1 Chapter 11 Adrenoceptor Antagonist Drugs Cao Yongxiao 曹永孝 Department of Pharmacology

2 receptors and prevent their activation by catecholamines and related agonists. Drugs blocking adrenoceptors vary dramatically according to the drug’s selectivity for αand βreceptors. Their major effect is to occupy eitherα, or β 西安交大医学院药理学系 曹永孝

3 Nonselectiveαantagonists can treat pheochromocytoma (secrete catecholamines). α 1 -selective antagonists are used in hypertension and benign prostatic hyperplasia (BPH). 西安交大医学院药理学系 曹永孝

4 Beta-receptor antagonist drugs are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, and other conditions. 西安交大医学院药理学系 曹永孝

5 I BASIC PHARMACOLOGY OF THE ALPHA- RECEPTOR ANTAGONIST DRUGS Mechanism of Action Alpha-receptor antagonists may be reversible or irreversible. Reversible antagonists can dissociate from receptors. Phentolamine, tolazoline, prazosin and labetalol are reversible. Phenoxybenzamine is irreversible. 西安交大医学院药理学系 曹永孝

6 Cardiovascular Effects In the case of epinephrine with both αand β 2 effects, αreceptor antagonism may convert a pressor to a depressor response which is called epinephrine reversal. α- antagonist drugs block α receptors, dilate vascular smooth muscle, lower peripheral resistance and BP; can prevent the pressor effects of αagonists. 西安交大医学院药理学系 曹永孝

7 Alpha-receptor antagonists may cause postural hypotension and reflex tachycardia. Postural hypotension is due to antagonism of sympathetic nervous system stimulation of α 1 receptors in venous smooth muscle. 西安交大医学院药理学系 曹永孝

Minor effects in other tissues miosis and nasal stuffiness. 西安交大医学院药理学系 曹永孝 The radial muscle is innervated by alpha receptor. Its blockade by antagonists results in miosis. The smooth muscles of the iris stuffiness

9 Alpha 1 -receptor blockade of base of the bladder and the prostate is associated with decreased resistance to the flow of urine. Benign Prostatic Hyperplasia (BPH). 西安交大医学院药理学系 曹永孝

10 SPECIFIC AGENTS Phentolamine is a potent competitive antagonist at bothα 1 and α 2 receptors. It reduces peripheral resistance through blockade of α. It can stimulate the heart due to baroreflex mechanisms resulting in sympathetic stimulation. It blocks α 2 receptors, enhance release of NE from sympathetic nerves, contributing to cardiac stimulation via β receptors. 西安交大医学院药理学系 曹永孝

11 Phentolamine also inhibits responses to serotonin (5-HT) and activate M and histamine (H) receptors, has multiple potential actions, The principal adverse effects are cardiac stimulation, such as tachycardia, arrhythmias, myocardial ischemia and nasal congestion as well as headache. Phentolamine has been used in pheochromocytoma. 西安交大医学院药理学系 曹永孝

12 Tolazoline is similar to phentolamine. It has limited clinical application in the treatment of pulmonary hypertension in newborn infants with respiratory distress syndrome. Ergot derivatives, eg ， Ergotamine, dihydroergotamine cause reversible α-receptor blockade. 西安交大医学院药理学系 曹永孝

13 Phenoxybenzamine binds covalently to αreceptors, causing irreversible blockade of long duration (2 d). It is somewhat selective for α 1 receptors. It reduces BP when sympathetic tone is high and little fall in BP in normal supine individuals. It inhibits reuptake of NE by blocking α 2 on presynaptic terminals and increase cardiac output. It also blocks histamine (H 1 ), ACh, and serotonin receptors as well as αreceptors. 西安交大医学院药理学系 曹永孝

14 The adverse effects of phenoxybenzamine derive from its α-receptor –blocking action. The most important are postural hypotension, tachycardia and nasal stuffiness. Since phenoxybenzamine enters the CNS, it may cause less specific effects, including fatigue, sedation, and nausea. 西安交大医学院药理学系 曹永孝

15 Prazosin is highly selective for α 1 receptors, leads to vasodilation. It is effective in the management of hypertension. It has relatively low affinity for α 2 receptors (1/ 1000). This may explain the relative absence of tachycardia. Terazosin is another reversible α 1 -selective antagonist that is effective in hypertension. Terazosin has high bioavailability but is extensively metabolized in the liver. Its half-life is 9-12 h.

16 II. Clinical Pharmacology of the Alpha-Receptor- Blocking Drugs Pheochromocytoma Phenoxybenzamine and phentolamine are most useful in the pre-operative management of pheochromocytoma. They can control hypertension and reverse chronic changes resulting from catecholamine secretion such as plasma volume contraction. Phenoxybenzamine is useful in the chronic treatment of inoperable or metastatic pheochromocytoma. Beta-receptor antagonists may be required to reverse the cardiac effects of excessive catecholamines. 西安交大医学院药理学系 曹永孝

17 HYPERTENSIVE EMERGENCIES Labetalol has been used in hypertensive emergency. The α-adrenoceptor antagonists are most useful when increased BP reflects excess of αagonists. In this circumstance, which may result from overdosage of sympathomimetic drugs, pheochromocytoma, phentolamine can be used to control high BP. 西安交大医学院药理学系 曹永孝

18 Chronic Hypertension Prazosin family of α 1 -selective antagonists are efficacious in the treatment of hypertension. However, their efficacy in preventing heart failure for hypertension has been questioned. The adverse effect is postural hypotension, which may be severe after the first dose. Nonselective α antagonists are not used in primary hypertension. 西安交大医学院药理学系 曹永孝

19 Peripheral Vascular Disease Theα-receptor-blocking drugs have been tired in the treatment of peripheral vascular occlusive disease. Local Vasoconstrictor Excess Phentolamine has been used to reverse the vasoconstriction caused by infiltration of αagonists (NE) into subcutis during intravenous administration. The αantagonist is administered by local infiltration into the ischemic tissue.

20 Urinary Obstruction Alpha-receptor blockade can improve urine flow in BPH. The mechanism involves reversal of smooth muscle contraction in the enlarged prostate and in the bladder base. Phenoxybenzamine, prazosin, doxazocin, and terazosin are efficacious, particularly in patients with hypertension. 西安交大医学院药理学系 曹永孝

21 III. Basic Pharmacology of the Beta-Receptor- Antagonist Drugs Beta-blocking drugs occupy βreceptors and reduce receptor occupy by catecholamines and other βagonists. Most β-blocking drugs are pure antagonists; ie, after being occupied, βreceptor causes no activation. Some are partial agonists; ie, they cause partial activation of the receptor, less than that caused by the full agonist. Partial agonists inhibit the activation of receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. 西安交大医学院药理学系 曹永孝

The partial agonist in this example has high affinity for the receptor, so it remains bound for a long time once it reaches the binding site. As a result, when the partial agonist is present at high concentration, most of the receptors are occupied most of the time. However, because it has lower "efficacy" than the full agonist, only a fraction of the bound receptors can activate effector molecule. Therefore, the maximum response produced by the partial agonist is less than 100% of the maximum response of the system. 西安交大医学院药理学系 曹永孝

Partial agonist Affinity Low intrinsic activity Low efficacy 对激动剂： 小剂量激动 大剂量拮抗 西安交大医学院药理学系 曹永孝

24 Another major difference among the β- receptor-blocking drugs concerns their relative affinities forβ 1 and β 2 receptors. Some of these antagonists have a higher affinity for β 1 than forβ 2 receptors The selectivity is dose-related, ie, it tends to diminish at higher concentrations. Other major differences among β antagonists relate to their pharmacokinetics. 西安交大医学院药理学系 曹永孝

25 Pharmacodynamics of theβ-Receptor- Antagonist Drugs However, some actions may be due to partial agonist activity at βreceptors and local anesthetic action, which differ among the β-blockers. Most of the effects of these drugs are due to occupancy and blockade of βreceptors. 西安交大医学院药理学系 曹永孝

Effects on the Cardiovascular System Beta-adrenoceptor-blocking drugs are of major clinical importance in the treatment of hypertension.. Conventional doses do not cause hypotension in healthy individuals with normal BP. The mechanisms include effects on the heart and blood vessels, the rennin- angiotensin system, and the CNS 西安交大医学院药理学系 曹永孝

Heart Beta-receptor antagonists have prominent effects on the heart. The negative inotropic and chronotropic effects. Slowed atrioventricular conduction with an increased PR interval is a related result of adrenoceptor blockade in the atrioventricular node. 西安交大医学院药理学系 曹永孝

Vascular System Theβ-antagonists blockade β 2 -receptors, contracting vessel, antagonize the release of rennin, dilating vessel. In any event, while the acute effects of these drugs may include a rise in peripheral resistance. Chronic drug administration leads to a fall in peripheral resistance in patients with hypertension.

Effects on the Respiratory Tract Beta 1 antagonists have advantage over nonselective βantagonists when blockade of β 1 in the heart is desired and β 2 blockade is undesirable. However, no available β 1 -selective antagonist is sufficiently specific to completely avoid interactions with β 2 adrenoceptors. They should be avoided in patients with asthma. Blockade of the β 2 receptors in bronchus increases airway resistance, particularly in asthma.

C. Effects on the Eye Several β-blocking agents reduce intraocular pressure, especially in glaucomatous eyes. 西安交大医学院药理学系 曹永孝 The mechanism usually is decreased aqueous humor production 西安交大医学院药理学系 曹永孝

D. Metabolic and Endocrine Effects Beta-receptor antagonists such as propranolol inhibit lipolysis. The effects on carbohydrate metabolism are less clear, but they should be used with caution in insulin-dependent diabetic patients. The chronic use of β-adrenoceptor antagonists has been associated with increased plasma VLDL and decreased concentrations of HDL cholesterol. 西安交大医学院药理学系 曹永孝

E. Effects not Related to Beta-Blockade Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several β-blockers. This action is the result of local anesthetic blockade of sodium channels. However, this effect is not important, since the concentration in plasma usually achieved by these routes is too low for the anesthesia. 西安交大医学院药理学系 曹永孝

Clinical Application Hypertension The β-adrenoceptor-blocking drugs are effective and well tolerated in hypertension. While many hypertensive patients will respond to a β- blocker used alone, the drugs is often used with either a diuretic or a vasodilator. 西安交大医学院药理学系 曹永孝

Ischemic Heart Disease Beta-adrenoceptor blockers reduce the frequency of anginal episodes and improve exercise tolerance in patients with angina. These actions relate to the blockade of cardiac βreceptors, resulting in decreased cardiac work and reduction in oxygen demand. Slowing of the heart rate may contribute to clinical benefits. 西安交大医学院药理学系 曹永孝

Cardiac Arrhythmias Beta antagonists are effective in both supraventricular and ventricular arrhythmias. By increasing the atrioventricular nodal refractory period, β antagonists slow ventricular rates in atrial flutter and fibrillation. They can also reduce ventricular ectopic beats, particularly precipitated by catecholamines. 西安交大医学院药理学系 曹永孝

Other Cardiovascular Disorders Beta-receptor antagonists can increase stroke volume in some patients with obstructive cardiomyopathy. This is due to the slowing of ventricular ejection and decreased outflow resistance. Beta-antagonists are useful in dissecting aortic aneurysm to decrease the rate of development of systolic pressure. 西安交大医学院药理学系 曹永孝

Glaucoma Timolol and related βantagonists are suitable for local use in the eye because they lack local anesthetic properties. Betaxolol, carteolol, levobunolol, and metipranolol are newer β-receptor antagonists for the glaucoma. β-blocking drugs can reduce production of aqueous humor and decrease intraocular pressure in glaucoma. 西安交大医学院药理学系 曹永孝

Hyperthyroidism These beneficial effects relate to blockade of adrenoceptors and to the inhibition of peripheral conversion of thyroxine to triiodothyronine. Propranolol has been used extensively in patients with thyroid storm. Excessive catecholamine action is an important aspect of hyperthyroidism. The β antagonists have salutary effects in this condition. 西安交大医学院药理学系 曹永孝

Neurologic Diseases Propranolol reduce the frequency and intensity of migraine headache. Other β-receptor antagonists with preventive efficacy include metoprolol and probably also atenolol, timolol, and nadolol. The mechanism is not known. 西安交大医学院药理学系 曹永孝

CHOIC OF A BETA-ADRENOCEPTOR ANTAGONIST DRUG Propranolol is the standard against. It is a safe and effective drug for many indications 布莱克 (1924 ～ ) 英国药理学家 1964 年研制出治疗冠心病的代 表药 — 心得安。 1988 年获 Nobel Prize 。 Sir James W. Black The Nobel Prize in Physiology or Medicine 1988 西安交大医学院药理学系 曹永孝

CLINICAL TOXICITY OF THE BETA- RECEPTOR ANTAGONIST DRUGS A variety of minor toxic effects have been reported. Beta 2 -receptor blockade by nonselective agents commonly causes worsening of preexisting asthma and airway obstruction in normal individuals. Beta-receptor blockade depresses myocardial contractility and excitability. Caution must be exercised in using β-receptor antagonists in compensated heart failure. 西安交大医学院药理学系 曹永孝

Beta-blockers may interact with the calcium antagonist; hypotension, bradycardia, heart failure, conduction abnormalities have all been described. These adverse effects may even arise in susceptible patients taking a topical (ophthalmic) β-blocker and oral verapamil. Patients with ischemic heart disease may be at increased risk if β-blockade is suddenly interrupted, which might involve up-regulation of the β- receptors. 西安交大医学院药理学系 曹永孝

I am glad to share my knowledge with you, and I want you to become a master of the subject, pharmacology Thanks a million for your co-operation 西安交大医学院药理学系 曹永孝