Adrenergic antagonists

The adrenergic antagonists cause direct blockade of adrenergic receptors. With one exception, all of the adrenergic antagonists produce reversible (competitive) blockade.

Unlike many adrenergic agonists, which act at alpha- and beta-adrenergic receptors, most adrenergic antagonists are more selective. As a result, the adrenergic antagonists can be neatly divided into two major groups: (1) alpha-adrenergic blocking agents (drugs that produce selective blockade of alpha-adrenergic receptors); and (2) beta-adrenergic blocking agents (drugs that produce selective blockade of beta receptors).* Members of these two groups are listed in Table 18–1.

TABLE 18–1

Receptor Specificity of Adrenergic Antagonists

Category	Drugs	Receptors Blocked
Alpha-Adrenergic Blocking Agents
Nonselective Agents	Phenoxybenzamine Phentolamine	alpha₁, alpha₂ alpha₁, alpha₂
Alpha₁-Selective Agents	Alfuzosin Doxazosin Prazosin Silodosin Tamsulosin Terazosin	alpha₁ alpha₁ alpha₁ alpha₁ alpha₁ alpha₁
Beta-Adrenergic Blocking Agents
Nonselective Agents	Carteolol Nadolol Penbutolol Pindolol Propranolol Sotalol Timolol Carvedilol Labetalol	beta₁, beta₂ beta₁, beta₂ beta₁, beta₂ beta₁, beta₂ beta₁, beta₂ beta₁, beta₂ beta₁, beta₂ beta₁, beta₂, alpha₁ beta₁, beta₂, alpha₁
Beta₁-Selective Agents	Acebutolol Atenolol Betaxolol Bisoprolol Esmolol Metoprolol Nebivolol	beta₁ beta₁ beta₁ beta₁ beta₁ beta₁ beta₁

Our approach to the adrenergic antagonists mirrors the approach we took with the adrenergic agonists. That is, we begin by discussing the therapeutic and adverse effects that can result from alpha- and beta-adrenergic blockade, after which we discuss the individual drugs that produce receptor blockade.

Remember that it is much easier to understand responses to the adrenergic drugs if you first understand the responses to activation of adrenergic receptors. Accordingly, if you have not yet mastered (memorized) Table 13–3, you should do so now (or at least be prepared to consult the table as we proceed).

Alpha-adrenergic antagonists

Adverse effects of alpha₁ blockade

Orthostatic hypotension.

Orthostatic hypotension is the most serious adverse response to alpha-adrenergic blockade. This hypotension can reduce blood flow to the brain, thereby causing dizziness, lightheadedness, and even syncope (fainting).

The cause of hypotension is blockade of alpha receptors on veins, which reduces muscle tone in the venous wall. Because of reduced venous tone, blood tends to pool (accumulate) in veins when the patient assumes an erect posture. As a result, return of blood to the heart is reduced, which decreases cardiac output, which in turn causes blood pressure to fall.

Patients should be informed about symptoms of hypotension (lightheadedness, dizziness) and advised to sit or lie down if these occur. In addition, patients should be informed that orthostatic hypotension can be minimized by avoiding abrupt transitions from a supine or sitting position to an erect posture.

Reflex tachycardia.

Alpha-adrenergic antagonists can increase heart rate by triggering the baroreceptor reflex. The mechanism is this: (1) blockade of vascular alpha₁ receptors causes vasodilation; (2) vasodilation reduces blood pressure; and (3) baroreceptors sense the reduction in blood pressure and, in an attempt to restore normal pressure, initiate a reflex increase in heart rate via the autonomic nervous system. If necessary, reflex tachycardia can be suppressed with a beta-adrenergic blocking agent.

Nasal congestion.

Alpha blockade can dilate the blood vessels of the nasal mucosa, producing nasal congestion.

Inhibition of ejaculation.

Since activation of alpha₁ receptors is required for ejaculation (see Table 13–3), blockade of these receptors can cause impotence. This form of drug-induced impotence is reversible and resolves when the alpha blocker is withdrawn.

The ability of alpha blockers to inhibit ejaculation can be a major reason for nonadherence to the prescribed regimen. If a patient deems the adverse sexual effects of alpha blockade unacceptable, a change in medication will be required. Because males may be reluctant to discuss such concerns, a tactful interview may be needed to discern if drug-induced impotence is discouraging drug use.

Sodium retention and increased blood volume.

By reducing blood pressure, alpha blockers can promote renal retention of sodium and water, thereby causing blood volume to increase. The steps in this process are as follows: (1) by reducing blood pressure, alpha₁ blockers decrease renal blood flow; (2) in response to reduced perfusion, the kidney excretes less sodium and water; and (3) the resultant retention of sodium and water increases blood volume. As a result, blood pressure is elevated, blood flow to the kidney is increased, and, as far as the kidney is concerned, all is well. Unfortunately, when alpha blockers are used to treat hypertension (which they often are), this compensatory elevation in blood pressure can negate beneficial effects. In order to prevent the kidney from “neutralizing” hypotensive actions, alpha-blocking agents are usually combined with a diuretic when used in patients with hypertension.

Adverse effects of alpha₂ blockade

The most significant adverse effect associated with alpha₂ blockade is potentiation of the reflex tachycardia that can occur in response to blockade of alpha₁ receptors. Why does alpha₂ blockade intensify reflex tachycardia? Recall that peripheral alpha₂ receptors are located presynaptically and that activation of these receptors inhibits norepinephrine release. Hence, if alpha₂ receptors are blocked, release of norepinephrine will increase. Since the reflex tachycardia caused by alpha₁ blockade is ultimately the result of increased firing of the sympathetic nerves to the heart, and since alpha₂ blockade will cause each nerve impulse to release a greater amount of norepinephrine, alpha₂ blockade will potentiate reflex tachycardia initiated by blockade of alpha₁ receptors. Accordingly, drugs such as phentolamine, which block alpha₂ as well as alpha₁ receptors, cause greater reflex tachycardia than do drugs that block alpha₁ receptors only.

Properties of individual alpha blockers

Eight alpha-adrenergic antagonists are employed clinically. Because the alpha blockers often cause postural hypotension, therapeutic uses are limited.

As indicated in Table 18–1, the alpha-adrenergic blocking agents can be subdivided into two major groups. One group, represented by prazosin, contains drugs that produce selective alpha₁ blockade. The second group, represented by phentolamine, consists of nonselective alpha blockers, which block alpha₁ and alpha₂ receptors.