Several sympathomimetic drugs are used primarily as vasoconstrictors for local application to the nasal mucous membrane or the eye: propylhexedrine (BENZEDREX, others), naphazoline (PRIVINE,
NAPHCON, others), oxymetazoline (AFRIN,OCUCLEAR, others), and xylometazoline (OTRIVIN, others) [see Table 10–1]. Ethylnorepinephrine (BRONKEPHRINE) is a b agonist that is used as a bron-chodilator; the drug also has a agonist activity, which may cause local vasoconstriction and thereby reduce bronchial congestion. Phenylephrine (see above), pseudoephedrine (SUDAFED, others) (a stereoisomer of ephedrine), and phenylpropanolamine are sympathomimetics used most commonly in oral preparations for the relief of nasal congestion. Pseudoephedrine is available without a prescription in a variety of solid and liquid dosage forms. Phenylpropanolamine shares the pharmacological properties of ephedrine and is approximately equal in potency except that it causes less CNS stimulation. The drug has been available over-the-counter (OTC), and numerous proprietary mixtures marketed for the oral treatment of nasal and sinus congestion contain one of these sympathomimetic amines, usually in combination with an H1histamine antagonist.
Because phenylpropanolamine increases the risk of hemorrhagic stroke, most manufacturers have voluntarily stopped marketing products containing phenylpropanolamine in the U.S. and the FDA is withdrawing approval for the drug.
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THERAPEUTIC USES OF SYMPATHOMIMETIC DRUGSSHOCK
Shock is a life-threatening condition characterized by inadequate perfusion of tissues, hypotension, and, ultimately, failure of organ systems. Treatment of shock consists of specific efforts to reverse the underlying pathogenesis as well as nonspecific measures aimed at correcting hemodynamic abnormalities. Regardless of etiology, the accompanying fall in blood pressure generally leads to marked activation of the sympathetic nervous system. This, in turn, causes peripheral vasocon-striction and an increase in the rate and force of cardiac contraction. In the initial stages of shock, these mechanisms may maintain blood pressure and cerebral blood flow, although blood flow to the kidneys, skin, and other organs may be decreased, leading to impaired production of urine and metabolic acidosis.
The initial therapy of shock involves basic life-support measures (maintenance of blood volume, etc.). Specific therapy (e.g., antibiotics for patients in septic shock) should be initiated immedi-ately. If these measures do not lead to an adequate therapeutic response, it may be necessary to use vasoactive drugs in an effort to improve abnormalities in blood pressure and flow. This ther-apy generally is empirically based on response to hemodynamic measurements. Many of these pharmacological approaches, while reasonable, are of uncertain efficacy. Adrenergic receptor agonists may be used in an attempt to increase myocardial contractility or to modify peripheral vascular resistance. In general terms, b receptor agonists increase heart rate and force of con-traction, a receptor agonists increase peripheral vascular resistance, and DA promotes dilation of renal and splanchnic vascular beds, in addition to activating b and a receptors.
Cardiogenic shock due to myocardial infarction has a poor prognosis; therapy is aimed at improving peripheral blood flow. Medical intervention is designed to optimize cardiac filling pres-sure (preload), myocardial contractility, and peripheral resistance (afterload). Preload may be increased by administration of intravenous fluids or reduced with drugs such as diuretics and nitrates. Sympathomimetic amines have been used to increase the force of contraction of the heart.
Some of these drugs have disadvantages: isoproterenol is a powerful chronotropic agent and can greatly increase myocardial O2demand; NE intensifies peripheral vasoconstriction; Epi increases heart rate and may predispose the heart to dangerous arrhythmias. DA is an effective inotropic agent that causes less increase in heart rate than does isoproterenol and also promotes renal arterial dila-tion (possibly useful in preserving renal funcdila-tion). When given in high doses (>10–20 mg/kg/min), DA activates a receptors, causing peripheral and renal vasoconstriction. Dobutamine has complex pharmacological actions that are mediated by its stereoisomers; it increases myocardial contrac-tility with little increase in heart rate or peripheral resistance.
In some patients, hypotension is so severe that vasoconstrictors are required to maintain a blood pressure sufficient for CNS perfusion. Alpha agonists (e.g., NE, phenylephrine, metaraminol, mephentermine, midodrine, ephedrine, Epi, DA, and methoxamine) have been used. This approach may be advantageous in patients with hypotension due to failure of the sympathetic nervous system (e.g., after spinal anesthesia or injury). In patients with other forms of shock, such as car-diogenic shock, reflex vasoconstriction generally is intense, and a receptor agonists may further compromise blood flow to organs such as the kidneys and gut and adversely increase the work of the heart. Indeed, vasodilating drugs such as nitroprusside are more likely to improve blood flow and decrease cardiac work in such patients by decreasing afterload if a minimally adequate blood pressure can be maintained.
The hemodynamic abnormalities in septic shock are complex and poorly understood. Most patients with septic shock initially have low or marginal peripheral vascular resistance, possibly reflecting excessive nitric oxide (NO) production. If the syndrome progresses, myocardial depres-sion, increased peripheral resistance, and impaired tissue oxygenation occur. The primary treat-ment of septic shock is antibiotics. Therapy with vasoactive drugs must be individualized according to hemodynamic monitoring.
HYPOTENSION
Drugs with predominantly a agonist activity can be used to raise blood pressure in patients with decreased peripheral resistance in conditions such as spinal anesthesia or intoxication with anti-hypertensive medications. However, hypotension per se is not an indication for treatment with these agents unless there is inadequate perfusion of organs such as the brain, heart, or kidneys.
Furthermore, adequate replacement of fluid or blood may be more appropriate than drug therapy for many patients with hypotension.
Patients with orthostatic hypotension (excessive fall in blood pressure with standing) often represent a pharmacological challenge. There are diverse causes for this disorder, including the Shy-Drager syndrome and idiopathic autonomic failure. Therapeutic approaches include physical
maneuvers and a variety of drugs (fludrocortisone, prostaglandin synthesis inhibitors, somato-statin analogs, caffeine, vasopressin analogs, and DA antagonists). The ideal agent would enhance venous constriction prominently and produce relatively little arterial constriction so as to avoid supine hypertension. No such agent currently is available. Drugs used include a1 ago-nists and indirect-acting agents. Midodrine shows promise in treating orthostatic hypotension.
HYPERTENSION
Centrally acting a2receptor agonists such as clonidine are useful in the treatment of hyperten-sion. Drug therapy of hypertension is discussed in Chapter 32.
CARDIAC ARRHYTHMIAS
During cardiopulmonary resuscitation, Epi and other a agonists increase diastolic pressure and improve coronary blood flow. a agonists also help to preserve cerebral blood flow. Thus, during external cardiac massage, Epi facilitates distribution of the limited cardiac output to the cerebral and coronary circulations. The optimal dose of epinephrine in patients with cardiac arrest is unclear. Once a cardiac rhythm has been restored, it may be necessary to treat arrhythmias, hypotension, or shock. Treatment of cardiac arrhythmias is detailed in Chapter 34.
HEART FAILURE
Use of b agonists and b antagonists in the treatment of heart failure is described in Chapter 33.
LOCAL VASCULAR EFFECTS OF A ADRENERGIC RECEPTOR AGONISTS
Epi is used in many surgical procedures in the nose, throat, and larynx to shrink the mucosa and improve visualization by limiting hemorrhage. Simultaneous injection of Epi with local anesthet-ics retards the absorption of the anesthetic and increases the duration of anesthesia (see Chapter 14).
Injection of a agonists into the penis may be useful in reversing priapism, a complication of the use of a receptor antagonists or PDE5 inhibitors (e.g., sildenafil) in the treatment of erectile dys-function. Both phenylephrine and oxymetazoline are efficacious vasoconstrictors when applied locally during sinus surgery.
NASAL DECONGESTION
aReceptor agonists are used extensively as nasal decongestants, as discussed above. Sympath-omimetic decongestants should be used with great caution in patients with hypertension and in men with prostatic enlargement and not used by patients who are taking MAO inhibitors. Oral decongestants are much less likely to cause rebound congestion but carry a greater risk of induc-ing adverse systemic effects. Indeed, patients with uncontrolled hypertension or ischemic heart disease generally should avoid the oral consumption of OTC products or herbal preparations containing sympathomimetics.
ASTHMA
Use of b adrenergic agonists in the treatment of asthma is discussed in Chapter 27.
ALLERGIC REACTIONS
Epi is the drug of choice to reverse the manifestations of serious acute hypersensitivity reactions (e.g., from food, bee sting, or drug allergy). A subcutaneous injection of Epi rapidly relieves itch-ing, hives, and swelling of lips, eyelids, and tongue. In some patients, careful intravenous infusion of Epi may be required to ensure prompt pharmacological effects. This treatment may be life saving when edema of the glottis threatens airway patency or when there is hypotension or shock in patients with anaphylaxis. In addition to its cardiovascular effects, Epi activates b receptors that suppress the release from mast cells of mediators such as histamine and leukotrienes.
Although glucocorticoids and antihistamines frequently are administered to patients with severe hypersensitivity reactions, Epi remains the mainstay.
OPHTHALMIC USES
Ophthalmic uses are discussed in Chapter 63.
NARCOLEPSY
Narcolepsy is characterized by hypersomnia. Some patients respond to treatment with tricyclic antidepressants or MAO inhibitors. Alternatively, CNS stimulants such as amphetamines may be useful. Therapy with amphetamines is complicated by the risk of abuse and the likelihood of the development of tolerance and a variety of behavioral changes (see above). Amphetamines may
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disturb nocturnal sleep, which increases the difficulty of avoiding daytime attacks of sleep in these patients.Modafinil (PROVIGIL), a CNS stimulant, may be beneficial via an unknown mechanism. In the U.S., modafinil is a schedule IV-controlled substance.
Occasionally, narcolepsy results from mutations in orexin neuropeptides (also called hypocre-tins), which are expressed in the lateral hypothalamus, or in their G protein–coupled receptors.
Although such mutations are not present in most subjects with narcolepsy, the levels of orexins in the CSF are diminished, suggesting that deficient orexin signaling may play a pathogenic role.
The association of these neuropeptides and their cognate GPCRs with narcolepsy provides an attractive target for the development of novel pharmacotherapies for this disorder.
WEIGHT REDUCTION
Optimally, weight loss is achieved by a gradual increase in energy expenditure from exercise com-bined with dieting to decrease the caloric intake. Amphetamine promotes weight loss by sup-pressing appetite rather than by increasing energy expenditure. Other anorexic drugs include methamphetamine, dextroamphetamine, phentermine, benzphetamine, phendimetrazine, phen-metrazine, diethylpropion, mazindol, phenylpropanolamine, and sibutramine (a mixed adrener-gic/serotonergic drug). These agents may be effective adjuncts in the treatment of obesity but they all present significant risk of adverse effects (see above). Available evidence does not support the isolated use of these drugs in the absence of a more comprehensive program that stresses exercise and diet modification.
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
ADHD, usually first evident in childhood, is characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness. A variety of stimulant drugs have been utilized in the treatment of ADHD, and they are particularly indicated in moderate-to-severe cases.
Methylphenidate is effective in children with ADHD and is the most common intervention; treat-ment may start with a dose of 5 mg in the morning and at lunch, increasing gradually over a period of weeks depending on the response as judged by parents, teachers, and the clinician.
The total daily dose generally should not exceed 60 mg. Methylphenidate has a short duration of action; thus, most children require 2–3 doses/day, with the timing individualized for effect.
Methylphenidate, dextroamphetamine, and amphetamine probably have similar efficacy in ADHD. Pemoline appears to be less effective, although like sustained release preparations of methylphenidate (RITALIN SR,CONCERTA,METADATE) and amphetamine (ADDERAL XR), pemoline may be used once daily in children and adults. Potential adverse effects of these medications include insomnia, abdominal pain, anorexia, and weight loss that may be associated with suppression of growth in children. Minor symptoms may be transient or may respond to adjustment of dosage or administration of the drug with meals.
II. ADRENERGIC RECEPTOR ANTAGONISTS
Adrenergic receptor antagonists inhibit the interaction of NE, Epi, and other sympathomimetic drugs with a and b receptors (see Figure 10–3). Detailed knowledge of the localization of adren-ergic receptors and of effector-response coupling is essential for understanding the pharmacologi-cal properties and therapeutic uses of this important class of drugs (see Tables 6–1, 6–6, 6–7, 6–8, 10–2 and 10–6).
AADRENERGIC RECEPTOR ANTAGONISTS
Effects of a adrenergic antagonists may be predicted from the consequences of a receptor stimula-tion. The a1adrenergic receptors mediate contraction of arterial and venous smooth muscle. The a2 receptors are involved in suppressing sympathetic outflow from the CNS, increasing vagal tone, facilitating platelet aggregation, inhibiting the release of NE and ACh from nerve endings, and reg-ulating metabolic effects (e.g., suppression of insulin secretion and inhibition of lipolysis) and con-traction of some arteries and veins.
areceptor antagonists are chemically heterogeneous and have a wide spectrum of pharma-cological specificities (Figure 10–3, Table 10–3). Prazosin is much more potent in blocking a1than a2receptors (i.e., a1selective), whereas yohimbine is a2selective;phentolamine has similar affinities for both of these receptor subtypes. Newer agents discriminate amongst the subtypes of a particular receptor (e.g., tamsulosin has higher potency at a1A than at a1B receptors). Table 10–3 summarizes the properties of three chemically distinct groups of ablockers.
Pharmacological Properties
CARDIOVASCULAR SYSTEM
A1 Receptor Antagonists Blockade of a1 adrenergic receptors inhibits vasoconstriction induced by endogenous catecholamines; vasodilation may occur in both arteriolar resistance ves-sels and veins. The result is a fall in blood pressure due to decreased peripheral resistance; the mag-nitude of such effects depends on the activity of the sympathetic nervous system, is less in supine than in upright subjects, and is enhanced by hypovolemia. For most a receptor antagonists, the fall in blood pressure is opposed by baroreceptor reflexes that cause increases in heart rate and cardiac output, as well as fluid retention. These compensatory reflexes are exaggerated if the antagonist also blocks a2receptors on peripheral sympathetic nerve endings, leading to enhanced release of NE and increased stimulation of postsynaptic b1receptors in the heart and on juxtaglomerular cells.
Since blockade of a1receptors inhibits vasoconstriction, pressor responses to Epi may be trans-formed to vasodepressor effects (“epinephrine reversal”) due to unopposed stimulation of b2 recep-tors in the vasculature with resultant vasodilation.
A2 Adrenergic Receptor Antagonists Activation of a2 receptors in the pontomedullary region of the CNS inhibits sympathetic nervous system activity and leads to a fall in blood pres-sure; these receptors are a site of action for drugs such as clonidine. Activation of presynaptic a2 receptors inhibits the release of NE and cotransmitters from peripheral sympathetic nerve endings.
Thus, blockade of peripheral a2receptors with selective antagonists such as yohimbine increases sympathetic outflow and potentiates the NE release, leading to activation of a1and b1receptors in the heart and peripheral vasculature with a consequent rise in blood pressure. Antagonists that simultaneously block a1and a2receptors cause similar effects on sympathetic outflow and NE release, but the net increase in blood pressure is prevented by inhibition of vasoconstriction (a1blockade).
The physiological role of vascular a2receptors in the regulation of blood flow within various vas-cular beds is uncertain. Vavas-cular a2receptors probably are preferentially stimulated by circulating catecholamines, whereas a1receptors are activated by NE released from sympathetic nerves.
OTHER ACTIONS
Catecholamines increase the output of glucose from the liver, predominantly via b receptors, although a receptors may contribute, and thus, a receptor antagonists may reduce glucose release. a2AReceptors facilitate platelet aggregation; the effect of blockade of platelet a2 recep-torsin vivo is not clear. Activation of a2receptors in the pancreatic islets suppresses insulin secre-tion; conversely, their blockade may facilitate insulin release (see Chapter 60). Alpha receptor antagonists reduce smooth muscle tone in the prostate and neck of the bladder, thereby decreas-ing resistance to urine outflow in benign prostatic hypertrophy (see below).
FIGURE 10–3 Classification of adrenergic receptor antagonists. Drugs marked by an asterisk (*) also block a1 receptors.
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