Nha 2009 Topics

2009

NHA LE

Group 1

11/16/2009

PHARMACOLOGY 1ST SEMESTER

NHA LE PHARMACOLOGY 1ST SEMESTER 2009

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PREFACE

Due to the change in topics this school year, I have dedicated my effort to compose this note for current and future usage. During the process of making it, there must be certain mistakes coming from either myself or the resources. If you find anything that needs to be corrected, you are welcome to inform or even to make changes. I would like to take this opportunity to give gratitude to many of my friends who were always there when I needed their support and advice. Furthermore, I can never present my appreciation enough to Mr. Takashi Matsumoto for his instant replies for any of my interrogating emails.

NHA LE


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TABLE OF CONTENT

Topic Page

1 A. Pharmacodynamic principles. Receptors and subtypes 6

B. General description of parasympathetic nervous system from pharmacological point

of view (neurotransmitter and receptors)

C. Antihypertensive mode of action of thiazide diuretics and the side effects, osmotic

diuretics

2 A. Dose-response relationships. Efficacy and potency 9

B. Directly acting parasympathomimetics

C. Calcium channel blockers

3 A. Graded and quantal dose-response relationships. Therapeutic index, therapeutic

window 13

B. Parasympatholytics

C. Centrally acting sympathoplegic drugs

4 A. Agonists and antagonists. Antagonism on the receptor level 18

B. Sympathomimetics

C. Pharmacology of renin/angiotensin system

5 A. Antagonism. Non-receptorial antagonism 24

B. Non-selective -adrenoreceptor blockers

C. General description of antiarrhythmic drugs. Vaughan Williams classification

6 A. Control of receptor expression. Receptor diseases and receptors and disease 28

B. -adrenoreceptor blockers

C. Treatment of myocardial ischemia especially the treatment of angina pectoris

7 A. Desensitization, tachyphylaxys and tolerance 33

B. Indirectly acting parasympathomimetics

C. Drugs used in the treatment of hyperlipidemias

8 A. The movement of drugs through biological membranes 39

B. Structure-activity relationships demonstrated among sympathomimetics

C. Drugs used for the treatment of congestive heart failure

9 A. Distribution of drugs in the body: the apparent volume of distribution (Vd) 44

B. General description of sympathetic nervous system from pharmacological point of

view (neurotransmitter and receptors)


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C. Characterization of quinidine, lidocaine, and amiodarone

10 A. Elimination of drugs: the half-life (T1/2) 49

B. Pharmacological tools to influence the sympathetic neurotransmission

C. Expectorants and antitussives

11 A. The clearance 53

B. Selective -adrenoreceptor blockers

C. Pharmacology of the liver and the gall bladder

12 A. Plasma concentration after repeated administration: loading dose and maintenance

dose 56

B. Metabolism of catecholamines and pharmacological modulation

C. Pharmacological treatment of bronchial asthma

13 A. Absorption of drugs and ion trap 60

B. Comparison of elimination of acetylcholine (Ach) and norepinephrine/noradrenaline

from the synaptic cleft and the possibilities of pharmacological modulation

C. Therapeutic importance of diuretics, mode of action and classification.

D. Antialdosterone compounds and other potassium-sparing diuretics

14 A. Bioavailability. AUC 65

B. Compare the effects of norepinephrine/noradrenaline, epinephrine/adrenaline and

isoprenaline

C. Inhibitors of carboanhydrase enzyme, thiazides and other sulfonamide type

diuretics, high-ceiling diuretics (loop diuretics) and antidiuretics

15 A. First pass effect 72

B. Synthesis, storage, release and elimination of acetylcholine (Ach). Demonstration of

Dales experiment

C. Agents used in anemias

16 A. Drug elimination: I. Biotransformation 75

B. Non-adrenergic, non-cholinergic (NANC) transmission

C. Drugs used in coagulation disorders

17 A. Factors influencing the drug elimination 81

B. Uptake mechanisms, substrates and inhibitors

C. Drugs used in acid-peptic disease

18 A. Drug elimination: II. Excretion 87

B. 2 sympathomimetics and the concept of false transmitter


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C. Laxatives, antidiarrheal drugs. Drugs in the treatment of chronic inflammatory bowel

disease, antiobesity drugs

19 A. Factors influencing the drug effect. Preclinical phase of drug development 94

B. Pharmacology of cardiac glycosides

C. Drugs promoting gastrointestinal motility. Emetics and antiemetic drugs

20 A. Drug interactions 100

B. Positive inotropic substances except cardiac glycosides

C. Pharmacotherapeutic approach to exocrine pancreatic diseases

21 A. Clinical phase of drug development 102

B. Adrenergic neuron blockers and reserpine. Antihypertensive mode of action of -

blockers

C. Botanical/herbal remedies


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TOPIC # 1 A. Pharmacodynamic principles. Receptors and subtypes.

1. Pharmacodynamic principles: - Definition: the influence of drug concentrations on the magnitude of the response. It

deals with the interaction of drugs with receptors, the molecule consequences of these interactions, and their effects in the patient.

- Fundamental principle: drugs only modify underlying biochemical and physiological processes; they do not create effects de novo.

2. Receptors and subtypes: - The interaction of the ligand with its receptor thus exhibits a high degree of specificity.

When binding to its ligand, the receptor changes its chemical conformation. - Major types:

a) Ligand-gated ion channel: Rapid response (few milliseconds) Examples: nicotinic receptor (Ach) activation results in sodium influx and action

potential creation; and, GABA receptor (GABA) activation results in chloride influx and hyperpolarization

Ion channels are important drug receptors including local anesthetics. b) G protein-coupled receptors:

Duration: several seconds to minutes Structure: a 7 trans-membrane domain and G protein ( subunit which binds

GTP and subunit) Activation results in dissociation of the G protein, leading to the increase in

concentration of a 2nd messenger such as cAMP (intracellular phosphorylation), IP3, DAG (from phospholipase C, regulating Ca influx) and cGMP (smooth muscle relaxation)

c) Enzyme-linked receptor: Duration: minutes to hours Ligand binding to extracellular domain of the receptor. Most coupled with a

tyrosine kinase enzyme. Most common: epidermal growth receptor, PDGF, atrial natriuretic peptide,

insulin. d) Intracellular receptors:

Lipid soluble ligands. Duration: hours to days Transported inside the body by attaching to albumin. The activated ligand-

receptor complex enters the nucleus to modify gene expression. - Subtypes:

a) Spare receptors: only a fraction of receptors needed to be occupied to elicit a maximal response from a cell. Examples: insulin receptors (99% is spare) and -blocker receptors (5-10% is spare)

b) Desensitization receptors: either the receptors are still present but unresponsive or they are down-regulated, or they undergo endocytosis and are sequestered.

B. General description of parasympathetic nervous system from pharmacological point of view (neurotransmitter and receptors)

- Preganglionic fibers, which are longer, arise from the cranium (from CN III, VII, IX and X) and from the sacral region of the spinal cord.

- Main neurotransmitter is Acetylcholine:a) Synthesis: from acetyl

which can be inhibited by the research drug transported into vesicles by VAT, which can be inhibited by the research drug vesmicol.

Parasympathetic

CNS

NHA LE PHARMACOLOGY 1ST SEMESTER

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General description of parasympathetic nervous system from pharmacological point of view (neurotransmitter and receptors)

Preganglionic fibers, which are longer, arise from the cranium (from CN III, VII, IX and X) and from the sacral region of the spinal cord. Main neurotransmitter is Acetylcholine:

Synthesis: from acetyl-CoA and choline by the enzyme choline acetylwhich can be inhibited by the research drug hemicholiniumtransported into vesicles by VAT, which can be inhibited by the research drug

NERVOUS SYSTEM

PNS

Efferent Division

Autonomic System

Enteric Sympathetic

Somatic System

Afferent Division

Sensory Input

CNS

CNS

Ganglion (Nicotinic receptor)

Effector Organ (Muscarinic receptor)

Ach

OLOGY 1ST SEMESTER 2009

General description of parasympathetic nervous system from pharmacological point of view

Preganglionic fibers, which are longer, arise from the cranium (from CN III, VII, IX and X)

CoA and choline by the enzyme choline acetyl-transferase hemicholinium and actively

transported into vesicles by VAT, which can be inhibited by the research drug


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b) Release: the coordination of VAMPs (synaptobrevin, synaptotagmin) and SNAPs (SNAP25, syntaxin) which can be inhibited by botulinum intoxication.

c) Termination: in the synaptic cleft due to the action of acetyl-cholinesterase. Products are recycled.

- Receptors: at the ganglionic junction is the nAChR (2 subtypes: muscular and neuronal), and at the effector orgarn is the mAchR (coupled with G protein, 5 subtypes: M1 common for exocrine gland and the CNS, M2 common for the heart, M3 common for smooth muscle and the lung, M4 is found in the CNS with inhibitory function, and M5 location is unknown)

C. Antihypertensive mode of action of thiazide diuretics and the side effects, osmotic diuretics

1. Antihypertensive mode of action of thiazide diuretics and the side effects: a) Prototypes and mechanism of action:

Prototypical agent is hydrochlorothiazide. All members belong to sulfonamide derivatives.

Active per os. Duration is 6-12h Major action: inhibit sodium chloride transport in the early segment of the distal

convoluted tubule. Thus, it causes sodium retention, followed by water. Blood volume is restored to normotensive.

b) Effects: Hypokalemic metabolic alkalosis may occur Reduction in sodium transport across the lumen results in decreasing

intracellular sodium content; thus, promoting sodium-calcium exchange at the basolateral membrane.

When used with a loop diuretic, a synergistic effect occurs with marked diuresis. c) Toxicity:

Hyponatremia Chronic usage often results in potassium wasting. Therefore, potassium needs

to be monitored when administering thiazide Diabetic patients may have significant hyperglycemia. Serum uric acid and lipid levels are also increased in some individuals. There is a potential sulfonamide allergenicity.

2. Osmotic diuretics: - Mannitol and urea are prototypical agents. They are both hydrophilic. Mannitol is given

per iv because it is not absorbed at all per os. Other drugs include glycerin, isosorbide, etc.

- These remain in the lumen of the tubule and hold the water by virtue of their osmotic effect. Major location is the proximal convoluted tubule.

- Urine volume increases. Sodium excretion is usually increased. Mannitol can also reduce brain volume and intracranial pressure by osmotically extracting water from the tissue into the blood.

- These drugs are used to maintain high urine flow, to reduce intraocular pressure in acute glaucoma and intracranial pressure in neurologic conditions.

- Some toxicities are: hyponatremia and pulmonary edema, headache, nausea, and vomiting.


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TOPIC # 2 A. Dose-response relationships. Efficacy and potency

1. Dose-response relationships: - These are relationships that describe the response of a receptor-effector system

towards a given dose in a continuously concentration-measured fashion (graded) or in a concrete intervals fashion, in which a response either happens or not (quantal)

- There are 2 types of dose-response relationships: a) Graded dose-response relations: as the concentration of a drug increases, the

magnitude of its pharmacologic effect also increases. It is a continuous and gradual interaction between these two. It is said that the response is a graded effect. Potency and efficacy (intrinsic activity) are two important properties of a drug that can be determined by graded dose-response relations.

1.0 Emax 0.5 Drug Concentration (C) log [Dose]

b) Quantal dose-response relations: the influence of the magnitude of the dose on the proportion of a population that responds. Quantal dose-response applied to any dividual would illustrate that the effect occurs or it does not. It is useful to determine at which dose the effect will be brought in a given population. Therapeutic index, thus, concerns about quantal dose-response relations.

2. Potency and Efficacy:

a) Potency: The amount of drug necessary to produce an effect of a given magnitude. Denoted as EC50, affinity of the drug for the receptor contributes stronly to its

dimension. Therapeutic preparations of drugs will reflect the potency. Examples: Candesartan is more potent (32mg) than Irbesartan (75-300mg).

b) Efficacy (intrinsic activity): The ability of a drug to illicit a physiologic response when it interacts with a

receptor. Is dependent on the number of drug-receptor complexes fromed and the

efficiency of the coupling of receptor activation to cellular response. A drug with greater efficacy is more therapeutically beneficial than one that is

more potent.

Dru

g ef

fect

EC50 Res

pons

e

B. Directly acting parasympathomimetics- Definition: parasympathomimetics are cholinergic agonists that mimic the effects of Ach

by binding directly to cholinoreceptors. They are classified into 2 groups: (Ach) and synthetic esters and natural alkaloids

1. Choline esters (Ach): - A quaternary ammonium compound cannot penetrate membranes.- Therapeutically of no importance- Both muscarinic and nicotinic activity- Actions:

a) Decrease in heart rate and cardiac output: Mimic the effects of vagal stimulation Injected per iv Negative chronotropy

b) Decrease in blood pressure: Vasodilation and lowering of blood pressure Activating M

nitric oxide from arginine It also stimulates protein kinase G production, leading to hyperpolarization and

smooth muscle relaxation Atropine blocks this mechanism

c) Other actions: Increase salivary secretion and intestinal secretion and motility Also increase detrusor urinae muscle tone Cause miosis by stimulating ciliary muscle contraction for near vision

Cholinergic Agonists

Reactivation of Acetylcholine

Esterase


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tly acting parasympathomimetics Definition: parasympathomimetics are cholinergic agonists that mimic the effects of Ach by binding directly to cholinoreceptors. They are classified into 2 groups:

synthetic esters and natural alkaloids (carbachol, bethnechol and p

A quaternary ammonium compound cannot penetrate membranes. Therapeutically of no importance Both muscarinic and nicotinic activity

Decrease in heart rate and cardiac output: effects of vagal stimulation

Injected per iv Negative chronotropy

Decrease in blood pressure: Vasodilation and lowering of blood pressure Activating M3 receptors found on endothelial cells, leading to the production of nitric oxide from arginine

stimulates protein kinase G production, leading to hyperpolarization and smooth muscle relaxation

blocks this mechanism

Increase salivary secretion and intestinal secretion and motilityAlso increase detrusor urinae muscle tone

e miosis by stimulating ciliary muscle contraction for near vision

Direct Acting

Ach

Bethanechol

Carbachol

Cevimeline

Pilocarpine

Indirect Acting

Reversible

Irreversible


Definition: parasympathomimetics are cholinergic agonists that mimic the effects of Ach by binding directly to cholinoreceptors. They are classified into 2 groups: choline esters

(carbachol, bethnechol and pilocarpine).

receptors found on endothelial cells, leading to the production of

stimulates protein kinase G production, leading to hyperpolarization and

Increase salivary secretion and intestinal secretion and motility

e miosis by stimulating ciliary muscle contraction for near vision

Bethanechol

Cevimeline


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2. Synthetic esters and naturally occurring alkaloids: a) Bethanechol:

Acetate = carbamate, choline is methylated. It is NOT hydrolyzed by Acytelcholinesterase Having strong muscarinic action Effects: increased intestinal motility

and tone, stimulated the detrusor muscles whereas the trigone and sphincter are relaxed (aid in urine emptying)

Usage: atonic bladder in postpartum or postoperative, nonobstructive urinary retention, neurogenic atony and megacolon.

Adverse effect: sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, bronchospasm.

b) Carbachol (carbamylcholine): No methyl group that is present in bethanechol. Having both muscarinic and nicotinic activity A poor substrate for acetylcholinesterase Duration: approximately 1h. Actions: both the cardiovascular system and the

gastrointestinal system. They first stimulate then depress. They can also cause epinephrine release from the adrenal medulla. If locally instilled into the eyes, they cause strong miosis.

Therapeutic uses: rarely, except in the eye as a miotic agent to treat glaucoma with little to no adverse effect.

c) Pilocarpine: A tertiary amine and is stable to hydrolysis by acetylcholinesterase. It is

uncharged, therefore, penetrate well the CNS Exhibiting only muscarinic activity Actions: when it is applied topically to the cornea, it produces a rapid miosis and

contraction of the ciliary muscle. However, it is known as one of the most potent stimulators of secretions. Thus, it is very beneficial in promoting salivation in patients with xerostomia and Sjrgrens syndrome (given oral pilocarpine tablets and cevimeline)

Therapeutic use in glaucoma: both narrow-angle (closed-angle) and wide-angle (opened-angle) glaucoma. It is extremely effective in opening the trabecular meshwork around Schlemms canal, causing an immediate drop of intraocular high pressure. This action can last up to 8h.

Adverse effects: it can enter the brain and cause CNS disturbances, or can cause exacerbating sweating and salivation.


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C. Calcium-channel blockers - These are antihypertensives. They are recommended when the preferred first-line

agents are contraindicated or ineffective. Besides, they are very effective in treating hypertension in patients with angina or diabetes.

1. Classes of calcium-channel blockers: there are three, distinguished from pharmacokinetic properties and clinical indications (dilation of coronary vessels, AV conduction and frequency of adverse effects)

a) Diphenylalkylamines: Verapamil is the only member. The least selective of any calcium-channel blocker that has effects on both

cardiac and vascular smooth muscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and migraine

headache. b) Benzothiazepines:

Diltiazem is the only member. Effects on both cardiac and vascular smooth muscle cells, but less pronounced

negative inotropic effect on the heart and a more favourable side-effect profile. c) Dihydropyridines:

First generation: nifedipine; second generation: amlodipine, felodipine, isradipine, nicardipine and nisoldipine.

All have a much greater affinity for vascular calcium channels than for calcium channels in the heart. Therefore, they are particularly attractive in treating hypertension

Amlodipine and nicardipine have little interaction with other cardiovascular drugs such as digoxin or wafarin.

2. Actions: - They block the inward movement of calcium by binding to L-type calcium channels in

the heart and in smooth muscle of the coronary and peripheral vasculature. - Result in relaxation and dilation mainly arterioles.

3. Therapeutic uses:

- They have an intrinsic natriuretic effect, so, do not usually require the addition of a diuretic.

- They are very useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

4. Pharmacokinetics:

- Most have short half-lives (3-8h) following an oral dose. Therefore, they are usually prescribed 3 times a day.

- Sustained-release preparations are available. However, amlodipine has a very long half-life and does not require a sustained-release formulation.

5. Adverse effects:

- Constipation in 10% patients treated with verapamil. - Dizziness, headache, fatigue - Vertigo, hypotension.


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TOPIC # 3 A. Graded and quantal dose-response relationships. Therapeutic index, therapeutic window

1. Graded dose-response relationship: - This is a continuous relationship between dose and response. - It can be mathematically described for many systems by application of the law of mass

action, assuming the simplest model of drug binding:

[Drug] + [Receptor] [Drug-Receptor complex]

- It determines 2 important properties of drugs: potency and efficacy (aka intrinsic activity)

- By making the assumption that the binding of one drug molecule does not alter the binding of subsequent molecules, we can mathematically express the relationship between the percentage (or fraction) of bound receptors and the drug concentration:

- Kd can be used to determine the affinity of a

drug for its receptor. The higher the Kd value, the weaker the interaction and the lower the affinity. It is important to note the similarity between these curves and those representing the relationship between dose and effect.

- Relationship of binding to effect: the binding of the drug to its receptor initiates events that ultimately lead to a measurable biologic response. Denoted [E] = the effect of the drug at concentration [D] and [Emax] = the maximal effect of the drug.

2. Quantal dose-response relationships: - The influence of the magnitude of the dose on the proportion of a population that

responds is the definition. Quantal responses for any individual mean that effect either occurs or it does not.

- 2 concepts are concerned: a) Therapeutic index:

The ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals:

B. Parasympatholytics

Antimuscarinic Agents

1. Atropine

2. Cyclopentolate

3. Ipratropium

4. Scopolamine

5. Tropicamide


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A measure of a drugs safety.

Therapeutic index = TD50/ED50

Warfarin (small therapeutic index): as the dose is increased, a greater fraction of the patients respond, desired response is a two-fold increase in prothrombin time.

Penicillin (large therapeutic index): often about ten-fold excess. Bioavailability does not critically alter the therapeutic effects.

Variation is most likely to occur with a drug showing a narrow therapeutic index. Agents with a low therapeutic index. Bioavailability critically alters the therapeutic effects.

b) Therapeutic window: The safe range between the minium

therapeutic concentration and the minimum toxic concentration of a drug.

Minimum effective concentration will usually determine the desired trough levels of a drug while minimum toxic concentration determines theplasma concentration.

Cholinergic Antagonists

Ganglionic Blockers

1. Mecamylamine

2. Nicotine

Neuromuscular Blokers

1. Atracurium

2. Cisatracurium

3. Doxacurium

4. Metocurine

5. Mivacurium

6. Pancuronium

7. Rocuronium

8. Succinylcholine

9. Tubocurarine

10. Vecuronium


A measure of a drugs safety.

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(small therapeutic index): as the dose is increased, a greater fraction of the patients

fold increase in

(large therapeutic index): ioavailability does not critically

Variation is most likely to occur with a drug showing a narrow therapeutic index. Agents with a low therapeutic index. Bioavailability critically alters the

window: The safe range between the minium

therapeutic concentration and the minimum toxic

Minimum effective concentration will levels of a drug while

minimum toxic concentration determines the permissible peak

Neuromuscular

8. Succinylcholine


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- They are also called cholinergic blockers, parasympatholytics or anticholinergic drugs. They are most useful in selectively blocking muscarinic synapses of the parasympathetic nerves. On the contrary, ganglionic blockers show a preference for the nicotinic receptors of the sympathetic and parasympathetic ganglia; but, they are the least important. The third family is neuromuscular blocking agents, which are used as adjuvants in anesthesia during surgery.

1. Antimuscarinic agents:

a) Atropine: - Its main action is illustrated in the eye (mydriasis, unresponsiveness to light, and

cyclophegia), the GIT (antispasmodic, not effective in promoting healing of peptic ulcer), the urinary system (reduction of hypermotility states of the urinary bladder), cardiovascular (decreasing heart rate at low dose due to M1 blockade; and, increasing it at high dose due to M2 blockade) and secretions (xerostomia and elevated body temperature).

- Therapeutic uses: Ophthalmic: permitting the measurement of refractive errors without

interference by the accommodative capacity of the eye. Antispasmodic: relax the GI tract and bladder (enuresis in children). Antidote for cholinergic agonists: treatment of overdoses of cholinesterase

inhibitor insecticides and some types of mushroom poisoning. Antisecretory: block secretions in the upper and lower respiratory tracts prior to

surgery - Pharmacokinetics: readily absorbed, partially metabolized by the liver, eliminated

primarily in the urine, half-life is about 4h. - Adverse effects: dry mouth, blurred vision, sandy eyes, tachycardia, constipation,

confusion, hallucination, hyperthermia. b) Scopolamine:

- Actions: one of the most effective anti-motion sickness drugs available. It has greater action on the CNS and a longer duration of action. It can also block short-term memory. Even though it can produce sedation, but at higher doses, it can produce excitement instead. It may produce euphoria.

- It is limited to treat motion sickness and short-term memory. However, it is much more effective prophylactically in motion sickness.

- Pharmacokinetics and adverse effects are similar to those of atropine. c) Ipratropium:

- Only in inhaled form, very useful in treating asthma in patients who are unable to take adrenergic agonists.

- Also beneficial in the management of chronic obstructive pulmonary disease. - It is positive charge, it does not enter the systemic circulation or the CNS.

d) Tropicamide and cyclopentolate: used as ophthalmic solutions for similar conditions as atropine, but duration is shorter (6h and 24h, respectively).

2. Ganglionic blockers:

- Specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia with no selectivity, not effective as neuromuscular antatgonists.

- Basically, they block the entire output of the autonomic nervous system at the nicotinic receptors.


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- It often serves as tools in experimental pharmacology. - Only 2 compounds are mentioned:

Nicotine: a poison to the human system, depolarizes autonomic ganglia, resulting first in stimulation and then in paralysis of all ganglia. It can first increase blood pressure and cardiac rate but at higher doses, blood pressure falls because of ganglionic blockade.

Mecamylamine: a competitive nicotinic blockade of the ganglia. Duration is about 10h; uptake via oral absorption is good.

3. Neuromuscular blocking drugs:

a) Nondepolarizing (competitive) blockers: - Mechanism of action:

At low dose: inhibit muscular contraction, but action can be overcome by increasing the concentration of Ach in the synaptic gap.

At high dose: block also the ion channels of the end plate, therefore further weakening of neuromuscular transmission.

- Actions: small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first. Those agents, which release histamine, can produce a fall in blood pressure, flushing, and bronchoconstriction.

- Therapeutic uses: adjuvant drugs in anesthesia during surgery. - Pharmacokinetics: all are injected intravenously. They penetrate membranes very

poorly and do not enter cells or cross the BBB. Many are not metabolized and actions are terminated by redistribution, except vecuronium and rocuronium are deacetylated in the liver.

- They are known with minimal side effects. - Drug interactions:

Cholinesterase inhibitors: if the neuromuscular blocker has entered the ion channel, cholinesterase inhibitors are not as effective in overcoming blockade.

Halogenated hydrocarbon anesthetics: enhance neuromuscular blockade. Aminoglycoside antibiotics: act synergistically. Calcium-channel blockers: may increase the neuromuscular block of

tubocurarine. b) Depolarizing agents:

- Mechanism of action: (succinylcholine as a prototype) it attaches to the nicotinic receptor and first depolarize the junction. However, it persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing a constant stimulation of the receptor. It gives only a transient twitching of the muscle (fasciculations), then the long depolarization gives way to gradual repolarization as the sodium channel closes or is blocked and causes resistance to depolarization (phase II) and a flaccid paralysis.

- Actions: the drug does not produce a ganglionic block except at high doses, but it does have weak histamine releasing action. It is not metabolized and redistribution to plasma is necessary for metabolism.

- Therapeutic uses: rapid endotracheal intubation is required during the induction of anesthesia, also employed during electroconvulsive treatment.

- Pharmacokinetics: injected per iv. It is rapidly hydrolyzed by plasma cholinesterase; therefore, it is usually given by continuous infusion.

- Adverse effects:


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Hyperthermia: halothane and succinylcholine together can produce malignant hyperthermia, can be treated by cooling the body with dantrolene.

Apnea: to patients who are genetically deficient in plasma cholinesterase. Hyperkalemia: it increases potassium release from intracellular stores; thus,

particularly dangerous for burnt patients or patients with massive tissue damage who are suffering from potassium loss from cells.

C. Centrally acting sympathoplegic drugs

- These drugs lower blood pressure by lowering the resistance in the blood vessels, inhibiting heart function, and increase pooling of blood in the vessels. They inhibit the function of the sympathetic nervous system. They are classified according to the site at which they damage the sympathetic reflex arc.

- There are 5 groups of them: centrally acting sympathoplegic, ganglion-blocking agents, adrenergic neuron-blocking agents, adrenoreceptor antagonists, and 1 blocker.

- Centrally acting sympathoplegic drugs, such as methyldopa and clonidine, act on the blood pressure centers of the brainstem. Newer drugs such as guanabenz and guanfacine, do not appear to offer any advantages over clonidine. a) Methyldopa is used in treating mild to moderately severe hypertension. It also

causes reduction in the resistance of vessels in the kidney. The therapeutic dose is 1-2 g per day orally in divided doses. The most common side effect of methyldopa is overt sedation, especially at the start of treatment.

b) Clonidine should not be given to patients who are at risk of mental depression and should be withdrawn if depression occurs during therapy.


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TOPIC # 4 A. Agonists and antagonists. Antagonism on the receptor level

1. Agonists and antagonists: - Agonists are drugs that bind to receptors and produce biologic responses that mimic the

response to the endogenous ligand. A full agonist has a strong affinity for its receptor and good efficacy.

- Antagonists are drugs that decrease the actions of another drug or endogenous ligand. Many antagonists act on the identical receptor that the agonists work. However, they are able to bind avidly to target receptors because they possess strong affinity.

- Partial agonists have efficacies (intrinsic activities) greater than zero, but less than that of a full agonist. Even if all the receptors are occupied, they cannot produce an Emax of as great a magnitude as that of a full agonist. They can have an affinity that is greater than, less than, or equivalent to that of a full agonist.

- A unique feature of a partial agonist is that under an appropriate condition, it may act as an antagonist of a full agonist. Therefore, partial agonists act both agonistically and antagonistically.

Aripiprazole is a partial agonist at selected dopamine receptors. When the pathway is overactive, the drug would tend to inhibit it. When the pathway is underactive, the drug would, then, stimulate it.

Aripiprazole, thus, is able to improve many of the symptoms of schizophrenia, a mental disorder or group of disorders characterized by disturbances in the form and content of thought, in mood, in sense of self and relationship to the external world, and in behavior.

2. Antagonism on receptor level: - Functional antagonism is defined that an antagonist may act at a completely separate

receptor, initiating effects that are functionally opposite those of the agonist. For example, histamine has an antagonistic activity towards epinephrine on bronchial smooth muscle but act on a different receptor. This functional antagonism is also known as physiologic antagonism.

- Types of antagonism on receptor level: a) Competitive pharmacologic antagonists are drugs that bind to, or very close to, the

receptor site in a reversible way without activating the effector system. Log dose-response curve is shifted to higher doses.

An irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present. Its effects cannot be overcome by adding agonists.

b) Irreversible pharmacologic antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present. Its effects cannot be overcome by adding agonists.

- Competitive antagonists increase the ED50; irreversible antagonists do not (unless spare receptors are present).

B. Sympathomimetics

1. Definition: adrenergic drugs that act directly on the adrenergic activating it are said to be sympathomimetic.

2. Characteristics of adrenergic agonists:- Most are derivatives of

number and location of OH substitutions on the benzenesubstituent on the amino nitrogen.

- According to the structural feature, they are categorized into 2 groups: Catecholamines (

have: high potency, rapid inactivation and poor Noncatecholamines (

half-lives, are not inactivated by COMT and have an increased lipid solubility which permits them a greater access to the CNS.

- It is very important to definbecause it can determine the

- There are 3 mechanisms of action of the adrenergic agonists: Direct-acting: Indirect-acting

release of NE from the cytoplasmic pools or vesicles of the adrenergic neuron (amphetamine, cocaine

Mixed-action agonists:

Direct-(Sympathomime

tics)

- Albuterol

- Clonidine

- Formoterol

- Metaproterenol

- Methoxamine

- Phenylephrine

- Pirbuterol

- Salmeterol

- Terbutaline

- Catecholamines: Epinephrine, Norepinephrine, Isoproterenol, Dopamine, Dobutamine


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Definition: adrenergic drugs that act directly on the adrenergic receptor (adrenoreceptor) by activating it are said to be sympathomimetic.

Characteristics of adrenergic agonists: Most are derivatives of -phenylethylamine. Two important structural features are the number and location of OH substitutions on the benzene ring and the nature of the substituent on the amino nitrogen. According to the structural feature, they are categorized into 2 groups:

Catecholamines (epinephrine, norepinephrine, isoproterenol have: high potency, rapid inactivation and poor penetration into the CNS.Noncatecholamines (phenylephrine, ephedrine and amphetamine

lives, are not inactivated by COMT and have an increased lipid solubility which permits them a greater access to the CNS.

It is very important to define the nature of the substitution on the amine nitrogen because it can determine the selectivity. There are 3 mechanisms of action of the adrenergic agonists:

acting: epinephrine, norepinephrine, isoproterenol and phenylephrineacting agents may block the uptake of NE (uptake blockers) or cause the

release of NE from the cytoplasmic pools or vesicles of the adrenergic neuron amphetamine, cocaine and tyramine).

action agonists: ephedrine, pseudoephedrine and metaraminol

Adrenergic Agonists

-acting (Sympathomime

tics)

Catecholamines: Epinephrine, Norepinephrine, Isoproterenol, Dopamine, Dobutamine

Indirect-actingDirect and

Indirect-acting (mixed action)


receptor (adrenoreceptor) by

phenylethylamine. Two important structural features are the ring and the nature of the

According to the structural feature, they are categorized into 2 groups: epinephrine, norepinephrine, isoproterenol and dopamine)

penetration into the CNS. amphetamine) have longer

lives, are not inactivated by COMT and have an increased lipid solubility

e the nature of the substitution on the amine nitrogen

phenylephrine. agents may block the uptake of NE (uptake blockers) or cause the

release of NE from the cytoplasmic pools or vesicles of the adrenergic neuron

metaraminol.


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3. Sympathomimetics: a) Epinephrine:

- It is synthesized naturally in the adrenal medulla. At low doses, effects (vasodilation) on the vascular system predominate, whereas at high doses, effects (vasoconstriction) are strongest.

- Its actions include Cardiovascular: positive inotropic and chronotropic through 1 action;

constriction of skin, mucous membrane and viscera arterioles through effects; dilation of liver and skeletal muscle vessels through 2 action. In general, there is an increase in systolic BP and a slight decrease in diastolic BP.

Respiratory: powerful bronchodilation, relieving all known allergic attack, rapidly relieving the dyspnea in an acute asthmatic attack.

Hyperglycemia through increasing glucagon level. Lipolysis

- Biotransformation occurs through 2 enzymatic pathways: MAO and COMT. Final metabolites (metanephrine and vanillylmandelic acid) are found in the urine.

- Therapeutic uses include: bronchospasm, glaucoma, anaphylactic shock, anesthetics.

- Pharmacokinetics: rapid onset but a brief duration of action, oral administration is ineffective, only metabolites are excreted in the urine.

- Adverse effects: CNS disturbances, hemorrhage, cardiac arrhythmias, pulmonary edema.

- Interactions with other drugs: Hyperthyroidism: leading to hypersensitive response. Cocaine: exaggerating cardiovascular actions. Diabetes: inducing hyperglycemia, thus insulin must be increased. -blockers: counteracting. Inhalationanesthetics: may lead to tachycardia.

b) Norepinephrine:

- Most effective with receptors. - It has cardiovascular actions include:

Vasoconstriction: of most vascular beds including the kidney (1 effect), both SP and DP increase.

Baroreceptor reflex Effect of atropine pretreatment: if atropine is given before NE, the stimulation

of the heart is evident as tachycardia. - Therapeutic usage focuses on treating shock. However, metaraminol is preferred

because it does not cause reduced blood flow to the kidney as does NE. NE can cause extravasation at injection site due to its potent vasoconstrictor effect.

- Pharmacokinetics: may be given per i.v. for rapid onset, duration is about 1-2min, poorly absorbed after subcutaneous injection and is destroyed in the gut if administered orally.

- Adverse effects: similar to those of Epi plus blanching and sloughing of skin along the injected vein.

c) Isoproterenol: - Predominantly stimulates both 1 and 2 nonselectively. - Its actions include:


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Cardiovascular: intense stimulation of the heart to increase its rate and force of contractions, useful in the treatment of AV block or cardiac arrest, increase SP slightly but greatly reduce MAP and DP.

Pulmonary: profound and rapid bronchodilation (2 action), rapid alleviation of an acute asthmatic attack (action lasts about 1h).

- Therapeutic usage is rare but can be a heart stimulator in emergency situations. - Pharmacokinetics: absorbed systematically by the sublingual mucosa, more reliably

absorbed when given parenterally or as an inhaled aerosol, marginal substrate for COMT and stable to MAO action.

- Adverse effects: similar to those of Epi. d) Dopamine:

- Occurs naturally in the CNS in the basal ganglia. - Can activate both and . At high doses, it can cause vasoconstriction by activating

1 receptors, whereas at lower doses, it stimulates 1 cardiac receptors. - It has 2 actions: vascular (both inotropic and chronotropic to the heart at low dose

and vasoconstriction at high dose) and renal and visceral (via D1 and D2 receptors, vasodilation)

- Therapeutic uses: drug of choice for shock and is given by continuous infusion. e) Dobutamine:

- It is a 1 agonist and available as a racemic mixture. It increases cardiac rate and output with few vascular effects.

- It does not significantly elevate oxygen demands of the myocardium. - It should be used with caution in atrial fibrillation because it increases AV

conduction. Tolerance can be observed after prolonged usage. f) Oxymetazoline: stimulates both 1 and 2, primarily used locally in the eye and nose as a

vasoconstrictor (reducing congestion), absorbed in the systemic circulation regardless of the route of administration, and may cause nervousness, headaches and trouble sleeping.

g) Phenylephrine: binds primarily to receptors and favors 1 receptors, not a substrate for COMT, induces reflex bradycardia when given parenterally, often used topically on nasal mucous membrane and in ophthalmic solutions for mydriasis. Large dose can cause hypertensive headache and cardiac irregularities.

h) Methoxamine: 1 favoured, affect on the vagus nerve, used clinically to relieve attackes of paroxysmal supraventricular tachycardia, can cause hypertensive headache and vomiting.

i) Clonidine: a sympathoplegic drug, 2 agonist, used to lower BP and to minimize the symptoms that accompany withdrawal opiates or benzodiazepines.

j) Metaproterenol: resistant to COMT, can be administered orally or inhaled, acts primarily on 2 receptors, produces dilation of the bronchioles and improves airway function.

k) Albuterol, pirbuterol and terbutaline: short-acting 2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler, produce equivalent bronchodilation with less cardiac stimulation.

l) Salmeterol and formoterol: 2 selective, long-acting bronchodilators (over 12h). Salmeterol is the agent of choice in treating nocturnal asthma.


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SUMMARY OF SYMPATHOMIMETICS Both and agonists Only agonists Only agonists

Epinephrine Norepinephrine (therapeutically receptors) Isoproterenol (more activity) Dopamine

Dobutamine Metaproterenol Terbutalline Albuterol

Phenylephrine Methoxamine Clonidine Albuterol, Pirbuterol, Terbutalline Salmeterol, Formoterol

C. Pharmacology of rennin/angiotensin system

1. ACE inhibitors: - The ACE inhibitors are recommended when the preferred first-line agents (diuretics or

-blockers) are contraindicated or ineffective. - Actions:

Lower BP by reducing peripheral vascular resistance without reflexively increasing cardiac output, rate, or contractility.

Decrease angiotensin II and increase bradykinin levels Decrease the secretion of aldosterone, resulting in decreased sodium and water

retention


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- They help to slow the progression of diabetic nephropathy and to decrease albuminuria. They are very effective in managing patients with chronic heart failure. They are a standard in the care of a patient following a MI, where therapy is started 24h after the end of the infarction.

- Adverse effects: dry cough, rash, fever, altered taste, hypotension, hyperkalemia, fetotoxic.

2. Angiotensin II-receptor antagonists:

- They are abbreviated as ARBs and are the alternatives to the ACE inhibitors because the block the AT1 receptors.

- Losartan is the prototypic drug; there are 6 additional ARBs. - They produce arteriolar and venous dilation and block aldosterone secretion; however,

they do not increase bradykinin levels. - They also help to decrease the nephrotoxicity of diabetes. - The risks of dry cough and angioedema are significantly decreased, but fetotoxicity

remains.

3. Renin inhibitors: - Aliskiren directly inhibits rennin and acts earlier in the rennin-AT-aldosterone system. - It can cause diarrhea, especially at the higher doses. Also, dry cough and angioedema

can be induced but probably less often then ACE inhibitors. It is contradictory for pregnant women. Hyperkalemia can be observed as well.

- The combination of maximum doses of aliskiren and valsartan decreased BP more than maximum doses of either agent alone but not more than would be expected with dual therapy consisting of agents of different classes.


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TOPIC # 5 A. Antagonism. Non-receptorial antagonism

1. Physiologic antagonists: - It binds to a different receptor molecule, producing an effect opposite to that produced

by the drug it antagonizes. - A pharmacologic antagonist interacts with the same receptor as the drug it is inhibiting.

2. Chemical antagonists:

- It interacts directly with the drug being antagonized to remove it or to prevent it from reaching its target and does not depend on interaction with the agonists receptor.

- Examples: demercaprol, a chelator of lead and some other toxic metals; pralidoxime combines avidly with the phosphorus in organophosphate cholinesterase inhibitors.

B. Non-selective -adrenoreceptor blockers

v These profoundly affect BP, resulting in decreased peripheral vascular resistance. v They also induce a reflex tachycardia resulting from the lowered BP. v There are only 2 agents that have limited clinical applications: phenoxybenzamine

and phentolamine. 1. Phenoxybenzamine

- It is non-selective, linking covalently to both 1-postsynaptic and 2-presynaptic receptors.

- The block is irreversible and non-competitive. - The only mechanism the body has for overcoming the block is to synthesize new

adrenoreceptors. Thus, the drugs action lasts about 24h after a single administration. - Before carrying out any effect, the molecule must undergo biotransformation to the

active form. a) Actions:

Cardiovascular effects: vasoconstriction of peripheral blood vessels by endogenous catecholamines. The decreased peripheral resistance provokes a reflex tachycardia. Its ability to block presynaptic inhibitory 2-receptors in the heart can contribute to an increased cardiac output. However, it is unsuccessful in maintaining lowering BP in hypertension.

Epinephrine reversal: vasoconstriction action is blocked but vasodilation (on receptors) is not. Therefore, systemic BP decreases in response to Epi given in the presence of phenoxybenzamine.

b) Therapeutic uses: in the treatment of pheochromocytoma (a catecholamine-secreting tumour of cells derived from the adrenal medulla), sometimes effective in treating Raynauds disease or autonomic hyperreflexia (predispose paraplegics to strokes).

c) Adverse effects: postural hypotension, nasal stuffiness, nausea, vomiting, inhibiting ejaculation, inducing reflex tachycardia, contradictory in patients with decreased coronary perfusion.


25

2. Phentolamine: - It produces a competitive block of 1 and 2 receptors. Duration of actions usually

lasts for 4h after a single administration. - It also produces postural hypotension, causes epinephrine reversal, induces reflex

cardiac stimulation, triggers arrhythmias and angina pain and is contradictory in patients with decreased coronary perfusion.

- It is also used for the short-term management of pheochromocytoma.

C. General description of antiarrhythmic drugs. Vaughan Williams classification 1. Overview of the arrhythmias:

a) Causes of arrhythmias: - The arrhythmias are the dysfunctions cause abnormalities in impulse formation and

conduction in the myocardium. - Abnormal automaticity may occur if the myocardial cells are damaged. These cells

may remain partially depolarized during diastole and, therefore, can reach the firing threshold earlier than normal cells. Abnormal automatic discharges may thus be induced.

- Some drugs cause the frequency of discharge to decrease an effect that is more pronounced in cells with ectopic pacemaker activity than in normal cells.

- Reentry can occur if a unidirectional block caused by myocardial injury or a prolonged refractory period results in an abnormal conduction pathway.

- Antiarrhythmic agents prevent reentry by slowing conduction and/or increasing the refractory period, thereby converting a unidirectional block into a bidirectional block.

b) Antiarrhythmic drugs: - The Vaughan Williams classification, introduced in 1970, is one of the most widely

used classification schemes for antiarrhythmic agents. This scheme classifies a drug based on the primary mechanism of its antiarrhythmic effect.

- There are 5 classes:


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Summary of antiarrhythmic drugs Classification of

Drug Description Mechanism of

action Comment Examples

IA - Bind more rapidly to open or inactivated Na channels then to channels that are fully repolarized following recovery from the previous depolarization cycle. This property is called use-dependence

Na channel blocker

- Slows Phase 0 depolarization in ventricular muscle fibers.

- Have an intermediate speed of association with activated/inactivated Na channels.

1. Quinidine 2. Procainamide 3. Disopyramide

IB - Shortens Phase 3 repolarization in ventricular muscle fibers.

- Rapidly interact with Na channels.

1. Lidocaine 2. Mexiletine 3. tocainide

IC - Markedly slows Phase 0 depolarization in ventricular muscle fibers.

- Bind slowly to Na channels.

1. Flecainide 2. Propafenone

II - Depressing automatically, prolong AV conduction and decreasing heart rate and contractility.

- Useful in treating tachyarrhythmias caused by increased sympathetic activity.

- Used for atrial flutter and fibrillation and for AV-nodal reentrant tachycardia.

Beta adrenoreceptor blocker

- Inhibits Phase 4 depolarization in SA and AV nodes.

1. Propranolol 2. Metoprolol 3. Esmolol

III - All Class III drugs have the potential to induce arrhythmias.

K channel blocker

- Prolongs Phase 3 repolarization in ventricular muscle fibers

1. Amiodarone 2. Sotalol 3. Dofetilide

IV - Slowing the conduction - May be contradictory in

patients with preexisting depressed cardiac function.

Ca channel blocker

- Inhibits action potential in SA and AV nodes

1. Verapamil 2. Diltiazem

V - Unknown mechanism of work

(probably nodal inhibition)

1. Digoxin 2. Adenosine


27

Class Clinical uses

Ia Ventricular arrhythmias prevention of paroxysmal recurrent atrial fibrillation (triggered by vagal overactivity),

*procainamide in Wolff-Parkinson-White syndrome

Ib

Treatment and prevention during and immediately after myocardial infarction, though this practice is now discouraged given the increased risk of asystole Ventricular tachycardia Atrial fibrillation

Ic Prevents paroxysmal atrial fibrillation Treats recurrent tachyarrhythmias of abnormal conduction system.

II Decrease myocardial infarction mortality Prevent recurrence of tachyarrhythmias

III In Wolff-Parkinson-White syndrome (Sotalol) ventricular tachycardias and atrial fibrillation (Ibutilide) atrial flutter and atrial fibrillation

IV Prevent recurrence of paroxysmal supraventricular tachycardia Reduce ventricular rate in patients with atrial fibrillation

V Used in supraventricular arrhythmias, especially in Heart Failure with Atrial Fibrillation,

contraindicated in ventricular arrhythmias.

http://en.wikipedia.org/wiki/Ventricular_arrhythmiahttp://en.wikipedia.org/wiki/Recurrent_atrial_fibrillationhttp://en.wikipedia.org/wiki/Vagus_nervehttp://en.wikipedia.org/wiki/Wolff-Parkinson-White_syndromehttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Asystolehttp://en.wikipedia.org/wiki/Ventricular_tachycardiahttp://en.wikipedia.org/wiki/Atrial_fibrillationhttp://en.wikipedia.org/wiki/Paroxysmal_atrial_fibrillationhttp://en.wikipedia.org/w/index.php?title=Recurrent_tachyarrhythmias&action=edit&redlink=1http://en.wikipedia.org/wiki/Electrical_conduction_system_of_the_hearthttp://en.wikipedia.org/wiki/Myocardial_infarctionhttp://en.wikipedia.org/wiki/Tachyarrhythmiahttp://en.wikipedia.org/wiki/Wolff-Parkinson-White_syndromehttp://en.wikipedia.org/wiki/Ventricular_tachycardiashttp://en.wikipedia.org/wiki/Atrial_fibrillationhttp://en.wikipedia.org/wiki/Atrial_flutterhttp://en.wikipedia.org/wiki/Atrial_fibrillationhttp://en.wikipedia.org/wiki/Paroxysmal_supraventricular_tachycardiahttp://en.wikipedia.org/wiki/Ventricular_ratehttp://en.wikipedia.org/wiki/Atrial_fibrillation


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TOPIC # 6 A. Control of receptor expression. Receptor diseases and receptors and disease

1. Receptor control mechanism: - In 7 transmembrane receptor, GRK phosphorylates the receptor and then Beta

arrestin can bind to the receptor for inhabitation of the signal cascade. Phosphorylated Beta arrestin turns off the signal.

- Down regulation of the gene expression level and internalization of receptor by endocytosis.

2. Receptor disease(Pathology of receptor, mutation, malfunction):

a) Leptin receptor mutation leads to resistant to leptin which lead to obesity. b) Tyrosine kinase receptor mutation (EGF, VEGF) leads to tumor growth because it might

cause receptor hyperfunction and lead to uncontrollable cell cycle (gain of function mutation). VEGF is site for the chemotherapy, while vascular supply to the tumor will be inhibited by chemotherapy treatment.

c) Androgens are required for the development of normal prostate and prostate cancer, through their action via the androgen receptor (AR). Androgen receptor malfunction leads to prostate tumor, and female phenotype in male (loss of function mutation)

d) In leukocyte adhesion disease, 2-intergrin receptor defect leads to high susceptibility against infection. (loss of function mutation)

e) In myasthenia gravis, autoantibody attack against nicotinic acetylcholine receptor leads to paralysis of the muscle function.

3. Receptor and disease (Receptor normal, extrinsic factor which leads to pathology):

- 1 agonist stimulation to adrenalin receptor leads to chronic hypertension due to high catecholamine level.

- Pheochromocytoma, malignancy which leads to high level of catecholamine secretion due to activation of 1-receptor.

- For pharmacologic research, 1- and 2-adrenoceptor antagonist drugs have been very useful in the experimental exploration of autonomic nervous system function. In clinical therapeutics, nonselective antagonists are used in the treatment of pheochromocytoma (tumors that secrete catecholamines), and 1-selective antagonists are used in primary hypertension and benign prostatic hyperplasia.

- receptor antagonist drugs have been found useful in a much wider variety of clinical conditions and are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, glaucoma, and other conditions.

- Insulin, an agonist binds to insulin receptor lead to glucose uptake into cell, glycogen synthesis and protein synthesis, while insulin is anabolic hormone. Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation.

- Lack of stimulation of serotonin receptor leads to depression. Low level of catecholamine and serotonin cause depression. Nevertheless, the amine hypothesis has provided the major experimental models for the discovery of new antidepressant drugs. As a result, all currently available antidepressants, except bupropion, are classified as having their primary actions on the metabolism, reuptake, or selective receptor antagonism of serotonin, norepinephrine, or both.


29

In addtion, MAO inhibitor can be used to enhance catacroimine leve lat synaptic cleft.

B. Beta adrenoreceptor blockers

v All the clinically available beta blockers are competitive antagonists. v Cardioactive beta antagonists primarily block 1 receptors. v Although all beta blockers lower BP in hypertension, they do not induce postural

hypotension, because the -receptors remain functional v Beta blockers are also effective in treating angina, cardiac arrhythmias, myocardial

infarction, congestive heart failure, hyperthyroidism, and glaucoma, as well as serving in the prophylaxis of migraine headache.

1. Propanolol (non-selective beta antagonist):

a) Actions: - Cardiovascular: diminishes cardiac output, having both negative inotropic and

chronotropic effects. It directly depresses SA and AV activity - Peripheral vasoconstriction: preventing 2-mediated vasodilation. The reduction in

cardiac output leads to decreased BP. A gradual reduction of both systolic and diastolic BP in hypertensive patients is brought.

- Bronchoconstriction: can precipitate a respiratory crisis in patients with COPD or asthma.

- Increased Na+ retention: a decrease in renal perfusion, resulting in an increase in Na+ retention and plasma volume.

- Disturbances in glucose metabolism: decreased glycogenolysis and decreased glucagon secretion. If a patient with Type I diabetes is taking this drug, a pronounced hypoglycemia may occur after insulin injection. Beta-blockers also attenuate the normal physiologic response to hypoglycemia.

- Blocked action of isoproterenol: all beta-blockers have the ability to block the actions of isoproterenol on the cardiovascular system.

b) Therapeutic effects: - Hypertension. - Glaucoma: they neither affect the ability of the eye to focus for near vision nor

change pupil size, as do the cholinergic drugs. - Migraine: mechanism may depend on the blockade of catecholamine-induced

vasodilation in the brain vasulature. - Hyperthyroidism: effective in blunting the widespread sympathetic stimulation that

occurs in hyperthyroidism. - Angina pectoris: propanolol decreases the oxygen requirement of heart muscle and,

therefore, is effective in reducing the chest pain on exertion that ins common in angina.

- Myocardial infarction: they reduce infarct size and hasten recovery. The mechanism for these effects may be a blocking of the actions of circulating catecholamines.

c) Adverse effects: - Bronchoconstriction. - Arrhythmias: treatment with beta blockers should never be stopped quickly. - Sexual impairment. - Disturbances in metabolism.


30

- Drug interaction: those that stimulate its metabolism such as barbiturates, phenytoin and rifampin can decrease its effects.

2. Timolol and nadolol (non-selective beta antagonists): - They are both more potent than propranolol. - Nadolol has a very long duration of action. Timolol reduces the production of

aqueous humour in the eye; therefore, it is used topically in the treatment of chronic open-angle glaucoma and, occasionally, for systemic treatment of hypertension.

3. Acebutolol, atenolol, metoprolol, and esmolol (selective 1 antagonist):

- These antagonize 1 receptors at doses 50- to 100- fold less than those required to block 2 receptors.

- Actions: Lower BP in hypertension and increase exercise tolerance in angina. Esmolol has a very short lifetime due to metabolism of an ester linkage. It is

only given iv. The cardiospecific blockers have relatively little effect on pulmonary

function, peripheral resistance, and carbohydrate metabolism. - Therapeutic use in hypertension:

Useful in hypertensive patients with impaired pulmonary function. Cardioselective -blockers are useful in diabetic hypertensive patients who

are receiving insulin or oral hypoglycemic agents.

4. Pindolol and acebutolol (antagonists with partial agonist activity): a) Actions:

- Cardiovascular: these are not pure antagonists and have the ability to weakly stimulate both 1 and 2 receptors and are said to have intrinsic sympathomimetic activity (ISA). Yet, they inhibit stimulation by the more potent endogenous catecholamines epinephrine and NE.

- Decreased metabolic effects: blockers with ISA minimize the disturbances of lipid and carbohydrate metabolism that are seen with other blockers.

b) Therapeutic use in hypertension: - Effective in hypertensive patients with moderate bradycardia. - Carbohydrate metabolism is less affected. - Valuable in the treatment of diabetics.

5. Labetalol and carvedilol (antagonists of both - and - adrenoreceptors):

a) Actions: - These are reversible -blockers with concurrent 1-blocking actions that produce

peripheral vasodilation, thereby reducing BP. - Useful in treating hypertensive patients for whom increased peripheral vascular

resistance is undesirable. - These do not alter serum lipid or blood glucose levels. Carvedilol also decreases lipid

peroxidaion and vascular wall thickening, effects that have benefit in heart failure. b) Therapeutic use in hypertension:

- Labetalol is useful for treating the elderly or black hypertensive patient in whom increased peripheral vascular resistance is undesirable.


31

- Labetalol may be employed as an alternative to methyldopa in the treatment of pregnancy induced hypertension.

c) Adverse effects: orthostatic hypotension and dizziness are associated with 1 blockade. C. Treatment of MI especially the treatment of angina pectoris

1. General treatment: - Treatment is designed to relieve distress, reverse ischemia, limit infarct size, reduce

cardiac workload, and prevent and treat complications. - Treatment occurs simultaneously with diagnosis. - A reliable iv route must be established, O2 given, and continuous single-lead ECG

monitoring started. - Maintaining normal bowel function with stool softeners (e.g. bisacody) to prevent

straining is important.

2. Treatment of MI: a) Fibrinolytics (thrombolytics):

- Reperfusion using fibrinolytics is most effective if given in the first few minutes to hours after onset of MI.

- The goal is a door-to-needle time of 30-60min. - Greatest benefit occurs within 3h, but the drugs may be effective up to 12h. - Indications:

ST-segment elevation in 2 or more continuous leads. LBBB (not known to be old). Posterior MI (a large R wave in V1 and ST-segment depression in leads V1-

V4, confirmed with a 12-lead ECG). - Absolute contraindications:

Aortic dissection. Pericarditis. Previous hemorrhagic stroke (at any time). Previous ischemic stroke within 1y. Active internal bleeding (not menses). Intracranial tumour.

- Relative contraindications: BP > 180/110mmHg (after initial antihypertensive therapy). Trauma or major surgery within 4 weeks. Active peptic ulcer. Pregnancy. Bleeding diathesis. Current anticoagulation (INR>2). Prolonged CPR (>10min). Patients who previously received streptokinase or anistreplase are not given

that drug. - Streptokinase, and anistreplase: the former may induce allergic reactions,

especially if it has been used previously, and must be given by infusion over 30-60min; however, it has a low incidence of intracerebral hemorrhage and is relatively inexpensive.

- Tenecteplase (TNK) and Reteplase (rPA): reteplase has the highest risk of intracranial hemorrhage and a recanalization rate similar to that of tenecteplase, and it is expensive.


32

- Alteplase (rTPA) is given in an accelerated or fron-loaded dosage over 90min. Alteplase with concomitant Iv heparin improves patency, is non-allergic, has a higher recanalization rate than other fibrinolytics and is expensive.

- All given iv, are plasminogen activators: they convert single chain plasminogen to double chain plasminogen, which has fibrinolytic activity.

b) PCI: - If done within 3h of MI onset by experienced personnel, PCI is more effective than

fibrinolytics and is the preferred mode of reperfusion. - Primary: done without prior thrombolytic therapy. - Rescue: if thrombolytic therapy failed. - After PCI, especially if a stent is used, adjunctive therapy with abciximab is begun

and continued for 18-24h thereafter. c) Emergency CABG may be best for about 3-5% of patients who have complex coronary

anatomy

3. Treatment for angina pectoris: a) Nitroglycerin: sublingually one fresh tablet may be repeated 3-5min intervals. b) Long-acting nitrates:

- Isosorbide dinitrate (10-40mg orally) 3 times daily. - Isosorbide mononitrate (10-40mg orally) twice daily.

c) Beta blockers d) Calcium channel blocking agents e) Ranolazie. f) Platelet-inhibiting agents: clopidogrel 75mg daily.


33

TOPIC # 7 A. Desensitization, tachyphylaxis and tolerance

1. Desensitization: the receptors are still present but are unresponsive to the ligand. Another type of desensitization occurs when receptors are down-regulated. Or, the receptor can undergo endocytosis and is sequestered from further agonist interaction.

2. Tachyphylaxis: when repeated administration of a drug results in a diminished effect.

3. Tolerance: when a subject's reaction to a drug (such as

an opiate painkiller, benzodiazepine or other psychotropic drug) decrease so that larger doses are required to achieve the same effect. Drug tolerance can involve both psychological drug tolerance and physiological factors. Characteristics of drug tolerance: it is reversible, the rate depends on the particular drug, dosage and frequency of use, differential development occurs for different effects of the same drug. Physiological tolerance also occurs when an organism builds up a resistance to the effects of a substance after repeated exposure. This can occur with environmental substances, such as salt or pesticides.

B. Indirectly acting parasympathomimetics:

v There are two group of indirectly acting parasympathomimetics: reversible and irreversible.

v The reversible agents are no other drug but anticholinesterases, which can cleave Ach to acetate and choline. It can locate both on pre- and postsynaptic membrane. On the latter, it is membrane-bound. These agents can prolong the lifetime of a Ach produced endogenously at the cholinergic nerve endings.

v The irreversible agents are synthetic organophosphate compounds, which bind covalently to acetycholinesterase, permanently inactivating the enzyme.

1. Reversible indirectly acting parasympathomimetics:

a) Physostigmine: - Actions: not only the muscarinic and nicotinic sites of the ANS but also the nicotinic

receptors of the neuromuscular junction are stimulated. Its duration is about 2-4h. it is considered to be an immediate-acting agents.

- Therapeutic use: increasing intestinal and bladder motility, which serve as its therapeutic action in atony of either organ; producing miosis and spasm of accommodation as well as a lowering of intraocular pressure; being used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine.

- Adverse effects: convulsions, bradycardia, a fall in cardiac output, paralysis of skeletal muscle.

b) Neostigmine: - It is a synthetic compound (quaternary nitrogen), is more polar and does not enter

the CNS. - Its effect on skeletal muscle is greater than that of physostigmine. It can stimulate

contractility before it paralyzes. - It has a moderate duration of action, usually 30min to 2h. - It is used to stimulate the bladder and GIT. - It can be used in symptomatic treatment of myasthenia gravis.

http://en.wikipedia.org/wiki/Opiatehttp://en.wikipedia.org/wiki/Benzodiazepinehttp://en.wikipedia.org/wiki/Psychological_drug_tolerancehttp://en.wikipedia.org/wiki/Physiological_tolerance


34

- Adverse effects: salivation, flushing, decreased BP, nausea, abdominal pain, diarrhea, bronchospasm.

c) Pyridostigmine and ambenomium: - Used in the chronic management of myasthenia gravis. - Their duration of action are intermediate (3-6h and 4-8h, respectively).

d) Demercarium: - Used to treat chronic open-angle glaucoma (primarily in patients refractory to other

agents) and closed-angle glaucoma after irredectomy. - Used for the diagnosis and treatment of accommodative esotropia.

e) Edrophonium: - Actions are similar to those of neostigmine, except that it is more rapidly absorbed

and has a short duration of action of 10-20min. - Used in the diagnosis of myasthenia gravis.

f) Tacrine, donepezil, rivastigmine and galantamine: - Used in treatment of Alzheimers disease as possible remedies for the loss of

cognitive function. - Tacrine was the first but it has been replaced by the others because of its

hepatotoxicity. - GIT distress is their primary adverse effect.

2. Irreversible indirectly acting parasympathomimetic (echothiphate):

a) Mechanism of action: - It is an organophosphate that binds covalently via its phosphate group to the serine-

OH group at the active site of acetylcholinesterase. - The enzyme is permanently inactivated.

b) Actions: - Generalized cholinergic stimulation, paralysis of motor function. - Convulsion and intense miosis.

c) Therapeutic use: - An ophthalmic solution of the drug is used directly in the eye for the chronic

treatment of open-angle glaucoma. The effect may last for a week. However, it has the potential to cause cataract.

d) Reactivation of acetylcholinesterase: - Pralidoxime can reactivate inhibited acetylcholinesterase but is unable to penetrate

into the CNS. It is a weak acetylcholinesterase inhibitor and, at higher doses, may cause side effects similar to other acetylcholinesterase inhibitors.

C. Drugs used in the treatment of hyperlipidemias

v Types of genetic hyperlipidemia: (1) Type I (familial hyperchylomicronemia) (2) Type IIA (familial hypercholesterolemia), increasing LDL (3) Type IIB (familial combined (mixed) hyperlipidemia), increasing VLDL and LDL (4) Type III (familial dysbetalipoproteinemia), increasing IDL (5) Type IV (familial hypertriglyceridemia), increasing VLDL (6) Type V (familial mixed hypertriglyceridemia), increasing chylomicron and VLDL

1. HMG CoA reductase inhibitors:

This group of antihyperlipidemic agents inhibof cholesterol synthesis. They are the firstpatients with elevated LDL cholesterol.

Therapeutic benefits include plaque stabilization, improvement of coronary endothelial functioinflammatory activity.

a) Mechanism of action:- Inhibition of HMG CoA reductase:

Lovastatin, simvastatin, pravastatinrosuvastatin

Lovastatin drug; while

All compete effectively to inhibit HMG CoA reductase. Rosuvastatin

statin drugs.- Increase in LDL receptors: a reduction in plasma cholesterol, both by lowered

cholesterol synthesis and by increased catabolism of LDL. Decreases in triglyceride also occur.

b) Therapeutic use: - These drugs are effective in lowering plasma cholesterol levels i

hyperlipidemias.- Patients who are homozygous for familial hypercholesterolemia lack LDL receptors

and, therefore, benefit much less from treatment with these drugs.c) Pharmacokinetics:

- Pravastatin andadmimistration; oral doses of

HMG Co-A reductase inhibitors

- Atorvastatin

- Fluvastatin

- Lovastatin

- Pravastatin

- Rosuvastatin

- Simvastatin

Fibrates

- Fenofibrate

- Gemfibrozil


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HMG CoA reductase inhibitors: This group of antihyperlipidemic agents inhibits the first committed enzymatic step of cholesterol synthesis. They are the first-line and more effective treatment for patients with elevated LDL cholesterol. Therapeutic benefits include plaque stabilization, improvement of coronary endothelial function, inhibition of platelet thrombus formation, and antiinflammatory activity.

Mechanism of action: Inhibition of HMG CoA reductase:

Lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin rosuvastatin are analogs of HMG. Lovastatin and simvastatin are lactones that are hydrolyzed to the active drug; while pravastatin and fluvastatin are active. All compete effectively to inhibit HMG CoA reductase. Rosuvastatin and atorvastatin are the most potent LDL cholesterol lowering statin drugs.

in LDL receptors: a reduction in plasma cholesterol, both by lowered cholesterol synthesis and by increased catabolism of LDL. Decreases in triglyceride

These drugs are effective in lowering plasma cholesterol levels ihyperlipidemias. Patients who are homozygous for familial hypercholesterolemia lack LDL receptors and, therefore, benefit much less from treatment with these drugs.

and fluvastatin are almost completely absorbed

admimistration; oral doses of lovastatin and simvastatin are from 30

Antihyperlipidemic drugs

Fenofibrate

Gemfibrozil

Niacin Bile acid sequestrants

- Colesevelam

- Colestipol

- Cholestyramine

Cholesterol absorption inhibitors

- Ezetimibe


its the first committed enzymatic step line and more effective treatment for

Therapeutic benefits include plaque stabilization, improvement of coronary n, inhibition of platelet thrombus formation, and anti-

, atorvastatin, fluvastatin and

are lactones that are hydrolyzed to the active

are the most potent LDL cholesterol lowering

in LDL receptors: a reduction in plasma cholesterol, both by lowered cholesterol synthesis and by increased catabolism of LDL. Decreases in triglyceride

These drugs are effective in lowering plasma cholesterol levels in all types of

Patients who are homozygous for familial hypercholesterolemia lack LDL receptors and, therefore, benefit much less from treatment with these drugs.

are almost completely absorbed after oral are from 30-50% absorbed.

Cholesterol absorption inhibitors

Ezetimibe


36

- Due to 1st pass extraction, the primary action of these drugs in on the liver. Excretion takes place principally through the bile and feces.

- Their half-lives range from 1.5-2h. d) Adverse effects: (only a few)

- Liver function should be evaluated carefully before administering these drugs. - Muscle: myopathy and rhabdomyolysis have been reported only rarely. Most of

these cases, patients usually suffered from renal insufficiency or were taking drugs such as cyclosporine, itraconazole, erythromycin, gemfibrozil, or niacin.

- Drug interactions: may also increase warfarin levels, important to evaluate INR times frequently.

- Contraindications: pregnancy and in nursing mothers. These drugs should not be used in children or teenagers.

2. Niacin (nicotinic acid): can reduce LDL by 10-20% and is the most effective agent for

increasing HDL. a) Mechanism of action:

- At gram doses, niacin strongly inhibits lipolysis in adipose tissue and causes a decrease in liver triacylglycerol synthesis, which is required for VLDL production, resulting in a decreased plasma LDL concentration.

- By boosting secretion of tissue plasminogen activator and lowering the level of plasma fibrinogen, niacin can reverse some of the endothelial cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis.

b) Therapeutic uses: - Particularly useful in the treatment of familial hyperlipidemia. - Also used to treat other severe hypercholesterolemias. - The most potent antihyperlipidemic agent for raising plasma HDL levels.

c) Pharmacokinetics: - Administered orally and converted in the body to nicotinamide, which is

incorporated into the cofactor NAD. - Other metabolites are excreted in the urine.

d) Adverse effects: - Most common side effects are intense cutaneous flush and pruritus. - The sustained-release formulation of niacin, which is taken once daily at bedtime,

reduces bothersome initial adverse effects. - Nausea, abdominal pain. - It also inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia

and gout. - Impaired glucose tolerance and heptotoxicity.

3. The fibrates: Fenofibrate and gemfibrozil

a) Mechanism of action: - The peroxisome proliferator-activated receptors (PPARs) are members of the

nuclear receptor supergene family that regulates lipid metabolism. Activated, they bind to peroxisome proliferator response elements that regulate the expression of genes encoding for proteins involved in lipoprotein structure and function. Fibrate-mediated gene expression ultimately leads to decreased triacylglycerol


37

concentrations by increasing the expression of lipoprotein lipase and decreasing apo CII concentration.

- It also increases the expression of apo AI and apo AII. b) Therapeutic uses:

- Used in the treatment of hypertriacylglycerolemias, causing a significant decrease in plasma triacylglycerol levels.

- Particularly useful in treating Type III hyperlipidemia. - Patients with type IV and V who do not respond to diet or other drugs may also

benefit from treatment with these agents. c) Pharmacokinetics:

- Both completely absorbed after an oral dose. - Distribute widely, bound to albumin. - Both undergo extensive biotransformation and are excreted in the urine as their

glucuronide conjugates. d) Adverse effects:

- GI effects. - Lithiasis is due to the increase biliary cholesterol excretion. - Muscle: myositis can occur with both drugs. - Drug interactions: both compete with the coumarin anticoagulants for binding sites

on plasma proteins, thus transiently potentiating anticoagulant activity. e) Contraindications:

- Pregnant or lactating women. - Patients with severe hepatic and renal dysfunction. - Patients with preexisting gallbladder disease.

4. Bile acid-binding resins:

a) Mechanism of action: - Cholestyramine, colestipol and colesevelam are anion-exchange resins that bind

negatively charged bile acids and bile salts in the small intestine. - The complex is excreted in the feces, thus preventing the bile acids from returning

to the liver by the enterohepatic circulation, causing the hepatocytes to increase conversion of cholesterol to bile acids, resulting in a replenished supply of these compounds.

- Intracellular cholesterol concentration decreases, increasing hepatic uptake of cholesterol containing LDL particles, leading to a fall in plasma LDL.

b) Therapeutic uses: - The drugs of choice (often in combination with diet or niacin) in treating Type IIa

and Type IIb hyperlipidemias. - Cholestyramine can also relieve pruritus caused by accumulation of bile acids in

patients with biliary obstruction. c) Pharmacokinetics:

- Insoluble in water and are very large; therefore, taken orally and neither absorbed nor metabolically altered by the intestine.

- Totally excreted in the feces. d) Adverse effects:

- GI effects: constipation, nausea, flatulence. - Impaired absorptions: at high doses, cholestyramine and colestipol impair the

absorption of the fat soluble vitamins A, D, E and K.


38

- Drug interactions: cholestyramine and colestipol interfere with the intestinal absorption of many drugs (tetracycline, Phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin and thiazide diuretics). Drugs should be taken at least 1-2h before, or 4-6h after, the bile-acide binding resins.

5. Cholesterol absorption inhibitors:

- Ezetimibe selectively inhibits intestinal absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver.

- It lowers LDL cholesterol by 17% and triacylglycerols by 6%, increases HDL cholesterol by 1.3%.

- It is primarily metabolized in the small intestine and liver via glucuronide conjugation, with subsequent biliary and renal excretion.

- Its half-life of approximately 22h. - No clinically meaningful effect on fat-soluble vitamins. - Patients with moderate to severe hepatic insufficiency should not be treated with

ezetimibe.


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TOPIC # 8 A. The movement of drugs through biological membranes

1. Routes of drug administration: - Route of administration is determined primarily by the properties of the drug. - Two major routes: enteral and parenteral.

Type of route Benefits Site of administration First pass

Ente

ral

Oral - Easily self administered

By mouth Yes

Sublingual - Diffuse into the capillary network directly

Under the tongue No

Pare

nter

al

Intravenous - A rapid effect and a maximal degree of control over the circulating levels of the drug

Injection into venous system

No

Intramuscular - Dissolves slowly, providing a sustained dose over an extended period of time

Into muscle layer in aqueous solution or specialized depot preparations

No

Subcutaneous - Minimizes the risks associated with intravascular injection

Under the skin No

Oth

ers

Inhalation - Rapid delivery of a drug across the large surface area

Through the mouth into the trachea

No

Intranasal - Involves admimistration of drugs directly into the nose

Into the nose No

Intrathecal/intraventricular Into the CSF No Topical - Achieve

systemic effects by application of drugs to the skin

Usually a transdermal patch

No

Rectal - For vomiting or unconscious patients

Given into the anal 50% absorbed into portal circulation


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2. Absorption of drugs: a) Transport of a drug from the GI tract:

- Passive diffusion: The driving force is the concentration gradient across a membrane

separating 2 body compartments. This process does not involve a carrier, is not saturable, and shows a low

structural specificity. Lipid-soluble drugs readily move across most biologic membrane due to

their solubility in the membrane bilayers. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores.

Other agents can enter the cell through carrier proteins via a process called facilitated diffusion. This type of diffusion does not require energy, can be saturated, and may be inhibited.

- Active transport: Involves specific carrier proteins that span the membrane. It is energy-dependent and is driven by the hydrolysis of ATP. It is capable of moving drugs against a concentration gradient. The process shows saturation kinetics for the carrier.

- Endocytosis and exocytosis: Transport drugs of exceptionally large size across the cell membrane. For example, vitamin B12

b) Effect of pH on drug absorption: - Most drugs are either weak acids or bases.

HA H++A- BH+B+H+

- Passage of an uncharged drug through a membrane is more readily then if it is charged. Therefore, in weak acids, uncharged HA can permeate through membranes whole for weak bases, only uncharged form B penetrates through.

- To determine how much drug will be found on either side of a membrane, the following equation can be employed:

For acids: !

"

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