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Chapter: Basic & Clinical Pharmacology : Adrenoceptor Antagonist Drugs

Pharmacodynamics of the Beta-Receptor Antagonist Drugs

Most of the effects of these drugs are due to occupation and blockade of β receptors.

Pharmacodynamics of the Beta-Receptor Antagonist Drugs

Most of the effects of these drugs are due to occupation and blockade of β receptors. However, some actions may be due to other effects, including partial agonist activity at β receptors and local anesthetic action, which differ among the β blockers (Table 10–2).

A. Effects on the Cardiovascular System

Beta-blocking drugs given chronically lower blood pressure in patients with hypertension . The mechanisms involved are not fully understood but probably include suppres-sion of renin release and effects in the central nervous system. These drugs do not usually cause hypotension in healthy individu-als with normal blood pressure.

Beta-receptor antagonists have prominent effects on the heart (Figure 10–6) and are very valuable in the treatment of angina  and chronic heart failure  and fol-lowing myocardial infarction . The negative ino-tropic and chronotropic effects reflect the role of adrenoceptors in regulating these functions. Slowed atrioventricular conduction with an increased PR interval is a related result of adrenoceptor blockade in the atrioventricular node. In the vascular system, β-receptor blockade opposes β2-mediated vasodilation. This mayacutely lead to a rise in peripheral resistance from unopposed α-receptor–mediated effects as the sympathetic nervous systemdischarges in response to lowered blood pressure due to the fall in cardiac output. Nonselective and β1-blocking drugs antagonize the release of renin caused by the sympathetic nervous system. Overall, although the acute effects of these drugs may include a rise in peripheral resistance, chronic drug administration leads to a fall in peripheral resistance in patients with hypertension.

B. Effects on the Respiratory Tract

Blockade of the β2 receptors in bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. Beta1-receptor antagonists such as metoprolol and atenolol may have some advantage over nonselective β antagonists when blockade of β1 receptors in the heart is desired and β2-receptor blockade is undesirable. However, no currently available β1-selective antagonist is sufficiently specific to completely avoid interactions with β2 adrenoceptors. Consequently, these drugs should generally be avoided in patients with asthma. On the other hand, many patients with chronic obstructive pulmonary disease (COPD) may tolerate these drugs quite well and the benefits, for example in patients with concomitant ischemic heart disease, may outweigh the risks.

C. Effects on the Eye

Beta-blocking agents reduce intraocular pressure, especially in glaucoma. The mechanism usually reported is decreased aqueous humor production. (See Clinical Pharmacology and Box: The Treatment of Glaucoma.)

D. Metabolic and Endocrine Effects

Beta-receptor antagonists such as propranolol inhibit sympathetic nervous system stimulation of lipolysis. The effects on carbohy-drate metabolism are less clear, though glycogenolysis in the human liver is at least partially inhibited after β2-receptor block-ade. Glucagon is the primary hormone used to combat hypogly-cemia; it is unclear to what extent β antagonists impair recovery from hypoglycemia, but they should be used with caution in insulin-dependent diabetic patients. This may be particularly important in diabetic patients with inadequate glucagon reserve and in pancreatectomized patients since catecholamines may be the major factors in stimulating glucose release from the liver in response to hypoglycemia. Beta1-receptor–selective drugs may be less prone to inhibit recovery from hypoglycemia. Beta-receptor antagonists are much safer in those type 2 diabetic patients who do not have hypoglycemic episodes.

The chronic use of β-adrenoceptor antagonists has been associ-ated with increased plasma concentrations of very-low-density lipoproteins (VLDL) and decreased concentrations of HDL choles-terol. Both of these changes are potentially unfavorable in terms of risk of cardiovascular disease. Although low-density lipoprotein (LDL) concentrations generally do not change, there is a variable decline in the HDL cholesterol/LDL cholesterol ratio that may increase the risk of coronary artery disease. These changes tend to occur with both selective and nonselective β blockers, though they may be less likely to occur with β blockers possessing intrinsic sym-pathomimetic activity (partial agonists). The mechanisms by which β-receptor antagonists cause these changes are not understood,though changes in sensitivity to insulin action may contribute.

E. Effects Not Related to Beta-Blockade

Partial β-agonist activity was significant in the first β-blocking drug synthesized, dichloroisoproterenol. It has been suggested that retention of some intrinsic sympathomimetic activity is desirable to prevent untoward effects such as precipitation of asthma or excessive bradycardia. Pindolol and other partial agonists are noted in Table 10–2. It is not yet clear to what extent partial ago-nism is clinically valuable. Furthermore, these drugs may not be as effective as the pure antagonists in secondary prevention of myo-cardial infarction. However, they may be useful in patients who develop symptomatic bradycardia or bronchoconstriction in response to pure antagonist β-adrenoceptor drugs, but only if they are strongly indicated for a particular clinical indication.

Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several β blockers (Table 10–2). This action is the result of typical local anesthetic blockade of sodium channels  and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. The membrane-stabilizing β blockers are not used topically on the eye, because local anesthesia of the cornea would be highly undesirable. Sotalol is a nonselective β-receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade .

The Treatment of Glaucoma

Glaucoma is a major cause of blindness and of great pharma-cologic interest because the chronic form often responds to drug therapy. The primary manifestation is increased intraoc-ular pressure not initially associated with symptoms. Without treatment, increased intraocular pressure results in damage to the retina and optic nerve, with restriction of visual fields and, eventually, blindness. Intraocular pressure is easily mea-sured as part of the routine ophthalmologic examination. Two major types of glaucoma are recognized: open-angle and closed-angle (also called narrow-angle). The closed-angle form is associated with a shallow anterior chamber, in which a dilated iris can occlude the outflow drainage pathway at the angle between the cornea and the ciliary body (see Figure 6–9). This form is associated with acute and painful increases of pressure, which must be controlled on an emergency basis with drugs or prevented by surgical removal of part of the iris (iridectomy). The open-angle form of glaucoma is a chronic condition, and treatment is largely pharmacologic. Because intraocular pressure is a function of the balance between fluid input and drainage out of the globe, the strategies for the treatment of open-angle glaucoma fall into two classes: reduction of aqueous humor secretion and enhancement of aqueous outflow. Five general groups of drugs—cholinomi-metics, α agonists, β blockers, prostaglandin F analogs, and diuretics—have been found to be useful in reducing intraoc-ular pressure and can be related to these strategies as shown in Table 10–3. Of the five drug groups listed in Table 10–3, the prostaglandin analogs and the β blockers are the most popu-lar. This popularity results from convenience (once- or twice-daily dosing) and relative lack of adverse effects (except, in the case of β blockers, in patients with asthma or cardiac pacemaker or conduction pathway disease). Other drugs that have been reported to reduce intraocular pressure include prostaglandin E2 and marijuana. The use of drugs in acute closed-angle glaucoma is limited to cholinomimetics, aceta-zolamide, and osmotic agents preceding surgery. The onset of action of the other agents is too slow in this situation.

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