Effects of Sympathomimetics

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Presentation transcript:

Effects of Sympathomimetics Effects depend on: Relative selectivity for α or β adrenoceptors. Pharmacologic actions at those receptors. Compensatory “baroreflex” mechanisms aimed at restoring homeostasis. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Cardiovascular Effects of Alpha1-Receptor Activation A relatively pure alpha agonist such as phenylephrine causes arterial and venoconstriction, increases peripheral arterial resistance and decreases venous capacitance. The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure. The rise in blood pressure elicits a baroreceptor -mediated increase in vagal tone with slowing of the heart rate, Cardiac output may not diminish, since increased venous return may increase stroke volume. If baroreflex function is removed by pretreatment with the ganglionic blocker trimethaphan, the pressor effect of phenylephrine is increased approximately tenfold, and bradycardia is no longer observed. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Effects of Alpha1-Receptor Activation Vasoconstriction in the: Skin vessels Splanchnic vessels. The blood vessels of the nasal mucosa and this explains their decongestant action. Epinephrine also activates β 2 receptors in skeletal muscle blood vessels, leading to their dilation. Consequently, total peripheral resistance may actually fall. Activation of β 2 receptors in skeletal muscle contributes to increased blood flow during exercise. Under physiologic conditions, epinephrine released from the adrenal gland, functions largely as a hormone by acting on distant cells. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Vascular Effects of Alpha2-Receptor Activation Alpha2 adrenoceptors are present in the vasculature, and their activation leads to vasoconstriction. This effect, however, is observed only when α 2 agonists are given locally, by rapid intravenous injection, or in very high oral doses. When given systemically, these vascular effects are obscured by the central effects of α 2 receptors, which lead to inhibition of sympathetic tone and blood pressure. Hence, α 2 agonists are used as sympatholytics in the treatment of hypertension 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Effects of Beta-Receptor Activation Stimulation of β receptors in the heart increases cardiac output by stimulating contractility (inotropic effect) and by a direct stimulation of the sinus node to increase heart rate(chronotropic effect). Also, conduction velocity in the atrioventricular node is increased (dromotropic effect), and the refractory period is decreased Beta agonists also decrease peripheral resistance by activating β 2 receptors, leading to vasodilation in certain vascular beds. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. Isoproterenol is a nonselective β agonist; it activates both β 1 and β 2 receptors. The net effect is to maintain or slightly increase systolic pressure and to lower diastolic pressure, so that mean blood pressure is decreased 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Effects of Dopamine-Receptor Activation Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of D1 receptors. Activation of the D1 receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Effects of Dopamine-Receptor Activation Dopamine activates β 1 receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular receptors, leading to vasoconstriction, including the renal vascular bed ( alpha receptor) Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Noncardiac Effects of Sympathomimetics Activation of β 2 receptors in bronchial smooth muscle leads to bronchodilation, and β 2 agonists are important in the treatment of asthma. In the eye, α receptor activation by drugs, such as phenylephrine, causes mydriasis . Alpha agonists also increase the outflow of aqueous humor from the eye and can be used clinically to reduce intraocular pressure. In contrast, beta agonists have little effect, but beta antagonists decrease the production of aqueous humor. These effects are important in the treatment of glaucoma, a leading cause of blindness. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Noncardiac Effects of Sympathomimetics The genitourinary organs, the bladder base, urethral sphincter, and prostate contain alpha receptors that mediate contraction and therefore promote urinary continence (control of urination). The specific subtype of α receptor involved in mediating constriction of the bladder base and prostate is uncertain, but α 1A receptors probably play an important role. Alpha-receptor activation in the ductus deferens, seminal vesicles, and prostate plays a role in normal ejaculation. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Noncardiac Effects of Sympathomimetics Insulin secretion is stimulated by β receptors and inhibited by α 2 receptors. Similarly, renin secretion is stimulated by β 1 and inhibited by α 2 receptors. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

CNS Noncardiac Effects of Sympathomimetics The catecholamines are almost completely excluded by blood-brain barrier. Peripheral effects of β -adrenoceptor agonistsm, such as tachycardia and tremor, are similar to the somatic manifestations of anxiety. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

CNS Effects of Sympathomimetics Noncatecholamine sympathomimetics, with indirect actions, such as amphetamines, can readily cross the BBB, and produce qualitatively very different central nervous system effects. These actions vary from mild alerting, with improved attention to boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior. These effects are not readily assigned to either β- or α -mediated actions and may represent enhancement of dopamine-mediated processes or other effects of these drugs in the central nervous system. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Metabolic Effects of Sympathomimetics Activation of β 3 adrenoceptors in fat cells leads to increased lipolysis with enhanced release of free fatty acids and glycerol into the blood. Sympathomimetic drugs enhance glycogenolysis in the liver, which leads to increased glucose release into the circulation, mainly by β receptors. Activation of β 2 receptors promotes the uptake of potassium into cells, leading to a fall in extracellular potassium. This may lead to a fall in the plasma potassium concentration during stress and protects against a rise in plasma potassium during exercise. Β receptors increase insulin secretion, while α 2 receptors decrease insulin secretion. However, the major regulator of insulin release is the plasma concentration of glucose. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Epinephrine (adrenaline) Is an agonist at both α and β receptors. It is very potent vasoconstrictor and cardiac stimulant. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly β 1 receptors) and the vasoconstriction induced in many vascular beds (α receptors). 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Norepinephrine (levarterenol, noradrenaline) Is an agonist at both α 1 and α 2 receptors. Norepinephrine also activates β 1 receptors with similar potency as epinephrine, but has relatively little effect on β 2 receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Dopamine Is the immediate precursor in the synthesis of norepinephrine Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. Its deficiency in the basal ganglia leads to Parkinson's disease, which is treated with its precursor levodopa. Dopamine receptor antagonists are also targets for antipsychotic drugs. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Direct-Acting Sympathomimetics Phenylephrine A relatively pure α 1 agonist. Reflexly activates the vagus leading to bradycardia. Because it is not a catechol derivative ,it is not inactivated by COMT and has a longer duration of action than the catecholamines. It is an effective mydriatic and decongestant and can be used to raise the blood pressure. Methoxamine Similar to phenylephrine 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Alpha2-selective agonists These are lipophilic compounds which can cross the BBB to work on central alpha 2 receptors which inhibit the sympathetic system leading to a drop in BP. Direct application to a blood vessel may cause vasoconstriction. Also, an intravenous dose of clonidine can have a peripheral alpha activity leading to overshoot of BP before the sustained drop in the BP. Clonidine Methyldopa Guanfacine, Are useful drugs in the treatment of hypertension 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Oxymetazoline Direct-acting α agonists, used topically as nasal decongestants because of promoting constriction of the nasal mucosa. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine -like effect Oxymetazoline has significant affinity for α 2A receptors. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Isoproterenol (isoprenaline) Is a very potent β -receptor agonist and has little effect on α receptors. The drug has positive chronotropic and inotropic actions. Because isoproterenol activates β receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Dobutamine Beta1-selective agents Related to dopamine, but its actions are mediated mostly by activation of α and β receptors. Dobutamine is a racemic mixture of (–) and (+) isomers. The (+) isomer is a potent β 1 agonist and an α 1 receptor antagonist. The (–) isomer is a potent α 1 agonist, causing vasoconstriction when given alone. The resultant cardiovascular effects of dobutamine reflect this complex pharmacology. Dobutamine has a positive inotropic action caused by the isomer with predominantly β1 receptor activity. It has relatively greater inotropic than chronotropic effect compared with isoproterenol. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Beta2-selective agents Salbutamol Terbutaline Important in the treatment of asthma. Ritodrine Used to achieve uterine relaxation in premature labor. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Mixed-Acting Sympathomimetics Ephedrine: Ephedra sinica, known in Chinese as ma huang has been used in traditional chinese medicine for 5,000 years for the treatment of asthma and hay fever, as well as for the common cold. Ephedrine is a noncatechol phenylisopropylamine , it has high bioavailability and a relatively long duration. Its ability to activate β receptors probably accounted for its earlier use in asthma. Because it gains access to the central nervous system, it is a mild stimulant. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Mixed-Acting Sympathomimetics Pseudoephedrine: One of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. Phenylpropanolamine : Was a common component in over-the-counter appetite suppressants. Was removed from the market because its use was associated with hemorrhagic strokes in young women. The mechanism of this potential adverse effect is unknown. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Indirect-Acting Sympathomimetics Can have one of two different mechanisms : First, they may enter the sympathetic nerve ending and displace stored catecholamine transmitter. Such drugs have been called “amphetamine-like “or "displacers”. Second, they may inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter, NET. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Amphetamine-Like Drugs Is a racemic mixture of phenylisopropylamine . Is an important agent, chiefly because of its use and misuse as a central nervous system stimulant . Pharmacokinetically, it is similar to ephedrine; however, amphetamine more readily enters the central nervous system, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite. Its D-isomer is more potent than the L-isomer. Amphetamine's actions are mediated through the release of norepinephrine and, to some extent, dopamine. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Amphetamine-Like Drugs Methamphetamine (N- methylamphetamine): Very similar to amphetamine with an even higher ratio of central to peripheral actions. Methylphenidate: An amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. May be effective in some children with attention deficit hyperactivity disorder. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Amphetamine-Like Drugs Modafinil: Is a psychostimulant that differs from amphetamine in structure, neurochemical profile, and behavioral effects. Inhibits both norepinephrine and dopamine transporters, and it increases interstitial concentrations not only of norepinephrine and dopamine, but also serotonin and glutamate while decreasing GABA levels. Used primarily to improve wakefulness in narcolepsy and some other conditions. It is often associated with increases in blood pressure and heart rate, though these are usually mild. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Amphetamine-Like Drugs Tyramine: A normal by-product of tyrosine metabolism and is also found in high concentrations in some fermented foods such as cheese. Readily metabolized by MAO in the liver and is normally inactive when taken orally because of the very high first-pass effect. If administered parenterally, it has an indirect sympathomimetic action caused by the release of stored catecholamines. In patients treated with MAO inhibitors , tyramine may cause marked increases in blood pressure. Patients taking MAO inhibitors must be very careful to avoid tyramine -containing foods. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Catecholamine Reuptake Inhibitors Many antidepressants, particularly tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic hyp as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking α 1 receptors, but the mechanism remains unclear. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Catecholamine Reuptake Inhibitors Atomoxetine: A selective inhibitor of the norepinephrine reuptake transporter. Used in the treatment of attention deficit disorders Sibutramine: A serotonin and norepinephrine reuptake inhibitor and is the only appetite suppressant approved by the FDA for long-term treatment of obesity. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Catecholamine Reuptake Inhibitors Cocaine: A local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses. Readily enters the central nervous system and produces an amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine. The major action of cocaine in the central nervous system is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain. These properties and the fact that it can be smoked, snorted into the nose, or injected for rapid onset of effect have made it a heavily abused drug. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Dopamine Agonists Levodopa: Fenoldopam: Converted to dopamine in the body, and of considerable value in the treatment of Parkinson's disease. Fenoldopam: D1-receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. Useful in the intravenous treatment of severe hypertension. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Treatment of acute hypotension: Sympathomimetic drugs may be used in a hypotensive emergency to preserve cerebral and coronary blood flow. The treatment is usually of short duration while the appropriate intravenous fluid or blood is being administered. Direct-acting agonists such as norepinephrine, phenylephrine, and methoxamine have been used in this setting when vasoconstriction is desired. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Cardiogenic shock and acute heart failure: Usually due to massive myocardial infarction. Positive inotropic agents such as dopamine or dobutamine may provide short-term relief of heart failure symptoms in patients with advanced ventricular dysfunction. In low to moderate doses, these drugs may increase cardiac output and cause relatively little peripheral vasoconstriction. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Chronic Orthostatic Hypotension: Impairment of autonomic reflexes that regulate blood pressure can lead to chronic orthostatic hypotension. This is more often due to medications that can interfere with autonomic function, diabetes and other diseases causing peripheral autonomic neuropathies. Midodrine, an orally active α 1 agonist, is frequently used for this indication. Other sympathomimetics, such as oral ephedrine or phenylephrine, can be tried. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Complete heart block, cardiac arrest and CPR: Isoproterenol and epinephrine have been used in the temporary emergency management of complete heart block and cardiac arrest. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Inducing local vasoconstriction: Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string for gingivectomy( excision of the gingiva). Cocaine is still sometimes used for nasopharyngeal surgery because it combines a hemostatic effect with local anesthesia. Occasionally, cocaine is mixed with epinephrine for maximum hemostasis and local anesthesia. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Prolonging duration of local anesthesia: Combining agonists with some local anesthetics greatly prolongs the duration of infiltration nerve block; the total dose of local anesthetic (and the probability of toxicity) can therefore be reduced. Epinephrine 1:200,000, is the favored agent for this application, but norepinephrine, phenylephrine, and other agonists have also been used. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Mucous membrane decongestants: Alpha agonists reduce the discomfort of hay fever and, to a lesser extent, the common cold by decreasing the volume of the nasal mucosa. Unfortunately, rebound congestion may follow the use of these agents. Phenylephrine is often used in nasal decongestant sprays. Oral ephedrine or pseudoephedrine produce a longer duration of action at the cost of much lower local concentrations and greater potential for cardiac and central nervous system effects. Oxymetazoline is a long-acting topical decongestant. Most of these mucous membrane decongestants are available as over-the-counter products 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Bronchial asthma: Sympathomimetics other than the β 2–selective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs. Albuterol (Salbutamol) Metaproterenol, Terbutaline Are all β 2-selective agents and widely used for this indication. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Anaphylaxis: Anaphylactic shock affects both the respiratory and the cardiovascular systems. The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine. Glucocorticoids and antihistamines (both H1- and H2-receptor antagonists) may be useful as secondary therapy in anaphylaxis; however, epinephrine is the life-saving treatment. 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Ophthalmic Applications: Phenylephrine is an effective short acting mydriatic agent frequently used to facilitate examination of the retina. It is also a useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes. β -blocking agents are among the most important therapies for glaucoma. Apraclonidine is an alpha 2-selective agonist that also lowers intraocular pressure. Its mechanism of action in treating glaucoma is still uncertain; 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Genitourinary Applications: β 2-selective agents relax the pregnant uterus. Ritodrine, terbutaline, and similar drugs have been used to suppress premature labor. Ephedrine or pseudoephedrine may be occasionally useful in the treatment of stress incontinence (loss of small amounts of urine associated with coughing, laughing, sneezing, or excercising, or other movements that increase intra-abdominal pressure and thus increase pressure on the bladder). 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE

Therapeutic Uses of Sympathomimetic Drugs Central Nervous System Applications Treatment of narcolepsy. Modafinil, a new amphetamine substitute, is claimed to have fewer side effects(excessive mood changes, insomnia and abuse potential) than amphetamine in this condition. . Attention-deficit hyperactivity disorder (ADHD): A behavioral syndrome of short attention span, hyperkinetic physical behavior, and learning problems. Some patients respond well to low doses of methylphenidate and related agents or to clonidine. Modafinil may also be useful in ADHD, 9/19/2018 Munir Gharaibeh, MD, PhD, MHPE