Sympatholytic Agents

a and ß adrenergic antagonists are mainstays of antihypertensive therapy (Table 32-2). ß Adrenergic Receptor Antagonists

ß receptor antagonists have antihypertensive effects. The pharmacology of these drugs is discussed in Chapter 10. Antagonism of ß adrenergic receptors affects blood pressure through a number of mechanisms, including reducing cardiac output. ß Adrenergic receptor antagonists also act on the juxtaglomerular complex to reduce renin secretion and thereby diminish production of circulating angiotensin II. Other mechanisms by which ß receptor antagonists may lower blood pressure include alteration of the control of the sympathetic nervous system at the level of the CNS, altered baroreceptor sensitivity, altered peripheral adrenergic neuron function, and increased prostacyclin biosynthesis.

PHARMACOLOGICAL EFFECTS The ß blockers vary in their lipid solubility, selectivity for the ß1 adrenergic receptor subtype, presence of partial agonist or intrinsic sympathomimetic activity, and membrane-stabilizing properties. While all of the ß receptor antagonists are effective as antihypertensive agents, these differences do influence the clinical pharmacokinetics and spectrum of adverse effects of the various drugs. Drugs without intrinsic sympathomimetic activity produce an initial reduction in cardiac output and a reflex-induced rise in peripheral resistance, generally with no net change in arterial pressure; peripheral resistance gradually returns to pre-treatment values or less. Persistently reduced cardiac output and possibly decreased peripheral resistance account for the reduced arterial pressure. Drugs with intrinsic sympathomimetic activity produce lesser decreases in resting heart rate and cardiac output; the fall in arterial pressure correlates with a fall in vascular resistance below pretreatment levels, possibly because of stimulation of vascular b2 adrenergic receptors that mediate vasodilation.

ADVERSE EFFECTS AND PRECAUTIONS The b adrenergic blocking agents should be avoided in patients with asthma, with sinoatrial or atrioventricular (AV) nodal dysfunction, or in combination with other drugs that inhibit AV conduction, such as verapamil. Patients with type 1 diabetes mellitus also are better treated with other drugs (e.g., ACE inhibitors).

b Receptor antagonists without intrinsic sympathomimetic activity increase concentrations of triglycerides in plasma and lower those of high-density lipoprotein (HDL) cholesterol. b Adrener-gic blocking agents with intrinsic sympathomimetic activity have little or no effect on blood lipids. The long-term consequences of these effects are unknown.

Sudden discontinuation of b adrenergic blockers can produce a withdrawal syndrome that is likely due to up-regulation of b receptors during blockade, causing enhanced tissue sensitivity to endogenous catecholamines; this can exacerbate the symptoms of coronary artery disease. The result, especially in active patients, can be rebound hypertension. Thus, b adrenergic blockers should be tapered over 10-14 days.

NSAIDs such as indomethacin can blunt the antihypertensive effect of propranolol and probably other b receptor antagonists. This effect may relate to inhibition of vascular synthesis of prostacyclin, as well as to Na+ retention.

Epinephrine can produce severe hypertension when used with a nonselective b receptor antagonist due to the unopposed stimulation of a receptors when vascular b2 receptors are blocked. Such paradoxical hypertensive responses to b adrenergic receptor antagonists have been observed in patients with hypoglycemia or pheochromocytoma, during withdrawal from clonidine, following administration of Epi as a therapeutic agent, or in association with the illicit use of cocaine.

THERAPEUTIC USES b receptor antagonists provide effective therapy for all grades of hypertension. Despite marked differences in their pharmacokinetic properties, the antihypertensive effect of all the b blockers is of sufficient duration to permit once or twice daily administration. Populations that tend to have a lesser antihypertensive response to b-blocking agents include the elderly and African Americans. However, this should not discourage the use of these drugs in individual patients, as intraindividual differences in antihypertensive efficacy generally are much larger than differences between racial or age-related groups.

b receptor antagonists do not usually cause salt and water retention, and diuretic administration is not necessary to avoid edema or the development of tolerance. However, diuretics do have additive antihypertensive effects when combined with b blockers. The combination of a b receptor antagonist, a diuretic, and a vasodilator is effective for patients who require a third drug. b Adren-ergic receptor antagonists are preferred drugs for hypertensive patients with conditions such as myocardial infarction, ischemic heart disease, or congestive heart failure.

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