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Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

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Alpha-Adrenoceptor Antagonists (Alpha-Blockers)

General Pharmacology

These drugs block the effect of sympathetic nerves on blood vessels by binding to alpha-adrenoceptors located on the vascular smooth muscle. Most of these drugs act as competitive antagonists to the binding of norepinephrine that is released by sympathetic nerves synapsing on smooth muscle. Therefore, sometimes these drugs are referred to as sympatholytics because they antagonize sympathetic activity. Some alpha-blockers are non-competitive (e.g., phenoxybenzamine), which greatly prolongs their action, whereas others are relatively selective for one type of alpha-adrenoceptor.

alpha receptors and Gq-proteins in vascular smooth muscle

Vascular smooth muscle has two types of alpha-adrenoceptors: alpha11) and alpha22). The α1-adrenoceptors are the predominant α-receptor located on vascular smooth muscle. These receptors are linked to Gq-proteins that activate smooth muscle contraction through the IP3 signal transduction pathway. Depending on the tissue and type of vessel, there are also α2-adrenoceptors found on the smooth muscle. These receptors are linked to Gi-proteins, and binding of an alpha-agonist to these receptors decreases intracellular cAMP, which causes smooth muscle contraction. There are also α2-adrenoceptors located on the sympathetic nerve terminals that inhibit the release of norepinephrine and therefore act as a feedback mechanism for modulating the release of norepinephrine.

α1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine to the smooth muscle receptors. Non-selective α1 and α2-adrenoceptor antagonists block postjunctional α1 and α2-adrenoceptors, which causes vasodilation; however, the blocking of prejunctional α2-adrenoceptors leads to increased release of norepinephrine, which attenuates the effectiveness of the α1 and α2-postjunctional adrenoceptor blockade. Furthermore, blocking α2-prejunctional adrenoceptors in the heart can lead to increases in heart rate and contractility due to the enhanced release of norepinephrine that binds to beta1-adrenoceptors.

Alpha-blockers dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial resistance vessels. Because most blood vessels have some degree of sympathetic tone under basal conditions, these drugs are effective dilators. They are even more effective under conditions of elevated sympathetic activity (e.g., during stress) or during pathologic increases in circulating catecholamines caused by an adrenal gland tumor (pheochromocytoma).

Therapeutic Uses

Alpha-blockers, especially α1-adrenoceptor antagonists, are useful in the treatment of primary hypertension, although their use is not as widespread as other antihypertensive drugs. The non-selective antagonists are usually reserve for use in hypertensive emergencies caused by a pheochromocytoma. This hypertensive condition, which is most commonly caused by an adrenal gland tumor that secretes large amounts of catecholamines, can be managed by non-selective alpha-blockers (in conjunction with beta-blockade to blunt the reflex tachycardia) until the tumor can be surgically removed.

Specific Drugs

Newer alpha-blockers used in treating hypertension are relatively selective α1-adrenoceptor antagonists (e.g., prazosin, terazosin, doxazosin, trimazosin), whereas some older drugs are non-selective antagonists (e.g., phentolamine, phenoxybenzamine). (Go to www.rxlist.com for specific drug information)

Side Effects and Contraindications

The most common side effects are related directly to alpha-adrenoceptor blockade. These side effects include dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon standing), nasal congestion (due to dilation of nasal mucosal arterioles), headache, and reflex tachycardia (especially with non-selective alpha-blockers). Fluid retention is also a problem that can be rectified by use of a diuretic in conjunction with the alpha-blocker. Alpha blockers have not been shown to be beneficial in heart failure or angina, and should not be used in these conditions.

Revised 06/25/13

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.