BETA+BLOCKERS

Beta-blockers
 * History:** Ahlquist hypothesized in 1948 that the physiologic effects of catecholamines were mediated by the activation or inhibition of specific receptors, which he termed alpha and beta.[303] This finding led to the development of antagonists at these receptors that would interfere with the effects of catecholamines. Although alpha-receptor-specific antagonists were available in the early 1950s (e.g., phentolamine and phenoxybenzamine), the first pure beta-blocker, propranolol, was not marketed until 1967. Subsequent to the discovery of propranolol, beta1- and beta2-selective agents, as well as drugs with intrinsic sympathomimetic activity within each subset, were developed. Today, no fewer than 15 beta-blockers have been marketed.

Although initially it was believed that beta-receptors on myocardial tissue were of the beta1 subtype, it is now accepted that beta2-receptors are also located on myocardial cells and are also important regulators of cardiac activity. In addition to cardiac tissue, beta-receptors are located on smooth muscle of the bronchioles, uterus, within the eye, on many blood vessels, in the liver, and in various organ and regulatory systems throughout the body.[307]

Further, it is increasingly being recognized that administration of beta-blockers following myocardial infarction exerts a beneficial effect on mortality. Beta-blockers have been beneficial for both primary and secondary myocardial infarction prophylaxis to prevent sudden death and also are beneficial for the acute treatment of myocardial infarction.[963]

Beta-blocking drugs have many non-cardiovascular applications including treatment of essential tremor, treatment of thyrotoxicosis, prevention of anxiety, prevention of migraine headache,[351] prevention of bleeding associated with esophageal varicies[1358] and, administered ophthalmically, beta-blockers are useful for the treatment of glaucoma. The use of beta-blockers for the prevention of GI bleeding or rebleeding due to esophageal varices is controversial. A meta-analysis of 4 trials of patients with esophageal varices without previous bleeding found that patients receiving nadolol or propranolol had a significantly lower incidence of GI bleeding or fatal bleeding compared to the control group, however, overall survival after 2 years was not different between the groups.[1358]

Ophthalmic beta-blockers are the most commonly used agents in the treatment of glaucoma. They reduce IOP and treat ocular hypertension. Beta-blockers provide an alternative mechanism for the treatment of glaucoma over the more traditional agents (e.g., pilocarpine, physostigmine). Some ophthalmically-administered beta-blockers are also available for systemic administration (e.g., betaxolol, carteolol, timolol), whereas other beta-blockers are only available as ophthalmic preparations (levobunolol, metipranolol).


 * Mechanism of Action:** In general, all beta-adrenergic antagonists compete with adrenergic neurotransmitters (i.e., catecholamines) for binding at sympathetic receptor sites. These drugs block sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscle. Blockade of beta1-receptors decreases both resting and exercise heart rate and cardiac output, decreases both systolic and diastolic blood pressure, and inhibits the reflex response to orthostatic hypotension. The fall in cardiac output induced by beta1 antagonism is often countered by a moderate reflex increase in peripheral vascular resistance that can be magnified by beta2 blockade (unopposed alpha stimulation). As a result, nonselective beta-blocking agents can produce a more modest decrease in diastolic blood pressure compared with selective beta1 antagonists. In addition, nonselective agents can competitively block beta2-adrenergic responses in the bronchial muscles, potentially inducing bronchospasm.[295]

Therapeutic actions of beta-blockers in the treatment of hypertension include a negative chronotropic effect that decreases heart rate at rest and after exercise; a negative inotropic effect; reduction of sympathetic outflow from the CNS; and suppression of renin release from the kidneys. Thus, beta-blockers affect blood pressure via multiple mechanisms.[295]

Actions that make beta-receptor antagonists useful in treating hypertension also apply to managing chronic stable angina. The reduction in myocardial oxygen demand induced by these agents decreases the frequency of anginal attacks, decreases nitrate requirements, and increases exercise tolerance. Other postulated anti-anginal actions include an increase in oxygen delivery to tissues as a result of beta-receptor antagonist's lowering of hemoglobin's affinity for oxygen; reduction of platelet aggregation is postulated to be related to interference with calcium ion flux.[295]

A critical result of beta blockade is a reduction in myocardial ischemia. Beta-blockers can limit the severity and recurrence of infarction, as well as a decrease in mortality secondary to myocardial infarction.[963] In addition to a decrease in myocardial oxygen demand, beta-blockers also possess antiarrhythmic properties at the nodal level of pacemaker control. Although beta blockade is most beneficial when initiated within the first few days following acute myocardial infarction, especially in the highest risk subgroup of patients, relative reductions in infarct size secondary to the use of beta-blockers can approach 10—30% per year.[308] As a result, beta-blockers should be considered standard therapy for secondary prevention of reinfarction and reduction of late mortality in all patients who do not have a clear contraindication to beta blockade.

Other clinical applications of beta-blockers make use of both the cardiovascular and the nervous system actions. The cardiovascular actions of beta-blockers are useful in the prevention of migraine and the treatment of portal hypertension to prevent bleeding of esophageal varicies. Sympatholytic effects make beta-blockers useful for the treatment of essential tremor, thyrotoxicosis, and to control situational anxiety.

Beta-blockers, especially propranolol, have been used for the treatment of thyrotoxicosis. Beta-blockade can ameloriate the symptoms associated with thyrotoxicosis such as tremor, palpitations, anxiety, and heat intolerance. In addition, D-propranolol and nadolol block the conversion of T4 to T3, but the therapeutic effect of this action is minimal.[691]

Beta-blockers have been used to treat portal hypertension and to prevent bleeding of esophageal varices. Nonselective beta-blockers such as nadolol and propranolol decrease blood flow in the superior portosystemic collateral circulation and blood flow in the splanchnic region, ultimately decreasing portal venous pressure.[652] A decrease in cardiac output may also reduce hepatic arterial and portal venous perfusion. Most trials utilized a therapeutic end point of a reduction in resting heart rate of 20—25% or a decrease in hepatic pressure of 25% (or < 12 mmHg).[652] Activation of unopposed alpha-receptors leads to splanchnic vasoconstriction, thus decreasing portal perfusion.[653] The efficacy of therapy appears to be related to compliance, lack of ascites, and patients with less severe disease.[652]

In the prevention of migraine headaches, beta-blockade can interfere with arterial dilation, inhibit renin secretion, and block catecholamine-induced lipolysis. Blocking lipolysis decreases arachidonic acid synthesis and subsequent prostaglandin production. Inhibition of platelet aggregation is secondary to a decrease in prostaglandins and blockade of catecholamine-induced platelet adhesion. Other actions include increased oxygen delivery to tissues and prevention of coagulation during epinephrine release.[350]

In the management of hereditary of familial essential tremor, beta-blockade controls the involuntary, rhythmic and oscillatory movements. Tremor amplitude is reduced, but not the frequency of tremor.

Beta-blockers can dampen the peripheral physiologic symptoms of anxiety. Beta-blockade can attenuate somatic symptoms of anxiety such as palpitations and tremor, but it is less effective in controlling psychologic components, such as intense fear.

Ophthalmic beta-blockers interfer with the production of aqueous humor via inhibition of adrenergically driven processes within the ciliary processes. As a result of their actions, IOP is reduced in patients with either elevated or normal IOP. This reduction occurs irrespective of the presence of glaucoma. Decreased aqueous humor may also be responsible for the ocular antihypertensive effects. Visual acuity, pupil size, and accommodation do not appear to be affected by beta-blockade.


 * Distinguishing Features:** Beta-adrenergic blockers can be divided into five primary categories: nonselective agents with or without intrinsic sympathomimetic activity (ISA) or partial agonist activity (PAA); cardioselective (e.g., beta1-selective) agents with or without ISA/PAA; and dual-acting (alpha- and beta-antagonist) agents. Nonselective agents without ISA include nadolol, propranolol, sotalol, and timolol. Cardioselective agents without ISA include atenolol, betaxolol, bisoprolol, esmolol, and metoprolol. The primary nonselective beta-adrenergic antagonist with ISA available in the United States is pindolol. Acebutolol is the only cardioselective beta-blocker with ISA. Carvedilol and labetalol are beta-adrenergic antagonists with alpha-blocking properties.

Another distinction can be made with respect to lipophilicity of the beta-blockers. The more lipophilic drugs tend to be metabolized to a greater extent, to exhibit greater serum concentration variability, and to have a shorter duration of activity. The most lipophilic beta-blockers are acebutolol, betaxolol, labetalol, metoprolol, propranolol, and timolol. The water-soluble beta-antagonists are atenolol, nadolol, and sotalol. There is some possibility that lipid-soluble beta-blockers may be more effective in prevention sudden cardiac death following myocardial infarction. Because the more lipid-soluble members of the class appear to be more effective for this use, a central mechanism of action is proposed.[963] Atenolol (water-soluble) and metoprolol (lipid-soluble) are approved by the FDA for early and late adjunctive treatment of acute myocardial infarction.

Propranolol is the only agent FDA approved for essential tremor, although metoprolol, nadolol and timolol are also effective. Atenolol, nadolol, propranolol, timolol have been used to prevent migraine headaches.

With respect to administration, esmolol is an ultra-short-acting agent with a half-life of 9 minutes that is given only by continuous infusion. When considering indications, most agents, except labetalol, are useful in one or more of the following conditions: angina, hypertension, arrhythmias, mild congestive heart failure, and post-MI adjunctive therapy.[295] [306] Clearly, the beta-adrenergic antagonists are a diverse and extremely important class of pharmacologic agents.

Few distinctions are available for the ophthalmic beta-blockers. The onset of action is similar for all agents, ranging from 30—60 minutes, with a duration of action ranging between 12—24 hours. Betaxolol is the only beta1-receptor specific ophthalmic beta-blocker. Levobunolol appears to be the most effective agent when given on a once daily basis.


 * Adverse Reactions:** The adverse effects of beta-blockers are generally mild and temporary; they usually occur at the onset of therapy and diminish over time. Most adverse reactions of beta-blockers are extensions of their therapeutic effects. Bradycardia and hypotension are rarely serious and can be reversed with IV atropine, if necessary. AV block, secondary to depressed conduction at the AV node, might necessitate sympathomimetic and/or pressor therapy or the use of a temporary pacemaker. Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of beta-blocker therapy.

Adverse CNS effects include dizziness, fatigue, and depression. Although much less common with hydrophilic beta-blockers, CNS depression can occur, resulting in mental disorders, fatigue, and, in some cases, vivid dreams. Diarrhea and nausea/vomiting are the most common GI adverse effects during therapy with beta-blockers. Bronchospasm and dyspnea are more likely to occur with nonselective beta-blockers or with high doses of cardioselective agents because the beta selectivity of the drug is lost. Patients with preexisting bronchospastic disease are at greater risk.

Both hypoglycemia and hyperglycemia can occur during beta-blocker therapy. Beta-blockers can interfere with glycogenolysis to cause hyperglycemia and can also mask signs of hypoglycemia. Beta-blockers should be used cautiously in brittle diabetics.

Beta-blockers have little effect on total cholesterol and plasma LDLs, but have been shown to increase triglycerides and decrease plasma HDLs. The role that the characteristics of cardioselectivity and intrinsic sympathomimetic activity of beta-blockers play in these effects are more controversial. In a recent meta-analysis, it was shown that agents with intrinsic sympathomimetic activity or cardioselectivity tend to have less effect on triglycerides and HDLs. Agents with both characteristics tended to reduce total cholesterol and LDLs.[995]

Adverse reactions from ophthalmic beta-blockers are usually limited to their ocular effects, such as transient burning, stinging, and blurred vision however, these preparations can be absorbed causing systemic adverse reactions, similar to oral or parenteral beta-blockers. Ophthalmic betaxolol appears to cause less systemic effects compared to ophthalmic timolol and levobunolol.[1383]

Despite the current knowledge of the diversity and function of beta-receptors within the human body, much remains to be learned about some of their regulatory roles in physiologic homeostasis. Although the variety of beta-receptor antagonists that are currently available is plentiful, the pharmacologic uses for beta-receptor antagonists is likely to continue to grow.