Alpha-receptor antagonists may be reversible or irreversible in their interaction with these receptors. Reversible antagonists dissociate from receptors, and the block can be surmounted with sufficiently high concentrations of agonists; irreversible drugs do not dissociate and cannot be surmounted. Phentolamine and prazosin (Figure 10–1) are examples of reversible antagonists. These drugs and labetalol—drugs used primarily for their antihypertensive effects—as well as several ergot derivatives (see Chapter 16) are also reversible α-adrenoceptor antagonists or partial agonists.
FIGURE 10–1 Structure of several α-receptor–blocking drugs.
Phenoxybenzamine forms a reactive ethyleneimonium intermediate (Figure 10–1) that covalently binds to α receptors, resulting in irreversible blockade. Figure 10–2 illustrates the effects of a reversible drug in comparison with those of an irreversible agent.
As discussed in Chapters 1 and 2, the duration of action of a reversible antagonist is largely dependent on the half-life of the drug in the body and the rate at which it dissociates from its receptor: The shorter the half-life of the drug in the body, the less time it takes for the effects of the drug to dissipate. In contrast, the effects of an irreversible antagonist may persist long after the drug has been cleared from the plasma. In the case of phenoxybenzamine, the restoration of tissue responsiveness after extensive α-receptor blockade is dependent on synthesis of new receptors, which may take several days. The rate of return of α1-adrenoceptor responsiveness may be particularly important in patients who have a sudden cardiovascular event or who become candidates for urgent surgery.
A. Cardiovascular Effects
Because arteriolar and venous tone are determined to a large extent by α receptors on vascular smooth muscle, α-receptor antagonist drugs cause a lowering of peripheral vascular resistance and blood pressure (Figure 10–3). These drugs can prevent the pressor effects of usual doses of α agonists; indeed, in the case of agonists with both α and β2 effects (eg, epinephrine), selective α-receptor antagonism may convert a pressor to a depressor response (Figure 10–3). This change in response is called epinephrine reversal; it illustrates how the activation of both α and β receptors in the vasculature may lead to opposite responses. Alpha-receptor antagonists often cause orthostatic hypotension and reflex tachycardia; nonselective (α1= α2, Table 10–1) blockers usually cause significant tachycardia if blood pressure is lowered below normal. Orthostatic hypotension is due to antagonism of sympathetic nervous system stimulation of α1 receptors in vascular smooth muscle; contraction of veins is an important component of the normal capacity to maintain blood pressure in the upright position since it decreases venous pooling in the periphery. Constriction of arterioles in the legs also contributes to the normal orthostatic response. Tachycardia may be more marked with agents that block α2-presynaptic receptors in the heart, since the augmented release of norepinephrine will further stimulate β receptors in the heart.
B. Other Effects