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Chapter: Modern Pharmacology with Clinical Applications: Adrenoceptor Antagonists

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beta-Adrenoceptor Blocking Agents

As a class, β -blocking agents have greater structural similarity to their corresponding agonists than do the α- blockers.

β-ADRENOCEPTOR BLOCKING AGENTS

A large number of β-blockers are on the market in the United States. Of these, propranolol, a nonselective β -antagonist, was the first to be introduced and is the prototypical drug with which the others are compared. Metoprolol was the first β1-selective drug and timolol the first β-blocker approved for ophthalmic use.

As a class, β -blocking agents have greater structural similarity to their corresponding agonists than do the α- blockers. This structural similarity also accounts for the greater specificity of action exhibited by the β-receptor blocking drugs than by the α -adrenoceptor blocking drugs.

The similarity in structure to β -agonists is most cer-tainly responsible for the finding that some β-blockers activate α -receptors; that is, they have some intrinsic sympathomimetic activity. The intrinsic activity of these compounds is generally modest in comparison with an agonist, such as isoproterenol, and they are generally re-ferred to as partial agonists .

Mechanism of Action

All of the β-blockers exert equilibrium-competitive an-tagonism of the actions of catecholamines and other adrenomimetics at β -receptors. Probably the best-recognized action of these compounds that is not medi-ated by a β-receptor is depression of cellular membrane excitability. This effect has been described as a mem-brane-stabilizing action, a quinidinelike effect, or a local anesthetic effect. This action is not too surprising in view of the structural similarities between β-blockers and local anesthetics. However, with the usual therapeu- tic doses, the actions of the -receptor blocking agents appear to be almost entirely accounted for by their -re-ceptor antagonism.

Because the β-receptors of the heart are primarily of the β 1 type and those in the pulmonary and vascular smooth muscle are β 2 receptors, β 1-selective antagonists are frequently referred to as cardioselective blockers. The intrinsic activity, cardioselectivity, and membrane-stabilizing actions of a number of β-blockers are sum-marized in Table 11.2.


Absorption, Metabolism, and Excretion

Propranolol (Inderal) is suitable for both parental and oral administration. Absorption from the gastrointesti-nal tract is extensive. The peak therapeutic effect after oral administration occurs in 1 to 1.5 hours. The plasma half-life of propranolol is approximately 3 hours. The drug is concentrated in the lungs and to a lesser extent in the liver, brain, kidneys, and heart. Binding to plasma proteins is extensive (90%). The liver is the chief organ involved in the metabolism of propranolol, and the drug is subject to a significant degree of first-pass metabo-lism. At least eight metabolites have been recovered from the urine, the major excretory route.

The pharmacokinetic profile of metoprolol (Lopres-sor) is similar to that of propranolol. Metoprolol is read-ily and rapidly absorbed after oral administration and is subject to a significant amount of first-pass metabolism by the liver. Curiously, the duration of metoprolol’s ac-tion is longer than one would predict from its plasma half-life, which ranges from 0.5 to 2.5 hours. The degree of binding of metoprolol to plasma proteins is modest (10%). The extensive distribution of metoprolol to the lungs and kidney is typical of a moderately lipophilic drug. Metoprolol undergoes considerable metabolism; only 3 to 10% of an administered dose is recovered as unchanged drug. 

The metabolites are essentially inactive as β-receptor blocking agents and are eliminated pri-marily by renal excretion. Small amounts of the drug are present in the feces.

Timolol (Timoptic) is almost completely absorbed from the gastrointestinal tract. Peak plasma levels occur 2 to 4 hours after oral administration; the plasma half-life of timolol is approximately 5.5 hours. The extensive tissue distribution of timolol into lung, liver, and kidney is similar to that of other β-blockers. Approximately 70% of the drug is excreted in the urine within 24 hours, mostly as highly polar unconjugated metabolites. Only 6% of an administered dose is recovered in the feces. Although timolol is approved for the topical treatment of elevated intraocular pressure, there is limited infor-mation about its pharmacokinetics following adminis-tration by this route. The drug apparently can reach the systemic circulation after intraocular instillation, but plasma levels are only about 7% of those achieved in the aqueous humor.

About half of an orally administered dose of acebu-tolol (Sectral) is absorbed. Approximately 25% of the drug is bound to plasma proteins, and its plasma half-life is about 4 hours. Metabolism of acebutolol produces a metabolite with β-blocking activity whose half-life is 10 hours.

Roughly half of an orally administered dose of atenolol (Tenormin) is absorbed. The drug is eliminated primarily by the kidney and unlike propranolol, under-goes little hepatic metabolism. Its plasma half-life is ap-proximately 6 hours, although if it is administered to a patient with impaired renal function, its half-life can be considerably prolonged.

Absorption of an oral dose of betaxolol (Kerlone, Betoptic) is almost complete. The drug is subject to a slight first-pass effect such that the absolute bioavail-ability of the drug is about 90%. Approximately 50% of administered betaxolol binds to plasma proteins, and its plasma half-life is about 20 hours; it is suitable for dos-ing once per day. The primary route of elimination is by liver metabolism, with only 15% of unchanged drug be-ing excreted.

Carteolol (Cartrol) is a long-acting β-blocker that is suitable for dosing once per day. It is almost completely absorbed and exhibits about 30% binding to plasma proteins. Unlike many β-blockers, carteolol is not ex-tensively metabolized. Up to 70% of an administered dose is excreted unchanged.

The β-blocker esmolol (Brevibloc) is unusual in that it is very rapidly metabolized; its plasma half-life is only 9 minutes. It is subject to hydrolysis by cytosolic es-terases in red blood cells to yield methanol and an acid metabolite, the latter having an elimination half-life of about 4 hours. Only 2% of the administered esmolol is excreted unchanged. Because of its rapid onset and short duration of action, esmolol is used by the intra-venous route for the control of ventricular arrhythmias in emergencies.

Nadolol (Corgard) is slowly and incompletely ab-sorbed from the gastrointestinal tract, and only 30% of an orally administered dose is absorbed. Appreciable metabolism does not seem to occur; nadolol is excreted primarily unchanged in the urine and feces. The plasma half-life is quite long, approaching 24 hours, which per-mits dosing once per day.

Pindolol (Visken) is extensively absorbed from the gastrointestinal tract. First-pass metabolism is estimated at about 15%, and its plasma half-life is on the order of 3 to 4 hours. The binding of pindolol to plasma proteins is approximately 50%. The metabolic fate of pindolol is not completely understood, although 50% of an admin-istered dose is recovered, primarily in the urine, as un-changed drug.

Pharmacological Actions

The most important actions of the β-blocking drugs are on the cardiovascular system. β β-blockers decrease heart rate, myocardial contractility, cardiac output, and con-duction 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 β-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 re-sults from a β-blocker–induced decrease in cardiac out-put. Vasoconstriction is mediated by α-receptors, and α - receptors are not antagonized by β -receptor blocking agents. Chronic administration of β-blockers, however, results in a reduction of blood pressure, and this is the reason for their use in primary hypertension . The mechanism of this effect is not well un-derstood, but it may include such actions as a reduction in renin release, antagonism of β β -receptors in the central nervous system, or antagonism of presynaptic facilita-tory β -receptors on sympathetic nerves.

Total coronary blood flow is reduced by the β-blockers. This effect may be due in part to the unop-posed α-receptor–mediated vasoconstriction that fol-lows β-receptor blockade in the coronary arteries. Additional contributing factors to the decrease in coro-nary blood flow are the negative chronotropic and in-otropic effects produced by the β-blockers; these ac-tions 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 coro-nary blood flow.

In view of the effects of the β -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 inade-quate myocardial perfusion. The chief benefit of the - blockers in this condition derives from their ability to decrease cardiac work and oxygen demand. The ability of β-blockers to decrease cardiac work and oxygen demand may also be responsible for the favor-able effects of these agents in the long-term manage-ment of congestive heart failure.

The release of renin from the juxtaglomerular cells of the kidney is believed to be regulated in part by - receptors; most β-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 . Nevertheless, - blockers are useful and logical agents to use when treat-ing 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 endoge-nous catecholamines are mediated by β-receptors and are subject to blockade by β-blockers. This metabolic antagonism exerted by the β-blockers is particularly pronounced if the levels of circulating catecholamines have been increased reflexively in response to hypo-glycemia. Other physiological changes induced by hy-poglycemia, such as tachycardia, may be blunted by β- blockers. These agents therefore must be used with caution in patients susceptible to hypoglycemia (e.g., di-abetics treated with insulin). Because the metabolic re-sponses to catecholamines are mediated by β 2-receptors and possibly by β 3-receptors, β 1-selective antagonists such as metoprolol and atenolol may be better choices whenever β-blocker therapy is indicated for a patient who has hypoglycemia.

Propranolol increases airway resistance by antago-nizing β2-receptor–mediated bronchodilation. Although the resulting bronchoconstriction is not a great concern in patients with normal lung function, it can be quite se-rious in the asthmatic. The cardioselective β-blockers produce less bronchoconstriction than do the nonselec-tive antagonists.

β-blockers can reduce intraocular pressure in glau-coma and ocular hypertension. The mechanism is be-lieved to be related to a decreased production of aque-ous humor.

Clinical Uses

The β-receptor blocking agents have widespread and important uses in the management of cardiac arrhyth-mias, angina pectoris, and hypertension. Even though acute administration of β-blockers can precipitate congestive heart failure in patients who are largely dependent on enhanced sym- pathetic nerve activity to maintain sufficient cardiac output, the β-blockers have been shown to be quite use-ful in the long-term management of patients with mild to moderate heart failure. The β-blockers also offer proven benefit in preventing the recurrence of a myo-cardial infarction (MI). For this purpose, it is best if β-blocker therapy is instituted soon after the MI and continued for the long term.

Hyperthyroidism

The β-blockers significantly reduce the peripheral man-ifestations of hyperthyroidism, particularly elevated heart rate, increased cardiac output, and muscle tremors. Although the β-blockers can improve the clinical status of the hyperthyroid patient, the patient remains bio-chemically hyperthyroid. The β-blockers should not be used as the sole form of therapy in hyperthyroidism. They are most logically employed in the management of hyperthyroid crisis, in the preoperative preparation for thyroidectomy, and during the initial period of adminis-tration of specific antithyroid drugs .

Glaucoma

β-blockers can be used topically to reduce intraocular pressure in patients with chronic open-angle glaucoma and ocular hypertension. The mechanism by which ocular pressure is reduced appears to depend on de-creased production of aqueous humor. Timolol has a somewhat greater ocular hypotensive effect than do the available cholinomimetic or adrenomimetic drugs. The β-blockers also are beneficial in the treatment of acute angle-closure glaucoma.

Anxiety States

Patients with anxiety have a variety of psychic and so-matic symptoms. The peripheral manifestations of anxi-ety may include a number of symptoms (e.g., palpita-tions) that are due in part to overactivity of the sympathetic nervous system. The β-blocking agents may offer some benefit in the treatment of anxiety.

Migraine

The β-blockers may offer some value in the prophylaxis of migraine headache, possibly because a blockade of craniovascular  β--receptors results in reduced vasodila-tion. The painful phase of a migraine attack is believed to be produced by vasodilation.

Adverse Effects and Contraindications

The most prominent side effects associated with the ad-ministration of the β-blockers are those directly attrib-utable to their ability to block  β--receptors. Although β-blockers prevent an increase in heart rate and cardiac output resulting from an activation of the autonomic nervous system, these effects may not be troublesome in patients with adequate or marginal cardiac reserve. However, they can be life threatening for a patient with congestive heart failure. Also, because conduction of impulses in the heart may be slowed by β-blockers, pa-tients with conduction disturbances, particularly through the atrioventricular node, should not be treated with β-blockers.

Caution must be exercised in the use of β-blockers in obstructive airway disease, since these drugs promote further bronchoconstriction. Cardioselective β-blockers have less propensity to aggravate bronchoconstriction than do nonselective β-blockers.

 

β-blockers potentiate hypoglycemia by antagoniz-ing the catecholamine-induced mobilization of glyco-gen. The use of β-blockers in hypoglycemic patients is therefore dangerous and must be undertaken with cau-tion. If β-blocker therapy is required, a cardioselective β-blocker is preferred.

Whenever β-blocker therapy is employed, the pe-riod of greatest danger for asthmatics or insulin-dependent diabetics is during the initial period of drug administration, since the greatest disruption of the au-tonomic balance will occur at this time. If marked toxi-city does not occur during this period, further doses are less likely to cause problems.

Although the β-blockers produce a number of cen-tral effects, it is not clear whether these effects are due to blockade of central  β--receptors. After high doses, pa-tients may have hallucinations, nightmares, insomnia, and depression.

Topical application of timolol to the eye is well tol-erated, and the incidence of side effects, which consist of burning or dryness of the eyes, is reported to be 5 to 10%.

In spite of the potential seriousness of some of their side effects, β-blockers as a class are well tolerated and patient compliance is good.

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