Adrenergic Agonists

Adrenergic agonists produce their effects by activating adrenergic receptors. Since the
sympathetic system acts through these receptors, responses to adrenergic and to the stimulation by the sympathetic nervous system are very similar. Because of this similarity, adrenergic agonists are often referred as sympathomimetics. Adrenergic agonists have a broad spectrum of clinical applications, ranging from the treatment of heart failure to relief of asthma to delay of of Chemical classification: The adrenergic agonists fall into two major chemical classes: catecholamines and noncathecolamines. The cathecolamines are so named because they contain a catechol group and an amine group. Noncathecholamines do not contain catechol portion that characterizes the catechol group.

Epinephrine
Therapeutic Uses; 1. Delay absorption of local anesthetics 2. Control Superficial bleeding 3. Reduce nasal congestion 4. Elevate blood pressure 5. Restore cardiac function in patients undergoing cardiac arrest 6. Promotes bronchodilation in patients with asthma 7. Treatment for anaphylactic shock Pharmacokinetics

Absorption. Epinephrine may be administered topically, by injection, and by inhalation. The drug cannot be given only because, as discussed, epinephrine and other catecholamines undergo destruction by MAO and COMT before reaching the systematic circulation. Inactivation. Epinephrine has a short half-life because of two processes; enzymatic inactivation and uptake into adrenergic nerves. The enzymes that inactivate epinephrine and other catecholamines are MAO and COMT. Because of the its ability to activate the four major adrenergic receptor subtypes, epinephrine can produce multiple adverse effects. Hypertensive Crisis. Vasoconstriction secondary to excessive alpha, activation can produce a dramatic increase in blood pressure. Cerebral hemorrhage can occur. Because of the potential for severe hypertension, patients receiving parenteral epinephrine must undergo continuous cardiovascular monitoring. Dysrhythmias. Excessive activation of beta, receptors in the heart can produce dysrhythmias. Because of their sensitivity to catecholamines, hyperthyroid patients are at a high risk for epinephrine-induced dysrhythmias. Angina Pectoris. By activating beta, receptors in the heart, epinephrine can increase cardiac work and oxygen demand is big enough, an angina attack may ensue. Precipitation of angina is especially likely in patients with coronary atherosclerosis. Necrosis Following Extravasation. If an IV line containing epinephrine becomes extravasted, the resultant localized vasoconstriction may cause necrosis.

Hyperglycemia. In diabetic patients, epinephrine can cause hyperglycemia. This results from breakdown of glycogen to activation of beta, receptors in liver and skeletal muscle. If hyperglycemia develops, insulin dosage should be increased.

Drug Interactions MAO inhibitors. MAO inhibitors suppress the activity of MAO. These drugs are used primarily to treat depression. Since MAO is one of the enzymes that inactivate epinephrine and other catecholamines, inhibition of MAO will epinephrines effects. As a rule, patients receving an MAO inhibitor should not receive epinephrine. Tricyclic Antideppressants. Tricyclic antidepressants block the uptake of catecholamines in to adrenergic neurons.

General Anesthetics. Several inhalation anesthetics render the myocardium hypertensive to activation by beta, agonists. When the heart is in this hypertensive state, exposure to epinephrine and other beta, agonists can cause dysrhythmias. Alpha-Adregenic Blocking agents. Drugs that block alpha adregenic receptors can prevent receptor activation by epinephrine. Beta Adrenergic Blocking Agents. Drugs that block beta adrenergic receptors can prevent receptor activation by epinephrine. Beta-blocking agents (e.g. propranolol) can reduce adverse effects (e.g. dysrhytmias, angina pain) caused by epinephrine and other beta, agonists. Preparations, Dosage, and Administration Epinephrine [Adrenalin, EpiPen] is dispensed in solution for administration by several routes; IV, SC, IM, intracardiac, intraspinal, inhalation, and topical. The solutions intended for intravenous administration are less concentrated than solutions intended for administration by most other routes. The reason that epinephrine must be diluted for IV use is that intravenous administration of a concentrated epinephrine solutions can produce potentially fatal reactions (severe dysrhytmias and hypertension). Therefore, before epinephrine is administered intravenously, the solution should be carefully checked to ensure that its concentration is appropriate! Aspirate prior to IM or SC injection to avoid inadvertent injection into a vein.

Norepinephrine Receptor specifity; alpha,, alpha, beta Chemical classification; catecholamine

Norepinephrine is similar to epinephrine in many respects, with regard to receptor specifity, NE differ from epinephrine only in that NE does not activate beta receptors. Adverse effects are nearly identical to those epinephrine: dysrhytmas, angina, hypertension, and local necrosis upon extravasation. In contrast to epinephrine, NE does not promote hyperglycemia, a response that is mediated by beta receptors. As with epinephrine, responses to NE can be modified by MAO inhibitors, tricyclic antidepressants, general anesthetics, adrenergic blocking agents. Despite its similarity to epinephrine, NE has limited clinical applications. The only recognized indications are hypotensive states and cardiac arrest. Norepinephrine [Levophed] is dispensed in solution (1 mg/ml) for administration by IV infusion only. Never leave patients unattended. Monitor cardiovascular status continuously. Take care to avoid extravasion.

Isoproterenol Theraputic Uses Cardiovascular. By activating beta, receptors on the heart, isoproterenol can benefit patients with cardiovascular disorders. Specifically, it can help overcome AV heart block, restart the heart following cardiac arrest, and increase cardiac output during shock.

Asthma. By activating beta, receptors in the lung, isoproterenol, can cause bronchodilation, thereby decreasing airway resistance. Following its introduction, isoproterenol became a mainstay of asthma therapy. However, because of the development of even more selective betaadrenergic agonists (i.e. drugs that activate beta, receptors only) use of isoprterenol for asthma has been abandoned.

Bronchopasm. Although isoproterenol is no longer used for asthma, it is used to treat brochopasm during anesthesia. Benefits derive from activating beta, receptors in the lung.

Adverse Effects Since isoproterenol does not activate alpha-adrenergic receptors, the drug produces fewer adverse effects than NE or epinephrine. The major undesired responses are cardiac. Excessive activation of beta, receptors in the heart can cause dysrhythmias and angina pectoris. In diabetic patients, isoproterenol can cause hyperglecemia by promoting beta,mediated glycogenolysis. Drug Interactions The major drug interactions of isoproterenol are nearly identical to those of epinephrine. Effects are enhanced by MAO inhibitors and tricylic antidepressants and reduced by beta adrenergic blocking agents. Like epinephrine, isoproterenol can cause dysrhythmias in patients receiving certain inhalation anesthetics.

Preaparation and Administration Isoproterenol hydrochloride [Isuprel] is available in solution (0.2 and 0.02 mg/ml) for parenteral administration.

When used to stimulate the heart, isoproterenol can be administered IV and IM and by intracardiac injection. The dosage for IM administration is about 10 times greater than the dosage employed by the other two routes. When used to relieve bronchospasm, isoproterenol is administered IV

Dopamine Receptor specificity: dopamine, beta, and, at high doses, alpha Chemical Classication: catecholamine

Theraputic Uses Shock Heart Failure Acute Renal Failure

Adverse Effects The most common adverse effects of Dopamine tachycardia, dysrhytmias, and anginal painresult from activation of beta, receptors in the heart.

Drug interactions MAO inhibitors can intensify the effects of dopamine on the heart and blood vessels. If a patient is receiving an MAO inhibitor, the dosage of dopamine must be reduced by at least 90%. Tricyclic antidepressants can also intensify dopamines actions, but not to the extent seen with MAO inhibitors. Certain general anesthetics can sensitize the myocardium to stimulation by dopamine and other catecholamines, thereby creating a risk of dysrhytmias. Diuretics can complement the beneficial effects of dopamine on the kidney.

Preparation, Dosage and Administration Preparations. Dopamine hydrochloride [Intropin] is dispensed in aqueous solutions that range in concentration from 40 to 60 mg/ml.

Dosage. Dopamine must be diluted prior to infusion. For treatment of shock, a dilution of 400ug,ml can be used. The recommendation initial rate of infusion is 2 to 5 ug/kg/min. Administration. Dopamine is administered IV. Because of extremely rapid inactivation by MAO and COMT, the drug must be given by continuous infusion.

Dobutamine Preparation, Dosage and Administration. Donbutamine hydrochloride [Dobutrex] is dispensed in solution (12.5mg/ml) in 20-ml vials. This concentrated solution must be diluted to at least 50ml prior to use. Because of rapid inactivation by MAO and COMT, dobutamine is administered by IV infusion only.

Phenylephrine Receptor specificity; alpha Chemical classification; noncatecholamine

Phenylephrine is a selective alpha, agonist. The drug can be administered locally to reduce nasal congestion and parenterally to elevate blood pressure. In addition, phenylephrine eye drops can be used to dilate the pupil. Also phenylephrine can be coadministered with local anesthetics to retard absorption of the anesthetic.

Terbutaline Receptor specificity; beta Chemical classification; noncatecholamine

Theraputic Uses Asthma. Terbutaline can reduce airway resistance in asthma by causing beta-mediated bronchodilation. Since terbutaline is selective for beta receptors, ir produces much less activation of cardiac beta, receptors than does isoproternol.

Delay of Preterm Labor. By activating beta receptors in the uterus, terbutaline can relax uterine smooth muscle, thereby delaying labor. However, although terbutaline can be employed to delay labor, a different beta agonist ritodrine- is the drug of choice for this indication.

Adverse Effects Adverse Effects are minimal at therapeutic doses. Tremor is most common. Of the dosage is excessive, terbutaline can cause tachycardia by activating beta, receptors in the heart.

Ephedrine
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Receptors. Indirect Receptor specificity; alpha, alpha, beta, beta Chemical classification; noncatecholamine

Ephedrine is reffered to as a mixed-acting drug because it activates adrenergic receptors by direct and indirect mechanisms. Direct activation result from binding of the drug to alpha and beta activation results from release of NE from adrenergic neurons.

Theraputic Uses Nasal Congestion. Ephedrine can reduce nasal congestion by causing alpha-mediated vasoconstriction. When used for this indication, the drug can be administered topically or by mouth. As a rule, topical administration is preferred. This is because systematic reactions to typical administration results in activation of adrenergic receptors throughout the body. Narcolepsy. Narcolepsy is a CNS disorder characterized by sudden and irresistible attacks of sleep. Ephedrine is one of several medications employed for treatment. Adverse Effects. Since ephedrine activates the same receptors as epinephrine, both drugs share the same adverse effects: hypertension, dysrhytmias, angina and hyperglycemia. In addition to these shared effects, ephedrine can act in the NCs to cause insomnia.

ALPHA-ADRENERGIC ANTAGONISTS PROPERTIES OF INDIVIDUAL ALPHA BLOCKERS Prazosin Actions and Uses. Prazosin [Minipress] is a competitive antagonist that produces selective blockade of alpha-adrenergic receptors. By blocking alpha, receptors, prazosin can cause dilation of arterioles and veins, and relaxation of smooth muscle in the bladder neck and prostatic capsule. The drug is approved only for hypertension. Pharmacokinetics. Prazosin is administered orally. Antihypertensive effects peak in 1 to 3 hours and persist for 10 hours. The drug undergoes extensive hepatic metabolism followed by excretion in the bile. Only about 10% is eliminated in the urine. The half-life is 2 to 3 hours

Adverse Effects. Blockade of alpha, receptors can cause orthostatic hypotension, reflex tachycardia, inhibition of ejaculation and nasal congestion. Preparation, Dosage and Administration. Prazosin hydrochloride [Minipress] is available in capsules (1,2, and 5 mg) for oral use. This initial adult dosage for essential hypertension is 1 mg taken 2 or 3 times a day. Per maintenance therapy, the dosage is 6 to 15 mg/day administred in divided doses.

Terazosin Actions and Uses. Like prazosin, terzosin [Hytrin] is a selective, competitive antagonist at alpha, adrenergic receptors. The drug is approved for hypertension and BPH. Pharmacokinetics. Terazosin is administered orally, and peal effects develop in 1 to 2 hours. The drugs half is prolonged (9 to 12 hours) allowing benefits to be maintain with just one dose a day. Terazosin undergoes hepatic metabolism followed by excretion in the bile and urine.

Adverse Effects. Like other alpha-blocking agents , terazosin can cause orthostatic hypotension, reflex tachycardia, nasal congestion and inhibition of ejaculation.

Preparation, Dosage and Administration. Terazosin [Hytrin] is available in capsules (1,2,5 and 10mg) for oral use. Antihypertensive therapy is initiated with a 1-mg dose, administered at bedtime to minimize the first-dose effect. Dosage can be gradually increased as needed and tolerated. The recommended dosage range for maintenance therapy is 1 to 5 mg once daily. Dosing for being prostatic hyperplasia is similar to that for hypertension except that a maintenance dosage of 10 mg/day is needed for most men.

Doxazosin Actions and Uses. Doxazosin [Cardura] is a selective, competitive inhibitor of alpha, adrenergic receptors. The drug is indicated for hypertension and BPH. Pharmacokinetics. Doxazosin is administered orally, and peak effects develop in 2 to 3hours. The drug has a prolonged half-life (22 hours), and once a day dosing is adequate. Most (98%) of drug in blood is protein bound. Doxazosin undergoes extensive hepatic metabolism followed by biliary excretion. Adverse Effects. Like prazosin and terazosin, doxazosin can cause orthostatic hypotension, reflex tachycardia, nasal congestion and inhibition of ejaculation. Preparation, Dosage and Administration. Doxazosin [Cardura] is dispensed in tablets (1,2,4 and 8mg) for oral administration. The initial dosage for hypertension or BPH is 1 mg once a day. The dosage may be gradually increased as needed, up to a maximum of 16mg once daily for hypertension or 8 mg once daily for BPH.

Tamsulosin Actions and Users. Tamsulosin [Flomax] is a selective alpha-adrenergic antagonist. The drug is approved only for BPH. It is not indicated ofr hypertension. In men with BPH, tamsulosin increases urine flow rate and decreases urine volume. Maximum benefits develop within two weeks. Pharmacokinetics. Tamsulosin is administered orally, and absorption iss slow. Food further decreases the rate and extent of absorption. The drug is metabolized in the liver and excreted in the urine. Adverse Effects and Interaction. Like other alpha, blockers, tamsulosin can cause orthostatic hypertension, nasal congestion and abnormal ejaculation.

Phentolamine Action and Uses. Like prazosin, phentolamine [Regitine] is a competitive adrenergic antagonist. However, in contrast to prazosin, phentolamine blocks alpha, receptors as well as alpha, receptors. Phentolamine has two applications: (1) treatment of pheochromocytoma and (2) prevention of tissue necrosis following extravasionof drugs that produce alpha-mediated vasoconstriction (e.g., norepinephrine)

Adverse Effects. Like prazosin, phentolamine can produce the typical adverse effects associated with alpha-adrenergic blockade: orthostatic hypotension, reflex tachycardia, nasal congestion and inhibition of ejaculation. Because of its ability to block alpha receptors, phentolamine produces greater reflex tachycardia than prazosin.

Preparation, Dosage and Administration. Phentolamine [Regitine] is dispense in solution(5mg/25ml) for IM and IV administration. The dosage for preventing hypertension during surgical excision of a pheochromocytoma is 5mg (IM or IV). Prevent necrosis following extravasion of IV norepinephrine, the reigon should be infiltrated with 5 to 10 mg of phentolamine diluted in 10ml of saline.

Phenoxybenzamine receptors. However, unlike all of the other alpha adrenergic antagonist, Phenoxybenzamine is a noncompetitive receptor antagonist. Hence, receptor blockade is not reversible. As a result, the effects of Phenoxybenzamine are long lasting. Like the other alpha-adrenergic anatagonists, Phenoxybenzamine can produce orthostatic hypotension, reflex tachycardia, nasal congestion, and inhibition of ejaculation. Reflex tachycardia is greater than that caused by prazosin and about equal to that caused by phentolamine.

Beta-Adrenergic antagonists: Properties of individual Beta Blockers -Can be nonselective and cardioselective beta blockers.

Propranolol Pharmacologic Effects -reduces heart rate, decrease the force of ventricular contraction and suppress impulse conduction through the AV node -Blockade of beta receptors has 3 major effects 1. Bronchoconstriction in the lung 2. Vasoconstriction in blood vessels 3. Inhibition of glycogenolysis in the liver and sleletal muscle Pharmacokinetics -Highly lipid soluble and therefore can readily cross membranes Therapeutic uses. The drugs most important indications are hypotension, angina pectoris, cardiac dysrhtyhmias and myocardial infarction. Adverse effects. Bradycardia, AV heart block, Heart failure, Rebound Cardiac excitation, bronchoconstriction, inhibition of glycogenolysis and CNS effects (insomnia, nightmares and hallucinations.) Precautions, warnings and contraindications This drug should be avoided in patients with a history of severe allergic reactions (anaphylaxis), Diabetic patients and patients with heart failure, AV heart block, sinus bradycardia, asthma and bronchospasm. Drug Interactions- reduction of heart rate, suppression of AV conduction and myocardial contractility. Preparations, Dosage and Administration

Available in 3 oral formulations, tablets (10-90 mg), sustained- release capsules (60-160 mg) and solution (4 and 8 mg/ml) 1 mg/ml for IV administration. The dosage for hypertensive patients is 40 mg twice a day; for angina pectoris is 160 mg/day (adult dosage).

Metoprolol

Pharmacologic effects. Has the same impact on the heart as propranolol. Pharmacokinetics. Moderately lipid soluble and well absorbed following oral administration. Metabolism takes place also in the liver just like the propranolol. Therapeutic uses. The primary indication of this drug is hypertension. Its also approved for angina pectoris, heart failure and myocardial infarction. Adverse effects. Bradycardia, reduction of cardiac output, AV heart block, and rebound cardiac excitation following abrupt withdrawal. Pr ecautions, warnings and contraindications. Should be used with great care in patients with heart failure, sinus bradycardia and AV heart block. Preparations, Dosage, and administration. Available in standard oral tablets (50 and 100mg, name Lopressor ), sustained release oral tablets(25, 50, 100 mg, name Toprol XL), solution ,IV (1 mg/ml).

INDIRECT- ACTING ANTIADRENERGIC AGENTS -Prevent stimulation of peripheral adrenergic receptors, but they do so by mechanisms that do not involve direct interaction with peripheral receptors. Adrenergic Neuron blocking receptors Reserpine -the primary indication is hypertension. The common side effect is severe depression. Mechanisms of action. It causes depletion of NE from postganglionic sympathetic neurons and neurotransmitters from the neurons of the CNS. Pharmacologic effects In CNS, it produces sedation, and a state of indifference in the environment; the peripheral effects, it slows heart rate and reduces cardiac output. Therapeutic uses The primary indication is hypertension. It can be used also to treat agitated psychotic patients, such as those who are suffering from schizophrenia. Adverse effects. Severe depression,Bradycardia, orthostatic hypotension and nasal congestion, causing cramps and diarrhea.

Preparations, Dosage and administration. Available in tablets (0.1 and 0.25mg) for oral use. May be administered with good if GI upset occurs. For hypotension the adult dosage is 0.5 mg/day 1 to 2 weeks. The maintenance dosage is 0.1 and 0.25mg/day.

Guanethidine Its just like Reserpine but this drug cannot cross the blood-brain barrier and hence can cause adverse CNS effects. Mechanisms of action- inhibition of NE release, can promote NE release and depletes NE from sympathetic nerves. Pharmacologic Effects- Bradycardia, decreased cardiac output, and great reduction in venous smooth muscle tone. Therapeutic use-the principal indication is hypertension Adverse effects- Diarrhea, orthostatic hypotension and hypertension. Drug interactions- Tryclic antidepressants block the uptake of this drug. Preparations, Dosage and Administration- 10 and 25 mg tablets for oral use. Initial dose in adults is 10 mg once a day. The dosage can be increased depending on the patients like those who have diarrhea. Guanadrel- Just like Guanethidine except it has a shorter half- life than Guanethidine hence it must be administered twice a day. The initial dosage for adults is 10 mg/day and maintenance doseages range from 20-75 mg/day.

CENTRALLY ACTING ALPHA 2 AGONISTS Drugs used to reduce the firing of sympathetic neurons, primarily for hypertension.

Clonidine An antihypertensive drug that acts within the CNS. Mechanism of action- reduces sympathetic outflow to blood vessels and the heart. Pharmacologic effects-Occur mostly in the heart and vascular system. It can cause bradycardia and a decrease in cardiac output, promotes vasodilation that results in decreased blood pressure.

Pharmacokinetics- this drug is very lipid soluble. Its readily absorbed following oral administration and is widely distributed throughout the body, including the CNS. Therapeutic uses- This drug is mainly used for the treatment of hypertension and secondly for the relief of severe pain. Adverse effects- Drowsiness, Xerostamia (dry mouth), rebound hypertension, fetal harmful, constipation, impotence, anxiety, vivid dreams and nightmares. Preparations, Dosage and administration- Available in oral (0.1-0.3mg tablets) and transdermal (2.5, 5 and 7.5 mg patches, that deliver 0.1, 0.2 and 0.3 mg/24 hours respectively) formulations. Transdermal patches are applied to a region of hairless intact skin on the upper arm or torso.

Guanabenz and Guanfacine The pharmacology of these drugs is very similar to that of clonidine. Its available in 4-8 mg tablets. Guanfacine is available in 1-2 mg tablets given at bedtime to prevent daytime sedation. Methldopa and Methyldopate An antihypertensive that lowers blood pressure by acting at sites within the CNS. Two side effects mainly hemolytic anemia and hepatic necrosis. Mechanisms of Action- similar to that of clonidine but itself are not alpha 2 agonist. Pharmacologic effects- the most prominent response is a drop in blood pressure. It causes vasodilation and not suppressing the heart. Therapeutic use- the only indication for this drug is hypertension. Its widely used and one of the earliest antihypertensive agents. Adverse effects- Hemolytic anemia, Hepatotoxicity(associated with hepatitis, jaundice and rarely fatal hepatic necrosis. Other adverse effects include sexual dysfunction, drowsiness, nightmares and depression. Preparations, Dosage and Administration Methlydopa(Aldomet) is available in tablets (125, 250, and 500 mg) and in a suspension(50 mg/ml) for oral use. Methyldopate(Aldomet) is available as an injection (50 mg/ml in 5 and 10vials) for IV use. For the treatment of hypertension the initial adult dosage is 250 mg 2 to 3 times a day. Daily maintenance dosages usually range from 0.5 to 2 gm administered in two to 4 divided doses. Methyldopate is administered by slow IV infusion, indicated for hypertensive emergencies.