Adrenoceptor Antagonists

ADRENOCEPTOR ANTAGONISTS

Their use in the treatment of hy-pertension is briefly described here. Drugs of this group are subdivided into α -adrenoceptor antagonists ( α- blockers) and β -adrenoceptor antagonists (β - blockers).

α -Blocking Drugs

Phenoxybenzamine and phentolamine have been avail-able for a number of years and are sometimes referred to as classical α-blockers. The frequency of their use for the treatment of primary hypertension has greatly di-minished in recent years because of the development of drugs such as prazosin that are relatively selective for α ₁-receptors. α ₁-Receptor–selective antagonists will not potentiate the release of norepinephrine from sympa-thetic nerves. Thus, the stimulation of the heart and renin release, actions that limit the usefulness of classi-cal α-blockers, are less with α₁-selective antagonists.

Unlike the vasodilators, which have a more promi-nent effect on arterial beds than on venous beds, the - blockers prevent vasoconstriction in both vascular beds. Because of the venous dilation, postural hypotension is a feature of  α-blockade, although less so with prazosin than with the classical α-blockers.

Prazosin and its derivatives that are selective for α₁-adrenoceptors are quite useful for the management of primary hypertension. The α₁-receptor–selective antag-onists can be used alone in mild hypertension. When hy-pertension is moderate or severe, prazosin is generally administered in combination with a thiazide and a β- blocker. The antihypertensive actions of prazosin are considerably potentiated by coadministration of thi-azides or other types of antihypertensive drugs.

Prazosin may be particularly useful when patients cannot tolerate other types of antihypertensive agents or when blood pressure is not well controlled by other drugs. Since prazosin does not significantly influence blood uric acid or glucose levels, it can be used in hy-pertensive patients whose condition is complicated by gout or diabetes mellitus. Prazosin treatment is associ-ated with favorable effects on plasma lipids. Thus, it may be of particular importance in managing patients with hyperlipidemia.

β -Blocking Drugs

β-blockers competitively antagonize the responses to catecholamines that are mediated by β-receptors . These drugs have a number of clinical uses, including treatment of cardiac arrhythmias  and angina pectoris , for which their therapeutic benefit is directly related to the blockade of β-receptors in the myocardium.

β-blockers are also used in the treatment of hyper-tension, although this seems to be somewhat paradoxical in that blockade of vascular smooth muscle β-receptors might be expected to unmask or leave unopposed re- sponses to catecholamines that occur through vascular β-receptors. Unopposed -mediated responses would be expected to increase, rather than decrease, blood pressure. Nevertheless, β-blockers have proved to be quite effective antihypertensive agents, and they have an important place in the treatment of primary hyperten-sion.

The mechanism by which β-blockers produce a sus-tained reduction in blood pressure in patients with primary hypertension is not completely understood, but it may include such actions as reduction in renin re-lease, antagonism of central nervous system (CNS) β-receptors, or antagonism of presynaptic facilitatory β-receptors on sympathetic nerves.

Decreases in heart rate and cardiac output are the most obvious results of administration of β-blockers. Initially, blood pressure is not much affected, since pe-ripheral vascular resistance will be reflexly elevated as a result of the drug-induced decrease in cardiac output. The reduction of blood pressure that occurs in chronic treatment correlates best with changes in peripheral vascular resistance rather than with a drug-induced variation in heart rate or cardiac output.

The reduction in plasma volume produced by - blockers contrasts with the increased volume seen with other types of antihypertensives. Tolerance to the anti-hypertensive actions of β-blockers therefore is less of a problem than with the vasodilating drugs. An additional difference from the vasodilators is that plasma renin ac-tivity is reduced, rather than increased, by propranolol (Inderal). Orthostatic hypotension does not occur with β-blockers.

The β-blockers are quite popular antihypertensive drugs. They are well tolerated, and serious side effects are seldom observed. When used alone over several weeks, β-blockers produce a significant reduction in blood pressure in approximately 30% of patients with mild to moderate hypertension. Thus, β-blockers can be employed as a first step in the management of high blood pressure. However, they are often used in conjunction with a diuretic when therapy with a single agent is not sat-isfactory. The combination of a β-blocker, thiazide di-uretic, and vasodilator provides significant control of moderate to severe hypertension in approximately 80% of patients.

From a hemodynamic viewpoint, there are several obvious advantages to using a β-blocker in combination with a vasodilator. Reflex-mediated cardiac stimulation is a common feature of vasodilator treatment and can severely limit its antihypertensive effectiveness. A β-blocker will reduce the cardiac stimulation and thus preserve the effectiveness of the vasodilator. Conversely, the vasodilator will prevent the increase in peripheral vascular resistance that occurs on initiation of treatment with a β-blocker. Furthermore, vasodilator treatment initiates reflexes that lead to an increase in plasma rennin activity. Thus, β-blockers, such as propranolol, that re-duce plasma renin activity are of obvious value.

Although the β-blockers are well-tolerated drugs and patient compliance is good, there may be problems with their administration, particularly in patients with decompensated hearts and cardiac conductance distur-bances.