Sheet 7 Adrenergic antagonists.pptx

Adrenoceptor antagonists Pharmacology Sheet 7 Adrenergic 1 anatagonisits Dr Salem Abukres Pharmacology Sheet 7 Adrenergic 2 anatagonisits Dr Salem Abukres CLASSIFICATION OF BLOCKING DRUGS 1- α-RECEPTOR BLOCKING AGEN...

Adrenoceptor antagonists Pharmacology Sheet 7 Adrenergic 1 anatagonisits Dr Salem Abukres Pharmacology Sheet 7 Adrenergic 2 anatagonisits Dr Salem Abukres CLASSIFICATION OF BLOCKING DRUGS 1- α-RECEPTOR BLOCKING AGENTS: The clinically important α-blockers fall primarily into three chemical groups: Haloalkylamines ( e.g., phenoxybenzamine) Imidazolines (e.g., phentolamine) Quinazoline derivatives (e.g., prazosin (Minipress), trimazosin (Cardovar), terazosin (Hytrin), and doxazosin (Cardura)). Of these three classes of α-adrenoceptor antagonists, the quinazoline compounds are of greatest clinical utility. The use of the haloalkylamines and imidazolines has diminished in recent years because they lack selectivity for α1- and α2-receptors. Pharmacology Sheet 7 Adrenergic 3 anatagonisits Dr Salem Abukres Mechanism of Action (for Quinazolines): The α-antagonism produced by prazosin and the other quinazoline derivatives is of the equilibrium-competitive type. The drugs are selective for α1-adrenoceptors, so that at usual therapeutic concentrations there is little or negligible antagonism of α2-adrenoceptors. Most of the pharmacological effects of prazosin are directly attributable to α1-antagonism, At high doses the drug can cause vasodilation by a direct effect on smooth muscle independent of α-receptors. This action appears to be related to an inhibition of phosphodiesterase enzyme. Pharmacology Sheet 7 Adrenergic 4 anatagonisits Dr Salem Abukres  Pharmacological Actions: Antagonize vascular smooth muscle contraction that is caused by either sympathetic nervous activity or the action of adrenomimetics. Postural hypotension during chronic treatment is also less of a problem. Also, increases in heart rate, contractile force, and plasma renin activity, which normally occur after the use of vasodilators and α-blockers, are much less prominent following chronic treatment with prazosin, because it blocks responses mediated by postsynaptic α1- receptors but has no effect on the presynaptic α2-receptors Pharmacology Sheet 7 Adrenergic 5 anatagonisits Dr Salem Abukres Clinical Uses: 1- Prazosin is effective in reducing all grades of hypertension. The antihypertensive actions of prazosin are considerably potentiated by co-administration of thiazides or other types of antihypertensive drugs. 2- Since prazosin does not significantly influence blood uric acid or glucose levels, it can be used in hypertensive patients whose condition is complicated by diabetes mellitus or gout. 3- Prazosin and other α-antagonists find use in the management of benign prostatic obstruction. 4- Reduces the symptoms of obstruction and the urinary urgency that occurs at night. Pharmacology Sheet 7 Adrenergic 6 anatagonisits Dr Salem Abukres Clinical Uses: 1- Prazosin is effective in hypertension. 2- Since prazosin does not significantly influence blood uric acid or glucose levels, it can be used in hypertensive patients whose condition is complicated by diabetes mellitus or gout. 3- Prazosin and other α-antagonists find use in the management of benign prostatic obstruction, especially in patients who are not candidates for surgery. 4- Reduces the symptoms of obstruction and the urinary urgency that occurs at night. Pharmacology Sheet 7 Adrenergic 7 anatagonisits Dr Salem Abukres Adverse Effects: Symptoms of postural hypotension, such as dizziness and light-headedness, are the most commonly reported side effects associated with prazosin therapy. These effects occur most frequently during initial treatment and when the dosage is sharply increased. Postural hypotension seems to be more pronounced during Na-deficiency, as may occur in patients on a low-salt diet or being treated with diuretics, β- blockers, or both. Pharmacology Sheet 7 Adrenergic 8 anatagonisits Dr Salem Abukres Pharmacology Sheet 7 Adrenergic 9 anatagonisits Dr Salem Abukres 2- β-ADRENOCEPTOR BLOCKING AGENTS: Propranolol: a nonselective β-antagonist, was the first to be introduced and is the prototypical drug with which the others are compared. Metoprolol: was the first β1-selective drug. Timolol: the first β-blocker approved for ophthalmic use. Their structural similarity accounts for the greater specificity of action exhibited by the β-receptor blocking drugs than by the α-adrenoceptor blocking drugs. Pharmacology Sheet 7 Adrenergic 10 anatagonisits Dr Salem Abukres Mechanism of Action: All of the β-blockers exert equilibrium-competitive antagonism of the actions of catecholamines and other adrenomimetics at β-receptors. Probably the best recognized action of these compounds that is not mediated by a β-receptor is depression of cellular membrane excitability. This effect has been described as a membrane- stabilizing action, a quinidine like effect, or a local anesthetic effect. Because the β-receptors of the heart are primarily of the β1 type and those in the pulmonary and vascular smooth muscle are β2 receptors, β1-selective antagonists are frequently referred to as cardioselective blockers. Pharmacology Sheet 7 Adrenergic 11 anatagonisits Dr Salem Abukres Pharmacological Actions: 1- The most important actions of the β-blocking drugs are on the cardiovascular system. β-Blockers decrease heart rate, myocardial contractility, cardiac output, and conduction velocity within the heart. After acute administration, blood pressure is only slightly altered. 2- Chronic administration of β-blockers, however, results in a reduction of blood pressure, and this is the reason for their use in primary hypertension. 3- useful for the prophylactic treatment of angina pectoris, Pharmacology Sheet 7 Adrenergic 12 anatagonisits Dr Salem Abukres Pharmacological Actions: The glycogenolytic and lipolytic actions of endogenous catecholamines are mediated by β-receptors and are subject to blockade by β-blockers. This metabolic antagonism exerted by the β-blockers is particularly pronounced if the levels of circulating catecholamines have been increased reflexively in response to hypoglycemia. These agents therefore must be used with caution in patients susceptible to hypoglycemia (e.g., diabetics treated with insulin). Pharmacology Sheet 7 Adrenergic 13 anatagonisits Dr Salem Abukres Pharmacological Actions: Propranolol increases airway resistance by antagonizing β2- receptor–mediated bronchodilation. Although the resulting bronchoconstriction is not a great concern in patients with normal lung function, it can be quite serious in the asthmatic. The cardioselective β-blockers produce less bronchoconstriction than do the nonselective antagonists. β-Blockers can reduce intraocular pressure in glaucoma and ocular hypertension. The mechanism is believed to be related to a decreased production of aqueous humor. Pharmacology Sheet 7 Adrenergic 14 anatagonisits Dr Salem Abukres Clinical Uses: 1- The β-receptor blocking agents have widespread and important uses in the management of cardiac arrhythmias, angina pectoris, and hypertension. 2- The β-blockers have been shown to be quite useful in the long-term management of patients with mild to moderate heart failure. The β-blockers also offer proven benefit in preventing the recurrence of a myocardial infarction (MI). 3-Hyperthyroidism: They are most logically employed in the management of hyperthyroid crisis, in the preoperative preparation for thyroidectomy, and during the initial period of administration of specific antithyroid drugs. Pharmacology Sheet 7 Adrenergic 15 anatagonisits Dr Salem Abukres 4- Glaucoma: They reduce intraocular pressure in patients with chronic open-angle glaucoma and ocular hypertension. Timolol has a somewhat greater ocular hypotensive effect than do the others. 5- Anxiety States: Patients with anxiety have a variety of psychic and somatic symptoms.The peripheral manifestations of anxiety may include a number of symptoms (e.g., palpitations) that are due in part to over activity of the sympathetic nervous system. 6- Migraine: The β-blockers may offer some value in the prophylaxis of migraine headache, possibly because a blockade of craniovascular β-receptors results in reduced vasodilation. The painful phase of a migraine attack is believed to be produced by vasodilation. Pharmacology Sheet 7 Adrenergic 16 anatagonisits Dr Salem Abukres Adverse Effects and Contraindications: Although β-blockers prevent an increase in heart rate and cardiac output resulting from an activation of the autonomic nervous system, these effects may not be troublesome in patients with adequate or marginal cardiac reserve. However, they can be life threatening for a patient with congestive heart failure. Caution must be exercised in the use of β-blockers in obstructive airway disease, since these drugs promote further bronchoconstriction. β-Blockers potentiate hypoglycemia by antagonizing the catecholamine-induced mobilization of glycogen. Pharmacology Sheet 7 Adrenergic 17 anatagonisits Dr Salem Abukres Adverse Effects and Contraindications: They produce a number of central effects, it is not clear whether these effects are due to blockade of central β- receptors. After high doses, patients may have hallucinations, nightmares, insomnia, and depression. Topical application of timolol to the eye is well tolerated, and the incidence of side effects, which consist of burning or dryness of the eyes, is reported to be 5 to 10%. Pharmacology Sheet 7 Adrenergic 18 anatagonisits Dr Salem Abukres 3- DRUGS WITH COMBINED α- AND β- BLOCKING ACTIVITY: A) Labetalol Labetalol possesses both α- blocking and β-blocking activity and is approximately one- third as potent as propranolol as a β-blocker and one-tenth as potent as phentolamine as an α-blocker. The ratio of β- to α-activity is about 3:1 when labetalol is administered orally and about 7: 1 when it is administered intravenously. Pharmacology Sheet 7 Adrenergic 19 anatagonisits Dr Salem Abukres 3- DRUGS WITH COMBINED α- AND β-BLOCKING ACTIVITY: A) Labetalol Mechanism of Action: Labetalol produces equilibrium-competitive antagonism at β-receptors but does not exhibit selectivity for β1- or β2- receptors. The α-blockade produced by labetalol is also of the equilibrium-competitive type. In a manner similar to prazosin, labetalol exhibits selectivity for α1-receptors. Labetalol appears to produce relaxation of vascular smooth muscle not only by α-blockade but also by a partial agonist effect at β2-receptors. Pharmacology Sheet 7 Adrenergic 20 anatagonisits Dr Salem Abukres Pharmacological Actions: The most common hemodynamic effect of acutely administered labetalol in humans is a decrease in peripheral vascular resistance and blood pressure without an appreciable alteration in heart rate or cardiac output. This pattern differs from that seen following administration with either a conventional α- or β-blocker. Acute administration of a β-blocker produces a decrease in heart rate and cardiac output with little effect on blood pressure, while acute administration of an α- blocker leads to a decrease in peripheral vascular resistance and a reflexively initiated increase in cardiac rate and output. Pharmacology Sheet 7 Adrenergic 21 anatagonisits Dr Salem Abukres Clinical Uses: 1- Hypertension Labetalol is useful for the chronic treatment of primary hypertension. It can be used alone but is more often employed in combination with other antihypertensive agents. Labetalol also has been used intravenously for the treatment of hypertensive emergencies. And may be useful for patients with coexisting hypertension and anginal pain due to ischemia. 2- pheochromocytoma. Labetalol, because it possesses both α- and β-blocking activity, is useful for the preoperative management of patients with a pheochromocytoma. Pharmacology Sheet 7 Adrenergic 22 anatagonisits Dr Salem Abukres