Page 171 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 10 Adrenoceptor Antagonist Drugs 157

HO
CH 3

N O CH 2 CH CH 2 CH 2 CI R 1 CH 2
N CH 2 C N N + + CI –
N
H C H CH 2 R 2 CH 2
3
Phentolamine Phenoxybenzamine Active (ethyleneimonium)
intermediate

O
N
CH O N N C
3
O
CH O N
3
NH 2
Prazosin
SO NH
O CH 2 CH 2 NH CH CH 2 2 2
CH 3
O CH 2 CH 3 O CH 3
Tamsulosin

FIGURE 10–1 Structure of several α-receptor–blocking drugs.

Phenoxybenzamine forms a reactive ethyleneimonium intermedi- of agonists with both α and β effects (eg, epinephrine), selec-
2
ate (Figure 10–1) that covalently binds to α receptors, resulting tive α-receptor antagonism may convert a pressor to a depres-
in irreversible blockade. Figure 10–2 illustrates the effects of a sor response (Figure 10–3). This change in response is called
reversible drug in comparison with those of an irreversible agent. epinephrine reversal; it illustrates how the activation of both α
As discussed in Chapters 1 and 2, the duration of action of and β receptors in the vasculature may lead to opposite responses.
a reversible antagonist is largely dependent on the half-life of Alpha-receptor antagonists often cause orthostatic hypoten-
the drug in the body and the rate at which it dissociates from sion and reflex tachycardia; nonselective (α = α , Table 10–1)
2
1
its receptor: The shorter the half-life of the drug in the body, blockers usually cause significant tachycardia if blood pressure is
the less time it takes for the effects of the drug to dissipate. In lowered below normal. Orthostatic hypotension is due to antago-
contrast, the effects of an irreversible antagonist may persist long nism of sympathetic nervous system stimulation of α receptors
1
after the drug has been cleared from the plasma. In the case of in vascular smooth muscle; contraction of veins is an important
phenoxybenzamine, the restoration of tissue responsiveness after component of the normal capacity to maintain blood pressure
extensive α-receptor blockade is dependent on synthesis of new in the upright position since it decreases venous pooling in the
receptors, which may take several days. The rate of return of periphery. Constriction of arterioles in the legs also contributes to
-adrenoceptor responsiveness may be particularly important in the normal orthostatic response. Tachycardia may be more marked
α 1
patients who have a sudden cardiovascular event or who become with agents that block α -presynaptic receptors in the heart, since
2
candidates for urgent surgery. the augmented release of norepinephrine will further stimulate
β receptors in the heart.
Pharmacologic Effects

A. Cardiovascular Effects B. Other Effects
Because arteriolar and venous tone are determined to a large Blockade of α receptors in other tissues elicits miosis (small
extent by α receptors on vascular smooth muscle, α-receptor pupils) and nasal stuffiness. Alpha 1 receptors are expressed in the
antagonist drugs cause a lowering of peripheral vascular resistance base of the bladder and the prostate, and their blockade decreases
and blood pressure (Figure 10–3). These drugs can prevent the resistance to the flow of urine. Alpha blockers, therefore, are
pressor effects of usual doses of α agonists; indeed, in the case used therapeutically for the treatment of urinary retention due