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Chapter 11 Adrenoceptor Antagonist Drugs

Chapter 11 Adrenoceptor Antagonist Drugs. Cao Yongxiao 曹永孝 Department of Pharmacology yxy@xjtu.edu.cn;029-82655140 http://pharmacology.xjtu.edu.cn. 1. Drugs blocking adrenoceptors vary dramatically according to the drug’s selectivity for αand βreceptors.

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Chapter 11 Adrenoceptor Antagonist Drugs

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  1. Chapter 11 Adrenoceptor Antagonist Drugs Cao Yongxiao曹永孝 Department of Pharmacology yxy@xjtu.edu.cn;029-82655140 http://pharmacology.xjtu.edu.cn 1

  2. Drugs blocking adrenoceptors vary dramatically according to the drug’s selectivity for αand βreceptors. Their major effect is to occupy eitherα, or β receptors and prevent their activation by catecholamines and related agonists. 2 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  3. Nonselectiveαantagonists can treat pheochromocytoma (secrete catecholamines). α1-selective antagonists are used in hypertension and benign prostatic hyperplasia (BPH). 3 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  4. Beta-receptor antagonist drugs are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, and other conditions. 4 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  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. 5 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  6. Cardiovascular Effects α- antagonist drugs block α receptors, dilate vascular smooth muscle, lower peripheral resistance and BP; can prevent the pressor effects of αagonists. In the case of epinephrine with both αand β2 effects, αreceptor antagonism may convert a pressor to a depressor response which is called epinephrine reversal. 6 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  7. Alpha-receptor antagonists may cause postural hypotension and reflex tachycardia. Postural hypotension is due to antagonism of sympathetic nervous system stimulation of α1 receptors in venous smooth muscle. 7 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  8. Minor effects in other tissues miosis and nasal stuffiness. The radial muscle is innervated by alpha receptor. Its blockade by antagonists results in miosis. The smooth muscles of the iris stuffiness 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  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). 9 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  10. SPECIFIC AGENTS Phentolamineis a potent competitive antagonist at bothα1 and α2 receptors. It reduces peripheral resistance through blockade of α. It can stimulate the heart due to baroreflex mechanisms resulting in sympathetic stimulation. It blocks α2 receptors, enhance release of NE from sympathetic nerves, contributing to cardiac stimulation via β receptors. 10 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  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. 11 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  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. 12 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  13. Phenoxybenzamine binds covalently to αreceptors, causing irreversible blockade of long duration (2 d). It is somewhat selective for α1 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 α2 onpresynaptic terminals and increase cardiac output. It also blocks histamine (H1), ACh, and serotonin receptors as well as αreceptors. 13 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  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. 14 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  15. Prazosin is highly selective for α1 receptors, leads to vasodilation. It is effective in the management of hypertension. It has relatively low affinity for α2 receptors (1/ 1000). This may explain the relative absence of tachycardia. Terazosin is another reversible α1-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. 15

  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. 16 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  17. HYPERTENSIVE EMERGENCIES Labetalol has been used in hypertensive emergency. The α-adrenoceptor antagonists aremost usefulwhen 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. 17 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  18. Chronic Hypertension Prazosin family of α1-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. 18 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  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. 19

  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. 20 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  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. 21 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  22. 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 yxy@xjtu.edu.cn; 029-82655140

  23. 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 yxy@xjtu.edu.cn; 029-82655140

  24. Another major difference among the β-receptor-blocking drugs concerns their relative affinities forβ1 and β2 receptors. Some of these antagonists have a higher affinity for β1 than forβ2 receptors The selectivity is dose-related, ie, it tends to diminish at higher concentrations. Other major differences among β antagonists relate to their pharmacokinetics. 24 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  25. Pharmacodynamics of theβ-Receptor- Antagonist Drugs Most of the effects of these drugs are due to occupancy and blockade of βreceptors. However, some actions may be due to partial agonist activity at βreceptors and local anesthetic action, which differ among the β-blockers. 25 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  26. 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 yxy@xjtu.edu.cn; 029-82655140

  27. 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 yxy@xjtu.edu.cn; 029-82655140

  28. Vascular System Theβ-antagonists blockade β2-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.

  29. Effects on the Respiratory Tract Blockade of the β2 receptors in bronchus increases airway resistance, particularly in asthma. • Beta 1 antagonists have advantage over nonselective βantagonists when blockade of β1 in the heart is desired and β2 blockade is undesirable . • However, no available β1-selective antagonist is sufficiently specific to completely avoid interactions with β2 adrenoceptors. • They should be avoided in patients with asthma.

  30. C. Effects on the Eye Several β-blocking agents reduce intraocular pressure, especially in glaucomatous eyes. The mechanism usually is decreased aqueous humor production 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  31. 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 yxy@xjtu.edu.cn; 029-82655140

  32. 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 yxy@xjtu.edu.cn; 029-82655140

  33. 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 yxy@xjtu.edu.cn; 029-82655140

  34. 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 yxy@xjtu.edu.cn; 029-82655140

  35. 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 yxy@xjtu.edu.cn; 029-82655140

  36. 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 yxy@xjtu.edu.cn; 029-82655140

  37. Glaucoma β-blocking drugs can reduce production of aqueous humor and decrease intraocular pressure in 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. 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  38. Hyperthyroidism Excessive catecholamine action is an important aspect of hyperthyroidism. The β antagonists have salutary effects in this condition. • 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. 西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

  39. 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 yxy@xjtu.edu.cn; 029-82655140

  40. 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 yxy@xjtu.edu.cn; 029-82655140

  41. 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 yxy@xjtu.edu.cn; 029-82655140

  42. 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 yxy@xjtu.edu.cn; 029-82655140

  43. 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 yxy@xjtu.edu.cn; 029-82655140

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