1. Actions: Labetalol [lah-BET-a-lole] and carvedilol [CAR-ve-dil-ol] are reversible β-blockers with concurrent α1-blocking actions that produce peripheral vasodilation, thereby reducing blood pressure. They contrast with the other β-blockers that produce peripheral vasoconstriction, and they are therefore useful in treating hypertensive patients for whom increased peripheral vascular resistance is undesirable. They do not alter serum lipid or blood glucose levels. Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure

2. Therapeutic use in hypertension: Labetalol is useful for treating the elderly or black hypertensive patient in whom increased peripheral vascular resistance is undesirable. [Note: In general, black hypertensive patients are not well controlled with β-blockers.] Labetalol may be employed as an alternative to methyldopa in the treatment of pregnancyinduced hypertension. Intravenous labetalol is also used to treat hypertensive emergencies, because it can rapidly lower blood pressure .

3. Adverse effects: Orthostatic hypotension and dizziness are associated with α1 blockade. Figure 7.10 summarizes the receptor specificities and uses of the β-adrenergic antagonists.

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Pindolol and acebutolol:

Antagonists with partial agonist activity 

1. Action: 

a. Cardiovascular: 

Acebutolol and pindolol [PIN-doe-lole] are not pure antagonists; instead, they have the ability to weakly stimulate both β1 and β2 receptors 

Figure : Comparison of agonists, antagonists,  and partial agonists  of β adrenoceptors.

and are said to have intrinsic sympathomimetic activity (ISA). These partial agonists stimulate the β receptor to which they are bound, yet they inhibit stimulation by the more potent endogenous catecholamines, epinephrine and norepinephrine. The result of these opposing actions is a much diminished effect on cardiac rate and cardiac output compared to that of β-blockers without ISA. 

b. Decreased metabolic effects: Blockers with ISA minimize the disturbances of lipid and carbohydrate metabolism that are seen with other β-blockers. 

2. Therapeutic use in hypertension:

β-Blockers with ISA are effective in hypertensive patients with moderate bradycardia, because a further decrease in heart rate is less pronounced with these drugs. Carbohydrate metabolism is less affected with acebutolol and pindolol than it is with propranolol, making them valuable in the treatment of diabetics. [Note: The b blockers with ISA are not used as antiarrhythmic agents due to their partial agonist effect.] 

Figure : summarizes some of the indications for βblockers. 

Acebutolol, atenolol, metoprolol, and esmolol:

Selective β1 antagonists Drugs that preferentially block the β1 receptors have been developed to eliminate the unwanted bronchoconstrictor effect (β2 effect) of propranolol seen among asthmatic patients. Cardioselective β-blockers, such as acebutolol [a-se-BYOO-toelole], atenolol [a-TEN-oh-lole], and metoprolol [me-TOE-proe-lole], antagonize β1 receptors at doses 50- to 100-fold less than those required to block β2 receptors. This cardioselectivity is thus most pronounced at low doses and is lost at high doses. [Note: Acebutolol has some intrinsic agonist activity.

1. Actions: These drugs lower blood pressure in hypertension and increase exercise tolerance in angina . Esmolol [EZ-moe-lole] has a very short lifetime  due to metabolism of an ester linkage. It is only given intravenously if required during surgery or diagnostic procedures (for example, cystoscopy). In contrast to propranolol, the cardiospecific blockers have relatively little effect on pulmonary function, peripheral resistance, and carbohydrate metabolism. Nevertheless, asthmatics treated with these agents must be carefully monitored to make certain that respiratory activity is not compromised

2. Therapeutic use in hypertension: The cardioselective β-blockers are useful in hypertensive patients with impaired pulmonary function. Because these drugs have less effect on peripheral vascular β2 receptors, coldness of extremities, a common side effect of β-blocker therapy, is less frequent. Cardioselective β-blockers are useful in diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents.


A nonselective β antagonist Propranolol [proe-PRAN-oh-lole] is the prototype β-adrenergic antagonist and blocks both β1 and β2 receptors. Sustainedrelease preparations for once-a-day dosing are available.

 1. Actions: 

a. Cardiovascular: 

Propranolol diminishes cardiac output, having both negative inotropic and chronotropic effects

Figure :Actions of propranolol and other β- blockers.

It directly depresses sinoatrial and atrioventricular activity. The resulting bradycardia usually limits the dose of the drug. Cardiac output, work, and oxygen consumption are decreased by blockade of β1 receptors; these effects are useful in the treatment of angina . The β-blockers are effective in attenuating supraventricular cardiac arrhythmias but generally are not effective against ventricular arrhythmias (except those induced by exercise).

b. Peripheral vasoconstriction:

Blockade of β receptors prevents β2-mediated vasodilation . The reduction in cardiac output leads to decreased blood pressure. This hypotension triggers a reflex peripheral vasoconstriction that is reflected in reduced blood flow to the periphery. On balance, there is a gradual reduction of both systolic and diastolic blood pressures in hypertensive patients. No postural hypotension occurs, because the α1adrenergic receptors that control vascular resistance are unaffected.

 c. Bronchoconstriction:

Blocking β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle . This can precipitate a respiratory crisis in patients with chronic obstructive pulmonary disease (COPD) or asthma. β-Blockers, and in particular nonselective ones, are thus contraindicated in patients with COPD or asthma.

 d. Increased Na+ retention: 

Reduced blood pressure causes a decrease in renal perfusion, resulting in an increase in Na+ retention and plasma volume . In some cases, this compensatory response tends to elevate the blood pressure. For these patients, β-blockers are often combined with a diuretic to prevent Na+ retention. By inhibiting β receptors, renin production is also prevented, contributing to Na+ retention.

e. Disturbances in glucose metabolism: 

β-blockade leads to decreased glycogenolysis and decreased glucagon secretion. Therefore, if a Type I (formerly insulin-dependent) diabetic is to be given propranolol, very careful monitoring of blood glucose is essential, because pronounced hypoglycemia may occur after insulin injection. βBlockers also attenuate the normal physiologic response to hypoglycemia

f. Blocked action of isoproterenol: 

All β-blockers, including propranolol, have the ability to block the actions of isoproterenol on the cardiovascular system. Thus, in the presence of a β-blocker, isoproterenol does not produce either the typical cardiac stimulation or reductions in mean arterial pressure and diastolic pressure

Figure : Summary of effects of adrenergic blockers on the changes in blood pressure induced by isoproterenol, epinephrine, and norepinephrine.

 [Note: In the presence of a β-blocker, epinephrine no longer lowers diastolic blood pressure or stimulates the heart, but its vasoconstrictive action (mediated by α receptors) remains unimpaired. The actions of norepinephrine on the cardiovascular system are mediated primarily by α receptors and are, therefore, unaffected.

2. Therapeutic effects:

 a. Hypertension:
Propranolol lowers blood pressure in hypertension by several different mechanisms of action. Decreased cardiac output is the primary mechanism, but inhibition of renin release from the kidney and decreased sympathetic outflow from the CNS also contribute to propranolol's antihypertensive effects.

 b. Glaucoma:
β-Blockers, particularly topically applied timolol, are effective in diminishing intraocular pressure in glaucoma. This occurs by decreasing the secretion of aqueous humor by the ciliary body. Many patients with glaucoma have been maintained with these drugs for years. They neither affect the ability of the eye to focus for near vision nor change pupil size, as do the cholinergic drugs. However, in an acute attack of glaucoma, pilocarpine is still the drug of choice. The β-blockers are only used to treat this disease chronically.

c. Migraine:
 Propranolol is also effective in reducing migraine episodes when used prophylactically . βBlockers are valuable in the treatment of chronic migraine, in which they decrease the incidence and severity of the attacks. The mechanism may depend on the blockade of catecholamine-induced vasodilation in the brain vasculature. [Note: During an attack, the usual therapy with sumatriptan or other drugs is used.]

d. Hyperthyroidism:
Propranolol and other β-blockers are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism. In acute hyperthyroidism (thyroid storm), β-blockers may be lifesaving in protecting against serious cardiac arrhythmias.

e. Angina pectoris:
Propranolol decreases the oxygen requirement of heart muscle and, therefore, is effective in reducing the chest pain on exertion that is common in angina. Propranolol is therefore useful in the chronic management of stable angina, but not for acute treatment. Tolerance to moderate exercise is increased, and this is measurable by improvement in the electrocardiogram. However, treatment with propranolol does not allow strenuous physical exercise, such as tennis.

 f. Myocardial infarction:
Propranolol and other β-blockers have a protective effect on the myocardium. Thus, patients who have had one myocardial infarction appear to be protected against a second heart attack by prophylactic use of β-blockers. In addition, administration of a β-blocker immediately following a myocardial infarction reduces infarct size and hastens recovery. The mechanism for these effects may be a blocking of the actions of circulating catecholamines, which would increase the oxygen demand in an already ischemic heart muscle. Propranolol also reduces the incidence of sudden arrhythmic death after myocardial infarction.

3. Adverse effects:

 a. Bronchoconstriction: Propranolol has a serious and potentially lethal side effect when administered to an asthmatic

Figure : Adverse effects commonly observed in individuals treated with propranolol.

An immediate contraction of the bronchiolar smooth muscle prevents air from entering the lungs. Deaths by asphyxiation have been reported for asthmatics who were inadvertently administered the drug. Therefore, propranolol must never be used in treating any individual with COPD or asthma.

b. Arrhythmias:
Treatment with β-blockers must never be stopped quickly because of the risk of precipitating cardiac arrhythmias, which may be severe. The β-blockers must be tapered off gradually for 1 week. Long-term treatment with a β antagonist leads to up-regulation of the β-receptor. On suspension of therapy, the increased receptors can worsen angina or hypertension.

c. Sexual impairment:
Because sexual function in the male occurs through α-adrenergic activation, β-blockers do not affect normal ejaculation or the internal bladder sphincter function. On the other hand, some men do complain of impaired sexual activity. The reasons for this are not clear, and they may be independent of β-receptor blockade.

d. Disturbances in metabolism:
β-Blockade leads to decreased glycogenolysis and decreased glucagon secretion. Fasting hypoglycemia may occur. [Note: Cardioselective β-blockers are preferred in treating asthmatic patients who use insulin (see β1-selective antagonists).]

e. Drug interactions:
Drugs that interfere with the metabolism of propranolol, such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects. Conversely, those that stimulate its metabolism, such as barbiturates, phenytoin, and rifampin, can decrease its effects.

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Yohimbine [yo-HIM-bean] is a selective competitive α2 blocker. It is found as a component of the bark of the yohimbe tree and is sometimes used as a sexual stimulant. Yohimbine works at the level of the CNS to increase sympathetic outflow to the periphery. It directly blocks α2 receptors and has been used to relieve vasoconstriction associated with Raynaud's disease. Yohimbine is contraindicated in CNS and cardiovascular conditions because it is a CNS and cardiovascular stimulant.