Adrenoceptor Blockers

and blockers differ markedly in their effects and clinical applications, these drugs are considered separately in the following discussion.

High-Yield Terms to Learn

Competitive blocker A surmountable antagonist (eg, phentolamine); one that can be overcome by increasing the dose of agonist Epinephrine reversal Conversion of the pressor response to epinephrine (typical of large doses) to a blood pressure-lowering effect; caused by blockers Intrinsic sympathomimetic activity (ISA) Partial agonist action by adrenoceptor blockers; typical of several blockers (eg, pindolol, acebutolol) Irreversible blocker A nonsurmountable inhibitor, usually because of covalent bond formation (eg, phenoxybenzamine) Membrane stabilizing activity (MSA) Local anesthetic action; typical of several blockers (eg, propranolol) Orthostatic hypotension Hypotension that is most marked in the upright position; caused by venous pooling (typical of blockade) or inadequate blood volume (caused by blood loss or excessive diuresis) Partial agonist A drug (eg, pindolol) that produces a smaller maximal effect than a full agonist and therefore can inhibit the effect of a full agonist Pheochromocytoma A tumor consisting of cells that release varying amounts of norepinephrine and epinephrine into the circulation

Alpha-Blocking Drugs

Classification

Subdivisions of the blockers are based on selective affinity for 1 versus 2 receptors or a lack thereof. Other features used to classify the -blocking drugs are their reversibility and duration of action.

Irreversible, Long-Acting

Phenoxybenzamine is the prototypical long-acting, irreversible blocker. It is only slightly 1 selective.

Reversible, Shorter-Acting

Phentolamine is a competitive, reversible blocking agent that does not distinguish between 1 and 2 receptors.

Alpha1-Selective

Prazosin is a highly selective, reversible pharmacologic 1 blocker. Doxazosin, terazosin, and tamsulosin are similar drugs. The advantage of 1 selectivity is discussed in the following text.

Alpha2-Selective

Yohimbine and rauwolscine are 2-selective competitive pharmacologic antagonists. They are used primarily in research applications.

Pharmacokinetics

Alpha-blocking drugs are all active by the oral as well as the parenteral route, although phentolamine is rarely given orally. Phenoxybenzamine has a short elimination half-life but a long duration of action—about 48 h—because it binds covalently to its receptor. Phentolamine has a duration of action of 2-4 h when used orally and 20-40 min when given parenterally. Prazosin and the other 1-selective blockers act for 8-24 h.

Mechanism of Action

Phenoxybenzamine binds covalently to the receptor, thereby producing an irreversible (insurmountable) blockade. The other agents are competitive pharmacologic antagonists—that is, their effects can be surmounted by increased concentrations of agonist. This difference may be important in the treatment of pheochromocytoma because a massive release of catecholamines from the tumor may overcome a reversible blockade.

Effects

Nonselective Blockers

These agents cause a predictable blockade of -mediated responses to sympathetic nervous system discharge and exogenous sympathomimetics (ie, the responses listed in Table 9-1). The most important effects of nonselective blockers are those on the cardiovascular system: a reduction in vascular tone with a reduction of both arterial and venous pressures. There are no significant direct cardiac effects. However, the nonselective blockers do cause baroreceptor reflex-mediated tachycardia as a result of the drop in mean arterial pressure (see Figure 6-4). This tachycardia may be exaggerated because the 2 receptors on adrenergic nerve terminals in the heart, which normally reduce the net release of norepinephrine, are also blocked (see Figure 6-3).

Epinephrine reversal (Figure 10-1) is a predictable result of the use of this agonist in a patient who has received an blocker. The term refers to a reversal in the blood pressure effect of large doses of epinephrine, from a pressor response (mediated by receptors) to a depressor response (mediated by 2 receptors). The effect is not observed with phenylephrine or norepinephrine because these drugs lack sufficient 2 effects. Epinephrine reversal is occasionally seen as an unexpected (but predictable) effect of drugs for which blockade is an adverse effect (eg, some phenothiazine tranquilizers, antihistamines).

FIGURE 10-1

The effects of an blocker, for example, phentolamine, on the blood pressure responses to epinephrine (epi) and phenylephrine. The epinephrine response exhibits reversal of the mean blood pressure change from a net increase (the response) to a net decrease (the 2 response). The response to phenylephrine is suppressed but not reversed, because phenylephrine is a “pure” agonist without action.

Selective Blockers

Because prazosin and its analogs block vascular 1 receptors much more effectively than the 2-modulatory receptors associated with cardiac sympathetic nerve endings, these drugs cause much less reflex tachycardia than the nonselective blockers when reducing blood pressure. These drugs also have important effects on smooth muscle in the prostate.