Labetalol

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. 

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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.

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Propranolol

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

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. 

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Prazosin

Prazosin [PRAY-zoe-sin], terazosin [ter-AY-zoe-sin], doxazosin [dox-AY-zoe-sin], and tamsulosin [tam-SUE-loh-sin] are selective competitive blockers of the α1 receptor. In contrast to phenoxybenzamine and phentolamine the first three drugs are useful in the treatment of hypertension. Tamsulosin and alfuzosin [al-FYOO-zoe-sin] are indicated for the treatment of benign prostatic hypertrophy (also known as benign prostatic hyperplasia or BPH). Metabolism leads to inactive products that are excreted in the urine except for those of doxazosin, which appear in the feces. Doxazosin is the longest acting of these drugs

1. Cardiovascular effects: All of these agents decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. Tamsulosin has the least effect on blood pressure. These drugs, unlike phenoxybenzamine and phentolamine, cause minimal changes in cardiac output, renal blood flow, and the glomerular filtration rate.

 2. Therapeutic uses: Individuals with elevated blood pressure who have been treated with one of these drugs do not become tolerant to its action. However, the first dose of these drugs produces an exaggerated orthostatic hypotensive response that can result in syncope (fainting). This action, termed a “first-dose” effect, may be minimized by adjusting the first dose to one-third or one-fourth of the normal dose and by giving the drug at bedtime. An increase in the risk of congestive heart failure has been reported when α1-receptor blockers have been used as monotherapy in hypertension. The α1-receptor antagonists have been used as an alternative to surgery in patients with symptomatic BPH. Blockade of the α receptors decreases tone in the smooth muscle of the bladder neck and prostate and improves urine flow. Tamsulosin is a more potent inhibitor of the α1A receptors found on the smooth muscle of the prostate. This selectivity accounts for tamsulosin's minimal effect on blood pressure. [Note: Finasteride and dutasteride inhibit 5α-reductase, preventing the conversion of testosterone to dihydrotestosterone. These drugs are approved for the treatment of BPH by reducing prostate volume in selected patients ]

3. Adverse effects: α1 Blockers may cause dizziness, a lack of energy, nasal congestion, headache, drowsiness, and orthostatic hypotension (although to a lesser degree than that observed with phenoxybenzamine and phentolamine). An additive antihypertensive effect occurs when prazosin is given with either a diuretic or a β-blocker, thereby necessitating a reduction in its dose. Due to a tendency to retain sodium and fluid, prazosin is frequently used along with a diuretic. Male sexual function is not as severely affected by these drugs as it is by phenoxybenzamine and phentolamine; however, by blocking a receptors in the ejaculatory ducts and impairing smooth muscle contraction, inhibition of ejaculation and retrograde ejaculation have been reported. Figure below summarizes some adverse effects observed with αblockers.

Figure : Some adverse effects commonly observed with nonselective α- adrenergic blocking agents.

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phentolamine

In contrast to phenoxybenzamine, phentolamine [fen-TOLE-a-meen] produces a competitive block of α1 and α2 receptors. The drug's action lasts for approximately 4 hours after a single administration. Like phenoxybenzamine, it produces postural hypotension and causes epinephrine reversal. Phentolamine-induced reflex cardiac stimulation and tachycardia are mediated by the baroreceptor reflex and by blocking the α2 receptors of the cardiac sympathetic nerves. The drug can also trigger arrhythmias and anginal pain, and it is contraindicated in patients with decreased coronary perfusion. Phentolamine is also used for the short-term management of pheochromocytoma. Phentolamine is now rarely used for the treatment of impotence (it can be injected intracavernosally to produce vasodilation of penile arteries.

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Phenoxybenzamine

 Phenoxybenzamine [fen-ox-ee-BEN-za-meen] is nonselective, linking covalently to both α1-postsynaptic and α2-presynaptic receptors

Figure : Covalent  inactivation of α1 adrenoceptor by phenoxybenzamine.



The block is irreversible and noncompetitive, and the only mechanism the body has for overcoming the block is to synthesize new adrenoceptors, which requires a day or more. Therefore, the actions of phenoxybenzamine last about 24 hours after a single administration. After the drug is injected, a delay of a few hours occurs before a blockade develops, because the molecule must undergo biotransformation to the active form.


1. Actions: 

a. Cardiovascular effects: 

By blocking α receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. The decreased peripheral resistance provokes a reflex tachycardia. Furthermore, the ability to block presynaptic inhibitory α2 receptors in the heart can contribute to an increased cardiac output. [Note: These receptors when blocked will result in more norepinephrine release, which stimulates β receptors on the heart to increase cardiac output]. Thus, the drug has been unsuccessful in maintaining lowered blood pressure in hypertension and has been discontinued for this purpose.


 b. Epinephrine reversal: 

All α-adrenergic blockers reverse the α-agonist actions of epinephrine. For example, the vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds caused by stimulation of β receptors is not blocked. Therefore, the systemic blood pressure decreases in response to epinephrine given in the presence of phenoxybenzamine .

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


 [Note: The actions of norepinephrine are not reversed but are diminished, because norepinephrine lacks significant β-agonist action on the vasculature.] Phenoxybenzamine has no effect on the actions of isoproterenol, which is a pure β agonist .

2. Therapeutic uses:

Phenoxybenzamine is used in the treatment of pheochromocytoma, a catecholamine-secreting tumor of cells derived from the adrenal medulla. Prior to surgical removal of the tumor, patients are treated with phenoxybenzamine to preclude the hypertensive crisis that can result from manipulation of the tissue. This drug is also useful in the chronic management of these tumors, particularly when the catecholamine-secreting cells are diffuse and, therefore, inoperable. Phenoxybenzamine or phentolamine are sometimes effective in treating Raynaud's disease. Autonomic hyperreflexia, which predisposes paraplegics to strokes, can be managed with phenoxybenzamine.

3. Adverse effects:

Phenoxybenzamine can cause postural hypotension, nasal stuffiness, nausea, and vomiting. It can inhibit ejaculation. The drug also may induce reflex tachycardia, mediated by the baroreceptor reflex, and is contraindicated in patients with decreased coronary perfusion.



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Phenylephrine

Phenylephrine [fen-ill-EF-rin] is a direct-acting, synthetic adrenergic drug that binds primarily to α receptors and favors α1 receptors over α2 receptors. It is not a catechol derivative and, therefore, not a substrate for COMT. Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures. It has no effect on the heart itself but rather induces reflex bradycardia when given parenterally. It is often used topically on the nasal mucous membranes and in ophthalmic solutions for mydriasis. Phenylephrine acts as a nasal decongestant and produces prolonged vasoconstriction. The drug is used to raise blood pressure and to terminate episodes of supraventricular tachycardia (rapid heart action arising both from the atrioventricular junction and atria). Large doses can cause hypertensive headache and cardiac irregularities.

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Oxymetazoline

Oxymetazoline [ok-see-met-AZ-of-leen] is a direct-acting synthetic adrenergic agonist that stimulates both α1- and α2adrenergic receptors. It is primarily used locally in the eye or the nose as a vasoconstrictor. Oxymetazoline is found in many over-the-counter short-term nasal spray decongestant products as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, or contact lens.

 The mechanism of action of oxymetazoline is direct stimulation of α receptors on blood vessels supplying the nasal mucosa and the conjunctiva to reduce blood flow and decrease congestion. Oxymetazoline is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping. When administered in the nose, burning of the nasal mucosa and sneezing may occur. Rebound congestion is observed with long-term use.

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Dobutamine

1. Actions: Dobutamine [doe-BYOO-ta-meen] is a synthetic, direct-acting catecholamine that is a β1-receptor agonist. It is available as a racemic mixture. One of the stereoisomers has a stimulatory activity. It increases cardiac rate and output

with few vascular effects. 

2. Therapeutic uses: Dobutamine is used to increase cardiac output in congestive heart failure ,as well as for inotropic support after cardiac surgery. The drug increases cardiac output with little change in heart rate, and it does not significantly elevate oxygen demands of the myocardium—a major advantage over other sympathomimetic drugs.

3. Adverse effects: Dobutamine should be used with caution in atrial fibrillation, because the drug increases atrioventricular conduction. Other adverse effects are the same as those for epinephrine. Tolerance may develop on prolonged use.



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Dopamine

Dopamine [DOE-pa-meen], the immediate metabolic precursor of norepinephrine, occurs naturally in the CNS in the basal ganglia, where it functions as a neurotransmitter, as well as in the adrenal medulla. Dopamine can activate α- and βadrenergic receptors. For example, at higher doses, it can cause vasoconstriction by activating α1 receptors, whereas at lower doses, it stimulates β1 cardiac receptors.

In addition, D1 and D2 dopaminergic receptors, distinct from the α- and βadrenergic receptors, occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilation. D2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with norepinephrine release. 

1. Actions:

 a. Cardiovascular: Dopamine exerts a stimulatory effect on the β1 receptors of the heart, having both inotropic and chronotropic effects . At very high doses, dopamine activates α1 receptors on the vasculature, resulting in vasoconstriction.

 b. Renal and visceral: Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors, thus increasing blood flow to the kidneys and other viscera. These receptors are not affected by α- or βblocking drugs. Therefore, dopamine is clinically useful in the treatment of shock, in which significant increases in sympathetic activity might compromise renal function. [Note: Similar dopamine receptors are found in the autonomic ganglia and in the CNS.]

 2. Therapeutic uses:

Dopamine is the drug of choice for shock and is given by continuous infusion. It raises the blood pressure by stimulating the β1 receptors on the heart to increase cardiac output, and α1 receptors on blood vessels to increase total peripheral resistance. In addition, it enhances perfusion to the kidney and splanchnic areas, as described above. An increased blood flow to the kidney enhances the glomerular filtration rate and causes sodium diuresis. In this regard, dopamine is far superior to norepinephrine, which diminishes the blood supply to the kidney and may cause renal shutdown. 

3. Adverse effects:

An overdose of dopamine produces the same effects as sympathetic stimulation. Dopamine is rapidly metabolized to homovanillic acid by MAO or COMT, and its adverse effects (nausea, hypertension, arrhythmias) are therefore short-lived.



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Isoproterenol

Isoproterenol [eye-soe-proe-TER-e-nole] is a direct-acting synthetic catecholamine that predominantly stimulates both β1and β2-adrenergic receptors. Its nonselectivity is one of its drawbacks and the reason why it is rarely used therapeutically. Its action on α receptors is insignificant

1. Actions:

 a. Cardiovascular: Isoproterenol produces intense stimulation of the heart to increase its rate and force of contraction, causing increased cardiac output 

Figure : Cardiovascular effects of intravenous infusion of isoproterenol.


 It is as active as epinephrine in this action and, therefore, is useful in the treatment of atrioventricular block or cardiac arrest. Isoproterenol also dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance. Because of its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressure .

b. Pulmonary: A profound and rapid bronchodilation is produced by the drug (β2 action).

Figure : Clinically important actions of isoproterenol and dopamine.

 Isoproterenol is as active as epinephrine and rapidly alleviates an acute attack of asthma when taken by inhalation (which is the recommended route). This action lasts about 1 hour and may be repeated by subsequent doses

c. Other effects: Other actions on β receptors, such as increased blood sugar and increased lipolysis, can be demonstrated but are not clinically significant. 

2. Therapeutic uses:
Isoproterenol is now rarely used as a broncho-dilator in asthma. It can be employed to stimulate the heart in emergency situations.

3. Pharmacokinetics: Isoproterenol can be absorbed systemically by the sublingual mucosa but is more reliably absorbed when given parenterally or as an inhaled aerosol. It is a marginal substrate for COMT and is stable to MAO action.

4. Adverse effects: The adverse effects of isoproterenol are similar to those of epinephrine.




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norepinephrine

Because norepinephrine [nor-ep-i-NEF-rin] is the neuromediator of adrenergic nerves, it should theoretically stimulate all types of adrenergic receptors. In practice, when the drug is given in therapeutic doses to humans, the α-adrenergic receptor is most affected

1. Cardiovascular actions:

a. Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (α1 effect). Both systolic and diastolic blood pressures increase.

Figure : Cardiovascular effects of intravenous infusion of norepinephrine.

 [Note: Norepinephrine causes greater vasoconstriction than does epinephrine, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles, etc. The weak β2 activity of norepinephrine also explains why it is not useful in the treatment of asthma.] 

b. Baroreceptor reflex: In isolated cardiac tissue, norepinephrine stimulates cardiac contractility; however, in vivo, little if any cardiac stimulation is noted. This is due to the increased blood pressure that induces a reflex rise in vagal activity by stimulating the baroreceptors. This reflex bradycardia is sufficient to counteract the local actions of norepinephrine on the heart, although the reflex compensation does not affect the positive inotropic effects of the drug.

c. Effect of atropine pretreatment: If atropine, which blocks the transmission of vagal effects, is given before norepinephrine, then norepinephrine stimulation of the heart is evident as tachycardia. 

2. Therapeutic uses: 

Norepinephrine is used to treat shock, because it increases vascular resistance and, therefore, increases blood pressure. However, metaraminol is favored, because it does not reduce blood flow to the kidney, as does norepinephrine. Other actions of norepinephrine are not considered to be clinically significant. It is never used for asthma or in combination with local anesthetics. Norepinephrine is a potent vasoconstrictor and will cause extravasation (discharge of blood from vessel into tissues) along the injection site. [Note: When norepinephrine is used as a drug, it is sometimes called levarterenol [leev-are-TER-a-nole].] 

3. Pharmacokinetics: 

Norepinephrine may be given IV for rapid onset of action. The duration of action is 1 to 2 minutes following the end of the infusion period. It is poorly absorbed after subcutaneous injection and is destroyed in the gut if administered orally. Metabolism is similar to that of epinephrine.

 4. Adverse effects: 

These are similar to those of epinephrine. In addition, norepinephrine may cause blanching and sloughing of skin along injected vein (due to extreme vasoconstriction).

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Epinephrine

Epinephrine [ep-i-NEF-rin] is one of four catecholamines—epinephrine, norepinephrine, dopamine, and dobutamine— commonly used in therapy. The first three catecholamines occur naturally in the body as neurotransmitters; the latter is a synthetic compound. Epinephrine is synthesized from tyrosine in the adrenal medulla and released, along with small quantities of norepinephrine, into the bloodstream. Epinephrine interacts with both α and β receptors. At low doses, β effects (vasodilation) on the vascular system predominate, whereas at high doses, α effects (vasoconstriction) are strongest.


1. Actions:

 a. Cardiovascular:
The major actions of epinephrine are on the cardiovascular system. Epinephrine strengthens the contractility of the myocardium (positive inotropic: β1 action) and increases its rate of contraction (positive chronotropic: β1 action). Cardiac output therefore increases. With these effects comes increased oxygen demands on the myocardium. Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle (β2 effects). Renal blood flow is decreased. Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure. 

Figure: Cardiovascular effects of intravenous infusion of low doses of epinephrine.

b. Respiratory: 
Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action). This action relieves all known allergic- or histamine-induced bronchoconstriction. In the case of anaphylactic shock, this can be lifesaving. In individuals suffering from an acute asthmatic attack, epinephrine rapidly relieves the dyspnea (labored breathing) and increases the tidal volume (volume of gases inspired and expired). Epinephrine also inhibits the release of allergy mediators such as histamines from mast cells

c. Hyperglycemia:
Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in the liver (β2 effect), increased release of glucagon (β2 effect), and a decreased release of insulin (α2 effect). These effects are mediated via the cAMP mechanism. d. Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue, which upon stimulation activate adenylyl cyclase to increase cAMP levels. Cyclic AMP stimulates a hormone-sensitive lipase, which hydrolyzes triacylglycerols to free fatty acids and glycerol.4 2. Biotransformations: Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways: MAO, and COMT, which has S-adenosylmethionine as a cofactor . The final metabolites found in the urine are metanephrine and vanillylmandelic acid. [Note: Urine also contains normetanephrine, a product of norepinephrine metabolism.]

 3. Therapeutic uses

a. Bronchospasm:
Epinephrine is the primary drug used in the emergency treatment of any condition of the respiratory tract when bronchoconstriction has resulted in diminished respiratory exchange. Thus, in treatment of acute asthma and anaphylactic shock, epinephrine is the drug of choice; within a few minutes after subcutaneous administration, greatly improved respiratory exchange is observed. Administration may be repeated after a few hours. However, selective β2 agonists, such as albuterol, are presently favored in the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory effect.

b. Glaucoma:
In ophthalmology, a two-percent epinephrine solution may be used topically to reduce intraocular pressure in open-angle glaucoma. It reduces the production of aqueous humor by vasoconstriction of the ciliary body blood vessels. c. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens. 

d. Cardiac arrest:
Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest regardless of the cause. 

e. Anesthetics:
Local anesthetic solutions usually contain 1:100,000 parts epinephrine. The effect of the drug is to greatly increase the duration of the local anesthesia. It does this by producing vasoconstriction at the site of injection, thereby allowing the local anesthetic to persist at the injection site before being absorbed into the circulation and metabolized. Very weak solutions of epinephrine (1:100,000) can also be used topically to vasoconstrict mucous membranes to control oozing of capillary blood. 

4. Pharmacokinetics: 

Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). In emergency situations, epinephrine is given intravenously for the most rapid onset of action. It may also be given subcutaneously, by endotracheal tube, by inhalation, or topically to the eye 

Figure :Pharmacokinetics of epinephrine.


Oral administration is ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes. Only metabolites are excreted in the urine

5. Adverse effects:

a. CNS disturbances: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor.
 b. Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of blood pressure.
c. Cardiac arrhythmias: Epinephrine can trigger cardiac arrhythmias, particularly if the patient is receiving digitalis.
d. Pulmonary edema: Epinephrine can induce pulmonary edema. 

6. Interactions: 

a. Hyperthyroidism: Epinephrine may have enhanced cardio-vascular actions in patients with hyperthyroidism. If epinephrine is required in such an individual, the dose must be reduced. The mechanism appears to involve increased production of adrenergic receptors on the vasculature of the hyperthyroid individual, leading to a hypersensitive response. 

b. Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions. This is due to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron; thus, like norepinephrine, epinephrine remains at the receptor site for longer periods of time

Figure  Synthesis and release of norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.)

c. Diabetes: Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased. 

d. β-Blockers: These agents prevent epinephrine's effects on b receptorsA. Ephedrine and pseudoephedrine Ephedrine [e-FED-rin], and pseudoephedrine [soo-doe-e-FED-rin] are plant alkaloids, that are now made synthetically. These drugs are mixed-action adrenergic agents. They not only release stored norepinephrine from nerve endings

but also directly stimulate both α and β receptors. Thus, a wide variety of adrenergic actions ensue that are similar to those of epinephrine, although less potent. Ephedrine and pseudoephedrine are not catechols and are poor substrates for COMT and MAO; thus, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS; however, pseudoephedrine has fewer CNS effects. Ephedrine is eliminated largely unchanged in the urine, and pseudoephedrine undergoes incomplete hepatic metabolism before elimination in the urine. Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation.

Ephedrine produces bronchodilation, but it is less potent than epinephrine or isoproterenol in this regard and produces its action more slowly. It is therefore sometimes used prophylactically in chronic treatment of asthma to prevent attacks rather than to treat the acute attack. Ephedrine enhances contractility and improves motor function in myasthenia gravis, particularly when used in conjunction with anticholinesterases .Ephedrine produces a mild stimulation of the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance.

Ephedrine has been used to treat asthma, as a nasal decongestant (due to its local vasoconstrictor action), and to raise blood pressure. Pseudoephedrine is primarily used to treat nasal and sinus congestion or congestion of the eustachian tubes. [Note: The clinical use of ephedrine is declining due to the availability of better, more potent agents that cause fewer adverse effects. Ephedrine-containing herbal supplements (mainly ephedra-containing products) were banned by the U.S. Food and Drug Administration in April 2004 because of lifethreatening cardiovascular reactions. Pseudoephedrine has been illegally converted to methamphetamine. Thus, products containing pseudoephedrine have certain restrictions and must be kept behind the sales counter.] 

e. Inhalation anesthetics: Inhalational anesthetics sensitizethe heart to the effects of epinephrine, which may lead to tachycardia.




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Adrenergic receptors (adrenoceptors)

In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, designated α and β, were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. The use of specific blocking drugs and the cloning of genes have revealed the molecular identities of a number of receptor subtypes. These proteins belong to a multigene family. Alterations in the primary structure of the receptors influence their affinity for various agents.

 1. α1 and α2 Receptors:

The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine 

Figure : Types of adrenergic receptors.

For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol. The α-adrenoceptors are subdivided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs. For example, the α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. Conversely, the drug clonidine selectively binds to α2 receptors and has less effect on α1 receptors.

a. α1 Receptors:
These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects—originally designated as α-adrenergic—involving constriction of smooth muscle. Activation of α1 receptors initiates a series of reactions through a G protein activation of phospholipase C, resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell 

Figure : Second messengers mediate  the effects of α receptors. DAG = diacylglycerol; IP3
 = inositol trisphosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate.

b. α2 Receptors: 
These receptors, located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released norepinephrine traverses the synaptic cleft and interacts with the α1 receptors. A portion of the released norepinephrine “circles back” and reacts with α2 receptors on the neuronal membrane.

The stimulation of the α2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron. This inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity. [Note: In this instance these receptors are acting as inhibitory autoreceptors.] 

α2 Receptors are also found on presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting acetylcholine release [Note: In these instances these receptors are behaving as inhibitory heteroreceptors.] This is another local modulating mechanism to control autonomic activity in a given area. In contrast to α1 receptors, the effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP.


c. Further subdivisions:
 The α1 and α2 receptors are further divided into α1A, α1B, α1C, and α1D and into α2A, α2B, α2C, and α2D. This extended classification is necessary for understanding the selectivity of some drugs. For example, tamsulosin is a selective α1A antagonist that is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland. 

2.β Receptors:

β Receptors exhibit a set of responses different from those of the α receptors. These are characterized by a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine 

For β receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine. The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3, based on their affinities for adrenergic agonists and antagonists, although several others have been identified by gene cloning. [It is known that β3 receptors are involved in lipolysis but their role in other specific reactions are not known] . β1 Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of β2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three β receptors results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell

3. Distribution of receptors:

Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor. For example, tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate. Other tissues may have one type of receptor exclusively, with practically no significant numbers of other types of adrenergic receptors. For example, the heart contains predominantly β1 receptors. 

4. Characteristic responses mediated by adrenoceptors:

It is useful to organize the physiologic responses to adrenergic stimulation according to receptor type, because many drugs preferentially stimulate or block one type of receptor. 

Figure : summarizes the most prominent effects mediated by the adrenoceptors. 

As a generalization, stimulation of α1 receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure. Conversely, stimulation of β1 receptors characteristically causes cardiac stimulation, whereas stimulation of β2 receptors produces vasodilation (in skeletal vascular beds) and bronchiolar relaxation.

5. Desensitization of receptors: 

Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitization. Three mechanisms have been suggested to explain this phenomenon:

 1) sequestration of the receptors so that they are unavailable for interaction with the ligand;

 2) down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis; and

 3) an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by either protein kinase A or β-adrenergic receptor kinase.

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