রাজশাহী বিশ্ববিদ্যালয়ের ফার্মেসী বিভাগের বি. ফার্ম (সম্মান) তৃতীয় বর্ষের সিলেবাস অনুযায়ী প্রণিতঃ
Syllabus
Drug Acting on ANS:
a) (i) Parasympathomimetic agents: Acetyl choline, Methacoline, Carbachol. (ii) Sympathomimetic drugs: Epinephrine, norepinephrine. (iii) Anticholinesterase agents: Physostigmine, Edrophonium. Organophosphorous compounds.
b) (i) Antimuscarinic Agents or Atropine Drugs: atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide. (ii) Drugs inhibiting adrenergic nerves and structures innervated by them, Adrenergic blocking agents.
c) Ganglion Stimulating and Blocking Agents.
β-Adrenoceptor antagonists
Drugs in this category share the common feature of antagonizing the effects of catecholamines at β adrenoceptors. Beta-blocking drugs occupy β receptors and competitively reduce receptor occupancy by catecholamines and other β agonists. Most β-blocking drugs in clinical use are pure antagonists; ie, the occupancy of a β receptor by such a drug causes no activation of the receptor. However, some are partial agonists; ie, they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol. Partial agonists inhibit the activation of β receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. Another major difference among the many β-receptor-blocking drugs concerns their relative affinities for β1 and β2 receptors. Some of these antagonists have a higher affinity for β1 than for β2 receptors, and this selectivity may have important clinical implications. Since none of the clinically available β receptor antagonists are absolutely specific for β1 receptors, the selectivity is dose-related, ie, it tends to diminish at higher drug concentrations.
Other major differences among β antagonists relate to their pharmacokinetic characteristics and local anesthetic membrane-stabilizing effects.
All the clinically available β-blockers are competitive antagonists. Nonselective β-blockers act at both β1 and β2 receptors, whereas cardioselective β-antagonists primarily block β1 receptors. These drugs also differ in intrinsic sympathomimetic activity, in central nervous system (CNS) effects, and in pharmacokinetics. Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension because the α-adrenoceptors remain functional; therefore, normal sympathetic control of the vasculature is maintained. β-blockers are also effective in treating angina, cardiac arrhythmias, myocardial infarction, and glaucoma, as well as serving in the prophylaxis of migraine headaches.
Drug Acting on ANS:
a) (i) Parasympathomimetic agents: Acetyl choline, Methacoline, Carbachol. (ii) Sympathomimetic drugs: Epinephrine, norepinephrine. (iii) Anticholinesterase agents: Physostigmine, Edrophonium. Organophosphorous compounds.
b) (i) Antimuscarinic Agents or Atropine Drugs: atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide. (ii) Drugs inhibiting adrenergic nerves and structures innervated by them, Adrenergic blocking agents.
c) Ganglion Stimulating and Blocking Agents.
β-Adrenoceptor antagonists
Drugs in this category share the common feature of antagonizing the effects of catecholamines at β adrenoceptors. Beta-blocking drugs occupy β receptors and competitively reduce receptor occupancy by catecholamines and other β agonists. Most β-blocking drugs in clinical use are pure antagonists; ie, the occupancy of a β receptor by such a drug causes no activation of the receptor. However, some are partial agonists; ie, they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol. Partial agonists inhibit the activation of β receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. Another major difference among the many β-receptor-blocking drugs concerns their relative affinities for β1 and β2 receptors. Some of these antagonists have a higher affinity for β1 than for β2 receptors, and this selectivity may have important clinical implications. Since none of the clinically available β receptor antagonists are absolutely specific for β1 receptors, the selectivity is dose-related, ie, it tends to diminish at higher drug concentrations.
Other major differences among β antagonists relate to their pharmacokinetic characteristics and local anesthetic membrane-stabilizing effects.
All the clinically available β-blockers are competitive antagonists. Nonselective β-blockers act at both β1 and β2 receptors, whereas cardioselective β-antagonists primarily block β1 receptors. These drugs also differ in intrinsic sympathomimetic activity, in central nervous system (CNS) effects, and in pharmacokinetics. Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension because the α-adrenoceptors remain functional; therefore, normal sympathetic control of the vasculature is maintained. β-blockers are also effective in treating angina, cardiac arrhythmias, myocardial infarction, and glaucoma, as well as serving in the prophylaxis of migraine headaches.
SAR
The O-CH2 group between aromatic ring and the ethylamino side chain is responsible for the antagonistic property.
Replacement of catechol hydroxyl group with chlorine or phenyl ring retains the beta blocking activity.
N,N- di substitution decrease beta blocking activity. Activity is maintained when phenylethyl, hydroxyl phenyl ethyl or methoxy phenyl ethyl groups are added to amine as a part of molecule.
The two carbon side chain is essential for the activity.
Nitrogen atom should be of secondary amine for optimum beta blocking activity.
The carbon side chain having hydroxyl group must be S- configuration for optimum affinity to beta receptor.(Ex- Levobunolol, Timolol)
The aryloxy propanolamines are more potent than aryl ethanolamines.
Replacement of ethereal oxygen in aryloxy propanolamines with S, CH2 or N-CH3 is decreased the beta blocking activity.
The most effective substituents at amino group is isopropyl and tertiary butyl group.
The aromatic portion of the molecules could be varied with good activity.
Converting the aromatic portion to phenanthrene or anthracene decrease the activity.
Cyclic alkyl substituents are better than corresponding open chain substituents at nitrogen atom of amine.
Alpha methyl group at side chain decrease activity.
PROPRANOLOL: A NONSELECTIVE β-ANTAGONIST
Propranolol is the prototype β-adrenergic antagonist and blocks both β1 and β2 receptors. Sustained release preparations for once-a-day dosing are available.
Propranolol was the first β-blocker shown to be effective in hypertension and ischemic heart disease. It is now clear that all β-adrenoceptor-blocking agents are very useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, β-blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality in patients with heart failure, and they are particularly advantageous for treating hypertension in that population.
The O-CH2 group between aromatic ring and the ethylamino side chain is responsible for the antagonistic property.
Replacement of catechol hydroxyl group with chlorine or phenyl ring retains the beta blocking activity.
N,N- di substitution decrease beta blocking activity. Activity is maintained when phenylethyl, hydroxyl phenyl ethyl or methoxy phenyl ethyl groups are added to amine as a part of molecule.
The two carbon side chain is essential for the activity.
Nitrogen atom should be of secondary amine for optimum beta blocking activity.
The carbon side chain having hydroxyl group must be S- configuration for optimum affinity to beta receptor.(Ex- Levobunolol, Timolol)
The aryloxy propanolamines are more potent than aryl ethanolamines.
Replacement of ethereal oxygen in aryloxy propanolamines with S, CH2 or N-CH3 is decreased the beta blocking activity.
The most effective substituents at amino group is isopropyl and tertiary butyl group.
The aromatic portion of the molecules could be varied with good activity.
Converting the aromatic portion to phenanthrene or anthracene decrease the activity.
Cyclic alkyl substituents are better than corresponding open chain substituents at nitrogen atom of amine.
Alpha methyl group at side chain decrease activity.
PROPRANOLOL: A NONSELECTIVE β-ANTAGONIST
Propranolol is the prototype β-adrenergic antagonist and blocks both β1 and β2 receptors. Sustained release preparations for once-a-day dosing are available.
Propranolol was the first β-blocker shown to be effective in hypertension and ischemic heart disease. It is now clear that all β-adrenoceptor-blocking agents are very useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, β-blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality in patients with heart failure, and they are particularly advantageous for treating hypertension in that population.Mechanism & Sites of Action
Propranolol's efficacy in treating hypertension as well as most of its toxic effects result from nonselective β-blockade. Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Other β-blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities.
Beta-blockade in brain, kidney, and peripheral adrenergic neurons has been proposed as contributing to the antihypertensive effect observed with β-receptor blockers. In spite of conflicting evidence, the brain appears unlikely to be the primary site of the hypotensive action of these drugs, because some β-blockers that do not readily cross the blood-brain barrier (eg, nadolol) are nonetheless effective antihypertensive agents.
Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β1-receptors). It is likely that propranolol's effect is due in part to depression of the renin-angiotensinaldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic β-adrenoceptors to reduce sympathetic vasoconstrictor nerve activity. In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension.
Propranolol's efficacy in treating hypertension as well as most of its toxic effects result from nonselective β-blockade. Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Other β-blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities.
Beta-blockade in brain, kidney, and peripheral adrenergic neurons has been proposed as contributing to the antihypertensive effect observed with β-receptor blockers. In spite of conflicting evidence, the brain appears unlikely to be the primary site of the hypotensive action of these drugs, because some β-blockers that do not readily cross the blood-brain barrier (eg, nadolol) are nonetheless effective antihypertensive agents.
Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β1-receptors). It is likely that propranolol's effect is due in part to depression of the renin-angiotensinaldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic β-adrenoceptors to reduce sympathetic vasoconstrictor nerve activity. In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension.
Pharmacokinetics
Most of the drugs in this class are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available.
Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low 30 (dose dependent), elimination half-life 3.5–6 hours. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition.
The β-antagonists are rapidly distributed and have large volumes of distribution. Propranolol is quite lipophilic and readily cross the blood-brain barrier. Most antagonists have half-lives in the range of 3–10 hours. Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine.
Most of the drugs in this class are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available.
Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low 30 (dose dependent), elimination half-life 3.5–6 hours. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition.
The β-antagonists are rapidly distributed and have large volumes of distribution. Propranolol is quite lipophilic and readily cross the blood-brain barrier. Most antagonists have half-lives in the range of 3–10 hours. Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine.
Dosage
Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol's β-blocking effect. Measures of these responses may be used as guides in regulating dosage. Propranolol can be administered once or twice daily.
Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol's β-blocking effect. Measures of these responses may be used as guides in regulating dosage. Propranolol can be administered once or twice daily.
Toxicity
The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial β-receptors. The most important of these predictable extensions of the β-blocking action occur in patients with bradycardia or cardiac conduction disease, asthma, peripheral vascular insufficiency, and diabetes. When propranolol is discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, or increase of blood pressure. Myocardial infarction has been reported in a few patients. Although the incidence of these complications is probably low, propranolol should not be discontinued abruptly. The withdrawal syndrome may involve up-regulation or supersensitivity of β-adrenoceptors.
Pharmacological Actions
Cardiovascular: Propranolol diminishes cardiac output, having both negative inotropic and chronotropic effects. It directly depresses sino-auricular and atrioventricular activity. The resulting bradycardia usually limits the dose of the drug. Cardiac output, work, and oxygen consumption are decreased by blockade of β1 receptors; these effects are useful in the treatment of angina. The β-blockers are effective in attenuating supraventricular cardiac arrhythmias but are generally not effective against ventricular arrhythmias (except those induced by exercise).
Peripheral vasoconstriction: Blockade of β receptors prevents β2-mediated vasodilation. The reduction in cardiac output leads to decreased blood pressure. This hypotension triggers a reflex peripheral vasoconstriction, which is reflected in reduced blood flow to the periphery. On balance, there is a gradual reduction of both systolic and diastolic blood pressures in hypertensive patients. No postural hypotension occurs, since the β-adrenergic receptors that control vascular resistance are unaffected.
Bronchoconstriction: Blocking β1 and β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle. This can precipitate a respiratory crisis in patients with chronic obstructive pulmonary disease or asthma. β-Blockers are thus contraindicted in patients with asthma.
Increased Na+ retention: Reduced blood pressure causes a decrease in renal perfusion, resulting in an increase in Na+ retention and plasma volume. In some cases this compensatory response tends to elevate the blood pressure. For these patients, β-blockers are often combined with a diuretic to prevent Na+ retention.
Disturbances in glucose metabolism: β blockade leads to decreased glycogenolysis and decreased glucagon secretion. Therefore, if an insulin-dependent diabetic is to be given propranolol, very careful monitoring of blood glucose is essential, since pronounced hypoglycemia may occur after insulin injection. β -Blockers also attenuate the normal physiologic response to hypoglycemia.
The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial β-receptors. The most important of these predictable extensions of the β-blocking action occur in patients with bradycardia or cardiac conduction disease, asthma, peripheral vascular insufficiency, and diabetes. When propranolol is discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, or increase of blood pressure. Myocardial infarction has been reported in a few patients. Although the incidence of these complications is probably low, propranolol should not be discontinued abruptly. The withdrawal syndrome may involve up-regulation or supersensitivity of β-adrenoceptors.
Pharmacological Actions
Cardiovascular: Propranolol diminishes cardiac output, having both negative inotropic and chronotropic effects. It directly depresses sino-auricular and atrioventricular activity. The resulting bradycardia usually limits the dose of the drug. Cardiac output, work, and oxygen consumption are decreased by blockade of β1 receptors; these effects are useful in the treatment of angina. The β-blockers are effective in attenuating supraventricular cardiac arrhythmias but are generally not effective against ventricular arrhythmias (except those induced by exercise).
Peripheral vasoconstriction: Blockade of β receptors prevents β2-mediated vasodilation. The reduction in cardiac output leads to decreased blood pressure. This hypotension triggers a reflex peripheral vasoconstriction, which is reflected in reduced blood flow to the periphery. On balance, there is a gradual reduction of both systolic and diastolic blood pressures in hypertensive patients. No postural hypotension occurs, since the β-adrenergic receptors that control vascular resistance are unaffected.
Bronchoconstriction: Blocking β1 and β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle. This can precipitate a respiratory crisis in patients with chronic obstructive pulmonary disease or asthma. β-Blockers are thus contraindicted in patients with asthma.
Increased Na+ retention: Reduced blood pressure causes a decrease in renal perfusion, resulting in an increase in Na+ retention and plasma volume. In some cases this compensatory response tends to elevate the blood pressure. For these patients, β-blockers are often combined with a diuretic to prevent Na+ retention.
Disturbances in glucose metabolism: β blockade leads to decreased glycogenolysis and decreased glucagon secretion. Therefore, if an insulin-dependent diabetic is to be given propranolol, very careful monitoring of blood glucose is essential, since pronounced hypoglycemia may occur after insulin injection. β -Blockers also attenuate the normal physiologic response to hypoglycemia.
