Adrenoceptor Antagonists

Adrenoceptor Antagonists


Excessive sympathetic nervous system activity contributes to a number of diseases, including common cardiovascular disorders such as hypertension, angina pectoris, and cardiac arrhythmias. Drugs that reduce sympathetic stimulation, sympatholytic drugs, are used in the management of cardiovascular diseases and other diseases such as glaucoma, migraine headache, and urinary obstruction. The adrenoceptor antagonists are the most important group of sympatholytic drugs used today. The sympathetic neuronal blocking agents discussed in Chapter 5 also have a sympatholytic effect but are largely obsolescent.

The adrenoceptor antagonists include drugs that block α-adrenoceptors, β-adrenoceptors, or both. Their therapeutic effects are almost entirely caused by blockade of α1– and β1-adrenoceptors. Blockade of α1-adrenoceptors relaxes vascular and other smooth muscles in tissues innervated by the sympathetic nervous system, whereas blockade of β1-adrenoceptors reduces sympathetic stimulation of the heart. Blockade of α2– or β2-adrenoceptors is responsible for many of the adverse effects of these drugs, and drugs that selectively block either α1– or β1-adrenoceptors have been developed in an effort to avoid these adverse effects.

α-Adrenoceptor Antagonists

The α-adrenoceptor antagonists, or α-blockers, can be distinguished on the basis of their selectivity for adrenoceptor subtypes and by their noncompetitive or competitive blockade of these receptors.

Nonselective α-Blockers

Agents that block both α1– and α2-adrenoceptors are called nonselective α-blockers. Phenoxybenzamine and phentolamine are examples. Phenoxybenzamine is a noncompetitive antagonist, and phentolamine is a competitive antagonist.


Pharmacokinetics and Mechanism of Action

Phenoxybenzamine is administered orally and undergoes nonenzymatic chemical transformation to an active metabolite that forms a long-lasting covalent bond with α-adrenoceptors, resulting in noncompetitive receptor blockade (Fig. 9-1). The drug exhibits a slow onset of action owing to the time required to form its active metabolite, but it has a long duration of action of 3 to 4 days because of its stable drug-receptor binding.

Effects and Indications

Phenoxybenzamine decreases vascular resistance and lowers both supine and standing blood pressure. As shown in Table 9-1, phenoxybenzamine is used to treat hypertensive episodes in patients with pheochromocytoma, which is a tumor of the adrenal medulla that secretes huge amounts of catecholamines, causing extremely high blood pressure. In this setting, phenoxybenzamine is used to control hypertension until surgery can be performed to remove the tumor (Box 9-1).

Box 9-1   A Case of Headache, Anxiety, and a Racing Heart

Case Presentation

A 38-year-old man complains of the recent onset of episodes of headache, nervousness, sweating, a racing heart, and rapid breathing. The episodes last from a few minutes to over an hour and occur several times a day. On physical examination his pulse is 86 beats/min, his respiration rate is 24/min, and his blood pressure is 210/110 mm Hg. The patient has no history of hypertension and is taking no medications. He is given oxygen and intravenous labetalol to gradually reduce heart rate and blood pressure. His 24-hour urinary vanillylmandelic acid concentration is 10.8 mg (normal <7 mg/24 hr), his epinephrine is elevated at 186 mcg (normal <22 mcg/24 hr), and norepinephrine is 135 mcg (normal 12 to 85 mcg/24 hr). A computed tomography image shows a 1.7 × 2.1 cm soft tissue density in the left suprarenal area but no other abnormalities, and he is placed on metoprolol to control high blood pressure until surgery, and phenoxybenzamine and metyrosine right before surgery. His blood pressure is gradually reduced to 118/65 mm Hg, and he is started on a high-salt diet to maintain plasma volume. A week later he undergoes laparoscopic left adrenalectomy and his medications are gradually withdrawn. His blood pressure stabilizes at 120/70 mm Hg, and he is discharged after an uneventful recovery with no discharge medication required.

Case Discussion

Pheochromocytoma is a rare tumor of the adrenal medulla that secretes huge quantities of epinephrine and norepinephrine. The peak age of onset is 40 years. Symptoms may be intermittent or continuous and include headache, anxiety, sweating, rapid breathing, and tachycardia. The diagnosis is established by abdominal imaging and measurement of urinary catecholamines and vanillylmandelic acid. If the tumor has not metastasized, it can be surgically removed with no sequelae. Blood pressure should be controlled until surgery with adrenoceptor antagonists, and phenoxybenzamine is often used for this purpose along with a β-blocker to reduce cardiac stimulation and prevent arrhythmias and cardiac ischemia. Alternatively, metyrosine (see Chapters 5 and 10) can be used with phenoxybenzamine to control blood pressure preoperatively, and the drug is useful in managing patients when surgery is contraindicated or when the tumor has metastasized. Patients are usually given a high-sodium diet (>5000 mg daily) to counteract catecholamine-induced volume contraction and the orthostatic hypotension caused by α-receptor blockade. If the tumor is unilateral, replacement of corticosteroids is not necessary after adrenalectomy.


Mechanisms, Pharmacologic Effects, and Clinical Uses of Selected Adrenoceptor Antagonists

Alfuzosin, tamsulosin Competitive α1-blocker Relax bladder, urethral, and prostate smooth muscle Urinary symptoms caused by benign prostatic hyperplasia
Doxazosin, prazosin, terazosin Competitive α1-blocker Cause vasodilation and decrease blood pressure; relax bladder, urethral, and prostate smooth muscle Hypertension; urinary symptoms caused by benign prostatic hyperplasia
Phenoxybenzamine Noncompetitive α1– and α2-blocker Causes vasodilation; decreases blood pressure Hypertension in pheochromocytoma
Phentolamine Competitive α1– and α2-blocker Causes vasodilation; decreases vascular resistance and blood pressure Hypertension in pheochromocytoma; treat necrosis and ischemia after injection of an α-adrenoceptor agonist
Acebutolol β1-Blocker with ISA and MSA Decreases cardiac rate, output, AV node conduction, and O2 demand; decreases blood pressure Hypertension; cardiac arrhythmias
Atenolol β1-Blocker Same as acebutolol Hypertension; angina pectoris; acute myocardial infarction
Esmolol β1-Blocker Same as acebutolol Acute supraventricular tachycardia and hypertension
Metoprolol β1-Blocker with MSA Same as acebutolol Hypertension; angina pectoris; acute myocardial infarction
Nadolol β1– and β2-Blocker Same as acebutolol Hypertension; angina pectoris; migraine headache
Pindolol β1– and β2-Blocker with ISA and MSA Same as acebutolol Hypertension
Propranolol β1– and β2-Blocker with MSA Same as acebutolol Hypertension; angina pectoris; cardiac arrhythmias; hypertrophic subaortic stenosis; essential tremor; migraine headache; acute thyrotoxicosis; acute myocardial infarction; pheochromocytoma
Timolol β1– and β2-Blocker Decreases cardiac rate, output, AV node conduction, and O2 demand; decreases blood pressure; decreases intraocular pressure Hypertension; acute myocardial infarction; migraine headache; glaucoma
α- and β-Blockers
Carvedilol β1– and β2-Blocker; α1-blocker Causes vasodilation; decreases heart rate and blood pressure in patients with hypertension; increases cardiac output in patients with heart failure Hypertension; heart failure
Labetalol β1– and β2-Blocker with MSA; α1-blocker Causes vasodilation; decreases heart rate and blood pressure Hypertension


AV, Atrioventricular; ISA, intrinsic sympathomimetic activity (partial agonist activity); MSA, membrane-stabilizing activity (local anesthetic activity).

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Adrenoceptor Antagonists

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