Dr. Steven I. Dworkin Principals of Pharmacology for the Health Sciences Lecture 1

Dr. Steven I. Dworkin

Principals of Pharmacology for the Health Sciences

Lecture 1


What is a Drug?

• A substance used in the treatment of disease: medicament, medication, medicine, pharmaceutical.

• A substance that affects the central nervous system and is often addictive: hallucinogen, narcotic, opiate.

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What is a Drug?

• Definition can depend on culture and can change within a culture

• Examples

– Herbal antidotes

– Vitamines

– Food additives

– Prescription Medications

– Illicit Substances

• Recreation

• Augment natural abilities


Pharmacology

– Scientific study of the actions of drugs and their effects on a living organism.

• Neuropharmacology

– How drugs effect the central nervous system.

• Psychopharmacology

– Drug-induced changes in mood, thinking, and behaviors.

• Behavioral Pharmacology

– Evaluate specific behavioral effects of drugs

• Change on-going patterns of behavior

• Produce reinforcement

• Produce specific internal states.


Human Nervous System

The nervous system has two major divisions: the central nervous system and the peripheral nervous system. Each of these has major subdivisions, as shown.


Drug Action

• Specific molecular changes produced by a drug when it binds to a particular target site or receptor.

• Drug effects – alterations in physiologic or psychological functions.– Specific Effects

• Therapeutic effect• Side effect

– Nonspecific Effects• Unique characteristics of the individual

– Context dependent tolerance– Placebo effects


Herbal Medicine

• Opium poppy – morphine

• Madagascar rosy periwinkle – chemotherapy

• Foxglove plant – digitalis

• Coca Plant

• Ephedra plant

Concerns

variations in potency

contain toxons

augment or attenuate effects of therapeutics

adverse side effects


Pharmacokinetic FactorsDetermine Drug Action

• Bioavailability

• amount of drug in the blood free to bind at specific target site to elicit a drug effect

– 1) Route of Administration

– 2) Absorption and distribution

– 3) Binding

– 4) Inactivation or biotransformation

– 5) Excretion


Methods of Drug Administration

– Determines amount of drug reaching site of action and how quickly drug effect occurs.

• Oral administration (PO)

– Safe and economical

– Drug must dissolve in stomach fluids and pass through stomach wall.

– Absorption by small intestine

– Influenced by stomach load

– First pass effect

• Metabolism by liver



• Intravenous (IV)– Rapid and accurate method of drug administration– Large potential for adverse effects

• Overdose• Allergic reaction• Hepatitis, HIV……

• Intramuscular (IM)– Slower more even distribution

• 10- 30 minutes – longer with a drug constricts blood vessels

– Muscle irritation



• Intraperitoneal (IP)

– Injection through abdominal wall into the peritoneal cavity

• Rapid

• Somewhat variable effects

• Subcutaneous (SC)

– Injection just below skin

– Absorption dependent on blood flow to site

• Fairly slow and steady

• Slow release metods



• Inhalation

– Rapid delivery

– Absence of first-pass effects

– Irritation of nasal mucosa and lungs

• Topical

• Transdermal

• Epidural

• Intracranial

• Intracerebralventricle


Pharmacokinetic factors that determine bioavailability or drugs From the site of administration (1),the dose moves through cell membranes to be absorbed into the blood (2), where it circulates to all cells in the body. Some of the dose molecules may bind to inactive sites such as plasma proteins or storage depots (3) and some to receptors in target tissue. Blood-borne dose molecules also enter the liver (4), where they may be transformed into metabolites and travel to the kidneys and other dis charge sites for ultimate excretion (5) from the body.



The time course of drug blood level depends on route of administration The blood level of the same amount of dose administered by different procedures to the same individual varies significantly. Intravenous (IV) produces an instantaneous peak when the dose is placed into the blood and rapid decline. Intramuscular (IM) administration produces rapid absorption and rapid decline, although IM administration in oil (IM-oil) shows slower absorption and gradual decline. Slow absorption following subcutaneous (SC) administration means some of the dose is metabolized before absorption is complete. For that reason, no sharp peak occurs and overall blood levels are Iower. Oral (PO) administration produces the lowest blood levels and a relatively short time over threshold for effective ness in this instance. (After Levine,1973.)


TABLE 1.1 Advantages and Disadvantages of Selected Routes of Drug Administration

Route ofadministration

Advantages Disadvantages

Oral (PO) Safe; self-administered; economical; Slow and highly variable absorption;

Intravenous (IV) no needle-related complicationsMost rapid; most accurate blood concentration

subject to first-pass metabolism;less predictable blood levelsOverdose danger; cannot be readily reversed;

Intramuscular (IM) Slow and even absorption requires sterile needles and medical techniqueLocalized irritation at site of injection;

Subcutaneous (SC) Slow and prolonged absorption needs sterile equipmentVariable absorption depending on blood flow

Inhalation Large absorption surface; very rapid onset; Irritation of nasal passages; small particles inhaled

Topical no injection equipment neededLocalized action and effects; easy to self-administer

may damage lungsMay be absorbed into general circulation

Transdermal Controlled and prolonged absorption Local irritation; useful only for lipid soluble drugs

Epidural Bypasses blood—brain barrier; Not reversible; needs trained anesthesiologist;

very rapid effect on CNS possible nerve damage


Transport Across Membranes

• Phospholipid

– Complex lipid molecules form cell membranes

– Negative charge at one end two uncharged lipid tails



• Lipid-soluble drugs

– Enter cells by passive diffusion across concentration gradient.

• Ionized drugs

– PH of the solution

– pKa (PH at which drug is 50% ionized

TABLE pH of Body Fluids

Fluid pH

Stomach fluid 1.0—3.0

Small intestine 5.0–6.6

Blood 7.35–7.45

Kidney urine 4.5–7.5

Saliva 6.2–7.2

CSF 7.3–7.4



Figure 1.5 Effect of ionization on drug absorption On the right side of the cell barrier in stomach acid (pH 2.0),the aspirin molecules tend to remain in the non-ionized form (1), which promotes the passage of the dose through the cell walls (2) to the blood. Once the intact aspirin molecules reach the blood (pH 7.4), they ionize (3) and are"trapped"in the blood to be circulated throughout the body. In the lower portion of the figure, when the aspirin has reached the intes tine, it tends to dissociate to a greater extent (4) in the more basic pH. Its more ionized form reduces passage (5) through the cells to the blood, so absorption from intestine is slower than from the stomach.

Effect of ionization on drug absorption On the right side of the cell barrier in stomach acid (pH 2.0),the aspirin molecules tend to remain in the non-ionized form (1), which promotes the passage of the dose through the cell walls (2) to the blood. Once the intact aspirin molecules reach the blood (pH 7.4), they ionize (3) and are"trapped"in the blood to be circulated throughout the body. In the lower portion of the figure, when the aspirin has reached the intes tine, it tends to dissociate to a greater extent (4) in the more basic pH. Its more ionized form reduces passage (5) through the cells to the blood, so absorption from intestine is slower than from the stomach.


Drug Distribution

• Once in blood carried throughout body in 1-2 min

• Areas with most blood flow highest concentration of drug

• Greatest concentration in heart, brain, kidneys and liver


Blood-Brain Barrier

Distribution of cerebrospinal fluid(A) The CSF (blue) is manufactured by the choroid plexus within the cerebral ventricles. In addition to filling the ventricles and their connecting aqueducts, CSF fills the space between the arachnoid membrane and the pia mater (subarachnoid space) to cushion the brain against trauma. (B) Enlarged diagram to show detail of CSF-filled subarachnoid space and the relationship to cerebral blood vessels. Notice how blood vessels penetrate the brain tissue.


Blood-Brain Barrier

Cross section of typical capillaries and brain capillaries (A) I he capillaries found throughout the body have characteristics that encourage the movement of materials between the blood and surrounding cells. (B) Brain capillaries minimize move ment of water-soluble molecules through the blood vessel wall because there are essen tially no large or small clefts or pinocytotic sites. (After Oldendorf, 1975.)


Biotransformation and Elimination

• Drug Clearance– First-order kinetics

• Constant fraction (50%) free drug in blood removed in each time interval.

– Half-life or T1/2– Zero-order kinetics

• Drug cleared at constant rate regardless of concentration

– Ethanol » 10-15 ml/hour or 1.0 ounce of 50%

alcohol/hour


Drug Elimination

First-order kinetics of drug clearance Exponential elimination of dose from the blood occurs when clear ance during a fixed time interval is always 50% of the dose remaining in blood. For example,the half-life of orally adminis tered dextroamphetamine (Dexedrine) is approximately 10 hours.Therefore,10 hours (1 half-life) after the peak plasma con centration has been reached, the dose concentration is reduced to about 50% of its initial value. After 20 and 30 hours (i.e.,2 and 3 half-lives) have elapsed, the concentration is reduced to 25% and 12.5%, respectively. After 6 half-lives,the dose is essentially eliminated, with 1.6% remaining.The curve representing the rate of clearance is steeper early on when the rate is more rapid and becomes more shallow as the rate of clearance decreases.


Half-Life of Some Common Drugs

Drug Trade/Street Name Half-life

Cocaine Coke, snow 0.5-1.5 hours

Nicotine Tobacco 2 hours

THC Marijuana 20-30 hours

Acetylsalicylic Acid Asprin 3-4 hours

Ibuprofen Advil 3-4 hours

Naproxen Aleve 12 hours

Ultram Tramidol 6-7 hours

ketoprofen Orudis 5 hours

Morphine Morphine 1.5-2 hours


Biotransformation

• Liver microsomal enzymes

– Phase 1 nonsynthetic modification

• Oxidation, reduction, hydrolysis

• Active metabolites

– Phase II synthetic

• Conjugation of drug with small molecule

• Inactive

• Cytochrome P450 enzyme family

– Enzyme induction


Factors Influencing Drug Metabolism

• Enzyme induction

– drug produced increase in liver enzymes

– Carbamazepine and oral contraceptives

– Cigarette smoke and antidepressants and caffeine

• Enzyme inhibition

– MAOIs and tyramine

• Drug competition

– Ethanol, barbiturates, benzodiazepines

• Age, sex, genetics

– Genetic polymorphisms


1. What do all drugs share in common?

2. Name one route of drug administration and list advantages and disadvantages of its use.

3. What are the two major divisions of the central nervous system?

4. What are the two major divisions of the peripheral nervous system?

5. Name two potential problems associated with herbal compounds.

6. List two of the major differences between lipid soluble and ionized drugs.

7. Describe the blood-brain barrier. What purpose does it serve?

8. I have just taken 2 Aleve tablets (50 mg/each), how long will the drug remain in my body.

9. During the past 3 hours I have consumed 3 glasses of wine (12% ethanol) and one large cigar. How long should I wait before trying to drive home safely?

10. What factors are important in estimating the latency from drug administration to drug effect (latency of drug action)?

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Dr. Steven I. Dworkin Principals of Pharmacology for the Health Sciences Lecture 1