response you get from the organ will depend on whether it affects alpha-receptors or beta-receptors. There are different types of alpha and beta-receptors, which is shown in the table. (LO – Neurochemistry, Question 3)

Type Subtype Action Location Description Alpha Alpha-1 IP3 Postjunctional sites on

effector organs innervated by the

sympathetic nerves and the Central Nervous

System.

If you activate the alpha-1-receptor with a drug, the effects can include

vasoconstriction and spur increases in blood pressure.

Alpha-2 Decrease cAMP

Prejunctional sites on sympathetic neurons, prejunctional sites on

cardiac parasympathetic neurons, and some

postjunctional sites on effector organs.

The alpha-2-receptors inhibit norepinephrine release. It is

predominantly presynaptic inhibitor of norepinephrine release.

Beta Beta-1 Adenylyl Cyclase

Cardiac muscle and conduction tissue,

adipocytes, and granular juxtaglomerular cells of

kidney, and central nervous system.

Activation of the beta-1 causes increased blood pressure and increased

sympathetic innervation (increased heart rate and force of contraction)

Beta-2 Adenylyl Cyclase

Postjunctional on arterioles and venules,

Activation of the beta-2 receptors causes bronchodilation.

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bronchioles, uterus, GI, liver, and Central Nervous

System You can remember with the mnemonic: “KISS and KICK ‘til you’re SICK of SEX” (QISS and QIQ ‘til you’re SIQ of SQS): This gives the G-protein type (Gq, Gi, or Gs) for all the receptors. Receptors are in alphabetical order:

§ Alpha-1: Q § Alpha-2: I § Beta-1: S § Beta-3: S § M1: Q § M2: I § M3: Q § D1: S § D2: I § H1: Q § H2: S § V1: Q § V2: S

A sympathetic ganglionic synapse involves the nerve coming out of the spinal cord, performing action potentials, and entering the sympathetic chain. The nerves release acetylcholine and stimulate nicotinic receptors, shown in the following diagram (LO – Physiology, Question 2):

It gets even interesting at the organ site. As you stimulate norepinephrine, and depending on the end organ, the response will depend on the receptors expressed.

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The arterial baroreflex is essential the body’s effort to bring it back to homeostasis. The arterial baroreflex arch involves passage of information along an afferent pathway, reaction of CNS sites to the received impulse, and resulting change in efferent discharge. For example, increases in arterial pressure, detected as

stretching at the aortic and carotid sinus baroreceptors, leads to vagal activation and inhibition of sympathetic discharge. Often, the clinical responses to autonomic drugs reflect not only the direct effects of the drug, but also the secondary effects induced by activation of the baroreceptor reflex. (LO – Physiology, Question 4) There are sensors (neurons) in the carotid sinus and the aorta that only sense pressure. When it gets too high, they become active. They take sensors to the brain, activate the neurons, and now know that pressure has gone up. It sensed it. The brain senses that pressure has gone up. The reflex response is to withdraw

sympathetic activity and activate sympathetic activity. The inverse is also true. In states of hemorrhage (when there is a drop in blood pressure), there is an increase in sympathetic activity and a decrease in parasympathetic activity. We can view the change in blood pressure in experimental studies. In one study, they infused phenylephrine into mouse

subjects and looked at the heart rate and pulse pressure. They noted that the heart rate and pulse pressure increased during phenylephrine infusion and dropped after halting the infusion. Phenylephrine is an alpha-1-agonist, and the mechanism of action translated to a systemic effect. Orthostatic hypotension, also known as postural hypotension, is a form of low blood pressure that happens when you stand up from sitting or lying down. Orthostatic hypotension can make you feel dizzy or lightheaded, and maybe even faint. This is due to an inappropriate response of the baroreflex. (LO – Physiology, Question 4)

1. AFFERENT INFORMATION *Drop in blood pressure *reduce stretch of baroreceptor *decreased afferent input

2. REFELX RESPONSE Efferent reflex via Autonomic NS: *decrease parasympathetic *increased sympathetic *increase TPR and blood pressure

08/26/98KL

11:33:2311:31:4311:30:03

-1

1

0

40

160

240

320

120

160

200

80

120

160

Pulse Pressure (mmHg)

Mean Pressure (mmHg)

Heart Rate (bpm)

Mean RSNA

Raw RSNA

Begin PE infusion stop

Orthostatic hypotension — also called postural hypotension — is a form of low blood pressure that happens when you stand up from sitting or lying down. Orthostatic hypotension can make you feel dizzy or lightheaded, and maybe even faint.

ORTHOSTATIC HYPOTENSION

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The following is a general summary in the review of the autonomic nervous system.

1. The pharmacological response to a class of autonomic drugs can be predicted if the organ innervation and receptor classification are known.

2. Drugs alter autonomic function by mimicking the activity of an endogenous agonist, by preventing the synthesis or release of an endogenous agonist, by preventing the degradation of an endogenous agonist or by blocking specific receptors normally stimulated by an endogenous agonist.

3. The pharmacological effect of an agonist is proportional to the dose administered.

4. The pharmacological effect of an antagonist is proportional to both the dose administered and the intensity of receptor stimulation by the endogenous agonist.

5. The structure of an endogenous agonist can be modified to increase both receptor specificity, duration of action, and lipid solubility.

6. Preventing its inactivation can increase both the intensity and duration of stimulation by an endogenous agonist.

7. If a drug inhibits the activity of one limb of the autonomic nervous system in a dually innervated organ, the side-effects associated with that drug will be caused by the unopposed activity of the other limb of the autonomic nervous system.

8. Any peripherally acting drug, which lowers blood pressure and does not interfere with the function of cardiac beta-adrenergic receptors will elicit a baroreflex-mediated tachycardia.

Case Study (adapted from Laurie Kelly McCorry, “Case Studies”, 2006) Joe leaves for work at 5:00 AM when it is still quite dark outside. On Halloween Eve, his neighbor’s son Johnny placed Matilda, a fully articulated human skeleton, in the driver’s seat of Joe’s pickup truck. Halloween morning, Joe arose at 4:45 AM, poured coffee, got ready for work and walked out to his truck in the driveway. Completely unsuspecting, when Joe opened the truck door, the sound of “Aghhhh!!!” shattered the quiet of the morning. Poor Joe stood by his truck wide-eyed and clutching his chest. Several events occurred in his body at once. His heart began racing, his blood pressure increased, his pupils dilated, he began sweating, the hair on his arms and the back of his neck stoof on end, and he felt a surge of adrenaline. The neighbor’s son Johnny jumped out from where he was hiding and cheerfully wished Joe a “Happy Halloween!” “What happened to Joe?” Answer: He essentially had a sympathetic overdrive.

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Lecture VI

Sympathetic Pharmacology Lecturer: Dr. Meredith Hay, PhD

Learning Objectives 1. To understand the basic mechanisms underlying the

pharmacological effects of sympathomimetic drugs. 2. To identify the organ location and function of alpha-adrenergic

receptor subtypes. 3. To review the classes and pharmacological effects of

sympathomimetic and sympatholytic alpha-adrenergic drugs. 4. To review the clinical uses for some alpha-adrenergic drugs. 5. To identify the organ location and function of beta-adrenergic

receptor subtypes. 6. To review the classes and pharmacological effects of

sympathomimetic and sympatholytic beta-adrenergic drugs. 7. To review the clinical uses for some beta-adrenergic drugs.

Lecture So, for any neurotransmitter system that we talk about, whether it is adrenergic or cholinergic or serotonergic, drugs are going to target one of the six sites. The following illustration describes the six potential sites involved in neurotransmission as well as the potential sites of drug action. We can observe this with the synthesis of norepinephrine (LO – S. Pharmacology, Question 1):

1. Synthesis of a Neurotransmitter: In norepinephrine, drugs can block the hydroxylation of tyrosine, the rate-limiting step in synthesis of norepinephrine. There are drugs that will inhibit the synthesis of epinephrine or norepinephrine.

2. Uptake Into Storage Vesicles: Neurotransmitters have to be packed into a storage vesicle. In the neuron, dopamine enters a vesicle and is converted to norepinephrine. Norepinephrine is protected from degradation in the vesicle. The transport into the vesicle is inhibited by reserpine.

3. Release of Neurotransmitter: The release of calcium causes fusion of the vesicle with the cell membrane. The neurotransmitter has to be release. A major way to inhibit the release of neurotransmitter is

44

to inhibit the influx of calcium. Drugs such as guanethedine and bretylium can block the release.

4. Binding to Receptor: the binding of the neurotransmitter activates Postsynaptic receptor. A majority of drugs will block binding to the receptor. There are direct acting blockers that will block binding. Receptors also take into account the selectivity.

5. Removal of Neurotransmitter: After release, the neurotransmitter gets taken up (reuptake) or removed. The releases norepinephrine is rapidly taken into the neuron. Drugs such as cocaine and imipramine can inhibit the reuptake.

6. Metabolism: In this example, norepinephrine is methylated by C0MT and oxidized by monamine oxidase (MAO).

To understand norepinephrine it is important to understand the synthesis of catecholamines. Tyrosine gets taken into the synaptic cleft. It is converted to dopa by tyrosine hydroxylase. Dopa is converted to dopamine by dopa-beta-decarboxylase. Individuals have made dopa to produce dopamine. Dopamine is converted to noradrenaline by dopamine beta-hydroxylase. In summary, the neurohumoral transmission process is simply this:

1. Synthesis and Storage of Neurotransmitter

2. Release of neurotransmitter 3. Interaction with Postjunctional

Cell and Initiation of Activity 4. Deactivation

This can also be shown in a diagrammatic form. Tyrosine is actively transported into the terminal. Tyrosine is converted to Dopa and Dopa is converted to Dopamine. Dopamine is converted to norepinephrine, packaged into these vesicles. The vesicles, with the influx of calcium cations, merge with the terminal, release the contents. The contents either binds to the receptor, get taken back up, or become metabolized. The catecholamines can be endogenous or exogenous. Epinephrine (Epi), norepinephrine (NE), dopamine (DA), and isoproterenol (synthetic catechol) are biogenic amines. Epi, NE, and DA are considered endogenous agonists, meaning that the body makes it itself. Isoproterenol, however, is an exogenous agonist. These direct sympathomimetic catecholamiens can be remembered by the mnemonic DINED:

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§ D – Dopamine § I – Isoproterenol § N – Norepinephrine § E – Epinephrine § D - Dobutamine

Different cardiovascular responses are seen with Epi, NE, and Iso due to differences in the ratios of the alpha and beta-receptor affinities. Predicting the receptor response is mainly on the receptor itself. In the vasculature, we are thinking about expression of beta-1 receptors. It means that the ratio leans towards beta-1 receptors. However, in the smooth muscle, there is a predominant expression of beta-2 receptors. Dopamine is a precursor to norepinephrine and is known to increase norepinephrine release. At low doses, dopamine activates DA1 receptors in some vascular beds to cause vasodilation. Dobutamine is a sympathomimetic drug used in the treatment of heart failure and cardiogenic shock. Dobutamine is a synthetic catecholamine known to selectively activate beta-1 receptors involved in contractility vs. chronotropy. They can be summarized in the following table: Receptor Typical Locations Result of Ligand Binding Alpha-1 Postsynaptic effector cells, especially smooth muscle.

Alpha-1 receptors are predominantly post-synaptic, especially in the smooth muscle (particularly smooth

muscle of vasculature.

§ Formation of IP3 and DAG § Increase intracellular calcium

Alpha-2 Presynaptic adrenergic neruron terminals, platelets, lipocytes, smooth muscle, and CNS. It essentially

inhibits transmitter release.

§ Involved in inhibition of adenylate cyclase

§ Decrease cAMP Beta-1 Postsynaptic effector cells, especially the heart,

lipocytes, brain, as well as presynaptic cholinergic and adrenergic terminals.

§ Stimulation of adenylate cyclase.

§ Increase cAMP. Beta-2 Postsynaptic effector cells, especially smooth muscle

and cardiac muscle, but mainly smooth muscle in bronchiole and GI tract. They activate a calcium activated potassium channel to relax and cause

bronchodilation

§ Stimulation of adenylate cyclase

§ Increase cAMP. .

Beta-3 Postsynaptic effector cells, especially lipocytes. § Stimulation of adenylate cyclase

§ Increase cAMP. D1 (DA1),

D5 Brain, effector tissues, especially smooth muscle of the

renal vascular bed § Stimulation of adenylate

cyclase § Increase cAMP.

D2 (DA2) Brains, effector tissues, especially smooth muscle, presynaptic nerve terminals.

§ Inhibition of adenylate cyclase § Increased potassium

conductance D3 Brain § Inhibition of adenylate cyclase D4 Brain, Cardiovascular System § Inhibition of adenylate cyclase

When considering the hemodynamic alterations produced by catecholamines and sympathomimetic amines, the information is more easily understood and retained if attention is given to:

1. The selectivity of each agent for the different of adrenoreceptors. It is important to discuss the affinity of a drug to certain types of receptors.

2. The direct agonistic effects of each agent in the various parts of the circulatory system.

3. The events, which occur secondary to the activation of the cardiovascular baroreflexes. It is important to NOT

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forget the baroreflex. Now it is important to discuss the sympathetic nervous system and the effector organs, receptor, and action. In the eye, we can look at the alpha-1 receptors in the iris. They are involved in pupil dilation. We know that it is the muscles contracting. Beta-1 receptors are predominantly in the heart. Beta-2 is predominantly in the lung. Blood vessels are predominantly alpha-1. Beta-2 receptor activation will be involved in relaxation in skeletal muscle. Alpha-1 is on the sphincter, causing constrction. Alphas and beta-2 are equally expressed, but predominantly decreasing. Sphincters are alpha-1 to constrict. The bladder wall contains bladder wall to facilitate relaxation. The penis and seminal vesicles have alpha-1 to facilitate ejaculation. The adrenal medulla is nicotinic. There is no synapse. The intermediate lateral horn branches a nerve out and the nerve goes into the gland.

Effector Organs Receptor Action Eye Radial Muscle (Iris) Alpha-1 Contraction (Mydriasis)

Ciliary Muscle Beta-2 Relaxation. Heart SA Node Beta-1 Increased heart rate

AV Node Beta-1 Increased conduction velocity Contractility Beta-1 Increased force of contraction.

Lung Bronchial Muscle Beta-2 Relaxation (Bronchodilation) Blood Vessels Most Blood Vessels Alpha-1 Constriction

Skeletal Muscle Beta-2 Relaxation Gastro-

intestinal Tract

Sphincter Alpha-1 Constriction Motility and Tone Alpha-1, Alpha-2, and

Beta-2 Decrease

Genito-Urinary

Tract

Sphincter Alpha-1 Constriction Bladder Wall Beta-2 Relaxation

Penis and Seminal Vesicles

Alpha-1 Ejaculation

Secretory Glands

Sweat Alpha-1 Localized Secretion Intestinal Alpha-2 Inhibition to moderate secretion. Bronchial Lacrimal

Metab-olism Adrenal Medulla Nicotinic Secretion of catecholamines Kidney Beta-1 Increase renin release

Skeletal Muscle Beta-2 Glycogenolysis Pancrease (Beta-Cell) Alpha-2 Decrease insulin release

Fat Cells Beta-3 Lipolysis

(LO – S. Pharmacology, Question 2, 5): Sympathomimetics mimic the effects of transmitter substances of the sympathetic nervous system. We have three different types of sympathetic drugs’ actions:

1. Direct Acting such as epinephrine, dobutamine, phenylephrine, norepinephrine, isoproterenol, and clonidine.

2. Indirect Acting, such as tyramine, amphetamine, and cocaine. 3. Mixed acting, such as dopamine, ephedrine, amphetamine,

metaraminol, and phenylpropanolamine. We can first discuss directly acting agonists. Directly acting agonists are agents that interact directly with adrenoreceptors. The following is a table of directly acting agonists and their affinities:

Drug Receptor Affinity Norepinephrine (Levarterenol) A > B1 > B2

Epinephrine (Adrenalin) B2 > B1 > A

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Dopamine (Intropin) D1 > B1 > B2 > A1 Phenylephrine (Neo-synephrine) A1 ONLY! This means that is selective to A1!

Oxymetazoline (Afrin) As only Tetrahydrozoline (Visine) As only

Dobutamine B1 > B2 and A1 Isoproterenol (Isuprel) B1 = B2 (Non-selective agonist)

Albuterol (Ventolin) B2 >> B1 Terbutaline (Brethine) B2 >> B1

We can summarize the sympathetic agonists/sympathomimetic and their receptor affinities into the following table:

Alpha-1 Alpha-2 Alpha and Beta Beta-1 Beta-2 Phenylephrine Methyldopa Epinephrine Dobutamine Metaproterenol Methoxamine Clonidine Norepinephrine Terbutaline

Oxymetazoline Guanabenz Dopamine Albuterol Mitodrine Guanfacine Ibopamine Isoetharine,

Pilbuterol Metaraminol Bitolterol, Fenoterol

Procaterol Alpha-1 and Alpha-2 Beta-1 and Beta-2

Naphazoline Tetrahydrozoline

We observe that the drug affinity or selectivity for a different type of receptor. We notice that epinephrine, norepinephrine, and dopamine are endogenous ligands. Phenylephrine is a selective alpha-1 agonist. It is very popular for OTC medications. It is often used for decongestants. Clonidine and guanfacine are alpha-2 selective agonists. Clonidine stimulates the alpha-2 receptor, but mainly acts in the brain. It has been used for lowering blood pressure. It has also been approved for ADHD treatments, acting on cortical receptors. It is also used as a sedative in veterinary practice. Guanfacine lowers both systolic and diastolic blood pressure. It does the same, but affects peripherally, decreasing the sympathetic drive in blood vessels. Tetrahydrozoline (Visine) is non-selective for alphas. It is also used in nasal sprays to spur vasoconstriction and minimize swelling. Albuterol is the predominantly beta-2 agonist. There are also special sympathomimetics:

1. Cocaine is one of them. Cocaine was used as a local anesthetic. Cocaine inhibits uptake 1. Consequently, it increases the availability of norepinephrine and cause increase in blood pressure, heart rate, and excitability. It also blocks peripheral sympathomimetic action. In the Central Nervous System, it inhibits reuptake of dopamine into neurons in the “pleasure centers” of the brain.

2. Tyramine is an indirect sympathomimetic because it gets packaged and released similar to norepinephrine. It is normally a by-product of tyrosine metabolism. It is found in fermented foods such as cheese and red wine. It is metabolized by monoamine oxidase. It is involved in the release of stored catecholamines, giving indirect sympathomimetic action.

(LO – S. Pharmacology, Question 3) There are also therapeutic uses of alpha-adrenergic agonists:

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1. Use with local anesthetics: Epinephrine is commonly used as a

vasoconstrictor agent with local anesthetic drugs. It causes pronounced local vasoconstriction and thereby localizes the action and delays the absorption of the anesthetic. Since norepinephrine is less potent an agonist than epinephrine, it is infrequently used in local anesthetic solutions.

2. Local hemostatic: vasoconstrictor effects of epinephrine may be used to control superficial bleeding of mucosal subcutaneous regions by application of moistened gauze sponges or by aerosol sprayed onto damaged region. Epinephrine solutions have been used topically during ophthalmic surgeries and dental extractions. Epinephrine is effective only against hemorrhage from capillaries and small arterioles and should not be used to control bleeding from major vessels. Epinephrine is often used in combination of local anesthetic agents to prolong the duration of anesthetic action. This would include articaine, bupivacaine, or lidocaine. This combination is used because epinephrine can induce vasoconstriction, thus limiting the diffusion of the local anesthetic from the site of injection.

3. Hypotension: Pressor amines are often used to maintain blood pressure during spinal surgery, and epinephrine is quite effective in treating hypotension associated with anaphylactic shock.

4. Cardiac Effects: Catecholamines are indicated in treatment of certain cardiac disorders such as cardiac arrest and atrioventricular block. During cardiac arrest, if CPR fails to restore heartbeat, epinephrine or isoproterenol may be given in an attempt to restore contractions.

5. Anaphylactic and Allergic Reactions: Epinephrine is extremely effective and often lifesaving in treatment of acute anaphylactic shock. It quickly reverses the fall in blood pressure and cardiac irregularies associated with this type of syndrome. Bronchiolar passageways are dilated by epinephrine as the results of relaxation

Epinephrine�is�often�used�in�combination�local�anesthetic�agents�to�prolong�the�duration�of�anesthetic�action.�This�would�include�articaine,�bupivacaine or�lidocaine.�This�combination�is�used�because�epinephrine�can�induce�vasoconstriction�thus�limiting�the�diffusion�of�the�local�anesthetic�from�the�site�of�injection.

Epinephrine�is�often�used�in�combination�local�anesthetic�agents�to�prolong�the�duration�of�anesthetic�action.�This�would�include�articaine,�bupivacaine or�lidocaine.�This�combination�is�used�because�epinephrine�can�induce�vasoconstriction�thus�limiting�the�diffusion�of�the�local�anesthetic�from�the�site�of�injection.

Epinephrine�is�often�used�in�combination�local�anesthetic�agents�to�prolong�the�duration�of�anesthetic�action.�This�would�include�articaine,�bupivacaine or�lidocaine.�This�combination�is�used�because�epinephrine�can�induce�vasoconstriction�thus�limiting�the�diffusion�of�the�local�anesthetic�from�the�site�of�injection.

49

of smooth muscle, and dyspnea is quickly counteracted. When you have constriction of the bronchioles, you need to active beta-2 to dilate the bronchioles.

6. Bronchial Asthma: Isoproterenol and epinephrine have been useful for providing immediate relief from bronchial asthma. These agents activate beta-2 receptors of the bronchial smooth muscle cells, causing relaxation and prompt relief by dilating the airways.

(LO – S. Pharmacology, Question 4): When we think about the transmitter getting into the vesicles, we now have an idea where these drugs act. A sympatholytic/sympathoplegic drug is a medication, which inhibits the postganglionic function of the sympathetic nervous system. Adrenergic blocking drugs are used in reference to a very explicit mechanism of action. These drugs interact with the adrenergic receptors by occupying these sites and do not allow an adrenergic agonist access to the receptor. They are binding to the receptor, preventing norepinephrine or epinephrine to bind to the receptor.

Drug Receptor Affinity Phenoxylbenzamine (Dibenzyline) A1 >> A2

Phentolamine (Regitine) A1 = A2 Prazosin A1 Labetalol A1

Yohimbine A2 The sympatholytics can be summarized into the following table:

Alpha-1 Alpha-2 Alpha and Beta Beta-1 Beta-2 Prazosin, Terazosin Yohimbine Labetalol Metoprolol Butoxamine

Ketanserin, Alfuzosin

Carvedilol Atenolol

Bunazosin, Tamsulosin

Acebutolol

Betaxolol Celiprolol Esmolol

Alpha-1 and Alpha-2 Beta-1 and Beta-2 Phenoxybenzamine

Phentolamine

(LO – S. Pharmacology, Question 6): Yohimbine reverses clonidine sedation and acts on the Central Nervous System. It is clinically used to offset the effective clonidine. Prazosin is a selective alpha-1 antagonist, designed to control blood pressure. It has been approved for PTSD and anxiety for its actions in the CNS. We can have orthostatic intolerance as a side effect. Phenoxybenzamine and phentolamine are non-selective alpha antagonists. Phenoxybenzamine is an irreversible noncompetitive blocker for 14-48 hours. It inhibits norepinephrine reuptake. It blocks H1, Ach and serotonin receptors. It blocks catecholamine-induced vasoconstriction. It is involved in epinephrine – reversal. The clinical indications for phenoxybenzamine include (1) pheochromocytoma, (2) male erectile dysfunction, and (3) peripheral vascular diseases. Advanced effects include postural hypotension and tachycardia.

50

Phentolamine is a competitive antagonist, lasting for four hours. It is also involved in epinephrine-reversal. It reduces PVR. It is involved in cardiac stimulation, activating the baroreflex and increase in norepinephrine release. It inhibits serotonin responses. It is indicated for pheochromocytoma and male erectile dysfunction. Adverse effects can include severe tachycardia, arrhythmias, myocardial ischemia, and gastrointestinal stimulation. An important limitation to therapy with non-selective alpha-blockers such as phentolamine and phenoxybenzamine is their paradoxical sympathomimetic activity, especially in the heart. There is a baroreceptor reflex when you’re giving a drug. When we give an alpha-blocker, you get an increase in heart rate. It is not because the alpha-receptor is affecting the heart. It is because of the blood vessel dilation. The baroreflex responds to the blood vessel dilation/decreased blood pressure causing it to spur epinephrine release. Administration of alpha-blockers can result in cardiac excitation and increased plasma concentration of epinephrine and norepinephrine. Historically, these effects were attributed to a triphasic adjustment in autonomic nerve activity instigated reflexly by the hypotensive response to inhibition of alpha-vasoconstrictor. These three phases in response to alpha blockade are:

1. Increased sympathetic efferent traffic over the cardioaccelerator nerves

2. Decreased vagal impulses to the sinoatrial node (pacemaker). 3. Increased sympathetic firing to the adrenal medulla.

The cardiovascular effects of alpha-adrenergic blocking agents are:

1. Epinephrine reversal: alpha adrenoreceptor antagonists convert the increase in mean arterial pressure, caused by epinephrine into a decrease in mean arterial pressure.

2. Yohimbine is highly lipid soluble and blocks central alpha-2 receptors and has some CNS stimulatory effect. It is sometimes used to reverse the effects of xylazine (a sedative that acts at CNS alpha-2 receptors) in dogs.

3. Some of the more selective alpha-antagonists have been used with varying degrees of success to reduce vasoconstriction in the treatment of peripheral vasospasm, hypertension, pheochromocytoma in humans.

A pheochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth, and secretes excessive amounts of catecholamines. They consequently cause the increase in synthesis and release of norepinephrine and epinephrine into

Pheochromocytoma

Tumor:�јsynthesis,�јrelease�of�NE�&�EPI�into�the�circulaƟon.Result:�јBP,�јHR�ї�hypertensive�crisisTreatment:�Ͳ surgical�removal�for�solid�tumorͲ DͲ /�EͲblocker�ie.�LabetatolͲ DͲblocker�ie,�phenoxybenzamine or�phentolamineͲ inhibitor�of�tyrosine�hydroxylase ie.�DͲmethylͲpͲtyrosineͲ EͲblocker�only�after�DͲblockade

51

the circulation. It results physiological in an increase in blood pressure and increased heart rate and a hypertensive crisis. Treatment is surgical removal for solid tumor. Pharmacologically we can use alpha and beta-blockers such as labetalol. We can use an alpha-blocker such as phenoxybenzamine or phentolamine. We can use an inhibitor of tyrosine hydroxylase such as alpha-methyl-p-tyrosine. We can also use a beta-blocker only after an alpha-blockade. We can use beta-adrenergic blocking agents (beta-blockers) to address blood pressure. Example of beta-adrenergic blocking agents (shown with the suffix –olol) are shown in the table:

Drug Receptor Affinity Propranolol (Inderal) B1 = B2 Timolol (Blocadren) B1 = B2 Nadolol (Corgard) B1 = B2

Metoprolol (Lopressor) B1 >> B2 Atenolol (Tenormin) B1 >>> B2

It can be shown by the previous shown table:

Alpha-1 Alpha-2 Alpha and Beta Beta-1 Beta-2 Prazosin, Terazosin Yohimbine Labetalol Metoprolol Butoxamine

Ketanserin, Alfuzosin

Carvedilol Atenolol

Bunazosin, Tamsulosin

Acebutolol

Betaxolol Celiprolol Esmolol

Alpha-1 and Alpha-2 Beta-1 and Beta-2 Phenoxybenzamine

Phentolamine To remember beta-blockers, the “-olols” that start from A to M are cardioselective (beta-1), while the “-olols” that start from N to Z are non-selective (beta-1 and beta-2). Labetalol and carvedilol are exceptions, which are both alpha and beta blockers. There are obvious clinical uses to beta-blockers. We can use it in angina (with non-selective or beta-1- selective). Beta-blockers are often given to address the workload of the heart. If you decrease the workload, due to cytokines released, you can increase the O2 demand. In the cardiac theatre, you can decrease oxygen demand more than oxygen supply. It is also used in arrhythmias (especially for beta-1-selective, LA-action). It keeps the heart from becoming dysrhythmic and keeps it constant. It decreases catecholamine-induced increases in conductivity and automaticity in the heart, and decreases the serum potassium cations (action in skeletal muscle). Non-selective beta-blockers are used in glaucoma to decrease aqueous humor formation, especially with Timolol. Other uses of beta-blockade include the block of tremor of peripheral origin, especially with beta-2A receptor in skeletal muscle. It is used as a prophylaxis for migraines, but the mechanism is unknown. It is used in the treatment of panic attacks and stage fright. In sympatholytic drugs, all of these agents directly or indirectly decrease the release of norepinephrine from peripheral

52

sympathetic neurons and thus lower blood pressure by reducing total peripheral resistance and/or cardiac output.

1. Reserpine (Serpasil) blocks the uptake and can be a sympathomimetic, but would deplete the terminal norepinephrine. It is a catecholamine-depleting agent that blocks the uptake of NE. It is slow-onset with a half-life of 75 hours.

2. Guanethidine (Ismelin) is an intravenous administration that causes immediate release of norepinephrine from terminals. This is followed by a blockade of norepinephrine uptake. After a few hours, guanethidine also inhibits voltage-dependent release of norepinephrine.

3. Bretylium (Bretyolol) blocks norepinephrine release from the terminals. It sdoes not deplete norepinephrine concentration in terminals.

(LO – S. Pharmacology, Question 7) The sympatholytics have limited use in humans as an antihypertensive. It has no use in veterinary medicine, except when used as a pharmacological tool in experimental animals. Drugs that inhibit norepinephrine metabolism include

1. Cocaine: blocks norepinephrine uptake thus increases norepinephrine in synapse.

2. Monoamine Oxidase Inhibitors/ MAO Inhibitors à Deprenyl (Eldepryl) is used to treat Parkinson’s disease. Phenelzine (Nardil) is the last choice of drug in the treatment of depression.

3. Tricyclic antidepressants (e.g. imipramine (Tofranil)): Imipramine is a tricyclic antidepressant. It inhibits norepinephrine and serotonin uptake. Orthostatic hypotension can occur due to alpha-receptor blockade. It is used also in sedation as a mild analgesic.

Study Questions What is the effect of timolol and other beta-blockers on the eye? Lungs? Heart? Blood Vessels? Glands? Bladder? GI Tract?

Beta-1 Selective Blocker

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract

Acebutolol No change. No change. Decreased heart rate, conduction

velocity, and

decreased force of

contraction.

No change. No change. No change. No change. Betaxolol Celiprolol Esmolol Atenolol

Metoprolol Propranolol

Non-

Selective Beta-

Blocker

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract

Timolol Decrease intraocular pressure, increased

Increased broncho-

constriction

Decreased heart rate

and force of contractility

Decreased blood

pressure from beta-

No change.

Relaxation of bladder

wall.

Decreased GI motility and tone.

Nadolol Propranolol

53

contraction of ciliary muscle.

blockade. Relaxation of skeletal muscles in

blood vessel.

What is the effect of albuterol and other beta-2 agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI Tract? (Usually, only blood pressure and heart effects are discussed – remember beta-agonists are selective, but not perfectly selective and you can get some interaction between receptor subtypes). Beta-2 Agonist Eye Lungs Heart Blood

Vessels Glands Bladder GI Tract

Albuterol Increased relaxation of ciliary muscle.

Relaxation of

bronchial muscles.

No change.

Increased relaxation of skeletal muscles.

No change.

Relaxation of bladder

wall.

Decreased motility

and tone. Metaproterenol

Terbutaline Isoetharine Pilbuterol Bitolterol Fenoterol Procaterol

What is the effect of EPI, NE, and DA on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI Tract? Kidney? Endogenous Agonist

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract

Epinephrine (B2>B1>A)

Contraction of radial muscle

(mydriasis), relaxation

of ciliary muscle.

Relaxation of

bronchial muscles.

Increased heart rate, conduction

velocity, and force

of contractio

n.

Constriction of blood

vessels and relaxation of skeletal

muscle.

Localized secretion, inhibition

of intestinal

and bronchial secretion,

and lacrimal

secretion.

Re-laxation

of bladder

wall.

Sphincter constriction,

and decreased GI motility and

tone.

Nor-epinephrine (A>B1>B2) Dopamine

(D1>B1>B2>A1)

What is the effect of methoxamine, phenylephrine, and other alpha agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI Tract? Baroreceptor reflex?

Alpha-1 Agonist

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract

Phenylephrine Contraction (Mydriasis)

of radial muscle.

No change.

No change.

Constriction of most blood

vessels.

Localized secretion of sweat glands.

Inhibition-Moderate Secretion.

Constriction of sphincter

and ejaculation from penis

and seminal vesicles.

Constriction of

sphincter. Decreased GI Motility and Tone.

Methoxamine Oxymetazoline

Mitodrine Metaraminol

Alpha-2 Agonist

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract

Methyldopa No change. No change. Lowers blood

pressure by

decreasing cardiac

output and peripheral vascular

resistance.

No change. Inhibition-Moderate Secretion

No change. Decreased GI motility and Tone.

Clonidine Guanabenz Guanfacine

54

What is the effect of non-specific alpha agonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI Tract? Baroreceptor reflex? What role does orthostatic hypotension play with these drugs? Name the other drugs discussed in this lecture which may cause orthostatic hypotension? Non-Specific

Alpha Agonist

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract Orthostatic Hypotension

Naphazoline No Change.

No Change.

No Change.

No Change.

Inhibition to

moderate secretion

from intestinal, bronchial,

and lacrimal glands.

No Change.

Decreased GI

Motility and tone.

No Change. Tetrahydro-

zoline

What is the effect of alpha antagonists on the eye? Lungs? Heart? Blood vessels? Glands? Bladder? GI Tract? Baroreceptor reflex? Orthostatic hypotension?

Alpha-2 Antaonist

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract Orthostatic Hypotension

Yohimbine No change.

No change.

No change,

but higher

doses can cause rapid heart

rate, high blood

pressure.

Higher doses can cause high

blood pressure.

Otherwise, no change.

No change.

No change.

Relaxation of GI

Sphincter. Increased GI Motility and Tone.

Possible orthostatic

hypotension from low

peripheral blood

pressure.

Non-

Specific Alpha

Antaonist

Eye Lungs Heart Blood Vessels

Glands Bladder GI Tract Orthostatic Hypotension

Phenoxy-benzamine

No change.

No change.

No change, but there will be an increased heart rate

due to baroreflex.

Relaxation of most blood

vessels.

No change.

No change.

Relaxation of GI

Sphincter. Increased GI Motility and Tone.

Possible orthostatic

hypotension from low

peripheral blood

pressure.

Phen-tolamine

55

Lecture VII

Parasympathetic/Cholinergic Pharmacology Lecturer: Dr. Meredith Hay

Lecture Objectives 1. To understand the basic mechanisms underlying the

pharmacological effects of parasympathetic drugs. 2. To review the cholinergic receptor classes and their organ location

and function. 3. To review the classes and clinical uses of muscarinic and nicotinic

agonists. 4. To review the classes and clinical uses of muscarinic and nicotinic

antagonists. 5. To review the indirectly acting parasympathomimetic drugs.

Lecture Acetylcholine is the neurotransmitter released from nerve endings which:

1. Innervate cells of the autonomic ganglia à Acetylcholine is the primary neurotransmitter of the somatic nervous system. It is also the primary neurotransmitter innervating the adrenal medulla. It is the common neurotransmitter for both the sympathetic and parasympathetic nervous system.

2. Innervate parasympathetic neuroeffector junctions (target organs). The first neuron comes out innervates nicotinic receptors.

3. Somatic neuromuscular neuromuscular junctions, with neurons that innervate skeletal muscle with the primary transmitter acetylcholine.

4. Innervate the adrenal medulla. Even with the sympathetic site of the adrenal medulla, acetylcholine does go through the sympathetic chain.

5. Innervate some sympathetic neuroeffector junctions, such that you will have parasympathetic innervation of a presynaptic junction of a sympathetic neuron.

6. Innervate some CNS regions. Therefore, it has a major CNS role.

Understanding of the parasympathetic nervous system allows us to create parasympathomimetic agents. Parasympathomimetic agents cover specifically pharmacological agents that are used in reference to an acetylcholine-like effect on effector cells innervated by postganglionic neurons of the parasympathetic nervous system. Essentially, these are drugs that mimic the parasympathetic nervous system. Another term

ACh N2

Nicotinic�2receptors

Smooth�muscleCardiac�musclegland

ganglion

Postganglionicfiber

Preganglionicfiber

Sympathetic

AdrenalMedulla

EpiNE

AChACh

Parasympathetic

SomaticNervous�system

CentralNervous�System

PeripheralNervous�System

Effector�Organ

AutonomicNervous�system

0

muscarinicreceptors

N1

Nicotinic�1receptors

D

E

Alpha/betareceptors

N1

56

utilized is a cholinergic agent. Cholinergic agents describe an acetylcholine-like effect without distinction to the anatomic site of action. The focus this time is specifically on the cholinergic synapses and the cholinergic release on the efferent junction and don’t forget the somatic nervous system, activating into nicotinic-2 receptors. There are fundamentally different types of receptors. The nicotinic channels are ligand-gated ion channels. There are five subunits that make up the ion channel, spanning the entire channel. When two acetylcholine molecules bind, there is a change in the structure of the channel, allowing sodium to enter, depolarizing the post-synaptic membrane and allowing propagation of the action potential. Nicotinic-1 and Nicotinic-2 are similar, but are different in the affinities for acetylcholine and other drugs in other sites. Muscarinic receptors are G-protein coupled receptors. There are different types of muscarinic receptors associated with different G-Protein coupled receptors. There are different types of action associated with the receptors due to different second messenger systems. In the smooth muscle, the M1 and M3 receptors is linked to a Gq protein, activating inositol-triphosphate, releasing calcium and causing calcium-dependent contractions. When you activate the parasympathetic nervous system in the gut, gut motility increases. You already know that there is M1 or M3 receptors in the gut. However, in the heart, there are M2 receptors, which activates potassium channels. When the parasympathetic nervous system is activated, heart rate decreases. Contraction is inhibited by potassium by hyperpolarization. We can start at the top with cholinergic synapses. We can break down the possible sites of drug targeting once again into six major steps:

1. Synthesis of Acetylcholine à Transport of choline is inhibited by hemicholinium.

2. Uptake Into Storage Vesicles à Acetylcholine is protected from degradation in the vesicle. Acetylcholine is packed into synaptic vesicles, and these synaptic vesicles have to fuse with the presynaptic membrane and release its contents.

3. Release of Neurotransmitter à Remember that this is done by membrane fusion with the vesicle. The release is blocked by botulinum toxin, and spider venom causes release of acetylcholine.

4. Binding to the Receptor à binding of the neurotransmitter activates Postsynaptic receptor.

5. Degradation of Acetylcholine à Acetylcholine is rapidly hydrolyzed by acetylcholinesterase in the synaptic cleft. If you block acetylcholinesterase, acetylcholine binds to the receptor.

57

6. Recycling of Choline à Choline is taken up by the neuron, and recycled to make more acetylcholine.

(LO – P. Pharmacology, Question 1) The botulinum toxin (BOTOX) works by inhibiting the SNARE proteins to promote vesicular fusion. It is a toxin made from a bacteria. Once again, we can summarize it into four major actions:

1. Synthesis and Storage of Neurotransmitter 2. Release of Neurotransmitter 3. Interaction with Postjunctional Cell and Initiation of Activity 4. Deactivation

Similar to the last time, we’re going to talk about the parasympathetic ganglionic synapse. The parasympathetic ganglionic synapse is located in the end organ. Most of them start in the medulla, travel to the organ that it is innervating and release acetylcholine (neurotransmitter). Acetylcholinesterase is here as well. Here is another diagram of the muscarinic receptor. The M1 receptors are primarily in the Central Nervous System and autonomic ganglia. M2s are found in the heart, and the M3s are found in glands and smooth muscle. M1 and M3 are linked to Gq that activates inositol-triphosphate that increase calcium and cause contraction. There is increased gland activation to spur releases of tears, sweat, or fluids. In the smooth muscle, there will be increased calcium to cause contraction of the smooth muscle. The following table can summarize the acetylcholine receptors:

Receptor Type Location Postreceptor Mechanism M1 Nerves IP3 and DAG cascade M2 Heart, Nerves, and Smooth

Muscles Inhibition of cAMP production and activation of K+

channels M3 Glands, Smooth Muscle,

Endothelium IP3 and DAG cascade

M4 ? CNS Inhibition of cAMP production M5 ? CNS IP3 and DAG cascade NM Skeletal Muscle

Neuromuscular Junction Na+, K+ depolarizing ion channel

NN Postganglionic Cell Body and Dendrites

Na+, K+ depolarizing ion channel

With these receptors, they are also distributed differently, depending on the organ.

Effector Organs Receptor Action Eye Circular Muscle M3 Contraction (Miosis)

Ciliary Muscle Contraction (Accomodation) Heart SA Node M2

Decreased heart rate

AV Node Decreased conduction velocity Contractility Decreased contraction

Lung Bronchial Muscle M3 Contraction Blood

Vessels Most blood vessels - -

(For the most part, there is not really parasympathetic innervation of the blood vessels. If

you give acetylcholine, there are acetylcholine

Skeletal Muscle

Autonomic�Receptor�Classification�at�Effector�Organs�and�Glands

A.��Cholinergic�(acetylcholine)�receptors1. Muscarinic��receptors�(IP3,�decrease�cAMP),

activation�of�K+�channel)a.����M1 receptors�(M1)�(IP3)��are�found�at:

1.��CNS2.��Autonomic�ganglia

b.����M2 receptors�(M2)�(up��IK,�decrease�cAMP)��are�found�at:�:1.��Heart;�SA,AV�nodes,�atria�muscle,ventricles

c. M3 receptors�(M3),�(IP3),�exocrine�glands,�smoothmuscle,�endothelial�cells

MuscarinicReceptor

G�protein

M2�=� IK,�decrease�cAMP

M3�=� IP3,��Ca++Glands,�SM,�endos

via�Gi

via�GqEffector

58

receptors on the blood vessels’ smooth muscle but no parasympathetic innervation. There is vasodilation

consequently due to release of nitric oxide) GIT Sphincter M3

Relaxation

Motility and Tone Increased GUT Trigone and Sphincter

Muscles M3

Relaxation

Bladder Wall and Detrusor Muscle

Increase

Penis and Seminal Vesicles Erection due to Ach-induced release of nitric oxide Secretory

Glands Sweat M Generalized Secretion

Intestinal M3 Increased secretion Bronchial M Increased secretion Lacrimal M Profuse Secretion

(LO – P. Pharmacology, Question 2) There are many clinical preparations for these agents. Cholinergic receptor agonists are utilized. However, acetylcholine itself is not use as systemic therapeutic agents because (1) it is non-receptor selective and affects multiple organs, and (2) it is rapidly degrade by cholinesterases. If you give it intravenously, you can see a transient decrease in Mean Arterial Pressure. This is due to activation of muscarinic receptors on the endothelial cells of the vasculature. The endothelial cells then release NO which diffuses to the vascular smooth muscle to cause vasodilation. Acetylcholine (marketed as Micohol) can be used to produce rapid and complete miosis before or after surgery involving the anterior portion of te eye. Carbochol (Isopot Carbachol) has been used in the past, and is selective for both muscarinic and nicotinic receptors. It causes miosis after surgery in the anterior chamber of the eye. It is used in the treatment of severe glaucoma. Parasympathetic agents prevent acetylcholine producing its characteristic effects in structures innervated by postganglionic parasympathetic fibers. They also inhibit the effects of acetylcholine on smooth muscle that respond to exogenous acetylcholine but lack cholinergic innervation. Muscarinic antagonists include atropine, scopolamine, homatropine (shorter acting than atropine with fewer gastrointestinal effects), and propantheline (quaternary compound with no effects on Central Nervous System). Homatropine and propantheline are selective muscarinic antagonists with lesser side effects. If it does not exert CNS effects, then it cannot cross the blood-brain barrier. Clinically, atropine is routinely used in the following:

1. Atropine is routinely used as an adjunct to general anesthesia to decrease salivary and airway secretions.

2. Atropine is routinely used in ophthalmic examinations and treatment of ocular disorders.

3. Atropine is the primary and essential antidote to anticholinesterase poisoning.

4. Parasympatholytic drugs are frequently used to control smooth muscle spasm and are used to decrease GI hypermotility.

59

Atropine and scopolamine are competitive antagonists. They both compete with acetylcholine for the muscarinic receptor and have atropine as a sympathomimetic, mainly because it gives the sympathetic nervous system a free-run. Atropine is a prototype and an isolate of the belladonna alkaloid. It has a high affinity for muscarinic receptors. It is also a central and peripheral muscarinic blocker. It causes reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors. IT causes reversible blockade of the actions of cholinomimetics at muscarinic receptors, giving unopposed sympathetic action. Anticholinergic effects can be remembered with this:

§ DRY AS A BONE – Dry mucous membranes, urinary retention, constipation

§ MAD AS A HATTER – Restlessness, tachycardia, palpitations, HA, dizziness

§ RED AS A BEET – Flushed, hot, and dry skin § BLIND AS A BAT – Pupillary dilation (mydriasis), blurred vision

(cycloplegia), photophobia. Other muscarinic agonists include methacholine (provocholine), which is selective for muscarinic receptors, but can bind to nicotinic receptors at high enough doses. Bethanechol (Urecholine) has a selective effect on the gastrointestinal and genitourinary smooth muscle. It can be used to treat bowel stasis, postoperative paralytic ileus, and urinary retention. The use of these drugs for colic and impactions should be closely monitored. Excessive peristalsis in a patient suffering from severe obstruction can promote rupture. Pilocarpine (Pilorcar) is extremely selective for muscarinic receptors over nicotinic receptors and are used for glaucoma. What is unique about it is that it is insensitive to acetylcholinesterase, giving it a longer half-life. It is in naturally occurring plant alkaloids primarily used in the treatment of acute glaucoma. (LO – P. Pharmacology, Question 4) Autonomic Ganglionic Blocking Drugs (or nicotinic antagonists are agents that act by competitive blockade of NN-cholinergic receptors at the autonomic ganglia and prevent all sympatheticparasympathetic nerve activity from reaching the end organs. They are competitive antagonists. If you are blocking a nicotinic receptor between the preganglionic and post-ganglionic neuron, it will affect parasympathetic and sympathetic nervous system. The pharmacological effects are easy to predict if the predominant autonomic tone to each organ is considered. Some nicotinic antagonists include:

1. Hexamethonium: used to treat chronic hypertension, but the non-specificity of such treatment led to its discontinuation.

60

2. Trimethaphan (Arfonad): used to produce controlled hypotension during vascular, ocular, and neurologic surgeries. It lowers blood pressure, and provides a controlled drop in blood pressure.

3. Chlorisondamine We can summarize it into the following table:

Susceptibility to cholinesterase

Muscarinic Effects Nicotinic Effects Therapeutic Effects

Ach + +++ +++ Miotic Metacholine + ++++ + Dx of bronchial

hyperactivity Carbachol - +++ ++ Miotic

Betanechol - ++ - Non-obstructive urinary retention

Drugs that affect acetylcholinesterase are also an indirectly acting parasympathomimetic. The pharmachological effects of cholinesterase inhibitors can be explained almost entirely by their characteristic inhibitory action on acetylcholinesterase. If you block acetylcholinesterase, you give an exacerbated response of the parasympathetic nervous system. There are two main types of acetylcholinesterase inhibitors: reversible (anticholinesterases) and irreversible (organophosphates). Remember that acetylcholine breaks down into choline and acetic acid in the presence of cholinesterase, and an anticholinesterase will inhibit cholinesterase, increasing the concentration

of acetylcholine 𝐴𝑐𝑒𝑡𝑦𝑙𝑐ℎ𝑜𝑙𝑖𝑛𝑒  !"#$%&"!!"#$%&'%()&%

𝐶ℎ𝑜𝑙𝑖𝑛𝑒 + 𝐴𝑐𝑒𝑡𝑖𝑐  𝐴𝑐𝑖𝑑 . Reversible inhibitors include:

1. Physostigmine (Antilirium): Physostigmine inhibits the CNS and consequently has CNS. This is because it is lipophilic and freely enters CNS. Therapeutic uses include glaucoma, atropine overdose, and Alzheimer’s disease.

2. Neostigmine (Prostigmin): Neostigmine is not active in the Central Nervous System. It is a partial agonist at Nicotinic-2 receptors. The therapeutic uses include atony of gastrointestinal and genitourinary smooth muscles, postoperative paralytic ileus, reversal of the action of neuromuscular blocing agents.

3. Edrophonium (Tensilon): It is not active in Central Nervous System, and a partial agonist of Nicotinic-2 receptors.

(LO – P. Pharmacology, Question 3) It can be described further in this table: Inhibitor Description CNS? DOA

(hrs.) Therapeutic Uses Adverse Effects

Physo-stigmine

Alkaloid, tertiary

ammonium grp

Enters the CNS

0.5 to 2 § Atony of intestines and bladder

§ Glaucoma à Lowers IOP

§ Antidote à Atropine, phenothiazines, TCA

§ NDMR

§ Convulsions § Bradycardia § CO

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(Tubocurarine) Reversal

Neo-stigmine

Quaternary Ammonium

grp

Does not enter the

CNS à peripheral

0.5 to 2 § Atony of intestines and bladder

§ Myasthenia Gravis

§ NDMR (tubocurarine) Antidote

§ Salivation § Flushing § Decreased blood

pressure § Nausea § Abdominal Pain § Diarrhea § Bronchospasm

Edro-phonium

Quaternary amine

Does not enter the

CNS à Peripheral

0.5 to 2 § Diagnosis of myasthenia gravis

§ NDMR (tubocuraine) antidote

§ Arrhythmias (SVT)

§ Antidote for atropine poisoning

§ Salivation § Flushing § Decreased Blood

Pressure § Nausea § Abdominal Pain § Diarrhea § BRonchospasm

There are also irreversible inhibitors of acetylcholinesterase. These compounds were developed to function as insecticides or nerve gases for chemical warfare. Organophosphates act as irreversible inhibitors of the cholinesterases in mammals. Organophosphates irreversibly phosphorylate acetylcholinesterase, because it is irreversible. The side effects of organophosphate poisoning are severe. These compounds irreversibly phosphorylate both acetylcholinesterase and pseudocholinesterases. Classic symptom includes extreme overexcitation of parasympathetic nervous system. Because endogenous acetylcholine is not inactivated, the resulting effects are due to the excessive preservation and accumulation of acetylcholine. Some organophosphates include:

Organophosphate Uses Malathion and Parathion Insecticides for plants and livestock

Dimpylate (Diazinon) Insecticide Carbaryl (Sevin) Insecticide (is slowly reversible carbomoylation)

Dichlorvos Oral anthelmintic, pesticide Soman, Serin Nerve gas

Organophosphate poisoning has diffuse cholinomimetic effects; with these signs reflect excess activation of muscarinic and nicotinic receptors of postganglionic parasympathetic neuroeffector junctions. The signs and symptoms include: (1) miosis, (2) salivations and frothy secretions, (3) sweating, (4) bronchial constriction, (5) vomiting and diarrhea, and (6) muscle fasciculation (muscle twitches in the face). Organophosphate poisoning is treated with therapy. It involves maintenance of vital signs for respiration, decontamination. Drugs utilize involve atropine and pralidoxime. Atropine sulfate involves 1 to 2 milligrams intravenously every 5-15 minutes until the muscarinic effect disappears. The maximum is 1 gram per day. Pralidoxime is utilized to help regenerate acetylcholinesterase and help generate new enzyme. It is a cholinesterase enzyme regenerator compound, and it is usually 1 to 2 grams given over thirty minutes by intravenous infusion. You can know this with “SLUDGE BAM”:

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§ S: Salivation § L: Lacrimation § U: Urination § D: Defecation § G: Gastrointestinal Distress § E: Emesis § B: Breathing Difficulty § A: Arrhythmias § M: Miosis

Nicotinic effects can be remembered with the “days of the week”:

§ M: Mydriasis § T: Tachycardia § W: Weakness § H: Hypertension & Hyperglycemia § F: Fasciculations

Myasthenia gravis causes weakness of the voluntary (skeletal) muscles. Voluntary muscles are those that are under your control. In other words, you think about moving your arm, and it moves. The muscle weakness of myasthenia gravis worsens with activity and improves with rest. The muscle weakness can lead to a variety of symptoms, including (1) difficulty breathing because of weakness of the chest wall muscles, (2) chewing or swallowing difficulty, causing frequent gagging, choking, or drooling, and (3) facial paralysis or weakness of the facial muscles. Medications that may be prescribed include neostigmine to improve the communication between the nerves and the muscles. (LO – P. Pharmacology, Question 5)

Cholinergic Pharmacology Study Questions Briefly discuss the synthesis and metabolism of acetylcholine. We can start at the top with cholinergic synapses. We can break down the possible sites of drug targeting once again into six major steps:

1. Synthesis of Acetylcholine à Transport of choline is inhibited by hemicholinium.

2. Uptake Into Storage Vesicles à Acetylcholine is protected from degradation in the vesicle. Acetylcholine is packed into synaptic vesicles, and these synaptic vesicles have to fuse with the presynaptic membrane and release its contents.

3. Release of Neurotransmitter à Remember that this is done by membrane fusion with the vesicle. The release is blocked by botulinum toxin, and spider venom causes release of acetylcholine.

4. Binding to the Receptor à binding of the neurotransmitter activates Postsynaptic receptor.

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5. Degradation of Acetylcholine à Acetylcholine is rapidly hydrolyzed by acetylcholinesterase in the synaptic cleft. If you block acetylcholinesterase, acetylcholine binds to the receptor.

6. Recycling of Choline à Choline is taken up by the neuron, and recycled to make more acetylcholine.

Where in the ANS are the cholinergic receptors located? The parasympathetic ganglionic synapse is located in the end organ. Most of them start in the medulla, travel to the organ that it is innervating and release acetylcholine (neurotransmitter). Acetylcholinesterase is here as well. It will typically originate in the medulla of the Central Nervous System.

Outline the effect of activating muscarinic receptors in the heart, lung, eye, glands, GI.

Receptor Heart Lung Eye Glands GI Muscarinic Decreased heart

rate, conduction velocity and contraction.

Contraction of bronchial muscle.

Contraction of the circular muscle and

ciliary muscle.

Increased generalized secretion.

Relaxation of the sphincter and

increased motility and tone.

Classify cholinergic receptors. The focus this time is specifically on the cholinergic synapses and the cholinergic release on the efferent junction and don’t forget the somatic nervous system, activating into nicotinic-2 receptors. There are fundamentally different types of receptors. The nicotinic channels are ligand-gated ion channels. There are five subunits that make up the ion channel, spanning the entire channel. When two acetylcholine molecules bind, there is a change in the structure of the channel, allowing sodium to enter, depolarizing the post-synaptic membrane and allowing propagation of the action potential. Nicotinic-1 and Nicotinic-2 are similar, but are different in the affinities for acetylcholine and other drugs in other sites. Muscarinic receptors are G-protein coupled receptors. There are different types of muscarinic receptors associated with different G-Protein coupled receptors. There are different types of action associated with the receptors due to different second messenger systems. The M1 receptors are primarily in the Central Nervous System and autonomic ganglia. M2 receptors are found in the heart, and the M3 receptors are found in glands and smooth muscle. M1 and M3 are linked to Gq that activates inositol-triphosphate that increase calcium and cause contraction. There is increased gland activation to spur releases of tears, sweat, or fluids. In the smooth muscle, there will be increased calcium to cause contraction of the smooth muscle. The following table can summarize the acetylcholine receptors:

Receptor Type Location Postreceptor Mechanism M1 Nerves IP3 and DAG cascade M2 Heart, Nerves, and Smooth

Muscles Inhibition of cAMP production and activation of K+

channels M3 Glands, Smooth Muscle,

Endothelium IP3 and DAG cascade

M4 ? CNS Inhibition of cAMP production M5 ? CNS IP3 and DAG cascade NM Skeletal Muscle

Neuromuscular Junction Na+, K+ depolarizing ion channel

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NN Postganglionic Cell Body and Dendrites

Na+, K+ depolarizing ion channel

With these receptors, they are also distributed differently, depending on the organ:

Effector Organs Receptor Action Eye Circular Muscle M3 Contraction (Miosis)

Ciliary Muscle Contraction (Accomodation) Heart SA Node M2

Decreased heart rate

AV Node Decreased conduction velocity Contractility Decreased contraction

Lung Bronchial Muscle M3 Contraction Blood

Vessels Most blood vessels - -

(For the most part, there is not really parasympathetic innervation of the blood vessels. If

you give acetylcholine, there are acetylcholine receptors on the blood vessels’ smooth muscle but no parasympathetic innervation. There is vasodilation

consequently due to release of nitric oxide)

Skeletal Muscle

GIT Sphincter M3

Relaxation Motility and Tone Increased

GUT Trigone and Sphincter Muscles M3

Relaxation Bladder Wall and Detrusor

Muscle Increase

Penis and Seminal Vesicles Erection due to Ach-induced release of nitric oxide Secre-tory Glands

Sweat M Generalized Secretion Intestinal M3 Increased secretion Bronchial M Increased secretion Lacrimal M Profuse Secretion

Classify cholinergic drugs. Cholinergic drugs are classified by the following:

1. Acetycholine Receptor Agonists (Pilocarpine, Muscarine, Nicotine) 2. Acetylcholinesterase Inhibitors (Neostigmine, Physostigmine,

Edrophonium, Organophosphates)

What is myasthenia gravis? Myasthenia gravis causes weakness of the voluntary (skeletal) muscles. Voluntary muscles are those that are under your control. In other words, you think about moving your arm, and it moves. The muscle weakness of myasthenia gravis worsens with activity and improves with rest. The muscle weakness can lead to a variety of symptoms, including (1) difficulty breathing because of weakness of the chest wall muscles, (2) chewing or swallowing difficulty, causing frequent gagging, choking, or drooling, and (3) facial paralysis or weakness of the facial muscles.

Name one cholinergic drug used to treat myasthenia gravis. Medications that may be prescribed include neostigmine or another anticholinesterase inhibitor to improve the communication between the nerves and the muscles.

Classify anti-cholinergic drugs (atropine substitutes) according to therapeutic use. Anti-cholinergic drugs are classified by the following:

1. Muscarinic Antagonists (Atropine, Scopolamine, Homatropine, Propantheline)

2. Nicotinic Antagonists (Hexamethonium, Trimethaphan, Chlorisondamine)

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Write short notes on (a) Pilocarpine (b) Physostigmine (c) Neostigmine (d) Edrophonium (e) Atropine (f) Treatment of Acute Glaucoma

Drug Description Pilocarpine Pilocarpine (Pilorcar) is extremely selective for muscarinic receptors over nicotinic receptors

and are used for glaucoma. What is unique about it is that it is insensitive to acetylcholinesterase, giving it a longer half-life. It is in naturally occurring plant alkaloids

primarily used in the treatment of acute glaucoma. Physostigmine Physostigmine inhibits the CNS and consequently has CNS. This is because it is lipophilic and

freely enters CNS. Therapeutic uses include glaucoma, atropine overdose, and Alzheimer’s disease.

Neostigmine Neostigmine is not active in the Central Nervous System. It is a partial agonist at Nicotinic-2 receptors. The therapeutic uses include atony of gastrointestinal and genitourinary smooth

muscles, postoperative paralytic ileus, reversal of the action of neuromuscular blocing agents. Edrophonium It is not active in Central Nervous System, and a partial agonist of Nicotinic-2 receptors.

Atropine Atropine is a prototype and an isolate of the belladonna alkaloid. It has a high affinity for muscarinic receptors. It is also a central and peripheral muscarinic blocker. It causes

reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors. It causes reversible blockade of the actions of cholinomimetics at muscarinic receptors, giving

unopposed sympathetic action. Treatment of

Acute Glaucoma

Carbochol (Isopot Carbachol) has been used in the past, and is selective for both muscarinic and nicotinic receptors. It causes miosis after surgery in the anterior chamber of the eye. It is

used in the treatment of severe glaucoma.

Discuss the steps of management of organophosphate poisoning. Organophosphate poisoning is treated with therapy. It involves maintenance of vital signs for respiration, decontamination. Drugs utilize involve atropine and pralidoxime. Atropine sulfate involves 1 to 2 milligrams intravenously every 5-15 minutes until the muscarinic effect disappears. The maximum is 1 gram per day. Pralidoxime is utilized to help regenerate acetylcholinesterase and help generate new enzyme. It is a cholinesterase enzyme regenerator compound, and it is usually 1 to 2 grams given over thirty minutes by intravenous infusion.

66

Lecture VIII

Review and Case Studies Lecturer: Dr. Meredith Hay

Application of the ANS to the Understanding of Human Health True understanding of autonomic physiology and pharmacology requires more than simply memorizing receptors, transmitters, and drugs. Applying your new knowledge to understanding how the ANS is altered during disease and how ANS drugs are used in therapy is essential for a deep understanding of the ANS. The case studies serve to separate students who have simply memorized aspects of the ANS from students who have a more thorough understanding of this system. Successful completion of the case studies requires higher level critical-thinking and problem-solving skills.

Case#1: Insecticide Poisoning CD is a 44-year-old woman who had spent much of the day working in her garden. A blustery wind caused her to unintentionally inhale the insecticide that she was spraying throughout the garden. When she began wheezing severely, she was taken to the emergency room. The attending physician observed other symptoms including constricted pupils and a slowed heart rate. CD was trated with the intravenous administration of atropine sulfate.

Insecticides contain organophosphates, which inhibit acetylcholinesterase. What is the function of acetylcholinesterase? Acetylcholinesterase is a serine protease that hydrolyzes the neurotransmitter acetylcholine. Its activity serves to terminate synaptic transmission.

Which types of autonomic receptors are excessively stimulated as a result of this inhibition? The receptors of the parasympathetic division of the autonomic nervous system are excessively stimulated due to the accumulation of acetylcholine in the synaptic terminals. The muscarinic receptors are excessively stimulated.

Which division of the ANS has been primarily affected, the sympathetic or the parasympathetic? The parasympathetic branch of ANS is affected.

Under what conditions does this division of the ANS normally predominate? The conditions this division of the ANS normally predominate is typically in a rest and digest situation.

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Explain how the insecticide resulted in her presenting symptoms. The organophosphates in the insecticide irreversibly inhibit acetylcholinesterase. The acetylcholine accumulates in the synaptic terminal, causing excessive parasympathetic stimulation. Remember the table.

Effector Organs Receptor Action Eye Circular Muscle M3 Contraction (Miosis)

Ciliary Muscle Contraction (Accomodation) Heart SA Node M2

Decreased heart rate

AV Node Decreased conduction velocity Contractility Decreased contraction

Lung Bronchial Muscle M3 Contraction Blood

Vessels Most blood vessels - -

(For the most part, there is not really parasympathetic innervation of the blood vessels. If

you give acetylcholine, there are acetylcholine receptors on the blood vessels’ smooth muscle but no parasympathetic innervation. There is vasodilation

consequently due to release of nitric oxide)

Skeletal Muscle

GIT Sphincter M3

Relaxation Motility and Tone Increased

GUT Trigone and Sphincter Muscles

M3

Relaxation

Bladder Wall and Detrusor Muscle

Increase

Penis and Seminal Vesicles Erection due to Ach-induced release of nitric oxide Secretory

Glands Sweat M Generalized Secretion

Intestinal M3 Increased secretion Bronchial M Increased secretion Lacrimal M Profuse Secretion

What effects may the insecticide have on the gastrointestinal system? Explain. It can cause relaxation of the sphincter of the gastrointestinal tract as well as cause increased gut motility and tone, causing nausea and diarrhea.

What effect may the insecticide have on generalized sweating in the patient? Localized sweating? Explain. It will have generalized sweating due to muscarinic activation in the secretory glands.

If exposed to high enough doses, what effect might the insecticide have on the patient’s skeletal muscles? Excessive acetylcholine will cause contraction of the patient’s skeletal muscles due to the nicotinic receptors in the skeletal muscle.

Would the administration of a beta-adrenergic receptor antagonist be useful in the treatment of this patient? Why or why not? A beta-adrenergic receptor antagonist would not be useful in the treatment of the patient because organophosphate toxicity presents with decreased heart rate, blood pressure, and force of contractility. It would be more damaging to give a beta-adrenergic receptor antagonist as a mode of treatment for a patient with this condition.

Would the administration of a beta-adrenergic receptor agonist be useful in the treatment of this patient? Why or why not? It will be useful to increase heart rate, blood pressure, and force of contractility of the heart while administering atropine and pralidoxime.

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Why is atropine an appropriate treatment? Atropine is an appropriate treatment because it is a competitive antagonist to the muscarinic receptor. It will compete with acetylcholine for the same binding site.

The “nerve gas,” sarin, is a potent, irreversible organophosphate. What is the likely cause of death resulting from exposure of this extremely toxic agent? The likely cause of death resulting from exposure of this extremely toxic agent is due to asphyxiation by excessive salivation and bronchoconstriction.

Case #2: Pheochromocytoma AF is a 55-year-old woman who had been experiencing hearts palpitations, a throbbing headache, sweating, pain in the abdomen, nausea, and vomiting. Because these symptoms had failed to subside, she went to see her primary care physician. A urinalysis revealed the presence of catecholamines and their metabolites, including vanillylmandelic acid (VMA). A subsequent CT scan confirmed the presence of a tumor in the adrenal medulla. Surgery to remove the tumor was scheduled.

What is a pheochromocytoma? A pheochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands, secreting excessive amounts of catecholamines, usually norepinephrine and epinephrine.

What are the catecholamines? Which is the predominant compound? The major catecholamines in the body are norepinephrine, epinephrine, and dopamine. Norepinephrine is the predominant compound. Norepinephrine is 80%, while epinephrine is 20%.

Describe the relationship of the adrenal medulla to the autonomic nervous system. Under what conditions are the catecholamines typically released? Catecholamines are typically released under fight or flight conditions, where survival is necessary.

How are catecholamines normally eliminated from the blood? Catecholamines are normally eliminated from the blood by methylation by catechol-O-methyltransferases (COMT) or by deamination by monoamine oxidase (MAO). Amphetamines and MAOIs bind to MAO in order to inhibit its action of catecholamine breakdown. Amphetamines not only cause a release of dopamine, epinephrine, and norepinephrine into the blood stream but also suppress re-absorption.

Is heart rate slower or faster than average in this patient? Why? What autonomic receptors are involved with this change in heart rate? Heart rate will increase because the catecholamines are acting on the beta-1 receptors.

Is blood pressure likely to be lower or higher than average in this patient? Why? What autonomic receptors are involved with this change in blood pressure? BP is high because of vascular constriction.

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Describe the mechanism of excessive sweating in the patient. What autonomic receptors are involved with this sweating?

Effector Organs Receptor Action Eye Radial Muscle (Iris) Alpha-1 Contraction (Mydriasis)

Ciliary Muscle Beta-2 Relaxation. Heart SA Node Beta-1 Increased heart rate

AV Node Beta-1 Increased conduction velocity Contractility Beta-1 Increased force of contraction.

Lung Bronchial Muscle Beta-2 Relaxation (Bronchodilation) Blood Vessels Most Blood Vessels Alpha-1 Constriction

Skeletal Muscle Beta-2 Relaxation Gastro-

intestinal Tract

Sphincter Alpha-1 Constriction Motility and Tone Alpha-1, Alpha-2, and

Beta-2 Decrease

Genito-Urinary

Tract

Sphincter Alpha-1 Constriction Bladder Wall Beta-2 Relaxation

Penis and Seminal Vesicles

Alpha-1 Ejaculation

Secretory Glands

Sweat Alpha-1 Localized Secretion Intestinal Alpha-2 Inhibition to moderate secretion. Bronchial Lacrimal

Metabolism Adrenal Medulla Nicotinic Secretion of catecholamines Kidney Beta-1 Increase renin release

Skeletal Muscle Beta-2 Glycogenolysis Pancrease (Beta-Cell) Alpha-2 Decrease insulin release

Fat Cells Beta-3 Lipolysis The excessive sweating is due to the binding of catecholamines to alpha-1 and alpha-2 receptors of secretory glands. There is an expectation of localized sweating, but the diaphoresis becomes generalized as more sweat glands are activated.

Would you expect the patient’s pupils to be constricted or dilated when her other symptoms are at a peak? What is the clinical term used to describe this condition? Patients’ pupils will dilate because the muscles contract and the receptors are alpha-1 in the radial muscles of the eye. This is known as mydriasis.

How does the duration of activity of the circulating catecholamines compare to that of neuronally released norepinephrine? Explain. Because there is more epinephrine and norepinephrine being secreted and not localized in a neuronal synapse, the effect of the systemic activity will be longer in duration.

How does the breadth of activity of the circulating catecholamines compare to that of neuronally released norepinephrine? Explain. Breadth of activity would be the larger compared to neuronally released norepinephrine. You’re activating more and systemic and longer.

In order to prepare the patient for surgery, what types of autonomic nervous system medications may be used to stabilize her blood pressure within the normal range? Treatment is surgical removal for solid tumor. Pharmacologically we can use alpha and beta-blockers such as labetalol. We can use an alpha-blocker such as phenoxybenzamine or phentolamine. We can use an inhibitor of tyrosine hydroxylase such as alpha-methyl-p-tyrosine. We can also use a beta-blocker only after an alpha-blockade. We can use beta-adrenergic blocking agents (beta-blockers) to address blood pressure.

70

Clinical Implications of ANS Pharmacology Understanding the clinical implications of ANS Pharmacology will be applicable to many different occupations including human medicine, veterinary medicine, pharmacy, nursing, or a physiologist or pharmacology researcher. The tables below displays exercises that will help you logically think through the effect of different ANS drugs on an induced physiological state or drug overdose. REMEMBER TO CONSIDER NOT ONLY THE DIRRECT EFFECT OF EACH DRUG OR PHYSIOLOGICAL STATE, but THE ROLE BAROREFLEX RESPONSE AS WELL. Fill in the following blanks with the symbols +, -, or NC to denote an increase, decrease, or no change, respectively, in the blood pressure of an awake cat. Each row represents the effects in a different animal. Assume that the effect of the antagonist lasts throughout the experiment.

Cats Pretreated

With

Cat’s collar is restricting blood flow to

the head

Dog enters

clinic and cat tries

to kill dog.

Cat presents in clinic with bee sting allergy. You overdose with too much epinephrine.

Cat presents in clinic after eating half the

client’s cocaine stash. (Cocaine blocks uptake of norepinephrine and

epinephrine)

Cat presents in clinic after eating three flea collars

(it’s a big cat)

Nothing (Control)

+ + + + -

Trimethaphan (Nicotinic receptor

antagonists à Both SNS and

PSNS are blocked.)

N.C. N.C. ++ (there is no baroreflex to

bring it down)

+ -

Bretylium (blocks NE

release)

N.C. N.C. + N.C. -

Prazosin (blocks alpha-

1)

N.C. N.C., but HR +

N. C. N.C. -

Phentolamine (Alpha-1 and

Alpha-2 blocker)

N.C. N.C., but HR +

N.C. but HR + due to reflex tachycardia

+ N.C.

Atropine (comp.

antagonist for muscarinic receptors)

+ + + + -

Atenolol (Beta-

blocker)

+ + + + N.C.

Labetalol (Beta-

blocker)

+ + + + N.C.

Trimethephan and

Phentolamine

N.C. N.C. ++ + -

Atropine, Bretylium,

and Phentolamine

N.C. N.C. N.C. N.C. N.C.

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Lectures IX

Cardiovascular Disease Pharmacotherapy #1 Lecturer: Dr. Joseph S. Alpert, M.D. What are the different kinds of cardiovascular diseases that are treated with pharmacological agents, that is, drugs? We need a little background, because if you don’t know the diseases and its manifestations, we won’t be able to understand the drugs. Disease is often a state of abnormal physiology, and drugs are utilized to reverse the damage associated with such abnormal physiology. In cardiovascular pharmacology, we often use drugs to treat these cardiovascular disorders (and many more):

§ Hypertension § Lipid (fats in the blood) disorders § Atherosclerotic disease – myocardial infarction (MI), angina, stroke

(CVA) § Heart failure (CHF) § Cardiac arrhythmias § Valvular heart disease § Cardiomyopathy § Congenital heart disease

Atherosclerosis is often known as the disease of industrial societies. It is the number one cause of death in the world. The cause of heart attacks is typically the change in diet, a transition from fresh vegetables and high-quality foods to hamburgers, pizza, and other junk food. There are genetic propensities, but those were not really translated to a phenotype mainly because individuals were not engaged into poor nutrition or a sedentary lifestyle. Cigarettes were not as plentiful and smoked as much before as it is today. It is seen all over the world, with 2,102,000 in North America, 6,044,000 in Europe, 3,564,000 in Asia, 1,116000 in Oceania, 436,000 in Africa, and 1,538,000 in South America. You can note that this is not a very small problem. So, let’s discuss myocardial infarction. The “Myocardial” refers to “muscle of the heart” and infarction means “death of tissue from lack of blood flow.” Lots of things can injure the heart and kill heart cells, such as trauma (injury) or viral infection (inflammation). However, a heart attack must have a lack of blood flow. It is caused by a sudden blockage of blood flow in a coronary artery by a blood clot leading to death of the heart muscle. Atherosclerosis is almost always the cause of the formation of the blood in the artery. The damaged heart often survives the myocardial infarction

The CVD Pandemic: Annual Incidence

1,538,000

6,044,000

1,116,000

2,102,000

Adapted from American Heart Association: Adapted from American Heart Association: Heart and Stroke Statistica l Update, 1998Heart and Stroke Statistica l Update, 1998 ..

3,564,000

Incidence rates based on 1995 dataIncidence rates based on 1995 data

436,000

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but may have reduced function, causing shortness of breath, leg swelling, and even arrhythmias that can cause sudden death at a later point in time. Often, a manifestation of myocardial infarction is sudden death. An individual can be perceived as healthy, but can suddenly die. Extensive programs are offered for emergency resuscitation and education in the community, as well as the availability of portable defibrillators in public areas. Many people are alive in public areas where they have cardiac arrests due to defibrillators that readily shock individuals back to a normal rhythm. So, here is the atherosclerotic process. It starts off with a normal blood vessel, and then gradually, there is the atherosclerotic change. Eventually, there will be blood flow, but to the point of significant encroachment on the channel. What happens is that when the heart needs to do more work, the heart will work harder and not enough blood goes through. It can lead to angina, which is essentially a signal that the body is not getting enough fuel. Atherosclerosis starts in early childhood, and progresses in some people to the point of excessive buildup. However, not everybody reaches that point. As you get older, especially towards middle life, the blood vessels begin to dilate. There is no guarantee that the blood vessels will have excessive buildup. Remember that acute myocardial infarction is defined as myocardial cell death due to prolonged myocardial ischemia (lack of blood flow). A blocked artery causes a section of the heart to become hypoxic and killed due to lack of oxygen and nutrition. This can be seen in autopsied sections of coronary vessels. You can see the normal coronary artery, and you can see a fibrous tissue cap and this cholesterol and inflammatory cell buildup. The fibrous tissue cap tends to rupture and the circulatory system will build a clot. Individuals with long-standing atherosclerosis will have very thick fibrous (scar) tissue over the atherosclerosis, and tends not to rupture. In older individuals, the heart attacks are smaller, because you don’t suddenly block the whole channel, whereas in younger individuals, the fibrous cap is smaller and is more likely to rupture. When the fibrous cap ruptures, it essentially sets off a cascade of clotting reactions. We have a very complex clotting system in order to address trauma and an important survival mechanism. However, it is not very useful in intrinsic trauma. You can also see an atherosclerotic lesion, with cracks, due to increased blood pressure, inflammatory cell action, and other factors not yet known. When the lesion cracks and the clot forms, it can eventually lead to occlusion in the artery and the heart muscle oxygenated by that artery is dead.

Definition of Myocardial Infarction

Acute myocardial infarction is defined as myocardial cell death due to prolonged myocardial ischemia.

Pathology

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A stroke (or cerebrovascular accident) is caused by sudden blockage of blood flow in an artery to the brain or in the brain leading to the death of brain tissue. Atherosclerosis is the most common cause of the formation of the blood clot in the artery. The damaged brain often survives the cerebrovascular accident but may have reduced function leading to disability. For example, a stroke can cause the inability to move one leg or one arm. Elderly individuals tend to not wish for a stroke because it often robs their independence. A little clot in the heart may not be as bad as a clot in the brain. A clot in the brain can cause major deficits. What are the factors that lead to atherosclerosis?

§ Increased low-density lipoprotein (LDL) Cholesterol § Decreased HDL (high-density lipoprotein) Cholesterol § Cigarette Smoking § Hypertension (affects a third of Americans) § Increased Age § Diabetes § Estrogen and Oral Contraceptive Agents à Studies have shown that

OCAs can lead to an increased risk for heart attacks due to estrogen’s effects in clotting. If clotting factors are excessive, women can have pulmonary emboli. Estrogen itself does decrease the risk of atherosclerosis, but excessive quantities can lead to the clotting cascades.

§ Physical Inactivity These risk factors are associated with the Western lifestyle. Stress is also a factor, but not exactly quantifiable. However, it is associated with the Western lifestyle. Additional risk factors that are difficult to address include:

§ Men § Obesity § Type A Personality § Positive Family History: Family History of heart attacks is often

associated with the problem of heart attacks. So, this is the atherosclerotic process. It is now known to be an inflammatory process. Something injures the lining of the blood vessel, causing cholesterol in the blood to get into the wall and causes an inflammatory action. Inflammatory cells get in, and they start eating the cholesterol. Some die, and fibrous tissue builds up. There is a very thick fibrous cap. You may have some angina, but the plaque will not rupture. If the cap is thinner, there may be rupture and clotting. What are the ways to prevent this from occurring? The American Heart Association laid out some prevention guidelines:

§ Smoking Cessation

Stroke Can Be Devastating

74

§ Blood Pressure Management § Physical Activity (Exercise should be fixed into your schedule every

day) § Weight Control § Diabetes Mellitus Management à The more controlled, the less

likely to have complications. § Antiplatelet/Anticoagulant Therapy to prevent further clotting § Angiotensin Converting Enzyme (ACE) Inhibitors à Have to do with

Renin-Angiotensin-Aldosterone System § Beta-Blockers à Block adrenaline effects § Lipid Management § No Hormone Replacement Therapy post-menopause, but it is still a

large debate. What is the leading cause of death in the United States? So far, it is cardiovascular disease, taking 1.3 million people. Cardiovascular disease kills more people each year than Alzheimer’s, accidents, and cancer combined. It has surpassed infectious diseases as the common cause of death. There are 1.3 million people killed each year in the United States. This translates roughly to about 3,500 people per day. There is one death every thirty seconds, and 1 in 3 will die from cardiovascular disease. What is the leading risk for cardiovascular disease? It is abnormal cholesterol and other lipids in the blood. Approximately 50% of adult Americans have high cholesterol levels, which is over 100 million people. It could be said that high cholesterol is almost always associated with cardiovascular disease. For many, the first sign of a problem is sudden death. Hyperlipidemia is high levels of various fats in the blood. There are several types of fats in the blood, including total cholesterol (contains the good and bad components), LDL cholesterol (bad), HDL cholesterol (good), triglycerides (commonly elevated in diabetics), and other components. This is an area of intense investigation. It absolutely has something to do with diet, but also with genetics. Hyperlipidemia increases the risk for myocardial infarction, congestive heart failure, and cerebrovascular accidents. It is related in part to heredity and in part to diet and lifestyle, for example, over eating and inactivity leading to obesity. As you can see, the relative risk for first heart attack and total blood cholesterol has a relationship. The Framingham Study showed that high cholesterol is a etiologic factor in the cause of heart attacks. This led to efforts towards lipid management. LDL (low-density lipoprotein) cholesterol is the bad cholesterol that gets into the lining of blood vessels and causes the inflammatory response. Cholesterol testing can be done to monitor hyperlipidemia and the risk for stroke. Sometimes diet modification and pharmacological agents may be used depending on the severity. Evidence-based medicine is opposed to eminence-based medicine. Evidence-based medicine means proven by carefully done blinded clinical

75

trials. Evidence-based medicine is based on facts and research, while eminence-based medicine is based on opinion and expertise. Pharmacology is central to these drugs because many of these trials are drug trials. The drugs that have the greatest reduction in major acute ischemic coronary events (MACE) of all agents used to prevent an initial or a second myocardial infarction (heart attack) are statins. What do statins do? Statins block the liver enzyme, HMG-CoA reductase, needed to synthesize cholesterol in the liver. Blockage of this enzyme leads to increased numbers of LDL receptors on the surface of the liver cell. Pharmaceutical companies invest $25 billion per year attempting to lower patients’ cholesterol levels. The top two prescription drugs sold worldwide are cholesterol-lowering medications (simvastatin and lovastatin). Most inhibit cholesterol production in the liver. Lipid-lowering Therapies are as follows:

LDL-C HDL-C TG Statins (atorvastatin, fluvastatin, lovastatin, pravastatin,

rosuvastatin, simvastatin) ê 18-63% é 5-15% ê 7-30

Bile Acid Sequestrants (Colesevalem, cholestyramine, colestipol) ê 15-30% é 3-5% 0 or é Nicotinic Acid ê 5-25% é 15-35% ê 20-50%

Fibric Acid Derivatives (Gemfibrozil, Fenofibrate) ê 5-20 or é é 10-20% ê 20-50% Cholesterol Absorption Inhibitor (Ezetimibe) ê 18% é 1% ê 7%

Omega-3 Fatty Acids (Fish Oil) (Prescription Strength Only) ? é 9% ê 45% So, in people who cannot tolerate the statins, there is consideration for herbal products with flaxseed (in pill or as the seeds). There are relatively modest changes. Red rice yeast has lovastatin, but in very low doses. The average lovastatin pill is 40 mg, and the pill of red rice yeast contains 1-2 mg of lovastatins. Statins were discovered in fungi, just like penicillin was found in a mold. The problem with the herbal products is that they are not standardized. The label may say it has these active ingredients, but you do not know what is actually in it and the amount of the active ingredients varies. Pharmacological agents originated as herbal products, but the problem with herbal products is that we cannot regulate the dose and the FDA does not control it so you do not know what you are getting. It is not a controlled environment. However, some natural products are helpful, but in fact that there is a prescription level and an over-the-counter level. Consumers need to be careful of what manufacturers are making these products. The problem is the need of the intelligent consumer towards safety during use. This diagram displays the whole variety of pathways of fats and cholesterol and the action of the different drugs:

76

Statins is an HMG-CoA reductase inhibitor. Bile acid sequestrants (BAS) increase the amount of bile transferred to the feces. Ezetimibe blocks NPC1L1. Fibrates work in CMr-C and IDL-C. Niacin is seen working in VLDL-C. All these processes have multiple steps, and these engineers are working on blocking at different levels. The end-result is the same. You will see multiple things like this, but there are multiple ones, but the best are the statins. This is because of the double blind, randomized trials showed the statins as the most effective and the most tolerated. Drugs are designed to be effective, but also minimal side effects. Why? This is because most of these drugs may have to be taken by the patient for the rest of their lives. LDL cholesterol lowering drugs (statins) decrease the rate of production of lipids by the liver and remove LDL from the blood vessels. You can also see cholesterol synthesis in the following reaction:

LDL cholesterol lowering drugs (statins) decreased production of cholesterol by the liver and increase removal of LDL. Serious side effects can include liver damage (rarely) and pain and weakness muscle damage (very rarely). Blood testing monitors this. They are extremely well tolerated, but not tolerated by all.

However, it can be observed that there is major coronary heart disease risk reduction with statin therapy. Statins decreased major coronary events by 30%. There were coronary deaths reduced by 30%, and cardiovascular deaths reduced by 30%, and no changes in noncardiovascular events. All in all, there were major improvements

with the use of statins. There is a log-linear relationship between LDL-C levels and relative risk for coronary heart disease (CHD). This relationship is consistent with a large body of epidemiologic data and data available from clinical trials of LDL-C-lowering therapy. These data suggest that for every 30-mg/dL change in LDL-C, the relative risk for CHD is changed by about 30%. The relative risk is set at 1.0 for LDL-C = 40 mg/dL. It is

Cholesterol Synthesis

39

CHD Risk Reduction with Statin Therapy

La Rosa JC et al. JAMA 1999;282:2340-2346. | Crouse JR III et al. Arch Intern Med 1997;157:1305-1310. | Pedersen TR et al. Am J Cardiol 1998;81:333-335.

Endpoints +20 –35 –30 –25 0 –5 –10 –15 –20

Relative Risk Reduction (%) –40 –45 –50

Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events Total mortality Strokes Intermittent claudication Angina

Log-Linear Relationship Between LDL-C Levels and Relative Risk for Coronary Heart Disease (CHD)

• This relationship is consistent with a large body of epidemiologic data and data available from clinical trials of LDL-C–lowering therapy.

• These data suggest that for every 30-mg/dL change in LDL-C, the relative risk for CHD is changed by about 30%.

• The relative risk is set at 1.0 for LDL-C = 40 mg/dL.

LDL-C = low-density lipoprotein cholesterol; CHD = coronary heart disease. Reprinted with permission from Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239.

LDL-C, mg/dL

Relative Risk for CHD, Log Scale

40 70 100 130 160 190

1.0

1.3

1.7

2.2

2.9

3.7

77

important to think about a typical patient’s LDL and the normal LDL. You can also see that the statins reduced the risk for death and MI from unstable angina, a previous myocardial infarction, post-angioplasty, post-coronary artery bypass graft, and individuals with elevated cholesterol. There is real science that says it works, not just opinion. High-density lipoprotein (HDL) is considered the “good” cholesterol. They can be increased with exercise and diet. A number of clinical studes show that high levels reduce risk of cardiovascular disease. It is important to remember that statins inhibit cholesterol synthesis in the liver and increase LDL receptors. It causes a 24-40% relative reduction in coronary events. The potential side effects include myopathy and elevated liver enzymes. Contraindications are for active liver disease. It should be used with caution with other drugs. Lowering LDL-Stating Drugs include:

§ Crestor (Rosuvastatin) § Lescol (Fluvastatin) § Lipitor (Atorvastatin) § Mevacor (Lovastatin) § Pravachol (Pravastatin) § Zocor (Simvastatin)

Atorvastatin (Lipitor) is the number one selling drug in the world. Lipitor lowers LDL cholesterol in one way: by inhibiting cholesterol production in the liver. It is sold by Pfizer Pharmaceutical and represents 20% of total company revenues. Simvastatin (Zocor) is the second largest selling drug in the world sold by Merck/Schering-Plough. It lowers LDL cholester one way, by inhibition of cholesterol production in liver. The following describes a comparative efficacy of the statins:

The following describes the pharmacokinetics of the HMG-CoA reductase inhibitors, that is statins:

Agent Major Metabolic

Isoenzymes

Lipophilic Bioavailability (%)

Protein Binding (%)

Active Metabolites

Half-life (hrs)

Fluvastatin 2C9 Yes 19-29 >98 No 3 Rosuvastatin 2C9, 2C19 No 20 88 Yes 20 Pravastatin None No 18 50 No 2 Lovastatin 3A4 Yes 5 >95 Yes 2

Simvastatin 3A4 Yes 5 >95 Yes 3 Atorvastatin 3A4 Yes 14 >98 Yes 14

STELLAR Trial: Jones PH et al. Am J Cardiol. 2003;92:152.

Mea

n ch

ange

in L

DL-

C fr

om u

ntre

ated

bas

elin

e, %

10 mg 20 mg 40 mg 80 mg

–55

–45

–35

–25

–15

–5

–28% –37%

–7%

–6%

–6%

–3%

–5%

–4%

–7%

–3%

Atorvastatin Rosuvastatin Simvastatin

–20%

–4% –6%

Pravastatin

Comparative Efficacy of the Statins

*P<0.001 vs atorvastatin 10 mg; simvastatin 20 mg and 40 mg; and pravastatin 10 mg, 20 mg, and 40 mg. †P=0.026 vs atorvastatin 20 mg

–46%*,†

UA Post MI PTCA CABG Primary

0

10

-10

-20

-30

-40

-50

-60

%R

isk

DeathMI

12 Trials 186,800 patient-years follow-up NEJM 1995;333:1301 Lancet 1994;344:1383 Circulation 1995;91:2528

Statins in Cardiovascular Disease

78

You can also note that pravastatin is not metabolized in the liver, and can be considerably safer to use with individuals with compromised livers in comparison to the other statins. With any drug, there are some characteristics that can predict toxicity with the statins:

§ Females > Males § Advanced Age (>80 years) § Small body size or frailty § Diminished renal and hepatic function § Multiple comorbities or medications § Hypothyroidism § Perioperative Periods § Alcohol Abuse

The next question in lipid management is what to do if statin therapy does not lower the lipids enough. Combining statins with other lipid lowering medicines is the next step. For example, ask the patient to take gemfibrozil or fenofibrate tablets in addition to the statin. The combination is more effective than either drug alone, but complications and side effects are more common with the combination program. One of the complications is rhabdomyolysis with statin/fibrate combination therapy. There is an increased risk of myopathy and rhabdomyolysis with statin/fibrate combination therapy. However, statin/fibrate combination therapy is NOT contraindicated. Fish oils plus statins may often be an alternative to fibrate or niacin plus statin. Fish oils may have other cardiovascular effects complementary to those of statins, such as:

§ Reduction in malignant ventricular dysrhythmias § Increased heart rate variability § Antithrombotic effects § Improved endothelial reactivity/relaxation § Anti-inflammatory effects § Slight lowering of blood pressure

The omega-3-acid ethyl esters (fish oil) may reduce the synthesis of triglycerides (TG) in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids. There are reduced very high triglycerides (TG) in patients with triglycerides (TG) greater than or equal to 500 mg/dL. It led to a reduction in non-HDL-C by 14%, a raise in HDL-C by 9%, and reduction in triglycerides by 45%. The most common adverse events reported were eructation (burping), infection, flu syndrome, dyspepsia, taste perversion, back pain, and rash. The dosing is typically four 1-gram capsules once daily. The 90% omega-3-acid ethyl esters are available by prescription only. When added to simvastatin therapy (COMBOS) there is essentially a doubling in the percentage of patients who achieved the non-HDL-C goal. There are safety concerns with both Omega-

Rhabdomyolysis with statin/fibrate combination therapy

• Increased risk of myopathy and rhabdomyolysis with statin/fibrate combination therapy

• However, statin/fibrate combination therapy is NOT contraindicated

Rhabdomyolysis

8.6

0.58

0

5

10

Fenofibrate +Statin

Gemfibrozil +Statin

Case

s p

er M

illio

n Pr

escr

iptio

ns (#

)

Am J Cardiol 2007;99[suppl]:3C–18C.

15-Fold Increase

Davidson MH et al. Clin Ther. 2007;29:1354-1367.

Effect of Adding P-OM3 to Simvastatin Therapy (COMBOS)

51.6

23.8

0

10

20

30

40

50

60

Pati

ents

ach

ievi

ng

non–

HD

L-C

goal

(%

)

P-OM3 (4 g/d) + simvastatin

Placebo + simvastatin

79

3 fatty acids and “fish oils”. With omega-3 fatty acids, there are no antithrombotic effects, but it is also not proven to increase bleeding risk. The rigorous manufacturing purification processes reduce risk of hypervitaminosis and exposure to environmental toxins (e.g., mercury, dioxin). The “fish oils” do not require USP verification not required for all products. It is not equal to the prescription omega-3 fatty acids, because the omega-3 fatty acids require regulation. Now, a final question arises, what is a normal human cholesterol value in a free-living human being and where would you find such a person? The total cholesterol is approximately 70-80 mg. The average total cholesterol is around 150-180 mg. The closest humans have reached are in tribes living in the highlands of New Guinea or deep in the Amazon River basin. There is now an advertisement from your family friendly cardiologist. Patients who survive a myocardial infarction and who are clinically stable but continue to smoke have a six-fold increased risk of dying during the next five years. Cigarette smoking is a major, worldwide cause of coronary heart disease. There is some good news, however. There are marked reductions of deaths due to coronary heart disease. This is often attributed to lifestyle modifications.

Case Examples Case 1: A 60-year-old man suffers an MI (heat attack). His lipids are abnormal: high total and high LDL cholesterol. Which of these drugs would be indicated?

A. Penicillin B. Advil C. Rolaids D. Geritol E. Atorvastatin

Case 2: A 42-year-old father with three children suffers a myocardial infarction (heart attack). His cholesterol is markedly elevated, but he has tried a statin drug in the past and it gave him terribly painful muscle cramps. Which of the following drugs would you NOT prescribe?

A. Pravastatin B. Omega 3 fish oil capsules C. Gemfibrozil D. Fenfibrate E. Cholestyramine

Some Good News

80

Lecture X

Cardiovascular Disease Pharmacotherapy #2 Lecturer: Dr. Joseph S. Alpert, M.D. One of the guidelines in the American Heart Association in the prevention of heart attacks and stroke is to manage blood pressure. There are a multitude of drugs that work against hypertension, but it continues to be a serious illness with fatal consequences. In order to discuss blood pressure medications, it is important to discuss the pathophysiology of hypertension. You can think of a blood vessel as a pipe and there needs to be a pressure to pump blood through the blood vessel. If we think of Ohm’s law and translate it into the circulation, we can convert 𝑉 =  𝐼×𝑅 to the formula 𝐵𝑙𝑜𝑜𝑑  𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 = 𝐶𝑎𝑟𝑑𝑖𝑎𝑐  𝑂𝑢𝑡𝑝𝑢𝑡  ×  𝑉𝑎𝑠𝑐𝑢𝑙𝑎𝑟  𝑅𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 . Patients with hypertension have increased vascular resistance, which leads to increase blood pressure, that is, hypertension. Approximately one-third of Americans have hypertension. About a third of Americans have our blood pressure set too high. The resistance is too high. There is an advantage to blood pressure for athletes, but the problem is the system is worn out over time. The heart is essentially overworked and there are long-term consequences. Patients with high blood pressure have increased vascular resistance. Chronic hypertension causes many complications:

§ Stroke (CVA) § Myocardial Infarction (MI = heart attack) § Heart failure – shortness of breath, fatigue, swelling of legs à the

heart is not pumping efficiently, there is eventually a point where the heart is worn out.

§ Kidney failure § Dementia – decreased intellectual capacity due to damaged neurons

in the brain § Arrhythmias – atrial fibrillation à the atria is quivering in the heart

and appears in Emergency Rooms. It seen commonly in the elderly and accompanied by other heart disease. Everyone has arrhythmias. Most are monitored to address recurrent arrhythmias. Of young people, it is 1 in 10,000 that have malignant arrhythmias.

§ Shortened life expectancy The consequences of uncontrolled hypertension can be shown in the graph. The problem with uncontrolled hypertension is that it can lead to extremely dangerous flow of vasculature, especially to the brain. It can lead to strokes, which can also be hemorrhagic. This is what contributed to the death of Franklin Delano Roosevelt towards the end of World War II. President Franklin Delano Roosevelt had around normal blood pressure but over time, but the blood pressure progressively increased, due to post-polio states and stress. They soon found that he

Consequences of Uncontrolled Hypertension

Messerli F. N Engl J Med 1995;332:1038-1039 Copyright © 1995 Massachusetts Medical Society. All rights reserved.

81

passed from a cerebral hemorrhage from stroke and severe hypertension. They gave him a series of early (1930) antihypertensive therapies, which were empirical and poorly regulated, but now we have other medications that are evidence-based. Some of these drugs work in a certain population, and some drugs in other populations. What about the public health statistics? The study showed that the number of people identified with hypertension has increased. There are individuals that are better treated for hypertension. Physicians are detecting patients better. However, adequate control is only about 50% in the 2005-2008 period, which means that there is still much work in controlling hypertension. Now the question remains: what approaches can be used to improve detection and control of hypertension? There are populations that are at higher risk and require treatment. There is a multitude of patient characteristics associated with high-risk hypertension:

§ High baseline blood pressure à Individuals in high school with elevated blood pressure can be considered at risk for developing hypertension.

§ Older age § Obesity § Excessive dietary salt ingestion: the American diet is high in salt

content § Chronic kidney disease à The kidney is the major regulator of blood

pressure. § Diabetes à due to decrease insulin sensitivity and consequent action

in the blood pressure. § Left ventricular hypertrophy à inadequately treated blood pressure § African American race à particularly prone to nasty hypertension § Female gender à Women tolerate hypertension less than men. § Residence in Southeastern United States à “Stroke Belt”, not so

much due to the prevalence of African-Americans but more due to the diet, which contains copious amounts with salt, fat, and lack fiber and organics, and possibly due to socio-economic factors.

There are also lifestyle factors contributing to hypertension, which can modified and are considered in therapy:

§ Obesity or overweight à Weight loss will help reduce risk, but is a challenging problem.

§ High salt diet à Decreasing salt intake can help reduce your risk for hypertension.

§ Physical inactivity à Exercise can decrease risk for hypertension. § Ingestion of low-fiber, high-fat diet. à The opposite can reduce the

risk. § Heavy alcohol ingestion à Alcohol cessation can halt the

progression of hypertension.

Vital Signs: Prevalence, Treatment, and Control of Hypertension — United States, 1999–2002 and

2005–2008

Centers for Disease Control and Prevention. Vital signs: Prevalence, treatment, and control of hypertension—United States, 1999-2002 and 2005-2008. MMWR Morb Mortal Wkly Rep 2011; 60:1-6.

82

Pharmacological therapy is usually considered in individuals with blood pressure that is consistently greater than 140/80 mm Hg. Diuretics make you urinate, essentially. Diuretics work in the nephron, either at the ascending loop of Henle (loop diuretics) or in the distal convoluted tubule (thiazide diuretics). They help in the sodium movement in the

nephron. Thiazide diuretics are an excellent first line therapy alone and in combination with other agents. This is the best therapy for the disease. These diuretics are also generic and therefore inexpensive. The most popular ones are the thiazide diuretics. They are shown to reduce cardiovascular events, for example, stroke, in patients with hypertension. The following describe common thiazide diuretics:

Absorp-tion (%)

T1/2 Relative Potency

Elimination (R = Renal, H=Hepatic, B= Biliary, U=

Unknown)

Anti-hypertensive dosing (typical)

Chlorothiazide 9-56 ≈1.5 0.1 R PO: 500-2000 mg/day in 2 doses Chlorthialidone ≈65 ≈47 1 65% R, 10% B, 25% U 12.5-25 mg PO once daily

Hydro-chlorothiazide

≈70 ≈2.5 1 R 12.5 -50 mg PO once daily

Indapamide ≈93 ≈14 20 > 95% H 1.25-5 mg PO once daily Metolazone ≈65 4-5 10 80% R, 10% H, 10% B 2.5-5 mg po once daily For

Mykrox: 0.5-1 mg PO QD Absorption is essentially how well the body is absorbing the drugs. Hydrocholorothiazide is considered the best one out there. It is absorbed very well in the stomach and stays in the blood for approximately 2.5 hours and is considered the gold standard. It’s potency is 1, which means you can give a normal dose, compared to indapamide where you have to give a smaller dose. The drugs to remember are hydrocholorothiazide and chlorthalidone. Chlorthalidone is slightly more potent and gives off slightly more side effects. There are major antihypertensive effects of hydrochlorothiazide versus chlorthalidone on blood pressure. There are statistically significant reductions in average systolic blood pressure. This made diuretics the mot prescribed medication. With chlorthalidone, there was statistically more significant reduction. It is a lot more effective, but hydrochlorothiazide is used more. However, there are adverse effects of thiazide diuretics:

§ Hypokalemia (dose-related and can affect clinical outcome) à Diuretics tend to wash potassium, so there is muscle pain. This can be ameliorated with potassium supplementation.

§ Glucose Intolerance (diabetic tendency) à Pushes individuals towards diabetes. What thiazide diuretics do is induce insulin resistance, so all cells become insulin resistant due to thiazides.

§ Gout à Joint problems and precipitation of uric acid.

§ Kidney Damage

Diuretics and Their Primary Sites of Action

Antihypertensive Effects of Hydrochlorothiazide versus Chlorthalidone on Blood Pressure

Khosla N, Chua DY, Elliott, WJ, Bakris G. The Journal of Clinical Hypertension 2005;7(6): 354-346.

Stroke Volume

Vascular Resistance

Contractility

Diuretics

Cardiac Output

Renin angiotensin blockers, Calcium channel blockers, Diuretics, Vasodilators, CNS sympathetic nervous system blockers

Filling of LV

Beta blockers Beta blockers, Some calcium blockers

Blood pressure

Drugs from JNC VII, hemodynamics from Houston MC. Primary Care. 1991;18:713.

Antihypertensive Drugs: Hemodynamic Mechanism of BP Reduction

Heart Rate

83

There are also less-commonly recognized substances impeding blood pressure control. Alcohol is a common interference to blood pressure. Alcohol raises blood pressure transiently, and can raise blood pressure even with pharmacological agents. Antidepressants also raise blood pressure. Ma huang (ephedra), bitter orange, blue cohosh, ginsent, guarana are over-the-counter and can also raise blood pressure. Some of the anticancer drugs (bevacizumab, sorafenib, and sunitinib), which inhibit vascular endothelial growth factor, can raise blood pressure. NSAIDs can also raise blood pressure. The drugs work in different areas. ACE inhibitors and ARBs work by decreasing vascular resistance. Beta-blockers decrease the heart rate. Diuretics work on the vascular resistance but also the filling of the left ventricle. Beta-blockers and some calcium blockers decrease the contractility of the heart. Some patients respond to drugs in one category and better in another category. There are also ethnic differences. African-Americans respond better to calcium blockers than to ACE inhibotors. Thus, there may be ethnic concerns to address, and can be noted that it may take more than one drug. Now, we need to discuss the renin-angiotensin-aldosterone system. The main organ for regulating blood pressure is the kidney. This is why patients with kidney disease often present with hypertension. Renin is released by the kidney in response to injury, and causes increases in blood pressure. The kidney is crucial to blood pressure regulation – the juxtaglomerular apparatus and renin release. Renin initiates a biochemical sequence that eventually converts angiotensinogen produced in the liver into angiotensin, a strong vasoconstrictor. Angiostensin stimulates release of aldosterone from te adrenal gland which causes the kidney to retain salt (NaCl) and water. Angiotensin stimulates release of anti-diuretic hormone from the pituitary gland, which causes the kidney to retain water. This system is part of the body’s defense against dehydration and/or blood loss. The idea is to restore blood volume to normal as quickly as possible. Here is a list of common drugs that act in the Renin-Angiotensin-Aldosterone System:

Drug Commonly used ACEi and AH blockers in treatment of HF with low EF

Initial daily dose Target dose

ACEi Captopril 6.25 mg tid 50 mg tid Enalapril 2.5 mg bid 10-20 mg bid Fosinopril 5-10 mg daily 40 mg daily Lisinopril 2.5-5 mg daily 20-40 mg daily

Perindopril 2 mg daily 8-16 mg daily Quinapril 5 mg bid 20 mg bid Ramipril 1.25-2.5 mg daily 10 mg daily

Trandolapril 1 mg daily 4 mg daily ARB Candesartan 4-8 mg daily 32 mg daily

Losartan 25-50 mg daily 50-100 mg daily Valsartan 20-40 mg bid 160 mg daily

However, there are also adverse effects with ACEi and ARB as a 1st line drug. With ACE inhibitors, there is kidney damage especially in individuals with prior damage, excessive drop in blood pressure, tongue and facial swelling due to allergic reaction. With angiotensin-receptor

Renin-Angiotensin-Aldosterone System

Angiotensinogen

Angiotensin I

Angiotensin II

AT1 Receptor

Renin

ACE

Bradykinin

Inactive Peptides

Non ACE Pathways ACE Pathways

Chymase CAGE

Cathepsin G t-PA

AT2-4 Receptors Antihypertrophic, proapoptotic ???

Cell Growth

Sodium & Fluid Retention

Sympathetic Activation

Vasoconstriction Aldosterone Release

Vagal Inhibition

Thirst Stimulation

AII-Receptor Blockers ACE-I

84

blockers, there is kidney damage especially in individuals with prior damage and excessive drop in blood pressure. Another set of drugs involved in the management of hypertension is known as aldosterone antagonists. Their mechanism of action involves the block of aldosterone binding at receptors in kidney, heart, blood vessels, and brain. The blockade of aldosterone in the renal tubule causes increased NaCl and water excretion and potassium retention. One known aldosterone inhibitor is spironolactone, which is a competitive antagonist of the aldosterone receptor, giving effects on myocardium, arterial walls, and kidney. It decreases retention of sodium cations and water (decreasing edema). It also decreases the excretion of potassium and magnesium cations (decreasing arrhythmias) and decreases collage deposition (decreasing fibrosis of myocardium vessels). Beta-blockers slow the heart rate and block sympathetic nerve stimulation to the kidney (decreasing renin release) and the peripheral nerves (decreasing vascular resistance). They are 2nd line agents for hypertension. They were discussed in sympathetic pharmacology in their function, mainly to decrease epinephrine binding to the beta-1 receptor of the heart and consequently decrease the rate of SA node firing. Beta-blockers are listed below:

Selec-tivity

Lipid Solubility

Bioavailbility (%)

Protein Binding (%)

T1/2

(h) Primary (secondary)

Elimination R=Renal, H=Hepatic Nadolol β1β2 L 30 25-30 20-24 R

Propranolol β1β2 H 30 90 3-5 H Timolol β1β2 L-M 75 < 10 4 H(R) Pindolol β1β2 M 90 57 3-4 H(R) Atenolol β1 L 50-60 < 5-10 6-9 R(H)

Metoprolol β1 M 50(77-XL) 10-12 3-7 H/R Bisoprolol β1 L 80 26-33 9-12 R(H) Acebutolol β1 L 40 15-25 3-4 H(R) Labetalol β1β2α1 M 18-30 50 5.5-8 R(H) Carvedilol β1β2α1 M 25-35 98 7-10 Bile

Adverse events of beta-blockers include fluid retention and worsening heart failure, but are more likely to occur during initiation and first several months. It requires daily weight and careful adjustment of diuretics. Hypotension is more likely with carvedilol, and consequently must be administered with food. It has been suggested to administer ACE inhibitor or temporarily reduce ACE-I. There is a risk of bradycardia and heart block and a risk of 5-10% as dose is increased. There is also fatigue and weakness, which may resolve with time or reduction in dose. Calcium channel blockers dilate arterioles (resistance vessels) and thereby decrease vascular resistance. The mechanism of action involves relaxation of vascular smooth muscle and thereby dilates arterioles and decrease vascular resistance. There are two forms: dihydroperidine and non-dihydroperidine. Dihydroperidine forms (such as nifedipine,

Beta Blocking Agents

Non-Selective Selective* Alpha-Blocking

Activity

Nadolol Propranolol Timolol Sotalol

Pindolol Carteolol Penbutolol

Atenolol Metoprolol Esmolol Betaxolol Bisoprolol Nevibolol

Acebutolol Celiprolol

Labetalol Carvedilol Bucindolol

- ISA + ISA + ISA - ISA

With

*Beta-1 Cardioselective

ESC Expert Consensus Document on B-adrenergic Receptor Blockers. Eur Heart J 2004:25;1341-1362

ALDOSTERONE

< Retention Na+ < Retention H2O

< Excretion K+ < Excretion Mg2+

Collagen deposition

Fibrosis myocardium vessels

Spironolactone

< Edema

< Arrhythmias

Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney)

Aldosterone Inhibitors

-

85

amilodipine, and nicardipine), at the doses used in humans, only dilate arterioles. There is no effect on the electrical system of the heart (the conduction system). Non-dihydroperidine calcium blockers (such as diltiazem and verapamil) dilate arterioles and also decrease the rate of passage of electrical impulses in heart muscle. Because of their effect on the electrical activity of the heart, they are often used to control arrhythmias. Other drugs that are used to treat hypertension include:

§ Minoxidil is a very potent vasodilator, but is also used to grow hair. § Clonidine – blocks sympathetic nerve activity in the brain and leads

to less sympathetic nervous system increase in vascular resistance.

§ Peripheral sympathetic receptor blockers in vascular smooth muscle – alpha-receptor blockers à these are not utilized as much due to reflex tachycardia.

As you can note, there is an ascending ladder. The first-line of therapy involves lifestyle modifications. If that does not work, then there is consideration for the use of diuretics, beta-blockers, calcium blockers, or ACE inhibitors. Then you can consider either adding a second drug, increasing the dose of the first drug, or substituting another drug. Then if that is unsuccessful, there may be addition of a different class or substitution of the second drug. Finally, there is further evaluation and referral or the addition of a third or fourth drug. Attempts should be made to step-down therapy and continue nonpharmacological approaches. As you can also note, there may be a number of antihypertensive agents necessary to achieve the target blood pressure. The average number of anti-hypertensive agents needed to achieve target blood pressure is between 3-4, and researchers and clinicians are making considerable efforts to reduce the number of drugs utilized to counter hypertension.

Case Examples Case #1 A 21-year-old U of A student is referred to you for evaluation of high blood pressure found in screening at a local mall. The blood pressure reading there was 145/90 mm Hg. What is your approach to this patient?

Answer: Re-check the blood pressure, because the screening itself is extremely random in comparison, and perform a history and physical. Consider only lifestyle modifications rather than pharmacological agents.

Case #2 A 55-year-old African American woman reports many years of hypertension treatment with less than ideal blood pressures. In your office

Average Number of Anti-hypertensive Agents Used to Achieve Target Blood Pressure

1. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.2. Estacio RO et al. Am J Cardiol. 1998;82:9R-14R. 3. Lazarus JM et al. Hypertension. 1997;29:641-650.4. Hansson L et al. Lancet. 1998;351:1755-1762.

5. Kusek JW et al. Control Clin Trials. 1996;16:40S-46S.6. Lewis EJ et al. N Engl J Med. 2001;345:851-860.7. ALLHAT. JAMA. 2002;288:2998-3007.

1 No. of Antihypertensive Agents

2 3 4

SBP 140/DBP 90 ALLHAT7

SBP 135/DBP 85 IDNT6

MAP 92 AASK5

DBP 80 HOT4

MAP 92 MDRD3

DBP 75 ABCD2

DBP 85 UKPDS1

Target BP (mm Hg)

Trial

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her blood pressure is 160/98 mm Hg. She says she takes her medicines regularly and faithfully. She takes small doses of an ACEi and small doses of a beta-blocker. What is your strategy here?

Answer: You can do many things. You can increase the dosages of the ACEi and/or beta-blocker, or you can give the patient (as she is African-American) an L-type calcium channel blocker, such as verapamil or amilodipine, and consider decreasing the doses (or discontinuing) the ACEi or beta-blocker.

Case #3 A 60-year-old patient seeks your advice for his poorly controlled blood pressure. He tells you that almost all of the medicines that have been tried cause him terrible side effects and that is why his blood pressure is so poorly controlled. He just cannot take the medicines without some “bad thing happening”. What is your strategy here?

Answer: Ask the patient the specifics of some “bad thing happening”. The “bad thing happening” can either be an adverse effect or simply lack fo compliance.

Case #4 A 56-year-old woman reports poor control of her blood pressure that recently led to an episode of heart failure treated in the hospital. She tells you that she has no medical insurance and that the blood pressure medicines her doctor prescribed were costing “way too much for me to able to take them every day.” What is your strategy here?

Answer: Consult with medical services for the underprivileged or discuss with a medical director on the financial course of action.

Case #5 A 25-year-old friend of yours has a very extensive family history of hypertension with many relatives suffering strokes and heart attacks in 40-50 years of age. He tells you that his doctor tells him that he also has high blood pressure with readings often in excess of 160/100 mm Hg. His doctor prescribed medicines for him but he thinks that some herbs he purchased at the health food store will control his blood pressure better than the medicines his doctor gave him. What is your advice?

Answer: Tell the patient that the herbs do not have enough regulation to ensure that his blood pressure will be maintained. Many of the drugs contain herbal origins, but are regulated enough to provide a much better effect in comparison to the herbs.

Case #6 An 82-year-old female was diagnosed with hypertension six months ago in January. She is taking lisinopril (an ACEi vasodilator) with excellent

87

control of her blood pressure. She lives here in Tucson all year. Recently on July 5th she tells you that she nearly passed out when getting out of bed in the morning. The same thing happened again later in the morning when she went shopping. What should be done with her medicines?

Answer: Her medication should be reduced to account for Tucson Summer Syndrome. Tell the patient also to drink a lot of water.

Questions Question #1 “Doctor, my blood pressure readings are all over the map. I never get the same reading two times in a row.” What is your response and how can you help this patient?

Answer: Tell that patient that blood pressure fluctuates throughout the day, and that they should consider taking blood pressure readings around a specific time throughout the day. If the blood pressure is consistently high, then it may be a better time to consult a physician.

Question #2 A 350-pound woman seeks your advice about her planned bariatric surgery. She has been hypertensive for years and is taking four different medicines with rather poor blood pressure control. She tells you that her friend had the bariatric operation 4 years ago and now does not need to take any medicines for blood pressure control. Can she expect the same thing to happen to her?

Answer: No. She may expect some weight loss, but lifestyle modifications will be needed to reach her goals.

Question #3 What is the best class of medicine to control blood pressure in a 44-year-old diabetic man with hypertension? His blood pressures at home runs around 155/90 mm Hg.

Answer: ACE inhibitors or ARBs are considered best to help manage his high blood pressure. However, the diabetes must also be managed, as blood pressure is difficult to manage with uncontrolled diabetes.

Question #4 Which of the following medicines is not used for the treatment of hypertension?

A. Propranolol B. Lisinopril C. Losartan

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D. Tamoxifen E. Nifedipine

Question #5 Are there “street drugs” that can cause hypertension? Are there products in the supermarket that can cause or worsen hypertension?

Answer: Yes. Cocaine and methamphetamine can cause severe rises in blood pressure. Coffee, energy drinks, and herbal medicines that are given in the supermarket can also increase blood pressure.

Question #6 Are most patients very faithful about taking their medicines for hypertension as prescribed by their physician or nurse clinician?

Answer: Not always, but we can always detect ways to determine if they are faithful in taking their medications through blood tests, toxicology screens, or even just counting the number of pills in the container.

Question #7 Which of the following classes of drugs are considered first line for the treatment of hypertension?

A. Beta blockers B. Calcium channel blockers C. Angiotensin receptors blockers D. Thiazide diuretics E. Central nervous system sympathetic blockers

Question #8 Are there lifestyle changes that should be made by patients with hypertension who have been started on medication to control their elevated blood pressure?

Answer: Yes! Some lifestyle changes that have been shown to benefit patients with hypertension alongside their medicines include weight loss, regular exercise, decreasing dietary salt consumption, mind body exercises such as meditation, and decreasing alcohol intake

Question #9 Which of the following foods are high in salt and therefore might increase blood pressure?

A. Ketchup B. Mustard C. Canned Soups D. V8 Tomato Juice Cocktail E. Dill Pickles F. All of the Above

89

Lecture XI

Cardiovascular Disease Pharmacotherapy #3 – Myocardial Infarction and Heart Failure Lecturer: Dr. Joseph S. Alpert, M.D. Heart attacks are the most commonly diagnosed diseases covered by Medicare, and the number one cause of death in the United States. In 2007, the American Heart Association released the statistics on heart disease and stroke. In 2004, the number of strokes per year was 700,000. The number of fatal strokes was 150,000, giving a fatality rate of appxoimately 21%. Myocardial infarctions lead to two million deaths per year. The same statistics revealed that the number of heart attacks per year was 865,000. The number of fatal heart attacks reached 158,000, with a fatality rate of 18%. The total number of deaths due to coronary artery disease reached 452,000. Atherosclerosis starts when there is an injury to the inner lining of the blood vessel (endothelium). From there, lipids are able to enter the endothelium, setting off the inflammatory process. Inflammatory cells come in, ingesting cholesterol and inflammatory cells, depositing into the lining. It causes the spiraling inflammatory cascade. There are a lot of things that can injury the lining, such as high blood pressure diabetes mellitus, viral infection, and tobacco use. What sets off atherosclerosis to a myocardial infarction (death of heart tissue from hypoxia) is a tear in the atherosclerotic plaque. When that happens, the first defense is the adhesion of platelets, which set off clotting factors and further platelet aggregation and clotting cascade. The clotting cascade yields several efforts to halt bleeding and injury. Lack of some of these factors is associated with hemophilia and disease. However, too much clotting activity can cause clots to occur inside the circulatory system, because they can do mischief. On the venous side, they can cause pulmonary embolism, which can be fatal. On the arterial side, they can cause heart attacks (MI), strokes, and kidney damage. There is a long list of unpleasantries when there are clots in the cardiovascular system.

90

What happens is the following: when the vessel wall is damaged. Platelets begin to adhere, causing the initiation of this cascade of clotting factors, leading to the product (thrombin), which joins with release of mediators and platelet aggregates to form fibrin (which is essentially an intrinsic scab/thrombus. Fibrin consists of strong protein strands, which is the end-stage step, which traps erythrocytes and platelets to yield thrombus. You have to have something to dissolve the clot. There are enzymes to dissolve the fibrin, and you are able to measure fibrin degradation products in a diagnostic laboratory (known as a D-Dimer). Venous clots are rather silent in comparison to arterial clots (which are seen by weakness in the face, arms, chest pain, or legs). You can see the entire clotting cascade, which is a lot more complicated. This is an area of considerable research and interest, because so many cardiovascular diseases are associated with clots. There are a lot of attempts to block this in various points of the clotting cascade. The major risk of blocking the clotting cascade is hemorrhage. There is a fine line between bleeding out and clotting. Consequently, the dosage is extremely controlled. In an atherosclerotic blood vessel, there is a build up of lipids and inflammation, and can rupture, causing clotting and occlusion of the artery. Depending on the location, it can lead to heart attacks and stroke. Remember the risk factors for heart attack and stroke:

§ Increased LDL Cholesterol § Decreased HDL Cholesterol § Cigarette Smoking § Hypertension § Increased Age § Diabetes (Less controlled diabetes can lead to greater risk of heart

attack and stroke) § Estrogen, Oral Contraceptive Agents § Physical Inactivity

Medication can often offset the risk for heart attacks and strokes. The therapeutic goals in patients with myocardial infarction is to:

§ Improve blood flow into the heart muscle with thrombolytic agents, anticoagulants, anti-platelet drugs with or without angioplasty.

§ Prevent further thrombosis, that is, blood clot formation § Decrease the work of the heart during the acute and chronic phase

of the illness. § Correct atherosclerotic risk factors.

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Thombolytic agents dissolve the fibrin skeletal structure of blood clots. On average, these drugs open 60-70% of thrombosed (clotted) coronary arteries. However, angioplasty is 95% effective. The earlier in the myocardial infarction they are administered, the more effective they are. How much the heart is pushing will vary. Therefore, it is important to open the artery within two hours of onset. These thrombolytic agents are given intravenously. Some thombolytic agents include streptokinase, tissue plasminogen activator (tPA), and its “cousins”, urokinase. Anticoagulants can be oral, intravenous, or subcutaneous. Heparin (IV or subcu) blocks the clotting cascade by its action on antithrombin 3, a component of the clotting cascade. Warfarin is given orally and blocks the synthesis of clotting factors II, VII, IX, and X in the liver. It is used in the management of pulmonary embolism, deep vein thrombosis, or atrial fibrillation to prevent further clotting. Atrial fibrillations can develop clots in the heart. However, it is not given for myocardial infarction. It has a very narrow therapeutic window, giving rise to under and overdosing. A rare adverse event is skin necrosis on the chest, but is extremely rare. A refined form of heparin (enoxaparin) contains the part of the molecule that is active in anticoagulation. Since the active site is preserved, the therapeutic window essentially becomes wider, preventing some degree of over and under-dosage of the drug. Enoxaprin (low molecular weight heparin) is also given subcutaneously, while unfractionated heparin (UFH) is given intravenously. EnoXaprin only acts on factor Xa. Newer anticoagulants include dabigatran, rivaroxaban and apixaban. Dabigatran bocks factor IIa in the clotting cascade. It is used to prevent stroke in atrial fibrillation and not used in myocardial infarction patients. Rivaroxaban and apixaban block factor Xa in the clotting cascade. It is used to prevent stroke in atrial fibrillation and not used in MI patients. Rivaroxaban is also used in patients with venous thrombosis and pulmonary embolism. Antiplatelet agents include aspirin, clopidogrel (Plavix), dipyridamole, as well as newer agents (prasugrel and ticagrelor). Aspirin is the most common oral anti-platelet agent, blocking platelet activation permanently. Clopidogrel is an oral, reversible platelet inactivator. Dipyridamole is an oral antiplatelet agent utilized for stroke or transient ischemic attack. It is

Odds ratio (95% CI)

Enoxaparin better UFH better

l

0.2 1 2.5

Name Enox UFH Odds ratio [95% CI]

ESSENCE 3.9 5.2 0.736 [0.525, 1.031]

TIMI 11B 5.1 6.2 0.804 [0.612, 1.056]

ACUTE II 6.7 7.1 0.921 [0.468, 1.813]

INTERACT 3.9 5.7 0.682 [0.349, 1.331]

A - Z 5.6 6.5 0.850 [0.647, 1.119]

SYNERGY 11.7 12.7 0.913 [0.810, 1.030]

Overview 8.0 9.1 0.864 [0.780, 0.957]

l

Intention-to-treat Population: Myocardial Infarction at 30 Days

MI Post MI Unstable angina CAD Primary

0

10

-10

-20

-30

-40

-50

-60

% R

ISK

DeathMI

Aspirin in Cardiovascular Disease

AHA Special Report Circulation 1993;87:659 86 Studies 670,000 patient years

AMI Post MI EF < 40% HF CAD

0

10

-10

-20

-30

-40

-50

-60

% R

isk

Death MI

Circulation 1994;90:2056 HOPE 42 Trials 332,000 patient years f/u

ACE Inhibitors in Cardiovascular Disease

92

a reversible agent that is combined with aspirin. Newer agents, such as prasugrel and ticagrelor) are also oral and reversible. The use of aspirin permitted marked reductions in incidences of death and myocardial infarction. Another treatment focus is to decrease the work of the heart, particularly in the left ventricle (larger, muscular portion) of the heart. Beta-blockers slow the heart rate and lower blood pressure thereby decreasing the heart work. ACE inhibitors and angiotensin-receptor blockers decrease blood pressure. Nitrates such as nitroglycerin or its longer acting “cousins”, isosorbide dinitrate or isosorbide mononitrate, shrink the heart and thereby lower wall stress and heart work. They also dilate small collateral (reserve) blood vessels. ACE inhibitors and angiotensin receptor blockers decrease blood pressure and decrease the work of the heart by dilating arteries. The major side effects include cough, dizziness, and hypotension, and ACE inhibitors and angiotensin-receptor blockers are contraindicated in pregnancy. Major ACE inhibitors and ARBs include:

§ Accupril (Quinapril) § Altace (Ramipril) § Lotensin (Benazepril) § Vasotec (Enalapril) § Zestril, Prinivil, Monopril

(Lisinopril) § Avapro (Irbesartan) § Atacand (Candesartan) § Cozaar (Losartan)

With the use of ACE inhibitors, there is a reduction in the incidences of myocardial infarction and death with health management with ACE inhibitors. Another major trial, the SAVE trial, there is a higher mortality in the trial group with the placebo (control) in comparison to the group with captopril. Beta-blockers decrease the work of the heart by decreasing the heart rate, decreasing blood pressure, and decreasing the force of contraction. Side effects include fatigue, dizziness, cold hands/feet, and impotence. It is contraindicated in those patients with asthma and severe chronic obstructive lung disease. Beta-blockers have markedly reduced the incidence of death and myocardial infarction in patients with myocardial infarction. Management also requires the minimization of atherosclerotic risk factors:

Recurrent Myocardial Infarction: SAVE Trial

0 1 2 3 4 Years

0

0.05

0.1

0.15

0.2 Event Rate

Placebo Captopril

RR 0.75 P=0.015

2231 pts post MI with LVEF < 0.40, asymptomatic Pfeffer NEJM 1992;327:669

UA AMI CAD (hx MI) HTN HF

0

10

-10

-20

-30

-40

-50

-60

% R

isk

Death MI

Beta-Blockers in Cardiovascular Disease

Yusuf Circ 1990;82:II-117 48 Trials 260,000 patient years

UA Post MI PTCA CABG Primary

0

10

-10

-20

-30

-40

-50

-60

%R

isk

DeathMI

12 Trials 186,800 patient-years follow-up NEJM 1995;333:1301 Lancet 1994;344:1383 Circulation 1995;91:2528

Statins in Cardiovascular Disease

93

§ Treatment of hyperlipidemia (abnormal LDL cholesterol levels) § Treatment of hypertension § Treatment of smoking addiction § Treatment of diabetes mellitus and decrease glucose intolerance

The LDL cholesterol treatment goal is less than 100 milligrams, and pharmacotherapy is indicated for LDL cholesterol that is greater than 130 milligrams. Current LDL-lowering drugs (statins) include:

§ Crestor (Rosuvastatin) § Lescol (Fluvastatin) § Lipitor (Atorvastatin) § Mevacor (Lovastatin) § Pravachol (Pravastatin) § Zocor (Simvastatin)

Low HDL levels (below 40 in men and below 50 in women) are associated with increased risk of death from cardiovascular disease. Increasing HDL levels decreases the risk of cardiovascular disease. The average HDL in US Adults is 51. Increasing HDL levels can be done with drugs, such as Niaspan (Niacin), Lopid (Gemfibrozil), Tricor (Fenofibrate), and statins. However these increases are not very effective in increasing HDL (around 10%). HDL levels can also increase with lifestyle modifications, such as regular exercise, smoking cessation, weight control, moderate alcohol consumption, and decreased dietary fat. Statins have markedly reduced the risk of cardiovascular disease in all groups. The Hypertension Treatment Guidelines are once again as follows:

Normal BP <120/80 Pre-Hypertension 120-139/80-89

Hypertension > 140/90 Aspirin has been used to prevent heart attacks and stroke since the 1950s, but the association was not established until the 1970s. In 1950, Lawrence Craven, MD, a general practitioner presented data that one aspirin tablet per day prevented heart attacks in men with risk factors. In 1956, he reported that aspirin also prevented strokes and “mini-strokes”. When he presented such data, the medical community met him with skepticism. No one believed him until the 1970s and 1980s when randomized clinical trials proved him to be correct. However, another controversy remains: what’s the right dose? All the physicians agree that the correct dose is either:

§ 81 milligrams (one baby aspirin) § 162 milligrams (two baby aspirin) § 325 mg (one adult aspirin)

The major side effect of aspirin is bleeding. In randomized clinical trials, the incidence of major bleeding is the same for 81 milligrams/day and for 162 milligrams/day. Bleeding rates were higher with 325 milligams/day. There were 1 to 2 cases per 1,000 years of treatment. Another question is who should take aspirin? In the absence of contraindications:

94

§ Patients with known cardiovascular disease § Adults with diabetes § Those with cardiovascular risk factors § Men age >50 § Post-menopausal women, but this is controversial, because aspirin is

less beneficial in women. Another groups of cardiovascular diseases are transient ischemic attacks (TIAs) and stroke. 15% of all strokes are preceded by a transient ischemic attack. TIAs are referred to as a “mini-stroke”. Symptoms include: partial loss of vision, weakness of arm or leg, speech or swallowing difficulty. The symptoms last less than 24 hours, and require prompt evaluation by a physician. There is evidence-based medical therapy proven to benefit patients following a myocardial infarction, with these drugs:

§ ACE inhibitors and angiotensin receptor blockers (lisinopril and losartan)

§ Aspirin, other platelet acting drugs such as clopidogrel § Beta blockers (metoprolol) § Statins and other lipid-lowering agents (pravastatin) § Anticoagulants in selected patients, such as for patients with atrial

fibrillation. The evidence-based medicine once again proves its point. There is a decrease in mortality as the number of recommended therapies increase. The death rate goes down. As hospitals increase in guideline adherence, there is also a decrease in mortality. The American Heart Association Prevention Guidelines include:

§ Smoking § Blood Pressure § Physical Activity § Weight Control § Diabetes Mellitus § Antiplatelet/Anticoagulant Agents § ACE Inhibitors § Beta Blockers § Lipid Management § Cessation of Hormone Replacement Therapy

Heart failure is when one of the ventricles (usually the left) cannot pump enough blood to satisfy the amount of blood flow that is required for daily activities. The body responds with compensatory mechanisms as if there were a state of dehydration or hemorrhage. Salt and water are retained in an attempt to correct the deficit in circulating blood volume with resultant shortness of breath and swelling, usually of the legs. Diuretics are usually given. Drugs in heart failure should be used to effectively control fluid retention. It is essential for fluid overload with resultant symptoms. The other drugs used attempt to improve heart function by decreasing heart

95

work and facilitate heart emptying. The following list once again describes the commonly used diuretics in heart failure:

Absorp-tion (%)

T1/2 Relative Potency

Elimination (R = Renal, H=Hepatic, B= Biliary, U=

Unknown)

Anti-hypertensive dosing (typical)

Chlorothiazide 9-56 ≈1.5 0.1 R PO: 500-2000 mg/day in 2 doses Chlorthialidone ≈65 ≈47 1 65% R, 10% B, 25% U 12.5-25 mg PO once daily

Hydro-chlorothiazide

≈70 ≈2.5 1 R 12.5 -50 mg PO once daily

Indapamide ≈93 ≈14 20 > 95% H 1.25-5 mg PO once daily Metolazone ≈65 4-5 10 80% R, 10% H, 10% B 2.5-5 mg po once daily For

Mykrox: 0.5-1 mg PO QD Loop diuretics primarily act in the thick ascending limb, which is also the site of the greatest sodium cation capacity (25% of the filtered sodium load). Nephron segments past this site do not possess reabsorptive capacity to reabsorb this high volume of fluid and salt. It is effective despite reduced kidney function. Thiazide iuretics are better antihypertensives than loop diuretics. They are supported by hard outcome data in hypertensive patients, with long-term reduction in vascular resistance. There is less electrolyte disturbances and attractive in mild heart failure particularly if there is concomitant hypertension. The initiation and maintenance of diuretics involves this: once fluid retention is resolved, a maintenance dose should be continued with dose reassessed and adjusted periodically. Patients should be educated on self-adjustment based on weight and symptoms. Physicians may need to use two or more diuretics (thiazide and loop) in combination for enhanced effect. Beta-blockers (particularly metoprolol, bisoprolol, and carvedilol) have been proven effective in heart failure. The following once again shows the pharmacokinetic properties of select beta-blockers:

Selec-tivity

Lipid Solubility

Bioavailbility (%)

Protein Binding (%)

T1/2

(h) Primary (secondary)

Elimination R=Renal, H=Hepatic Nadolol β1β2 L 30 25-30 20-24 R

Propranolol β1β2 H 30 90 3-5 H Timolol β1β2 L-M 75 < 10 4 H(R) Pindolol β1β2 M 90 57 3-4 H(R) Atenolol β1 L 50-60 < 5-10 6-9 R(H)

Metoprolol β1 M 50(77-XL) 10-12 3-7 H/R Bisoprolol β1 L 80 26-33 9-12 R(H) Acebutolol β1 L 40 15-25 3-4 H(R) Labetalol β1β2α1 M 18-30 50 5.5-8 R(H) Carvedilol β1β2α1 M 25-35 98 7-10 Bile

Beta-blockers’ mechanism of action involves cardiac myocyte protection of receptors from catecholamines and prevents binding of autoantibodies to adrenoceptors. Studies have shown that it caused a 34-35% reduction in risk for mortality in heart failure with reduced left ventricular ejection fraction. Its effects are in three areas:

Sodium Reabsorption Sites in the Nephron 70% Proximal Tubule

5% Distal Tubule

1-4% 20% Loop of Henle

Collecting Tubule

Glomerulus

Thiazide Diuretics Loop

Diuretics

Beta Blocking Agents - Orange means proven effective in heart failure

Non-Selective Selective* Alpha-Blocking

Activity

Nadolol Propranolol Timolol Sotalol

Pindolol Carteolol Penbutolol

Atenolol Metoprolol Esmolol Betaxolol Bisoprolol Nevibolol

Acebutolol Celiprolol

Labetalol Carvedilol Bucindolol

- ISA + ISA + ISA - ISA

With

*Beta-1 Cardioselective

ESC Expert Consensus Document on B-adrenergic Receptor Blockers. Eur Heart J 2004:25;1341-1362

96

§ Improved (diastolic) coronary artery flow and greater myocardial oxygenation.

§ Improved force-frequency relationship

§ Cardiac myocyte energy conservation.

ACE inhibitors remain the cornerstone of anti-renin-angiotensin-aldosterone-type therapy in heart failure with reduced heart function. ACE inhibitors and/or ARBs can be used in patients with moderate kidney disease. It is used in first-line therapy for the treatment of heart failure. The following are the ACE inhibitors and ARBs:

Drug Commonly used ACEi and AH blockers in treatment of HF with low EF

Initial daily dose Target dose

ACEi Captopril 6.25 mg tid 50 mg tid Enalapril 2.5 mg bid 10-20 mg bid Fosinopril 5-10 mg daily 40 mg daily Lisinopril 2.5-5 mg daily 20-40 mg daily

Perindopril 2 mg daily 8-16 mg daily Quinapril 5 mg bid 20 mg bid Ramipril 1.25-2.5 mg daily 10 mg daily

Trandolapril 1 mg daily 4 mg daily ARB Candesartan 4-8 mg daily 32 mg daily

Losartan 25-50 mg daily 50-100 mg daily Valsartan 20-40 mg bid 160 mg daily

Another method of reducing work on the heart is with aldosterone inhibitors, such as spironolactone, which is a competitive antagonist of the aldosterone receptor in the myocardium, arterial walls, and kidney. They ultimately decrease the retention of water and sodium (reducing edema) as well as decrease the excretion of potassium and magnesium (reducing arrhythmias). It has also been known to decrease collagen deposition (fibrosis) in the myocardium and the vessels. Aldosterone antagonists work by blocking aldosterone binding in two areas: (1) at the mineralocorticoid receptors in kidney, heart, blood vessels, and brain, and at (2) the distal renal tubule, causing increased sodium chloride and water excretion and potassium retention. Spironolactone has shown efficacy in heart failure, reducing total mortality by 30% over 2 years in NYHA late III and IV patients (fairly late heart failure) and reduced need for hospitalization. A final medication utilized in the management of heart failure is a digitalis glycoside known as digoxin. Digitalis is from the foxglove plant. It is a last resort drug due to its ineffectiveness in comparison to beta-blockers, ARBs, and ACE inhibitors. Digoxin works by inhibition of sodium-potassium ATPase in three areas:

§ Cardiac Cells (increasing contractility) § Non-Cardiac Cells (sensitization of cardiac baroreceptors and

decreasing sympathetic CNS outflow)

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2

Relative risk and 95% confidence intervals

CIBIS-II 1.3 years placebo 228/1320 (17%) bisoprolol 156/1327 (12%)

MERIT-HF 12 months placebo 217/2001 (11%) metoprolol-XL 145/1990 (7%)

COPERNICUS ~ 12 months Placebo 190/1133 (18.5%) carvedilol 130/1156 (11.4%)

P = 0.0001

P = 0.0062

P = 0.0014

Beta-adrenergic Blocking Therapy All-Cause Mortality in HF with reduced LVEF

RR 34% 34%

35%

CIBIS-II Investigators and Committees. Lancet 1999; 353:9-13. The Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA 2000;283:1295-1302. Packer et al. For The COPERNICUS Trial Study Group. N Engl J Med 2001;344:1651-8.

97

§ Renal Cells (reduction in renal tubular absorption of sodium and increased presentation to distal tubules) à suppression of renin secretion

Studies have shown that digitalis has been associated with an increased force of contraction, which can be seen with comparison of Starling Curves. One large randomized trial that confirmed the effectiveness of digoxin was the DIG Trial. The DIG Trial was done to evaluate the effects of digoxin in patients with normal sinus rhythm with heart failure with reduced left ventricular function. The study found that there were no statistical differences. It did not decrease mortality, and did not decrease mortality was due to cardiovascular causes and worsening heart failure. The improvement was in symptoms, but not in mortality. However there were two findings in favor of digoxin. It decreased hospitalizations for worsening heart failure and hospitalization for any cause. Essentially, it was not effective as ACE inhibitors, beta-blockers, and ARBs. Physicians often do not use it, or use it as a third-line therapy. Individuals who had low levels did better in comparison to high levels, because higher levels are associated with complications. In summary, treatment of Heart Failure is in ABCDE:

§ A: ACE Inhibitors/Angiotensin-Receptor Blockers § B: Beta-blockers § C: Calcium channel blockers § D: Diuretics § E: Endothelin-converting enzyme inhibitors

Initiation and monitoring requires low doses of 0.125 milligrams to 0.250 milligams daily. Digoxin is mostly eliminated by the kidney in the urine, with a long half-life (18 hours), with distribution and levels. It is important for physicians to check baseline digoxin blood levels and again if there are changes in clinical condition, suspicion of toxicity, changes in renal function, and addition of an interacting drug (such as amiodarone). In conclusion, pharmacological heart failure therapy has improved tremendously during the last forty years. Survival of these patients is better than in the past but is still markedly reduced. Intense research continues in this area in an attempt to improve the function of the failing heart.

Rathore S., et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289:8710878. Copyright 2003. American Medical Association. All rights reserved.

DIG Trial: Survival Analysis Based on Serum Drug Concentration

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LECTURE XII

Cardiovascular Disease Pharmacotherapy #4 Lecturers: Joseph S. Alpert, MD and Michelle Kaczynski, PharmD

Case #1: A 45-year-old man is being treated for hypertension and diabetes mellitus. What is the most feared complication of this combination of diseases and which drugs would you likely choose for this patient?

Answer The most feared complications of this combination of diseases are cardiovascular diseases, mainly stroke and heart attack. Address the hypertension with beta-blockers or ACE inhibitors, and address the diabetes mellitus with antihyerglycemic agents, namely Metformin.

Case #2 (1): An 86-year-old patient with hypertension and mild dementia is taking metoprolol, lisinopril, HCTZ, nifedipine, lovastatin, aspirin, clopidogrel, warfarin, and valium. What do you think of this program?

Answer There are too many drugs to address the hypertension, and the mild dementia can possibly be associated with drug-drug interactions.

Case #2 (2): During July in Tucson, the patient reports fainting once and feeling faint on many occasions in the last few weeks. What might be the problem here and how would you correct it? Remember that the patient is 86-years-old and has some dementia.

Answer Reduce the dosage and number of medications. Encourage hydration. It is important to also observe environmental influences.

Case #3: A 27-year-old homeless man who smokes heavily and has used “crystal meth” frequently in the past reports severe, squeezing chest pain whenever he walks up a slight hill.

Part 1. What is the likely diagnosis?

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Answer Angina secondary to methamphetamine use.

Part 2. What sudden life-threatening event might happen to this man?

Answer Myocardial Infarction.

Part 3. What pharmacological therapy does he probably require?

Answer Discontinuation of methamphetamine use and administration of beta-blockers and/or ACE inhibitors or ARBs.

Case #4 A 60-year-old man with hypertension tells you that he does not want to take his prescribed medicines because they are “artificial chemicals that cause cancer.” Instead he is taking twelve different herbal preparations from the health food store. What is your advice and why?

Answer Tell him that the herbal preparations are not regulated.

Case #5: A 47-year-old woman with long standing hypertension tells you that she cannot tolerate any of the medicines she has received from her doctor in the past. She is obese, loves salted chips pretzels, and peanuts. What advice would you give her and what pharmacological therapy might you suggest?

Answer Choose most benign drug and get her started with that drug. Tell her also that she needs to engage in lifestyle modifcations to improve her tolerance to pharmaceutical agents.

Question? Are there “street drugs” that can cause hypertension?

Answer Yes. Methamphetamines and cocaine. Are there products in the supermarket that can cause or worsen hypertension?

Answer Yes. Alcohol, licorice, caffeine, ginseng, NSAIDs, salt, spam? Anything with sympathomimetic amines.

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Which of the following classes of drugs are considered first line for the treatment of hypertension?

A. Beta blockers B. Calcium channel blockers (indicated for African Americans) C. Angiotensin receptor blockers D. Thiazide diuretics E. Central nervous system sympathetic blockers

Which of the following foods are high in salt and therefore might increase blood pressure?

A. Ketchup B. Mustard C. Canned soups D. V8 Tomato Juice Cocktail E. Dill Pickles F. All of the Above

Case #6 A 56-year-old woman reports poor control of her blood pressure that recently led to an episode of heart failure treated in the hospital. She tells you that she has no medical insurance and that the blood pressure medicines her doctor prescribed were costing “way too much for [her] to able to take them every day”. What is your strategy here?

Answer Consult with free clinics and financial services to manage costs for patient.

Question? Are most patients very faithful about taking their medicines for hypertension as prescribed by their physician or nurse clinician?

Answer Patient compliance is (at best) around 50%.

Case #7 A 74-year-old man has heart failure and is receiving digoxin therapy among other drugs. He develops an arrhythmia and is started on oral amiodarone, a drug that binds with great intensity to proteins. Two weeks after starting amiodarone, the man reports severe nausea, changes in color vision, and two fainting spells. What has happened to the patient?

Answer Drug interactions. Digoxin and amiodarone are not to mix. Discontinue the digoxin.

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Case #8 A 79-year-old woman is taking the oral anticoagulant, warfarin, because of a previous stroke. The patient regularly takes aspirin for her arthritis. Early this morning, she became nauseous and vomited bright red blood isn copious amounts. Why might this have occurred?

Answer Hemorrhage due to antiplatelet and anticoagulant agents.

Case #9 A fifty-year-old man with severe, end stage liver disease from chronic alcohol abuse develops pneumonia and is admitted to the hospital. He has severe degenerative osteoarthritis and complains of severe back pain. He is given intravenous morphine and 15 minutes later, he stops breathing. What happened?

Answer Overdose of morphine in individual with severe, end stage liver disease.

Question? Which of the following drugs would NOT be appropriate for a patient with heart failure?

A. Beta-blocker B. Angiotensin Receptor Blocker C. Digoxin D. Furosemide E. Penicillin

Which of the following drugs would be appropriate for a patient with hypertension and what is their mechanism of action:

A. Beta-blocker-Blocking the SNS action B. Angiotensin Converting Enzyme Inhibitor – modulation of RAA

Axis. C. Methotrexate D. Prednisone E. Furosemide

Case #10 A 69-year-old man suffers an acute myocardial infarction (heart attack). His lipid tests were as follows: total cholesterol = 270 mg%, LDL cholesterol = 160 mg%; HDL cholesterol = 35 mg%. What class of medication should he receive and why?

Answer Statins to regulate cholesterol levels.

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What is the mechanism of action of statin drugs? In other words, how do they lower cholesterol levels?

Answer Statins are beta-hydroxy-beta-methylglutarate coenzyme A reductase inhibitors.

Question? Which of the following diseases is the #1 cause of death in the world?

A. Cancer B. Pneumonia C. HIV/AIDS D. Cirrhosis E. Trauma F. Cardiovascular Disease

Which of the following is NOT a cause of myocardial infarction (heart attack)?

A. Cigarette Smoking B. High Blood Pressure C. Diabetes Mellitus D. Cancer E. High Blood Pressure

Case #11 A 45-year-old man develops severe central chest pain early in the morning. He is nauseated and sweaty. He calls 911 and is brought to the emergency ward. What treatment would be best for him if he is found to be having a heart attack?

Answer Get him into the cardiac catheterization lab, as it is 90% effective in elimination of blockage.

Case #12 A 99-year-old man has severe valvular heart disease and severe heart failure. He has advanced kidney failure and Alzheimer’s disease. His family wants “everything possible done for him”. What therapy would you recommend?

Answer Conservative/supportive therapy and pain management in an effort to permit nature to take its course painlessly à With such advanced heart and kidney disease, there is not much possibly to do.

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Case #13 A 29-year-old man with severe familial hypertension always has elevated blood pressures when he comes into the office. What questions would you ask him?

Answer Calm the patient down and ask him about his lifestyle.

Case #14 The 33-year-old father of a 5-year-old girl has an acute heart attack and survives. His total cholesterol = 356 mg% and his LDL cholesterol = 201 mg%. You are the girl’s pediatrician. What would you recommend to the parents?

Answer Measure her cholesterol levels and possibly focus on reduction of cholesterol levels with lifestyle modification or pharmacological agents.

Question? Which of the following values for total and LDL cholesterol are seen in natives living in the rain forest highlands of New Guinea?

a. Total chol = 180 mg%; LDL = 98 mg% b. Total chol = 80 mg%; LDL = 40 mg% c. Total chol = 200 mg%; LDL 140 mg% d. Total chol = 20 mg%; LDL 10 mg%

Case #15 A fifteen-year-old male reports that he develops a fast irregular heart rate following his daily 2-hour vigorous workout. You are his doctor. What would you suggest for this patient?

A. Record his heart beats for 24 hours with a portable ECG recorder. B. Do nothing and reassure the patient. C. Treat the patient with oral amiodarone. D. Suggest a consultation with a cardiac surgeon. E. Treat the patient with a beta-blocker, and an angiotensin receptor

blocker.

Case #16 A 44-year-old homeless woman has had two heart attacks in the past and reports shortness of breath while walking quietly as well as swollen ankles.

Part 1. Can this patient get the drug therapy she needs?

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Answer Only if she can reach the appropriate financial services, including family. Most likely she will be unable to attain the drug therapy mainly because of her homeless status, inaccessibility to services, and lack of social support in management of drug therapy.

Part 2. What drugs should be given?

Answer • Beta-blockers • ACE Inhibitors or ARBs • Digoxin (third-line) • Loop diuretics or thiazide diuretics • Aldosterone Inhibitors (Spironolactone)

Question? Which of the following drugs can worsen kidney function in a patient with pre-existing kidney disease?

A. Digoxin B. Angiotensin receptor blocker C. Ibuprofen (Motrin/Advil) D. Furosemide (a diuretic) E. Penicillin

Which of the following drugs has been shown in randomized, double-blind clinical trials to decrease the risk of death in patients with angina and coronary artery disease?

A. Beta-blockers B. HCTZ C. Angiotensin Converting Enzyme Inhibitor D. Aspirin

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Lectures XIII

Drugs Targeting Central Nervous System Lecturer: Dr. Edward French, Ph.D.

Introduction Vertebrate animals have developed unique anatomical and neurochemical systems that reinforce goal-directed behaviors such as feeding, drinking and sex. These behaviors seem to have evolved to ensure the survival of the individual and the continued existence of the species. The successful attainment of each goal leads to a rewarding stimulus (good feelings, pleasure, etc.), which further reinforces the behavior, making it more likely to be repeated. This I will call positive-reinforcement. Later on we can discuss how negative consequences can also make it more likely that some behaviors will be repeated. There is considerable evidence to suggest that drugs of abuse activate the same biochemical pathways as natural rewards such as a palatable meal or a stimulating social interaction. In fact, drugs such as cocaine may activate these systems so strongly that the individual spends increasing amounts of time acquiring and administering the drug. Natural rewards can become insignificant or unimportant compared to the euphoria or rush produced by the supraphysiological reinforcements of some drugs of abuse.

Drug Addiction

Drug addiction is a complex biochemical and behavioral syndrome that exists along a continuum from minimal use, to abuse to addiction (O’Brien, 1996). Addiction is defined as a chronic, relapsing brain disease characterized by compulsive drug seeking and use, despite harmful consequences (eg. significant health, economic and/or social costs to the individual). In a nutshell, addiction is commonly thought of as a “loss of

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control”. The addiction cycle has been characterized by: impulsivity (binge/intoxication) leading to withdrawal/negative effects causing preoccupation/anticipation, thus shifting from impulsivity to compulsivity to addiction. Generally, addictive drugs can act as positive reinforcers (producing euphoria) or as negative reinforcers (alleviating symptoms of withdrawal or dysphoria). It is considered a brain disease because drugs change the brain—they change its structure and how it works. Brain imaging studies from drug-addicted individuals show physical changes in areas of the brain that are critical to judgment, decision making, learning and memory and behavior control. These brain changes can be long lasting, and can lead to the harmful behaviors seen in people who abuse drugs. Other terms are often associated inappropriately with addiction. Terms such as “tolerance” and “physical dependence” are frequently mentioned. Tolerance refers to a reduction in a particular effect produced by a given drug following repeated administration of that same drug. Higher doses of the drug are needed to produce the original level of effect. Physical dependence is a physiological response to continued drug administration. The body compensates in an effort to return it to homeostasis. If the drug is suddenly withdrawn, a physical withdrawal syndrome may occur. This withdrawal syndrome may produce effects which are opposite to those produced by the drug. Sometimes this is referred to as the “abstinence syndrome”, which occurs following cessation of drug taking (abstinence from the drug). A withdrawal syndrome can also often be produced by administering an antagonist to the drug (“precipitated abstinence”). Heroin is an excellent example of a commonly abused drug, which produces all of the effects listed above. The administration of heroin produces euphoria, which leads to further heroin use (positive reinforcement). Repeated exposure to the same dose of heroin then results in a progressive decrease in the euphoric effect (tolerance). In order to achieve the same degree of euphoria the user must take a larger dose. Substituting a different opiate (eg. oxycodone) for heroin in an attempt to elicit the same degree of euphoria similarly shows a decreased level of effect - this is an example of “cross-tolerance” between heroin and the other opiate. Repeated exposure to heroin also can produce physical dependence. The user needs heroin in order to maintain a newly established level of homeostasis and to prevent withdrawal from the drug. Heroin withdrawal produces an abstinence syndrome which is accompanied by a wide variety of autonomic signs including sweating, chills, piloerection which makes the skin look like gooseflesh (hence, the term, “cold-turkey”), diarrhea, and involuntary muscle spasms (thus, “kicking the habit”). The gastrointestinal response is an example of the adaptation made by the body to counteract the effects of an opiate. Heroin and other opiates are famous for producing constipation and, in fact the

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two accepted medical uses of opiates are as analgesic agents and as antidiarrheal medications. Withdrawal from opioid dependence can also be “precipitated” by administration of naloxone, an opioid receptor antagonist. It is important to realize that in many cases tolerance and physical dependence are present but neither is necessary or sufficient for a diagnosis of addiction (O’Brien, 1996). A person with chronic back pain, for example, may be treated over a long period of time with an opioid resulting in tolerance and physical dependence. It is unlikely, however, that the patient will develop the behavior of compulsive drug use. Although sometimes this can and does occur. As mentioned, there are many factors that contribute to drug addiction. Such diverse factors as the availability of a particular drug, the route of administration, the social setting and the availability of non-drug reinforcers can all influence an individual’s pattern of drug use. The primary driving force behind drug addiction, however, is the reinforcing actions of the drug. The drug produces a sense of well being, euphoria or some other behavioral change that makes the person want to repeat the experience. In order to understand how drugs of abuse produce their reinforcing effects, an understanding of the neurobiology of reward is essential. Much of what is known about the mammalian reward system is derived from animal research using procedures such as intracranial self-stimulation (ICSS) and drug self-administration.

Intracranial Self-Stimulation (ICSS) In the early 1950s, James Olds and Peter Milner were investigating whether electrical stimulation of the rat reticular activating system would increase attention and learning. Small electrical currents were delivered to this brain region via a chronically implanted small wires. They observed that one of the rats kept returning to the place on a table top enclosure where it had received a small electrical stimulation. Fortunately, they decided to pursue the observation. They checked the location of the electrode and found that they had placed it by accident near the anterior commissure (you do not need to know the neuroanatomy). They implanted additional rats with electrodes in a variety of brain regions and made the electrical stimulation contingent on the rats pressing a lever. In some brain regions rats would press the lever thousands of times in an hour while neglecting natural rewards such as food or a receptive mate. The studies in rats were also extended to include ICSS behavior in goldfish, guinea pigs, dolphins, dogs and monkeys, suggesting that there is a reward system in place for probably every vertebrate species.

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There have also been several reports of humans undergoing therapeutic electrical stimulation in deep brain structures. They have reported pleasurable feelings from the stimulation. In fact, patients will perform a nominal task to receive this stimulation. Many of the same structures that support ICSS in rats, such as the lateral hypothalamus, also produce subjective effects of pleasure when stimulated in humans. Though these studies were interesting, there were alternative explanations for the observed behavior. The implantation of the electrode, for example, could have produced a painful state that was relieved by the electrical stimulation. It took many additional studies to validate the procedures and advance our understanding of the brain’s reward systems. Initial studies focused on the anatomical sites in the brain that supported ICSS behavior. Not surprisingly, a number of these areas were located in what is called the limbic system (a primitive collection of neuronal nuclei involved in the very basics of survival behaviors). This includes the septal area, nucleus accumbens, (often referred to as the ventral striatum) lateral hypothalamus, areas in the amygdala and the cingulate cortex. It should be noted that stimulation of other regions produces neutral or aversive stimuli (e.g. spinothalamic tract). Stimulation of the lateral hypothalamus, in particular, supported robust ICSS. The medial forebrain bundle (MFB) is one of the transversing neural pathways in the hypothalamus and contains the neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) nerve fibers that originate in brainstem nuclei and terminate throughout the limbic system (see Figure 1). When electrodes were implanted anywhere along the MFB, robust ICSS behavior could be elicited. In Panel A, animals are trained to press a lever to obtain a drug or saline (self-administration) or to receive intracranial current in brain-rewarding loci (ICSS). In Panel B, the animal is placed in a box with two discrete chambers (environments), and then injected with a drug (eg. on days 1, 3 and 5) in one chamber and then with saline (eg. on days 2, 4, and 6) in the other chamber. On the drug-free test day (day 7) the animal is allowed access to both chambers, and the amount of time spent in each is recorded. If the drug is positively reinforcing the animals will spend more time in the chamber in which it received the drug and less in the chamber in which it received saline. This is called “place preference”.

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The widespread MFB innervation of the limbic system suggested that this system was involved with regulation of the autonomic nervous system, drives and emotions. The observation that ICSS is increased in hungry animals and decreased in satiated animals further indicated that there was a close relationship between the physiological state of the animal and its sensitivity to natural rewards. The mesolimbic circuit includes projections from the ventral tegmental dopamine neurons to the nucleus accumbens, amygdala and hippocampus. This circuit has been implicated in acute reinforcing effects, memory, and craving. The mesocortical circuit includes projections from the ventral tegmental dopamine neurons to the prefrontal cortex, orbitofrontal cortex and anterior cingulated. It is involved in conscious experience of the effects of drugs, craving, and compulsion to take drugs.

The important issue of which neurotransmitters regulate the reward pathway and ICSS behavior, was studied through the use of specific chemical antagonists and neurotoxins. Stimulation of the locus coeruleus, which gives rise to NE axons in the MFB, did not support ICSS. Furthermore, destruction of NE neurons in the locus coeruleus or selective blockade of NE receptors with antagonists had no effect on MFB ICSS. Similar studies using 5-HT antagonists saw a slight increase in MFB ICSS, suggesting that 5-HT inhibits this system. Studies that manipulated DA levels on the other hand, played a critical role in ICSS. Dopamine agonists facilitated ICSS while lesions of DA neurons in the midbrain and the administration of DA antagonists, dramatically reduced ICSS. In conclusion, it became apparent that the neurotransmitter dopamine was critical to ICSS. With the development of the ICSS procedures it was logical to ask what effect, if any, do drugs of abuse have on ICSS? One might predict that if cocaine makes a rat feel good, then the rat might not press for ICSS as much. On the other hand, rats, like humans, are hedonists and might push

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the lever as much or more under the influence of cocaine. Experiments confirmed the second hypothesis. If you give a rat an injection of cocaine before its test session, you get a dramatic increase in lever pressing for ICSS. Other drugs of abuse also increased pressing. The interaction between drugs of abuse and ICSS makes better sense if you consider that the rate of lever pressing is related to the intensity of the electrical stimulus. The greater the electrical current (up to the point that you start getting tissue damage), the faster the rats press the lever. It was concluded that drugs like cocaine and morphine were affecting neurotransmission, and like the stimulating electrodes, effectively increasing the output of these neurons to produce a more rewarding stimulus.

Drug Self-Administration Studies Contemporaneous with the experiments of Olds and Milner, other experimenters were searching to explain how various drugs acted in the central nervous system to alter behavior. In particular, why do humans find some drugs pleasurable? Through the use of the animal model of self-administration of drugs it became possible to begin assessing the role of the neurotransmitters norepinephrine, serotonin and dopamine in drug taking behavior. As before, the same limbic structures and the catecholamine neurotransmitter dopamine were found to be involved. For example:

1. In rats trained to lever press for the intravenous infusion of a drug, pretreatment with a selective antagonist of dopamine receptors blocks the self-administration of amphetamine, cocaine, heroin and other abused substances. Dopamine antagonists also prevent the euphoric effects of these drugs in humans, as well as the pleasurable effects of naturally rewarding stimuli. Norepinephrine receptor blockers do not.

2. Selective depletion of dopamine from the nucleus accumbens by the neurotoxin 6-hydroxydopamine disrupts cocaine and amphetamine self-administration in animals.

3. Injections of dopamine antagonists directly into the nucleus accumbens blocks intravenous cocaine self-administration in ani-mals.

4. Rats will press a lever for injections of cocaine or amphetamine directly into the nucleus accumbens or prefrontal cortex. This effect can also be blocked by the peripheral injection of a dopamine receptor blocker.

5. Rats will self-administer morphine directly into the ventral tegmental area, the collection of dopamine neurons providing dopamine innervations to the mesolimbic forebrain structures. Morphine stimulates those cells and increases dopamine release in the nucleus accumbens.

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6. Intra-ventral tegmental area injections of morphine will also facilitate ICSS.

7. Naloxone injections directly into the ventral tegmentum will prevent the intravenous self-administration of morphine and heroin.

Thus, the mesolimbic (nucleus accumbens) and mesocortical (prefrontal cortex) dopamine systems appear to serve as a central pathway in mediating the positive reinforcing properties of a number of behaviors including addictive drug use. The problem with attempting to develop a unifying theory for addiction based upon dopamine neurotransmission in limbic areas is that the various classes of drugs of abuse act on different receptors, localized in different parts of the brain, and they may produce totally opposite effects on neuronal excitability (e.g., heroin and cocaine; alcohol and amphetamine; nicotine and marijuana) (See Table 1). Nevertheless, a theory of addiction was developed that centered on a factor common to all the major classes of abused drugs and other rewarding behaviors (food, thirst, sex): (1) they increase dopamine levels in limbic structures and (2) they elicit approach or forward locomotion. In rats, approach behaviors and positive reinforcement can be elicited by electrical stimulation of the MFB, and drugs, which serve as positive reinforcers, elicit forward locomotion. This notion has been called the psychomotor stimulant theory of addiction with the mesolimbic-mesocortical dopamine structures (nucleus accumbens, prefrontal cortex and ventral tegmental area) serving as the substrates for the rewarding properties of drugs of abuse.

The Psychomotor Stimulant Theory If we administer a dopamine antagonist to animals, we can block cocaine’s reinforcing effects. In addition, dopamine antagonists can block, or attenuate, the reinforcing effects of almost any drug of abuse or natural reward. This includes morphine, THC, PCP, nicotine and sexual behavior. In addition, it is possible to measure neuronal activity and neurotransmit-ter release in discrete brain regions. For this reason, it has been hypothesized that “drugs of abuse or natural rewards increase dopami-nergic activity and the release of dopamine in the reward system”. The psychomotor stimulant theory of addiction incorporated the above findings into a workable hypothesis. Although drugs of abuse have many different primary mechanisms of action, they all increase CNS levels of dopamine. Furthermore, any event that elicits approach or forward locomotion (49-5) will serve as a positive reinforcer (psychomotor stimulant). It is thus hypothesized that certain stimuli (food, drugs of abuse, etc.) increase the animals level of arousal, elicit approach behaviors and reinforce the interaction by activating dopamine reward systems. Dopamine may play an important role in directing the animals’ attention to motivationally

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relevant stimuli. This theory also has important ramifications with regard to drug abuse. One addictive drug could produce the same general type of stimuli that a different drug produces. This could explain why many drug users are polydrug users. Furthermore, a recovering heroin addict may be prone to relapse if he or she drinks alcohol. It is worth noting here that all the major drugs of abuse lower the threshold for ICSS and are self-administered. For the clinician, then, it is important to realize that for an individual in a drug rehabilitation program (say for heroin addiction), that they may be susceptible to other drugs for which they are not being treated but which may activate the same neural circuitry as heroin and thus put the ex-addict at risk of relapse. An important question is “How does an inhibitory drug of abuse such as alcohol or heroin increase dopamine release?” One explanation is that these drugs inhibit tonically active inhibitory interneurons in the VTA, i.e., inhibiting the inhibitory neuron (see Figure 2). This is termed disinhibition and leads to an increase in activity of the neurons (in this case a dopamine neurons) that project to the limbic structures via the MFB.

Drugs as Surrogates of Natural Reward How do addictive drugs fit into the natural reward systems? Lets use cocaine as an example. A group of friends suggest that you try cocaine at a party. This might activate the dopamine system enough for you to become interested and approach the table (fig. 3). If you decide to try the drug you are likely to further stimulate the dopamine reward system and associate the drug (primary incentive) and the environment (secondary incentive) with a sense of well-being. Continued use of the drug will further strengthen the bonds between primary and secondary incentives of the drug use and a sense of pleasure. You can also get an appreciation of how hard it might be to break an addiction, even after you separate yourself from the drug and the social group that you were involved with. The sight of a white powder, for example, may bring back a flood of good memories that triggers an intense craving for the drug. Of course, there are differences between stimuli such as food and cocaine. The primary incentive properties of cocaine, for example, (bitter taste, lack of smell, white chalk-like powder) may not be as strong as it is for food. The incentive learning phase of drug abuse thus plays an important role in the development of drug self-administration behaviors, namely the establishment of secondary incentives.

Summary We have mentioned that behaviors essential to the survival of the individual and the species include feeding and drinking, as well as mater-nal, social and sexual interactions. By pairing these behaviors with immediate feedback in the form of pleasure, natural selection has provided

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the species with a means to increase the likelihood that the behavior will be repeated (reinforcement). Drugs of abuse can also stimulate the reward systems that reinforce these behaviors. What is common to almost all drugs of abuse is their ability to directly or indirectly stimulate dopaminergic reward systems. It is the powerfully reinforcing actions of these drugs that can make them surrogates for natural rewards (and possibly becoming the focus of an addiction).

Learning Objectives List several sites in the rat CNS that support intracranial self-stimulation.

• Ventral Tegmental Area • Lateral Hypothalamus • Septal area/Nucleus Accumbens • Parts of the amygdala (Posterior amygdala) • Cingulate cortex • Caudate

Name the three monoamine pathways whose axons comprise the medial forebrain bundle. The three major monoamine pathways whose axons comprise the medial forebrain bundle are:

• Dopaminergic • Noradrenergic • Serotonergic

Detail the neuroanatomical pathways of the mesolimbic and mesocortical dopamine systems (i.e. where do the neurons originate, in which fiber tract do they travel and where do they terminate).

Pathway Neuronal Origin Fiber Tract Traveled By Termination

Mesolimbic Ventral Tegmental Area of the Midbrain

Medial Forebrain Bundle Nucleus Accumbens, limbic cortices, septo-hippocampal

complex, and amygdala Mesocortical Ventral Tegmental Area of

the Midbrain Meso-cortical dopamine

projections Cerebral Cortex (particularly the

frontal lobes), innervates prefrontal and insular corticies

Nigrostriatal Substantia Nigra Basal Ganglia Corpus Striatum (Caudate and Putamen)

Tubero-infundibular

Arcuate nucleus of the mediobasal hypothalamus

Dopamine neuronal projections

Projection to the median eminence

Lecture XIV

Antipsychotics Lecturer: Edward D. French, Ph.D.

Psychosis Psychosis is a severe syndrome principally characterized by disordered thinking, alterations in perception, affect and behavior. It’s symptoms include paranoid delusions, hallucinations (visual and auditory), loss of affect, loss of ego boundaries and volition, and impaired interpersonal functioning and relationship to the external world. The etiology of psychoses can be either organic or idiopathic. Organic psychosis can occur in response to a defined toxic (eg. methamphetamine psychosis), metabolic or neuropathological change resulting in delirium (confusion and disorientation) and dementia (memory deficits). In age-related dementia some individuals show agitation and disorder thinking when the sun sets. Idiopathic psychosis is characterized by disturbances in thought, affect and behavior for which there is no definable underlying pathology. Dopamine over-activity in the limbic and frontal cortical structures of the CNS is postulated to play a pivotal role in the psychotic disorder of schizophrenia. The resulting dopamine hypothesis for schizophrenia was proposed and was based largely upon a number of pharmacological observations consisting of:

1. Virtually all antipsychotic drugs block dopamine receptors in the CNS;

2. Levodopa, a drug used to treat Parkinson’s disease, augments dopamine activity within the CNS and can elicit occasionally schizophreniform behavior;

3. Psychomotor stimulants which act through increasing synaptic levels of dopamine can mimic some aspects of schizophrenic symptoms (eg. amphetamines, cocaine);

4. PET (positron emission tomography) scans in both drug-free and neuroleptic treated patients have found increased densities of dopamine receptors compared to nonschizophrenic subjects.

However, the dopamine hypothesis has limitations because antipsychotic drugs do not completely eliminate all psychotic symptoms. The “positive symptoms” of schizophrenia, delusions, hallucinations, bizarre behavior, and thought disorder, appear more responsive to drugs, which block the dopamine D-2 receptor. However, newer antipsychotic agents (clozapine, olanzepine and risperidone) have higher affinity for other receptors (i.e. serotonin) and are efficacious for treating a broader range of psychotic symptoms, including the “negative symptoms” consisting of affective

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blunting, poverty of speech, avolition/apathy, anhedonia and attentional impairment This latter group of drugs has been referred to as atypical neuroleptics, and they are often favored because their use is associated with a lower incidence of extrapyramidal movement disorders. Molecular cloning techniques have identified five dopamine receptors (D-1 to D-5) in the CNS. Although the relative importance of these five types in the etiology of schizophrenia has not been determined, there is a very high positive correlation between an antipsychotic drug's clinical potency and its ability to bind to D2 dopamine receptors (Figure 1). The therapeutic effect of these agents is postulated to result from a blockade of D2 receptors in the limbic and mesocortical (prefrontal) brain areas. However, the blockade of D2 receptors in the nigrostriatal pathway is likely the cause of the extrapyramidal movement disorders caused by these drugs. These movement disorders are Parkinsonian-like and are consistent with a decrease in dopamine function within the caudate- putamen. Remember that these drugs act in all areas of the brain that receive dopamine innervation. They do not prevent dopamine from being released. In fact, through feedback processes they actually cause an increase in dopamine release through their blockade of presynaptic autoreceptors. Nevertheless, the concurrent blockade of the postsynaptic dopamine receptor results in a net decrease in dopamine function in the central nervous system.

Figure 1: Correlation of clinical potency to D-2 receptor-binding activities of neuroleptic drugs. Clinical potency is expressed as the daily dose used in treating schizophrenia, and binding activity is expressed as the concentration needed to produce 50% inhibition of haloperidol binding (Synapse 1:133, 1987). Although antipsychotic drugs are highly selective for dopamine receptors they also have some affinity for alpha-adrenergic, cholinergic and histaminergic receptors, with the newer atypicals having considerable affinity for serotonin-2 receptors (5-HT2). Actions at alpha- adrenergic sites may help control excitement, but also cause postural hypotension, while

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blockade of histamine receptors may produce some sedation. Blockade of muscarinic cholinergic receptors may produce the atropine-like side effects of dry mouth, blurred vision, constipation and difficulty in urination,. On the other hand the anticholinergic actions of neuroleptics will reduce the intensity of the Parkinsonian-like side effects that occur with the older types of antipsychotic agents.

Indications For Antipsychotic Drugs Schizophrenia is the primary indication for use of neuroleptics, but not all patients are responders and a full response occurs infrequently. Schizoaffective disorders, which bear some resemblance to schizophrenia, may also benefit from these drugs, which may also be used in conjunction with antidepressants or lithium. The manic episode in bipolar affective disorder can also be effectively treated with neuroleptics, which can be withdrawn upon subsidence of the mania. Other conditions for the use of neuroleptics include: intractable hiccups, the chorea of Huntington's disease, ballism, and Tourette's syndrome, and psychotic depression.

Drug Choice Differences between chemical structures (potency, pharmacokinetics) and pharmacological differences (receptor affinities) between classes of compounds may be the best rationale for choosing a given antipsychotic medication. Past response and potential adverse effects best determine drug selection. Remember that for schizophrenia there is virtually no evidence that a given compound can target given symptoms. Presently, there is an increasing tendency in psychiatry to begin treatment with one of the “atypicals” such as clozapine, risperidone, olanzepine, quetiapine or aripiprazole.

Doses Since the range of effective doses among the various antipsychotics is so large this must be empirically determined for each drug that is most effective in an individual patient. With greater milligram potency (i.e. smaller recommended dose) there is less sedation and hypotension but generally more acute extrapyramidal reactions. Attempts to monitor the therapeutic plasma concentrations can be so disparate from patient to patient that it is not warranted. The daily oral dose can be given in smaller amounts initially to minimize adverse reactions, and then reduced to one or two doses unless there is an adverse reaction. A single dose at bedtime is often preferred since it takes advantage of the drug’s sedative effects and decreases the incidence of

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postural hypotension. However, long-acting depot forms of drugs, such as fluphenazine decanoate are quite useful for treating those patients who are non-compliant for a variety of reasons. The depot preparations can be given intramuscularly at intervals of one to several weeks, depending upon the release characteristics. However, adverse effects from depot injections will be difficult to reverse.

Drug Combinations Different antipsychotics should not be combined. However, tricyclic antidepressants can be concurrently administered when there is clear indication of a co-existing clinical depression. ANTIPSYCHOTIC DRUGS - DO NOT MEMORIZE THIS TABLE

Drug Equivalent Oral Dose

Sedation Autonomic Extrapyramidal Reactions

Fluphenazine Permitil Prolixin

2 + + +++

Haloperidol Haldol

2 + + +++

Sertindole Serlect

4 + 0 0

Thioxene Navane

5 + + +++

Trifluoperazine Stelazine

5 ++ + +++

Risperidone Risperdal

5 + +++ +

Olanzepine* Zyprexa

10 + 0 0

Perphenazine Trilafon

10 ++ + ++/+++

Molindone Moban

10 ++ + +

Pimozide Orap

10 + + +++

Loxapine Loxitane

15 ++ +/++ ++/+++

Aripiprazole Abilify

15 0/+ 0/+ 0?

Acetophenazine Tindal

20 ++ + ++/+++

Chlorprothixene Taractan

45 +++ +++ +/++

Mesoridazine Serentil

50 +++ ++ +

Clozapine Clozaril

50 +++ +++ 0?

Ziprasidone Geodon

80 + 0 0

Chlorpromazine Thorazine

100 +++ +++ ++

Thioridazine Mellaril

100 +++ +++ 0

Quentiapine Seroquel

150 + ++ 0

* Also used for treating OCD

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Pharmacological Properties Of Neuroleptics 1. Neuroleptic Syndrome: This consists of suppression of

spontaneous movement and complex behavior, (spinal reflexes remain intact). Neuroleptics reduce initiative and interest in one's surroundings and they lessen displays of emotion or affect. Psychotic patients become less agitated and restless, and withdrawn or autistic patients sometimes become more responsive and communicative. Aggressive and impulsive behavior diminishes, and gradually (several days to weeks) hallucinations, delusions, and disorganized (i.e. cognitive) thinking lessens. Remember antipsychotic drugs do not cure the disorder, but only manage the symptoms. Almost all drugs presently prescribed for psychosis also have been found to produce some bradykinesia (extreme slowness of moving), mild rigidity, and tremor that resemble that of Parkinson’s disease, and occasional subjective restlessness (akathisia). Since all antipsychotic drugs elicit the neuroleptic syndrome to varying degrees they are commonly lumped into the category of "neuroleptics". Clozapine, olanzepine, risperidone, seroquel, and ziprasidone produce fewer extrapyramidal side effects, and for this reason are referred to as atypical neuroleptics. Generally speaking, neuroleptic drugs are found to be very unpleasant when given to a normal (i.e. non-psychotic) person.

2. Normalization of sleep disturbances often seen with psychoses. Phenothiazine and thioxanthene type neuroleptics should be used with extreme caution in untreated epileptics and in patients undergoing withdrawal from central depressants because they can lower seizure threshold.

3. Increase in prolactin secretion through blockade of the hypothalamic-tuberinfundibular dopaminergic pathway. There is little to no tolerance to this effect with neuroleptic treatments and thus they produce breast engorgement and galactorrhea (also in males), which reverses upon discontinuation. Clozapine does not appear to have this effect.

4. Little effect on brain stem processes so that even large suicidal doses usually do not produce coma or death, making them relatively safe compounds. Exceptions: thioridazine and loxapine can be dangerous in overdose.

5. Interactions with other drugs: potent potentiation of sedatives and analgesics, antihistamines and cold remedies, and alcohol; may enhance the peripheral and central effects of anticholinergics, such as the tricyclic antidepressants and antiparkinsonian agents.

6. Prevent vomiting in nonsedative doses through the blockade of dopamine receptors in the chemotrigger zone of the medulla and peripherally on receptors in the stomach. However, thioridazine does not possess anti-emetic actions.

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7. Also chlorpromazine can be used to control intractable hiccups. 8. Management of Tourette's syndrome, which is characterized by

tics, involuntary movements, grunts, and vocalizations (often obscene) and the choreoathetotic movements of Huntington's disease.

Side Effects and Toxic Reactions Autonomic nervous system

1. Moderate alpha-adrenergic blockade and weak cholinergic blockade causing blurred vision, mydriasis, constipation and decreased gastric secretion and motility, decreased sweating and salivation, inhibition of ejaculation without interfering with erection, orthostatic hypotension and reflex tachycardia, vasodilation and antiarrhythmic effects on the heart. Abnormal electrocardiograms are more prevalent with thioridazine (Mellaril) and pimozide (Orap).

Endocrine effects 1. Gynecomastia and galactorrhea, amenorrhea; 2. Interference with pituitary growth hormone secretion; 3. Weight gain and increase in appetite, weak diuretic effects from

inhibition of ADH release. 4. Weight gain and an increased incidence of diabetes mellitus has been

reported in patients taking clozapine and olanzepine. 5. disruption of hypothalamic thermoregulatory control may lead the

patient to complain of being cold, or worse still develop into hypo- or hyperthermia.

Hypersensitivity reactions 1. Agranulocytosis is uncommon, yet associated with some of the lower

potency neuroleptics, and with clozapine (Clozaril) in about 1% of patients.

2. Dermatitis and increased pigmentation may occur with long-term high dose therapy of low potency and neuroleptics.

3. Chlorpromazine can induce photosensitivity. 4. Pigmentary degeneration of the retina with thioridazine, resembling

retinitis pigmentosa characterized by a "browning" of vision. These effects are reduced with lower dosage.

Neurological effects 1. Parkinsonian syndrome: characterized by a generalized slowing of

movement (akinesia) with mask facies. The most noticeable signs are rigidity and tremor at rest, especially of the upper extremities. Parkinsonian side effects may be mistaken for depression since the flat facial expression and retarded movements resemble signs of

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depression. This reaction may be self-limiting but can usually be managed by antiparkinsonian agents with anticholinergic properties. Levodopa is contraindicated since it may induce agitation and worsening of the psychotic illness. Antiparkinsonian drugs should be discontinued every few months for a reassessment of the adverse side effects.

2. Neuroleptic malignant syndrome: resembles a very severe form of parkinsonism with catatonia plus labile pulse and blood pressure, hyperthermia, stupor and sometimes myoglobinemia. >10% mortality, thus immediate medical attention is required. May be more prevalent with the use of high doses of the more potent agents. Dantrolene, which interferes with muscle utilization of calcium, has been used for treatment.

3. Akathisia: strong subjective feelings of distress or discomfort, often referred to the legs, as well as to a compelling need to be in constant motion. It can be mistaken for agitation--the distinction is critical, since agitation might be treated appropriately with an increase in the dose of the antipsychotic drug, but make the situation worse. Parenteral administration of benztropine (a muscarinic cholinergic antagonist) allows a differential diagnosis between the two conditions since psychosis does not respond to benztropine. Treatment typically requires reduction of antipsychotic drug dosage, with moderate doses of propranolol reported to be very beneficial. Importantly, this syndrome is commonly not diagnosed and frequently interferes with a patient's acceptance of neuroleptic treatment.

4. Acute Dystonic Reactions: facial grimacing and torticollis (stiff neck caused by spasmodic contraction of neck muscles drawing the head to one side with chin pointing to the other side) which may be associated with oculogyric crisis. They respond dramatically to parenteral use of anticholinergic antiparkinsonian drugs.

5. Tardive Dyskinesia: a late-appearing syndrome associated with long-term neuroleptic therapy that is characterized by stereotyped involuntary movements consisting in sucking and smacking of the lips, lateral jaw movements, and fly- catching dartings of the tongue. There may be choreiform or purposeless quick movements of the extremities. Slower, more dystonic, athetoid movements and postures of the extremities, trunk, and neck may also be seen, especially in younger males. These movements disappear during sleep. They are thought to occur from an imbalance of dopamine-cholinergic function within the caudate- putamen. Symptoms may persist indefinitely after discontinuation of the drug, although sometimes they will disappear with time (weeks to years). Higher doses of neuroleptics will only mask the dyskinetic effects but worsen its course, and antiparkinsonian drugs typically worsen this problem. No adequate therapy has been devised for its treatment.

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Tardive dyskinesia is hypothesized to result from compensatory hyperdopaminergic function. Thus, antidopaminergic drugs tend to ameliorate tardive dyskinesia, while dopaminergic agonists worsen the condition; and antimuscarinic agents worsen it, while cholinergic ones sometimes help. It is the opposite for those with tardive dystonia.

Tolerance Tolerance does not develop to the antipsychotic effects, but does develop to many of the side effects (eg. sedation). The following table summarizes these side effects and the mechanism by which they occur:

Type Manifestations Mechanisms Autonomic nervous system Dry mouth; loss of accommodation;

difficulty in urinating; constipation Muscarinic blockade

Orthostatic hypotension impotence; failure to ejaculate

Alpha adrenergic blockade

Central nervous system Parkinson's syndrome; akathisia; dystonia

Dopamine receptor blockade

Tardive dyskinesia Dopamine receptor supersensitivity

Toxic confusional state Muscarinic blockade Endocrine system Galactorrhea; amenorrhea;

secondary �infertility; impotence blockade

Hyperprolactinemia to dopamine receptors

Learning Objectives Describe the behavioral effects referred to as the neuroleptic syndrome that is induced by antipsychotic drugs whose primary site of action is blockade of the D-2 dopamine receptor. Neuroleptic syndrome is a neurological disorder that consists of suppression of spontaneous movement and complex behavior, (spinal reflexes remain intact). Neuroleptics reduce initiative and interest in one's surroundings and they lessen displays of emotion or affect. Psychotic patients become less agitated and restless, and withdrawn or autistic patients sometimes become more responsive and communicative. Aggressive and impulsive behavior diminishes, and gradually (several days to weeks) hallucinations, delusions, and disorganized (i.e. cognitive) thinking lessens. Remember antipsychotic drugs do not cure the disorder, they only manage the symptoms. Almost all drugs presently prescribed for psychosis also have been found to produce some bradykinesia (extreme slowness of moving), mild rigidity, and tremor that resembles that of Parkinson’s disease, and occasional subjective restlessness (akathisia). Since all antipsychotic drugs elicit the neuroleptic syndrome to varying degrees they are commonly lumped into the category of "neuroleptics". Clozapine, olanzepine, risperidone, seroquel, and ziprasidone produce fewer extrapyramidal side effects, and for this reason

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are referred to as atypical neuroleptics. Generally speaking, neuroleptic drugs are found to be very unpleasant when given to a normal (i.e. non-psychotic) person.

Describe the relationship between milligram potency of neuroleptic drugs and their adverse effects on the autonomic nervous system. With greater milligram potency (i.e. smaller recommended dose) there is less sedation and hypotension but generally more acute extrapyramidal reactions. The daily oral dose can be given in smaller amounts initially to minimize adverse reactions, and then reduced to one to two doses unless there is an adverse reaction.

Describe how dopamine receptor blockage increases prolactin secretion. Dopamine receptor blockage causes increases in prolactin secretion through blockade of the hypothalamic-tuberinfundibular dopaminergic pathway. There is little to no tolerance to this effect with neuroleptic treatments and thus they produce breast engorgement and galactorrhea (also in males), which reverses upon discontinuation. Clozapine does not appear to have this effect.

Describe the symptoms of the neuroleptic malignant syndrome and a drug that can be used to treat it. Neuroleptic malignant syndrome resembles a very severe form of Parkinsonism with catatonia plus labile pulse and blood pressure, hyperthermia, stupor and sometimes myoglobinemia. >10% mortality, thus immediate medical attention is required. The mechanism can depend on decreased levels of dopamine activity due to (1) dopamine receptor blockade and (2) genetically reduced function of dopamine receptor D2. May be more prevalent with the use of high doses of the more potent agents. Dantrolene, which interferes with muscle utilization of calcium, has been used for treatment. Neuroleptic malignant syndrome can be remembered with FALTER:

§ F – Fever § A - Autonomic Instability § L – Leukocytosis § T – Tremor § E - Elevated enzymes (elevated creatine phosphokinase) § R - Rigidity of muscles

Describe the conditions other than psychosis for which antipsychotic drugs can be used. Conditions other than psychosis for which antipsychotic drugs can be used are:

§ Schizophrenia § Schizoaffective disorders § Manic phase of Bipolar Affective Disorder § Intractable hiccups

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§ Huntington’s chorea § Ballism § Tourette’s Syndrome § Psychotic Depression

List the major receptor classes mediating the therapeutic and side effects of antipsychotic drugs. The major receptor classes mediating the therapeutic and side effects of antipsychotic drugs are:

§ Dopamine Receptors (D1, D2, D3, D4, and D5). D2 receptors in the limbic and mesocortical (prefrontal) brain areas is the target of therapeutic drugs.

§ Serotonin receptors: 5-HT-1A, 2A, 3, 6, 7 § Norepinephrine: alpha-1 and alpha-2 § Muscarinic acetylcholine: mACh-1 and mACh-4 § Dopamine, norepinephrine, and serotonin transporters § Alpha-adrenergic § Cholinergic § Histaminergic Receptors (Histamine: H-1 and H-2) § NMDA-glutamate receptors

Newer atypicals having affinity for serotonin-2 receptors (5-HT2). At therapeutic doss, the “typical” antipsychotics occupy >75% of dopamine D-2 receptors. 85% occupancy is needed to get extrapyramidal side effects.

Distinguish between the positive and negative symptoms of schizophrenia. Positive symptoms are mainly symptoms that most individuals do not normally experience but are present in the disorder. They are attributed to the overactivity of dopamine in limbic regions. They include:

§ Hallucinations § Delusions § Bizarre Behavior § Thought disorder

Negative symptoms are symptoms that are not present or that are diminished in the affected persons but are normally found in healthy persons. They are attributed to NMDA-glutamate hypofunction. They include:

§ Affective blunting § Poverty of speech § Avolition/apathy § Anhedonia § Attentional impairment

Positive symptoms are more responsive to drugs that block the dopamine D2 receptor. However, newer antipsychotic agents are known to address the negative symptoms.

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Lecture XV

Antidepressants Lecturer: Dr. Edward French, Ph.D.

Depression Depression afflicts about 5% of the adult population of the U.S., with about 1-2% of adults having acute manic-depressive (bipolar) illness. About 70% of patients respond to antidepressant therapy and can experience a complete recovery from their depression. Electroconvulsive therapy can help patients whose disorder is refractory to antidepressants (about 20%). The remaining 10% of patients with depression are resistant to all known types of therapy. Depression is considered a heterogenous disorder with disturbances in affect which can be generally classified as: major depression: no previous history of psychiatric illness except for episodes of depression or mania. It is considered a genetically determined biochemical disorder with age of onset generally in the 30's, but episodes can occur at almost any age. It afflicts 2-3 times as many females as males. secondary mood disorders: occur during the course of some other primary psychiatric or medical disorder. Sometimes referred to as reactive depression. The hallmark signs of major depression are given in Table 1. Type of Symptom Depression Mania

Physical § Anhedonia (decreased interest in things previously (inappropriate - enjoyed; loss of sex drive) Fatigability, loss of energy �

§ Social withdrawal � § Psychomotor retardation or agitation § Insomnia with fatigue § Somatic complaints � § Loss of appetite, loss of weight § Decreased hygiene � § Crying spells for no significant

reason

§ Increased activities and energy buying, phoning, driving, and sexual behavior.

§ Increased gregariousness § Increased talkativeness,

pressured speech § Decreased need for sleep

without fatigue § Increased intake of alcohol,

drunkenness § Physically threatening,

combative, dangerous behavior

Cognitive § Decreased ability to concentrate § Indecisiveness

§ Distractability § Flight of ideas, speeded

thinking, racing thoughts, poor jugement, impulsive actions and decisions

Emotional § Dysphoric mood, sad thoughts or attempts at suicide

§ Hopelessness, helplessness § Worthlessness, guilt, shame

§ Elevated mood, increased self-confidence, euphoria, grandiosity

§ Irritability, hostility § Easily angered

TABLE 1.

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Antidepressant Drugs The major classes of compounds used for treating depression include:

1. Tricyclics, named for their characteristic 3-ring nucleus, eg. amitriptyline.

2. Selective serotonin reuptake inhibitors (SSRI's, eg. fluoxetine) 3. Other agents (buproprion) 4. Monoamine oxidase inhibitors (MAOI's, eg. tranylcypromine)

Although drugs from the first three groups can be selected to begin drug therapy for depression, the general consensus among physicians is that SSRI’s now constitute the first line of pharmacological therapy. However, in recent studies it was found that SSRIs may be no better than tricyclics, and in some cases no better than placebo. MAO inhibitors are used when drugs from the other classes give unsatisfactory results or in patients with co-existing phobias.

Basic Pharmacology All tricyclics block the reuptake of both norepinephrine and serotonin into nerve terminals although their potency at these two sites varies dramatically. Since this interferes with the primary mode for inactivating neurotransmitters, this leads to elevated synaptic levels of these monoamines. Selective serotonin uptake inhibitors are potent blockers of serotonin inactivation by reuptake and have very little or no effect on norepinephrine uptake. Other cyclics have mixed effects on norepinephrine and serotonin uptake as well as blockade of specific post-synaptic receptors. Monoamine oxidase inhibitors (MAOIs) act by preventing the metabolism of monoamine neurotransmitters which then leads to elevated levels of the amines (norepinephrine, serotonin and dopamine) in the nerve terminals and a greater amount of transmitter in the synapse. Some agents (e.g. venlafaxine, duloxetine) have been referred to as SNRIs (serotonin and norepinephrine reuptake inhibitors). The original amine hypothesis of mood disorders suggested a lack of CNS biogenic amines in depression. However, substantial research data in both animals and humans has shown serious inconsistencies in the simplistic amine hypothesis especially when we shift attention from acute drug effects to the long-term adaptive changes that occur with chronic antidepressant treatment. In particular, the biochemical effects of antidepressant drugs occur immediately, yet their therapeutic effectiveness is not seen for several days to weeks (Figure 1). Current thinking is that the therapeutic benefits of antidepressants occurs through desensitized autoreceptors and heteroreceptors on noradrenergic and serotoninergic nerve terminals, both of which normally reduce serotonin release but when desensitized cause elevated postsynaptic levels of serotonin (i.e. enhancement of serotonin neurotransmission).

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Figure 1.

Although poorly understood, the postsynaptic serotonin-1A (5HT-1A) receptor does not desensitize (Figure 2). Thus, the current thinking is that depression may be due to a dysregulation or diminished function of serotonin or norepinephrine neurotransmission. In support of this hypothesis, all clinically efficacious antidepressants augment serotonin or norepinephrine activity. It is interesting to note that tryptophan depletion in remitted patients who are taking serotonergic antidepressants (SSRIs) will cause a prompt relapse of their depression as will catecholamine depletion in patients who are taking noradrenergic acting drugs.

Figure 2. Increased synaptic levels of NE and 5-HT produced by currently available antidepressants over a period of weeks lead to down-regulation (subsensitive) of the presynaptic serotonin (5-HT1A/B) and presynaptic NE (α2) receptor which then allows even more 5-HT and NE to be released. The postsynaptic neuronal response to 5-HT (via the 5-HT1A receptor) is apparently not down-regulated while that of the alphal and beta (not

3

All tricyclics block the reuptake of both norepinephrine and serotonin into nerve terminals although their potency at these two sites varies dramatically. Since this interferes with the primary mode for inactivating neurotransmitters, this leads to elevated synaptic levels of these monoamines. Selective serotonin uptake inhibitors are potent blockers of serotonin inactivation by reuptake and have very little or no effect on norepinephrine uptake. Other cyclics have mixed effects on norepinephrine and serotonin uptake as well as blockade of specific post-synaptic receptors. Monoamine oxidase inhibitors (MAOIs) act by preventing the metabolism of monoamine neurotransmitters which then leads to elevated levels of the amines (norepinephrine, serotonin and dopamine) in the nerve terminals and a greater amount of transmitter in the synapse. Some agents (e.g. venlafaxine, duloxetine) have been referred to as SNRIs (serotonin and norepinephrine reuptake inhibitors). The original amine hypothesis of mood disorders suggested a lack of CNS biogenic amines in depression. However, substantial research data in both animals and humans has shown serious inconsistencies in the simplistic amine hypothesis especially when we shift attention from acute drug effects to the long-term adaptive changes that occur with chronic antidepressant treatment. In particular, the biochemical effects of antidepressant drugs occur immediately, yet their therapeutic effectiveness is not seen for several days to weeks (Figure 1). Current thinking is that the therapeutic benefits of antidepressants occurs through desensitized autoreceptors and heteroreceptors on noradrenergic and serotoninergic nerve terminals, both of which normally reduce serotonin release but when desensitized cause elevated postsynaptic levels of serotonin (i.e. enhancement of serotonin neurotransmission).

Figure 1 Although poorly understood, the postsynaptic serotonin-1A (5HT-1A) receptor does not desensitize (Figure 2). Thus, the current thinking is that depression may be due to a dysregulation or diminished function of serotonin or norepinephrine neurotransmission. In support of this hypothesis, all clinically efficacious antidepressants augment serotonin or norepinephrine activity. It is interesting to note that tryptophan depletion in remitted patients who are taking serotonergic antidepressants (SSRIs) will cause a prompt relapse of their depression as will catecholamine depletion in patients who are taking noradrenergic acting drugs.

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shown) receptors is thought to be made subsensitive. Thus, it appears that antidepressants establish an increase in serotonin neurotransmission in the CNS.

Clinical Pharmacology of Antidepressants Indications: Antidepressants are broad spectrum psychotropics used to treat depression, but also used for panic or phobic disorders, obsessive-compulsive disorder, enuresis (bed wetting), anorexia nervosa, and bulimia. Pain specialists have also found tricyclics to have some beneficial effects in patients with neuropathic (deafferentation) pain. Drug choice: Initial drug selection is determined by: type of mood disorder, past response to a particular drug, pharmacologic considerations (eg. degree of sedation or anticholinergic effects), the patient's susceptibility to side effects, and compatibility with other drugs the patient is taking. A meta-analysis found that SSRI's and TCA's are in general equally effective. However the use of SSRI's has become more prevalent. Common causes of non-adherence include oversedation, intolerance to the anticholinergic side effects of the tricyclics, or sexual dysfunction with SSRI's.

Tricyclic Side Effects There are a number of side effects associated with tricyclics that are mostly due to effects on the autonomic nervous system: These include dry mouth, blurred vision, constipation and urinary retention and speech blocking (see Table 2 & 3) resulting from blockade of muscarinic cholinergic receptors. However, tolerance usually develops to these symptoms within a few weeks.

§ Postural hypotension, resulting from blockade of alpha adrenergic receptors with a resultant reflex tachycardia.

§ Tachycardia, arrhythmias and ECG abnormalities; high-grade atrioventricular block, due to antimuscarinic effects.

§ Sedation is a common side effect so have patient take medication at bedtime.�Weight gain may occur because of both a remission of the depression and central actions of the antidepressants.

§ Tremor, akathisia and jittery feeling (propranolol may help).� § Sexual dysfunction (will usually resolve with time for the less

serotonergic TCA's) but may be a chronic problem with SSRI's.

SSRI Side-Effects § Nausea, headache, nervousness and insomnia to which tolerance

develops after approximately 1-2 weeks § Some sedation § �Anorgasmia, impotence, decrease libido § Possible fatal interaction with MAOI's (SEROTONIN

SYNDROME). Need to allow 14 days between discontinuation of MAOI and beginning of SSRI. Also allow 2 weeks from

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discontinuation of SSRI (except for Prozac which should be 5 weeks) to beginning of MAOI's. Prozac has an active metabolite with a 128 hr. half-life.

MAOI SIDE EFFECTS: § Dry mouth, constipation and difficulty urinating even though

MAOI's do not have direct anticholinergic actions. § Insomnia § Weight gain § �Sexual dysfunction: erectile impotence and anorgasmia in both

males and females. § Cardiovascular side effects: orthostatic hypotension. Nifedipine for

sublingual use in case of hypertensive "cheese-effect" crisis (N.B. tyramine and some common sympathomimetic ingredients in over-the counter cold remedies are the most common culprits in this "cheese- effect".

§ Serotonin-syndrome

Drug-Drug Interactions: The depressive effects of alcohol are markedly increased by tricyclic antidepressants and patients should be warned of this interaction especially with regard to driving an automobile. MAOI's enhance the effects of indirectly acting sympathomimetics, such as tyramine. Tyramine is found in a variety of foods including cheeses, beer, red wine, pickled herring, chicken liver, chocolates, yogurt and tomatoes. Normally, gastrointestinal MAOs metabolize tyramine. However, if MAOIs are present, tyramine is absorbed and enters nerve endings where it produces a massive release of NE which can result in a hypertensive crisis, characterized by tachycardia, severe throbbing headache, chest pain, dilated pupils, nausea and sweating. Patients need to be advised of this wine and cheese effect, and be given dietary restrictions.

Toxicity A tricyclic overdose causes excitement and delirium which can be accompanied by convulsions followed by coma and respiratory depression lasting several days. Cardiac dysrhythmias (atrial and ventricular extrasystoles) can occur and death from ventricular fibrillation. Dysrhythmias are often non-responsive to beta-blockers. Most cardiac effects can only be treated using supportive measures. However, the main CNS effects can be treated with anticholinesterase inhibitors (eg. physostigmine). SSRI's are generally very safe even on overdose. Generally, seizure threshold is lowered by tricyclics, as well as by bupropion and mirtazapine. MAOI intoxication produces agitation, delirium, neuromuscular excitability followed by obtunded consciousness, seizures, shock and

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hyperthermia which is best treated by supportive measures, although sedative phenothiazines with alpha-blocking properties (ego chlorpromazine) may be useful. NOTE: It has been documented that suicidal thoughts and suicidal behavior occur in approximately 4% of children/teenagers when put on anti-depressants. In response to these findings the FDA now requires all antidepressants to carry a Black Box Warning. TABLE 2. �Pharmacological Properties of Antidepressants and Their Possible Clinical Consequences

Property Possible Clinical Consequences Blockade of

norepinephrine uptake at nerve

endings

§ Tremors § Tachycardia § Erectile and ejaculatory dysfunction § Augmentation of pressor effects of sympathomimetic amines

Blockade of serotonin uptake at nerve endings

§ Gastrointestinal disturbances § Increase or decrease in anxiety (dose dependent) § Sexual dysfunction § Extrapyramidal side effects § Interactions with L-tryptophan, monoamine oxidase inhibitors, and fenfluramine

Blockade of dopamine uptake at nerve endings

§ Psychomotor activation § Antiparkinsonian effect § Aggravation of psychosis

Blockade of histamine H1

receptors

§ Potentiation of central depressant drugs § Sedation, drowsiness § Weight gain

Blcoakde of muscarinic receptors

§ Blurred vision § Dry mouth § Constipation § Urinary retention § Memory dysfunction

Blockade of alpha-adrenergic receptors

§ Potentiation of the antihypertensive effect of receptor blockers prazosin, terazosin, doxazosin, and labetalol

§ Postural hypotension, dizziness § Reflex tachycardia

Blockade of dopamine receptors

§ Extrapyramidal movement disorders § Endocrine changes § Sexual dysfunction (males)

Lithium The primary therapeutic indication for the use of lithium is in the treatment of the manic episodes of bipolar affective disorder. Bipolar disorder is characterized by swings of mood (mania- depression) that are generally unrelated to life events. A manic syndrome is characterized by:

§ Inflated self-esteem or grandiosity § Flight of ideas § Increase in goal-directed activity § Decreased need for sleep § Distractibility� § Excessive talkativeness

The exact biological disturbance, although generally considered to be genetically determined, remains unknown even though dysfunctional

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biogenic amine mechanisms are considered prime suspects. Drugs that increase catecholaminergic activity exacerbate mania, while drugs that reduce their activity reduce manic symptoms.

Basic Pharmacology Lithium is a monovalent cation most closely related to sodium. It can substitute for sodium in generating action potentials except it is not readily pumped out and tends to accumulate inside the neurons. This may lead to partial depolarization of nerve cells. Lithium also affects neurotransmitters in complex ways, but the compelling case for lithium's mechanism of action is its effects on second messenger systems in neuronal tissues resulting in reduced responsiveness of neurons to muscarinic and alpha-adrenergic stimulation.

Clinical Pharmacology Indications: Lithium carbonate is the primary therapeutic agent for the treatment of acute mania or recurrences of bipolar manic-depressive illness. Because its onset of action is slow, antipsychotic and benzodiazepine drugs are often used for the immediate control of severe manic behavior. Accumulating clinical evidence also supports lithium's use as an alternative to tricyclic antidepressants in severe recurrent depression (nonbipolar manic-depressive illnesses) and as a supplement to antidepressant treatment in acute, major depression. Treatment: Lithium has a narrow therapeutic index. This means that the plasma concentration producing its therapeutic effects is not much less than that associated with side effects. Lithium's narrow therapeutic serum concentration (0.8-1.2 meq/L) makes monitoring blood levels essential. These measurements should be made about 5 days after the start of treatment at 10-12 hrs after the last dose.

Adverse Effects and Toxic Reactions 1. Tremor is the most common adverse effect; in addition ataxia.

Propranolol can alleviate lithium-induced tremor. 2. Decreased thyroid function in most patients; this is reversible 3. Polydipsia and polyuria are frequent but reversible; this is due

interference with ADH (anti-diuretic hormone) action in the kidneys.

4. Edema. 5. ECG abnormalities are reversible. The sinus node is susceptible to

toxic effects of lithium, with depression of its normal pacemaker function, and therefore, lithium is contraindicated in patients with a "sick sinus" syndrome.

6. Lithium is excreted in breast milk and may cause lithium toxicity in newborns.

7. Therapeutic overdoses are more common than deliberate or accidental overdoses and usually result from an accumulation of

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lithium caused by a change in the patient's physical status, such as the use of diuretics, change in renal function or pregnancy. This condition can be treated with hemodialysis or peritoneal dialysis until plasma concentrations fall below the usual therapeutic range. �

Other Drugs Carbamazepine, valproic acid and other anticonvulsants are also being used in some patients who experience rapid cycling of mania and depression. The atypical antipsychotic Olanzapine (Zyprexa®) has also been FDA approved for treatment of mania. TABLE 3 SIDE EFFECTS OF ANTIDEPRESSANTS DO NOT MEMORIZE!

Antidepressants Cardiac Side Effects

Orthostatic Hypotension

Sedation Weight Gain

Anticholinergic Side Effects

Gastrointestinal Upset

Agitation/Insomnia Lower Seizure

Threshold

TCA

s (3

O)

Amitryptyline (Elavil)

+++ ++++ ++++ +++ ++++ 0 0 ++

Clomipramine (Anafranil)

+++ +++ ++ ++ +++ 0 0 +++

Doxepin (Sinequan)

++ ++++ ++++ +++ +++ + 0 ++

Imipramine (Tofranil)

+++ +++ ++ +++ +++ 0 + ++

Trimipramine (Surmontil

+++ +++ ++++ +++ +++ 0 0 ++

TCA

s (2

O)

Amoxapine (Asendin)

++ ++ ++ + ++ 0 ++ ++

Desipramine (Norpramin)

++ ++ + + 0 + +

Nortriptyline (Pamelor)

++ + ++ + + 0 0 +

Protriptylene (Vivactil)

+++ ++ + ++ 0 + ++

Mis

cella

neou

s

Buproprion (Wellbutrin)

0 0 0 0 0 0 ++ ++++

Maprotiline (Ludiomil)

++ ++ +++ ++ +++ ++ + 0/+

Mirtazapine (Remeron)

++/++ ++++ ++ ++ 0 0 +++

Neazodone (Serzone)

0/++ ++ +++ + 0 ++ 0 0

Trazodone (Desyrel)

0/+ ++ +++ + 0 + 0 0

Venlafaxine (Effexor)

0/+ 0/+ 0/+ + +++ ++ 0

Duloxetine (Cymbalta)

0 0 + 0 0/+ +/++ 0 0

SSR

Is

Fluoxetine (Prozac)

0 0 0 0 0 + ++ 0

Fluvoxamine (Luvox)

0 0 0/+ 0 0 ++ + 0

Paroxetine (Paxil)

0 0 + 0 0/+ +++ ++ 0

Sertraline (Zoloft)

0 0 0/+ 0 0 +++ + 0

Citalopram (Celexa)

0 0 0 0 0 ++ +/0 0

Escitalopram (Lexopro)

0 0 0 0 0 + 0 0

MA

OIs

Phenelzine (Nardil)

0 +++ + ++ + + + 0

Tranylcypromise (Pamate)

0 ++ 0/+ + 0 + + 0

0=none; ++ = moderate; +++ = moderate to high; +++ = high

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Learning Objectives Describe the major classes of antidepressants. The major classes of antidepressants are as follows:

§ Tricyclics § SSRIs § SNRIs § MAOIs § Other cyclics

Describe the general mechanism of action of tricyclic and SSRI antidepressant drugs on biogenic amine neurotransmitters. The general mechanism of action is to address the amine hypothesis of mood disorders, in which a lack of CNS biogenic amines is implicated in the onset of depression. However, current thinking is that depression may be due to a dysregulation or diminished function nof serotonin or norepinephrine transmission. Class General Mechanism of Action TCAs Block the reuptake of both norepinephrine and serotonin into nerve terminals. This leads to elevated

synaptic levels of the monoamines. However, their potency at these two sites vary dramatically. SSRIs Potent blockers of serotonin inactivation by reuptake and have little or no effect on norepinephrine

uptake. SNRIs Potent blockers of both serotonin and norepinephrine inactivation by reuptake. MAOIs Act by preventing the metabolism of monoamine neurotransmitters to make elevated levels of the

amines in the nerve terminals and a greater amount of transmitter in the synapse.

Describe the major side effects of tricyclic and SSRI antidepressants. Class Major Side Effects TCAs § Antimuscarinic effects (dry mouth, blurred vision, constipation, urinary retention, and

speech blocking) § Postural hypotension (due to blockade of alpha adrenergic receptors with reflex tachycardia. § Tachycardia, arrhythmia, and ECG abnormalities; high-grade atrioventricular block à due to

antimuscarinic effects § Sedation § Weight gain § Tremor, akathisia, and jittery feeling § Sexual dysfunction

SSRIs § Nausea, headache, nervousness, and insomnia (tolerance develops after 1-2 weeks) § Some sedation § Anorgamia, importence, or decreased libido § Possible fatal interaction with MAOIs.

MAOIs § Dry mouth, constipation, and difficulty urinating § Insomnia § Weight gain § Sexual dysfunction § Cardiovascular side effects

The TCA side effects can be memorized with TCA’S:

§ T: Thrombocytopenia § C: Cardiac (arrhythmia, MI, strokes) § A: Anticholinergic (tachycardia, urinary retention, etc.) § S: Seizures

The side effects of SSRIs can be remembered with the mnemonic SSRI:

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§ S: Serotonin Syndrome § S: Stimulate CNS § R: Reproductive dysfunction in males § I: Insomnia

Describe the syndrome that can be caused by an interaction between SSRI’s and MAOI’s. Serotonin syndrome is a life-threatening drug reaction following therapeutic drug use, inadvertent drug interactions, overdose of drugs, and recreational use of certain drugs. It is a consequence of excessive serotonin activity in the central nervous system and peripheral serotonin receptors. Serotonin Syndrome is remembered because its components cause HARM:

§ H: Hyperthermia § A: Autonomic Instability (Delirium) § R: Rigidity § M: Myoclonus

Understand the basis for dietary restrictions when prescribing MAOI’s. MAOIs enhance the effects of indirectly acting sympathomimetics, such as tyramine. Tyramine is found ina variety of foods, including cheeses, beer, red wine, pickled herring, chicken liver, chocolates, yogurt, and tomatoes. Normally, gastrointestinal MAOs metabolize tyramine. However, if MAOIs are present, tyramine is absorbed and enters nerve endings where it produces a massive release of norepinephrine which can result in a hypertensive crisis, characterized by tachycardia, severe throbbing headache, chest pain, dilated pupils, nausea, and sweating. Patients need to be advised of this wine and cheese effect, and be given dietary restrictions.

Understand the importance of assessing renal function when prescribing lithium. Lithium has an extremely narrow therapeutic index. This means that the plasma concentration producing its therapeutic effects is not much less than that associated with side effects. Lithium’s narrow therapeutic serum concentration (0.8-1.2 mEq/L) makes monitoring blood levels essentials. These measurements should be made about 5 days after the start of treatment at 10-12 hours after the last dose. In long-term use, therapeutic concentrations of lithium have been thought to cause histological and physiological changes in the kidney. Because it has an extremely low volume of distribution (as it is an ion), it often will get passed (with sodium) through the kidneys. Lithium interferes with the regulation of sodium and water levels in the body, and can induce dehydration, causing lithium levels to further increase. Lithium toxicity is compounded with sodium depletion, and diuretics concurrently used with lithium are discouraged due to lithium’s reabsorption in the proximal

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convulated tubule, causing potentially toxic levels. Therefore, it is important to have patients on lithium to receive regular serum level tests and monitor for kidney and thyroid function. The side effects of lithium are best remembered with LITH:

§ L: Lithium § I: Insipidus § T: Tremors § H: Hypothyroidism

Lithium has the following adverse effects:

1. Tremor is the most common adverse effect; in addition ataxia. 2. Decreased thyroid function in most patients (reversible) 3. Polydipsia and polyuria are frequent but reversible à due

interference with ADH (antidiuretic hormone) action in the kidneys 4. Edema 5. ECG abnormalities (reversible). The sinus node is susceptible to

toxic effects of lithium, with depression of its normal pacemaker function, and therefore, lithium is contraindicated in patients with a “sick sinus” syndrome.

6. Lithium is excreted in breast milk and may cause lithium toxicity in newborns.

7. Therapeutic overdoses are more common than deliberate or accidental overdoses and usually result from an accumulation of lithium caused by a change in the patient’s physical status, such as the use of diuretics, change in renal function or pregnancy. This condition can be treated with hemodialysis or peritoneal dialysis until plasma concentrations fall below the usual therapeutic range.

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LECTURE XVI

Sedative-Hypnotic Drugs Lecturer: Dr. Edward French, Ph.D.

Introduction Drugs assigned to the sedative-hypnotic class are able to cause sedation, relieve anxiety, and promote sleep. Anxiety states and sleep disorders are very common problems worldwide, and so is the use of sedative-hypnotics. Anxiety creates physiological and psychological consequences that when combined result in feelings of uneasiness, apprehension and worry. In its moderate state, anxiety (and some degree of neurosis) can be regarded as a “normal” behavior that increases alertness to the dangers around us and thereby increases the chance of survival in a threatening environment. When excessive, however, anxiety can interfere with normal daily activities and becomes classified 0as an anxiety disorder. Physical effects, such as increased heart rate, nausea, chest pain, and shortness of breath, stomach pain, sweating, and headaches, can also accompany anxiety. Physically, the body is preparing to deal with a threat. Because of anxiety parents are protective of their children’s safety, which results in the survival of the children. Anxiety can also be a motivator to succeed, as the fear of failure produces anxiousness. There are many types of anxiety disorders that include panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, specific phobias, and generalized anxiety disorder. As is the case for many of the functions of the central nervous system, “normal” equilibrium is determined by a balance between excitatory and inhibitory influences, and each individual has a different behavioral “steady-state” or threshold. Therefore, different “normal” people become anxious or panicked at different levels of stimuli. Clearly, the “normal” population includes people who are normally “anxious” and others who are relatively “laid back”. The therapeutic target population includes those on the anxious side of the normal distribution, as well as those characterized as suffering from an anxiety “disorder.” Most of the excitation in the CNS is produced by the action of the neurotransmitter glutamate on a variety of excitatory amino acid receptors, whereas the synaptic inhibition that keeps excitation in balance is mediated by the action of the neurotransmitter GABA on several of its receptors. The GABA receptor that mediates most of the inhibition in the brain is the ionotropic GABA-A receptor, which when activated opens a chloride channel allowing the negative chloride to enter the cell, making its potential more negative (hyperpolarization) and decreasing the

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probability of that cell reaching a potential that would trigger an action potential (Figure 1).

Figure 1: Schematic of the GABA-chloride ionophore and site of action for barbiturates and benzodiazepines. The GABA-A receptor is assembled from 5 subunits. The 2 binding sites for GABA are located between adjacent α-1 and β-1 subunits, and the binding pocket for benzodiazepines is between an α-1 and γ-2 subunit. Zolpidem (Ambien) (and other z-drugs) interact only with GABA-A receptor isoforms that contain α-1 subunits.

Pharmacology An effective sedative/anxiolytic medication should reduce one’s level of anxiety and produce a calming effect. This should occur at a dose that does not produce a large degree of CNS depression. A hypnotic drug should produce drowsiness and facilitate the onset and maintenance of sleep. Figure 2 shows the hypothetical dose-response of two different drugs. One can see that the response profile of drug B is more desirable. The benzodiazepines fit with the actions of drug B. There are several chemical versions of benzodiazepines, differing in their pharmacokinetic properties (i.e. short- to long-acting). Drugs that would be included in the drug A response are barbiturates (eg. thiopental and pentobarbital which are used in some states for lethal injection in death penalty cases) and a few non-barbiturate sedative-hypnotics.

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Sedative-hypnotics are used for: relief of anxiety, insomnia, sedation and amnesia before and during medical and surgical procedures, treatment of epilepsy and seizure states, control of ethanol or other sedative-hypnotic withdrawal states, muscle relaxation in specific neuromuscular disorders, diagnostic aids for treatment in psychiatry.

Figure 2. Above are dose-response curves for two hypothetical sedative hypnotics. Drug B would be preferred over Drug A because of its larger safety margin. Below are several barbiturate-related sedative/hypnotics. The benzodiazepines are newer structures with a somewhat different mechanism of action. What sets one benzodiazepine apart from another is basically its pharmacokinetic properties (onset of action, duration of action). The Z-sedative hypnotics (eg. zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta) are newer sedative/hypnotics with novel chemical structures. Although structurally different from the benzodiazepine class of agents they do share a similar mechanism of action, i.e. augmentation of GABA’s effect on the GABA-A receptor ionophore.

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Figure 3. Chemical structures of barbiturates, benzodiazepines, and Z-drugs. There are also a number of other CNS acting drugs that have sedative properties, including some antipsychotics, antidepressants and antihistamines (best known one is Benadryl). The British committee for review of medicines found that: �“all benzodiazepines are efficacious in the short-term treatment of symptoms of anxietyand insomnia. There is no evidence, which can justify the particular use of any particular benzodiazepine in either anxiety or

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insomnia. The usual division of benzodiazepines into rigid treatment categories of antianxiety agents and hypnotics does not appear to be based on the known pharmacological or clinical properties of this group of compounds.” Although this is apparently true for anxiety and insomnia, it is important to understand that different benzodiazepines have additional actions (as muscle relaxants, anticonvulsants, and anesthetics, amnestics, for example), and different half-lives. Differences among compounds in their clinical properties are apparently due to actions at two different sites of the GABA-A receptor. Furthermore, differences among benzodiazepines in their elimination half-lives means that elderly patients with impaired hepatic metabolism (the liver being the primary site for their metabolism) can be given short-acting drugs for insomnia and agitation that do not significantly impair them the next day

Drugs useful in the treatment of anxiety disorders Generic Name Trade Name Half-Life (hrs) Dosage (mg/day)

Long

-Act

ing

Ben

zodi

azep

ines

(C

FC D

rugs

)

Diazepam Valium 20-80 2-60 Chlordiazepoxide Librium 24-48 15-100

Clorazepate Tranxene 100 7.5-60

Estazolam ProSom 10-24 0.5-2.0 Prazepam Centrax 100 20-60 Quazepam Doral 30-100 7.5-15 Halazepam Paxipam 15-100 20-160

Clonazepam* Klonopin 34 1.5-20

Flurazepam+ Dalmane 100 15-30

Shor

t-A

ctin

g B

enzo

diaz

epin

es (

LATE

–

Inte

rmed

iate

; TOM

– S

hort

)

Oxazepam Serax 8 30-120 Lorazepam Ativan 15 2-6 Alprazolam Xanax 12 0.5-6

Temazepam+ Restoril 11 15-30 Triazolam+ Halcion 2 0.125-0.5 Midazolam# Versed 2 2-4

Non

-Ben

zodi

azep

ine

Seda

tive

/Hyp

noti

cs Buspirone BuSpar Serotonin 1a partial agonist

Zolpidem Ambien Potentiates GABA by binding to GABAA receptors in the same location as benzodiazepines

Zaleplon Sonata Agonist of GABA A ɣ 1 subunit Meprobamate Miltown Affects multiple sites of central nervous system, including

thalamus and limbic system. It binds to GABAA receptors, interrupting neuronal communication in reticular

formation and spinal cord. Chloral hydrate Noctec Enhances GABA receptor complex, causing dependency

and withdrawal symptoms. *marketed as an anti-convulsant +marketed as a hypnotic #parenteral only

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Mechanism of action of benzodiazepines Sedative-hypnotic drugs have a variety of clinical actions including anxiolytic, hypnotic, muscle-relaxant, anti-convulsant, and anesthetic effects. Although it is not known exactly which brain structures cause anxiety, it has recently become clear how benzodiazepines produce their anti-anxiety effect. The GABA-A receptors that mediate altered membrane permeability to chloride are pentameric structures made up of a variety of subunits (alpha, beta, and gamma).

Figure 4. The GABA-A receptor and its ligand binding sites. Benzodiazepines and barbiturates bind to unique sites of the receptor to potentiate the effect of endogenous GABA. Benzodiazepines do not activate the receptor directly. Benzodiazapines increases the frequency of chloride channel opening produced by GABA. Barbiturates increase the duration of chloride channel opening produced by GABA. There is also a separate binding site for alcohol. This likely explains how the combination of alcohol with benzos or barbs can potentiate each other and become lethal. Different GABA-A receptors in different brain regions have different subunit compositions, and the expression of specific subunits can be altered by activity. Normally, benzodiazepines (e.g. the prototype diazepam) bind to alpha subunits to increase the chloride channel opening initiated by GABA binding to its binding site. Recent studies indicate that

141

the anxiolytic effects of diazepam are abolished by molecular alteration of the alpha-2 subunit, which is in high concentration in brain regions thought to mediate emotional responses. Therefore, the mechanism by which benzodiazepines decrease anxiety is by binding to the alpha-2 subunit of the GABA-A receptor, which increases inhibition of cells in brain regions, that mediate anxiety. However, other actions of some benzodiazepines are apparently mediated by actions at different subunits of the same GABA-A receptor. For example, zolpidem, an alpha-1 preferring agonist, displays sleep- inducing effects and is used clinically as a treatment for insomnia. Studies indicate that the alpha-1 subunit of the GABA-A receptor mediates the sedation, amnesia and ataxic effects of the benzodiazepines, while the alpha-2 and -3 subunits are involved in the anxiolytic and muscle-relaxing effects.

Properties of benzodiazepines The prototype benzodiazepine is diazepam (Valium). It is highly lipid-soluble. Therefore, it is absorbed orally and crosses the blood-brain barrier, as well as the placental barrier. These highly lipid-soluble drugs are converted by the liver to more water-soluble metabolites for excretion by the kidney. Hepatic metabolism of several benzodiazepines (diazepam, chlordiazepoxide, prazepam, and clorazepate) forms the same product, desmethyldiazepam, which is itself active, with a long half-life. Desmethyldiazepam is then converted to oxazepam (Serax), which is a short-acting metabolite used in its own right for brief sedation. Although benzodiazepines induce sleep, and some are used as anesthetics, respiratory depression is not as great with benzodiazepines as with barbiturates. This is reason behind using large doses of barbiturates instead of benzodiazepines for lethal injections. At plasma concentrations exceeding the anxiolytic range, benzodiazepines cause impairments of mental and motor function, confusion and amnesia. Short acting benzodiazepines (eg. midazolam) are given for conscious sedation procedures (eg. colonscopy) for its amnestic properties. Fatal overdose is uncommon, except when taken in conjunction with alcohol. The main expected side effects of benzodiazepines include sedation, ataxia, and dependence. Withdrawal of tolerant individuals must be gradual to avoid hyperexcitability and possibe seizures, which occur more frequently following the abrupt discontinuation of short-acting than long-acting benzodiazepines. The sedative effects of benzodiazepines can be blocked by the benzodiazepine receptor antagonist flumazenil. Flumazenil can also be used in those situations involving ingestion of large amounts of a benzodiazepine. However, flumazenil will precipitate withdrawal signs in patients dependent on a benzodiazepine (anxiety, insomnia, convulsions).

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Flumazenil does not antagonize the action of barbiturates or alcohol. You can remember this with “Ben is off with the flu.” Benzodiazepine effects are off with flumazenil.

Therapeutic indications for benzodiazepines 1. Anxiety and insomnia 2. Sedation in mania or to control drug-induced hyperexcitability (e.g.

PCP intoxication) 3. Spasticity due to cerebral palsy or tetanus toxin toxicity 4. Anesthesia 5. Alcohol detoxification 6. Seizures (clonazepam in myoclonic disorders; diazepam,

medazolam, and lorazepam in �status epilepticus) 7. Anesthesia

Important practical points about benzodiazepine use One central principle of benzodiazepine use is to use the lowest effective dose for the shortest possible time. This minimizes the potential for dependence and withdrawal. Second, discontinuance withdrawal is most common with short-acting benzodiazepines because cessation of use of the long-acting drugs produces a tapering effect due to a long elimination half-life. However, patients require weeks to months to be weaned from these compounds. Fortunately, serious withdrawal signs, such as hallucinations and seizures, are rare. Despite these caveats, benzodiazepines generally produce few medical complications, and do not interact adversely with most other medications.

Newer sedative/hypnotics Although benzodiazepines are the current drugs of choice for anxiety and insomnia, they produce undesirable daytime sedation and drowsiness, CNS depression in combination with alcohol, and a potential for dependence. Several new compounds that do not act on GABA-A receptors, or more selective drugs that may interact only with specific GABA-A receptor subunits have become available.

Buspirone (BuSpar) Buspirone relieves anxiety without producing sedation, and unlike diazepam, is not a muscle relaxant or anti-convulsant. Also, it does not cause withdrawal signs upon abrupt withdrawal. Buspirone does not interact with the GABA-A receptor, and may produce its desired effects as a partial agonist at the serotonin 1a receptor, suggesting a role for serotonin in anxiety. Also unlike the benzodiazepines, buspirone does not act immediately; it takes a week to become effective. Therefore, buspirone

143

is used for chronic anxiety states. It also produces less memory loss, less sedation and less impairment of motor skills in addition to exhibiting minimal addictive potential. Unlike benzodiazepines it lacks hypnotic, anticonvulsant and muscle relaxant properties. Buspirone is rapidly absorbed orally and undergoes a rapid first-pass effect. Its elimination half-life is 2-4hr and it is largely metabolized by the liver.

Zolpidem (Ambien) Zolpidem is structurally unrelated to benzodiazepines but produces its sedative properties by binding to one of the sites on the GABA-A receptors that also bind benzodiazepines. Consistent with this observation is the fact that zolpidem’s effects are blocked by the benzodiazepine receptor antagonist flumazenil. However, unlike benzodiazepines, zolpidem has minimal muscle relaxing and anticonvulsant effects. Zolpidem also appears to have less potential for dependence and withdrawal. Its elimination half-life is 1.5-3.5 hours and it is largely metabolized by the liver.

Learning Objectives Identify the therapeutic uses of benzodiazepines. Sedative-hypnotics are used for:

§ Relief of anxiety § Insomnia § Sedation § Amnesia before and during medical and surgical procedures § Treatment of epilepsy and seizure states § Control of ethanol or other sedative-hypnotic withdrawal states § Muscle relaxation in specific neuromuscular disorders § Diagnostic aids for treatment in psychiatry

Benzodiazepines have the following therapeutic indications

§ Anxiety and insomnia § Sedation in mania or to control drug-induced hyperexcitability (e.g.

PCP intoxication) § Spasticity due to cerebral palsy or tetanus toxin toxicity § Anesthesia § Alcohol detoxification § Seizures (clonazepam in myoclonic disorders; diazepam, midazolam,

and lorazepam in status epilepticus) § Anesthesia

Identify the mechanism of action of benzodiazepine anti-anxiety drugs. Benzodiazepines do not activate the receptor directly. Benzodiazapines increases the frequency of chloride channel opening produced by GABA.

144

Barbiturates increase the duration of chloride channel opening produced by GABA. There is also a separate binding site for alcohol. This likely explains how the combination of alcohol with benzos or barbs can potentiate each other and become lethal. Different GABA-A receptors in different brain regions have different subunit compositions, and the expression of specific subunits can be altered by activity. Normally, benzodiazepines (e.g. the prototype diazepam) bind to alpha subunits to increase the chloride channel opening initiated by GABA binding to its binding site. Recent studies indicate that the anxiolytic effects of diazepam are abolished by molecular alteration of the alpha-2 subunit, which is in high concentration in brain regions thought to mediate emotional responses. Therefore, the mechanism by which benzodiazepines decrease anxiety is by binding to the alpha-2 subunit of the GABA-A receptor, which increases inhibition of cells in brain regions that mediate anxiety. However, other actions of some benzodiazepines are apparently mediated by actions at different subunits of the same GABA-A receptor. For example, zolpidem, an alpha-1 preferring agonist, displays sleep- inducing effects and is used clinically as a treatment for insomnia.

Identify the adverse effects of anti-anxiety drugs. Although benzodiazepines induce sleep, and some are used as anesthetics, respiratory depression is not as great with benzodiazepines as with barbiturates. This is reason behind using large doses of barbiturates instead of benzodiazepines for lethal injections. At plasma concentrations exceeding the anxiolytic range, benzodiazepines cause impairments of mental and motor function, confusion and amnesia. Short acting benzodiazepines (eg. midazolam) are given for conscious sedation procedures (eg. colonscopy) for its amnestic properties. Fatal overdose is uncommon, except when taken in conjunction with alcohol. The main expected side effects of benzodiazepines include sedation, ataxia, and dependence. Withdrawal of tolerant individuals must be gradual to avoid hyperexcitability and possibe seizures, which occur more frequently following the abrupt discontinuation of short-acting than long-acting benzodiazepines.

Identify the agent that can reverse the effects of benzodiazepines. The sedative effects of benzodiazepines can be blocked by the benzodiazepine receptor antagonist flumazenil. Flumazenil can also be used in those situations involving ingestion of large amounts of a benzodiazepine. However, flumazenil will precipitate withdrawal signs in patients dependent on a benzodiazepine (anxiety, insomnia, convulsions). Flumazenil does not antagonize the action of barbiturates or alcohol.