Principles of Pharmacology July 25, 2002 9:10- 10:00 am Aneesa Niravel ADRENERGIC AGONISTS (Starting from the bottom of page 6) c. Isoproterenol (Isuprel) Isoproterenol is an synthetic catecholamine that is a strong agonist at R, and R2 receptors with virtually no effect at alpha receptors. It increases both heart rate and force of contraction through its R, effects. Cardiac output increases. Myocardial oxygen demands also increase. Having no alpha activity, 02 mediated vasodilation of skeletal muscle vasculature results in a fall in diastolic blood pressure. Increased cardiac output tends to offset the drop in peripheral resistence such that systolic blood pressure is either only slightly increased or slightly decreased. Mean blood pressure is decreased. Although a catecholamine, isoproterenol is a marginal substrate for COMT and is resistant to MAO. As such, it has a parenteral half-life of 2 hours. Isoproterenol has been used in the acute treatment of asthma in the past, but has been replaced by the selective (32 agonists that have fewer cardiac effects. In this application, it was given by the inhalation route. Isoproterenol is still utilized in the temporary emergency management of complete heart block or cardiac arrest. Electronic pacemakers are safer and more effective in heart block. If the heart block is continuous, isoproterenol should only be administered until the pacemaker can be inserted. Isoproterenol increases myocardial oxygen demands on already ischemic tissue. It can easily cause arrhythmias in this situation. *Isoproterenol has a much longer half life than epinephrine * Use of of isoproterenol in shock patients leads to death d. Dopamine (Intropin) Dopamine is an endogenous catecholamine that is far less potent at alpha and beta receptors than epinephrine or norepinephrine. It does bind potently to D, and DZ dopamine receptors which are distinct from alpha and beta receptors. Dz receptors are found presynaptically and block release of transmitter. D, receptors are found on the renal vasculature where dopamine causes vasodilation and increases (or preserves in the case of shock) renal blood flow. Higher concentrations of dopamine stimulates R, receptors, increasing heart rate and force of contraction. At extremely high concentrations, dopamine can activate alpha receptors and produce vasoconstriction. Dopamine is only administered intravenously. Dopamine is metabolized by MAO and COMT and has a short half-life. The only therapeutic indication for the use of dopamine is in the treatment of shock. As described above (See epinephrine), volume replacement and treating the underlying disease are currently favored over the use of sympathomimetics in the treatment of shock. Norepinephrine and epinephrine can completely shut down blood flow to the kidney through their alpha effects. Dopamine causes vasodilation of the renal vasculature through its D, effects. This vasodilation opposes the strong sympathetic drive on the renal vasculature that normally accompanies shock. e. Dobutamine (Dobutrex) Dobutamine is a synthetic catecholamine that is a relatively selective R, agonist. Dobutamine has relatively more inotropic than chronotropic effects on the heart than isoproterenol. It produces primarily increased force of contraction and increased cardiac output. Dobutamine is only administered intravenously. Dobutamine is metabolized by MAO and COMT and has a short half-life of only 2 minutes. Dobutamine is used in the short-term treatment of cardiac decompensation that follows cardiac surgery or in patients with congestive heart failure or acute myocardial infarction. It increases force of contraction and cardiac output with little increase in heart rate in these patients. Usually, increases in blood pressure are modest. It is not used continuously for more than a few days due the rapid development of tolerance to its effects. *Dobutamine doesn’t increase myocardial oxygen demands, unlike other catecholamines * 2. Alpha, agonists a. Phenylephrine (Neo-Synephrine) Phenylephrine is primarily an a, agonist that is 100 fold less potent than epinephrine. Nonetheless, in sufficient doses it does produce significant a, activity. It is resistant metabolism by COMT, but not MAO. It has a longer half-life than the catecholamines. It is orally active and does penetrate the blood brain barrier. Its subjective CNS effects are considered to be undesirable. It increases diastolic and systolic blood pressure and elicits a reflex bradycardia. It is used as an nasal decongestant, mydriatic in ophthalmic preparations, for the treatment chronic orthostatic hypotension, and in combination with local anesthetics to prevent their diffusion away from the injection site. Phenylephrine is superior to epinephrine in this last usage because its lacks the cardiac stimulant properties of epinephrine and systemic absorption following local injection will not increase heart rate. *No Beta activity b. Methoxamine (Vasoxyl) Methoxamine is an alpha agonist that is relatively selective for a, receptors. It increases blood pressure and elicits reflexive bradycardia. Methoxamine is used to treat chronic orthostatic hypotension. c. Midodrine (ProAmatine) Midodrine is a newer orally active alpha agonist used to treat chronic orthostatic hypotension. d. Xylometazoline (Otrivin, Neo-Synephrine) Oxymetazoline (Afrin, Neo-Synephrine 12 Hour) Xylometazoline and oxymetazoline are alpha agonists that are used as topical decongestants. Topical application causes vasoconstriction of the nasal mucosa and a decongestant effect. *Just be able to recognize these drug names, no need to memorize 3. Alpha2 agonists a. Clonidine (Catapres) Clonidine is a selective a2 agonist that is used primarily as an antihypertensive agent. Theoretically, presynaptic agonist effects would decrease release of norepinephrine from postganglionic sympathetic neurons which should lower blood pressure. This mechanism contributes little to the antihypertensive effect of clonidine. Clonidine's major hypotensive mechanism is to decrease central outflow of impulses in the sympathetic nervous system by activating a2 receptors in the brainstem. Clonidine is also used to decrease the increased sympathetic activity that accompanies opiate withdrawal. b. Guanabenz (Wytensin) Guanfacine (Tenex) Guanabenz and guanfacine are a2 agonists that are used to lower blood pressure through a central mechanism like clonidine. c. Apraclonidine (lopidine) Apraclonidine is a selective a2 agonist that is used topically to lower intraocular pressure in patients with glaucoma. The mechanism seems to involve decreased secretion of aqueous humor. 4. Beta, agonists a. Dobutamine (Dobutrex) See above. 5. Beta2 agonists In general, R2 agonists are not completely selective and do possess some weak R, agonist activity. They are used for their bronchodilator effects in the treatment of asthma or bronchospasm. Inhalation tends to reduce their R, effects on the heart. In doses used to treat asthma or bronchospasm, they produce far less cardiac stimulation than isoproterenol or epinephrine. These drugs also are used to reduce contractions in premature labor. The cardiovascular effects are usually mild. R2 induced vasodilation of skeletal muscle vasculature decreases diastolic pressure which elicits a reflexive tachycardia. The slight direct R, effects on the heart also contributes to the tachycardia. a. Albuterol (Ventolin) Albuterol is a relatively selective R2 agonist that can be administered orally or by inhalation. Its primary use is in the long-term treatment of obstructive airway diseases or emergency treatment of bronchospasm. It can also be used to delay premature delivery (See Ritodrine below.) b. Terbutaline (Brethine) Terbutaline is a relatively selective R2 agonist that can be administered orally, subcutaneously or by inhalation. Its primary use is in the long-term treatment of obstructive airway diseases or emergency treatment of bronchospasm. It can be given parenterally in the emergency treatment of status asthmaticus. It can also be used to delay premature delivery (See Ritodrine below.) c. Ritodrine (Yutopar) Ritodrine is a relatively selective 02 agonist is used to reduce uterine contractions in premature labor. It is given intravenous to initially control contractions. If labor is delayed, it can be given orally if further pharmacological intervention is necessary. Albuterol and terbutaline are used "off label" for the same purpose. 6. Miscellaneous adrenergic agonists Many of these miscellaneous adrenergic agonists are indirect acting agonists, causing the release of norepinephrine from presynaptic terminals or blocking the uptake of norepinephrine. Some have direct sympathomimetic activity. Many of these agents readily cross the blood brain barrier and produce central effects, some of which are therapeutic. *Some are abused a. Ephedrine (generic) Ephedrine is a natural alkaloid found in numerous plants that has been used in China for over 2000 years. It was introduced in this country as the first orally active sympathomimetic over 70 years ago. Ephedrine acts primarily by causing the release of stored catecholamines, but does have some direct adrenergic activity. It is a nonselective sympathomimetic with a spectrum of activity that resembles epinephrine. Ephedrine has a high oral bioavailability and long duration of action (half-life 3-6 hrs). It does cross the blood brain barrier and produces CNS stimulation. Ephedrine raises heart rate and cardiac output through its beta effects and increases peripheral resistence through its alpha effects. Blood pressure is usually increased. Most of ephedrine's applications have been replaced by newer, more selective agents. Currently the use of ephedrine is limited to clinical situations when a long acting, orally active sympathomimetic is desired for decongestant or pressor effects. Still, the use of ephedrine in these capacities carries the risk of hypertension and arrhythmias. It also can cause insomnia. b. Pseudoephedrine (Sudafed) Pseudoephedrine is actually one of 4 ephedrine stereoisomers. It is less potent the ephedrine in producing tachycardia, increased blood pressure and CNS stimulation, but still can, particularly in sensitive individuals. It is found in OTC decongestants either alone or with an antihistamine. c. Amphetamine (generic) Methamphetamine (generic) Phenmetrazine (generic) Methylphenidate (Ritalin) Pemoline (Cylert) As a group, all of these drugs are orally active, indirect acting sympathomimetics that cross the blood brain barrier and are long acting. They all are strong CNS stimulants that are often abused. All but methylphenidate act by causing the release of stored catecholamines. Methylphenidate acts by blocking the uptake of dopamine. Their CNS stimulant effects are due to the release of dopamine or dopamine uptake blockade. In the periphery, these agents act as nonspecific sympathomimetics due to the release of catecholamines. As a group, these agents increase diastolic and systolic blood pressure, heart rate can be increased, but may be reflexively slowed, and finally, cardiac output may increased or unchanged. They can cause arrhythmias. Methylphenidate again is the exception. Because it only blocks the uptake of dopamine, methylphenidate lacks peripheral sympathomimetic effects. As a group, these drugs are contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs). MAOIs result in a build up norepinephrine in presynaptic terminals. Indirect acting sympathomimetics will release this massive build up of norepinephrine which can lead to hypertensive crisis and death. All of these drugs suppress appetite (produce anorexia). Amphetamine, methamphetamine and phenmetrazine have been extensively utilized in the past and still are used to promote weight loss. Anorexia is a side effect of methylphenidate or pemoline treatment of attention deficit hyperactivity disorder (ADHD) in children. Tolerance develops to anorexic effects of these agents, limiting their effectiveness in weight reduction. In addition, weight loss tends not to be permanent after these drugs are discontinued. Coupled with adverse cardiovascular effects and potential for abuse, the use of these drugs for weight loss is of questionable value. All of these drugs can be used to treat narcolepsy. Narcolepsy is characterized by hypersomnia with sudden daytime attacks of sleep. All of these drugs can be used in the treatment of ADHD disorder in children. This syndrome is characterized by excessive motor activity, difficulty in sustaining attention and poor impulse control. By far, methylphenidate is the most widely utilized, most likely due to its lack of peripheral sympathomimetic effects and the stigma attached to more abused drugs in the group. c. Phenylpropanolamine (generic) Phenylpropanolamine is an orally active, indirect acting sympathomimetic that resembles ephedrine in pharmacological spectrum and potency, but does not seem to produce the same degree of CNS stimulation. It is available OTC in numerous weight loss preparations. Its effectiveness in weight loss is no more than that of the CNS stimulants above. It is also found in combination with antihistamines in OTC cold remedies where it is used for its decongestant effects. Although it is alleged to be safe is recommended dosage, it has been associated with significant elevation of blood pressure and target organ damage in patients ingesting large doses. It is currently the target of a class action lawsuit. d. Tyramine Tyramine is not a drug, but rather an indirect acting sympathomimetic found in various fermented foods and beverages such as cheese and red wine. It causes release of catecholamines from storage sites and slight sympathomimetic effects under normal conditions. However, if an individual has been taking a MAGI, tyramine can cause a massive release of norepinephrine and hypertensive crisis. e. Cocaine Cocaine is a local anesthetic that produces both CNS stimulation and peripheral sympathetic stimulation. CNS stimulation is due to blockade of dopamine uptake. Sympathetic stimulation is due uptake blockade of norepinephrine. At doses used for its euphoric effects, cocaine can cause significant elevation of blood pressure and tachycardia. Toxic doses can produce convulsions, arrhythmias and death. f. Tricyclic antidepressants Tricyclic antidepressants comprise a large group of drugs and produce their antidepressant effects through the blockade of norepinephrine and/or serotonin in the CNS. Those that block norepinephrine uptake can cause indirect sympathomimetic effects. D. Adverse Effects Adverse effects of sympathomimetic drugs are extensions of their receptor effects in the cardiovascular and central nervous systems. Marked elevation of blood pressure (a,) can cause cerebral hemorrhage or pulmonary edema. R, agonists can increase cardiac work load and oxygen demand and can precipitate severe angina or myocardial infarction. R, agonists can also cause sinus arrhythmias and can provoke severe ventricular arrhythmias. Sympathomimetics must be used with caution in elderly patients or in patients with hypertension or coronary artery disease. CNS toxicity is not observed with catecholamines. With drugs like phenylephrine, CNS toxicity is generally mild. Amphetamines can cause anxiety, restlessness, tremor, insomnia and eventually a paranoid psychosis. Cocaine can cause convulsions, cerebral hemorrhage, arrhythmias or myocardial infarction.
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