The most important actions of the p-blocking drugs are on the cardiovascular system. p-Blockers decrease heart rate, myocardial contractility, cardiac output, and conduction velocity within the heart. These effects are most pronounced when sympathetic activity is high or when the heart is stimulated by circulating agonists.
The actions of p-blockers on blood pressure are complex. After acute administration, blood pressure is only slightly altered. This is because of the compensatory reflex increase in peripheral vascular resistance that results from a p-blocker-induced decrease in cardiac output. Vasoconstriction is mediated by a-receptors, and a-receptors are not antagonized by p-receptor blocking agents. Chronic administration of p-blockers, however, results in a reduction of blood pressure, and this is the reason for their use in primary hypertension (see Chapter 20).The mechanism of this effect is not well understood, but it may include such actions as a reduction in renin release, antagonism of p-receptors in the central nervous system, or antagonism of presynaptic facilita-tory p-receptors on sympathetic nerves.
Total coronary blood flow is reduced by the p-blockers. This effect may be due in part to the unopposed a-receptor-mediated vasoconstriction that follows p-receptor blockade in the coronary arteries. Additional contributing factors to the decrease in coronary blood flow are the negative chronotropic and in-otropic effects produced by the p-blockers; these actions result in a decrease in the amount of blood available for the coronary system. The decrease in mean blood pressure may also contribute to the reduced coronary blood flow.
In view of the effects of the p-receptor blocking agents on coronary blood flow, it seems paradoxical that these drugs are useful for the prophylactic treatment of angina pectoris, a condition characterized by inadequate myocardial perfusion. The chief benefit of the p-blockers in this condition derives from their ability to decrease cardiac work and oxygen demand. The use of the p-blockers in angina is considered in Chapter 17. The ability of p-blockers to decrease cardiac work and oxygen demand may also be responsible for the favorable effects of these agents in the long-term management of congestive heart failure.
The release of renin from the juxtaglomerular cells of the kidney is believed to be regulated in part by preceptors; most p-blockers decrease renin release. While the drug-induced decrease in renin release may contribute to their hypotensive actions, it is probably not the only factor (see Chapter 20). Nevertheless, p-blockers are useful and logical agents to use when treating hypertension that is accompanied by high plasma renin activity, although angiotensin converting enzyme inhibitors are also widely used in this situation.
The glycogenolytic and lipolytic actions of endogenous catecholamines are mediated by p-receptors and are subject to blockade by p-blockers. This metabolic antagonism exerted by the p-blockers is particularly pronounced if the levels of circulating catecholamines have been increased reflexively in response to hypoglycemia. Other physiological changes induced by hy-poglycemia, such as tachycardia, may be blunted by p-blockers. These agents therefore must be used with caution in patients susceptible to hypoglycemia (e.g., diabetics treated with insulin). Because the metabolic responses to catecholamines are mediated by p2-receptors and possibly by p3-receptors, p1-selective antagonists such as metoprolol and atenolol may be better choices whenever p-blocker therapy is indicated for a patient who has hypoglycemia.
Propranolol increases airway resistance by antagonizing p2-receptor-mediated bronchodilation. Although the resulting bronchoconstriction is not a great concern in patients with normal lung function, it can be quite serious in the asthmatic. The cardioselective p-blockers produce less bronchoconstriction than do the nonselec-tive antagonists.
p-Blockers can reduce intraocular pressure in glaucoma and ocular hypertension. The mechanism is believed to be related to a decreased production of aqueous humor.
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