Shock. Shock is a clinical syndrome characterized by inadequate perfusion of tissues; it usually is associated with hypotension and ultimately with the failure of organ systems (Hollenberg et al., 1999). Shock is an immediately life-threatening impairment of delivery of oxygen and nutrients to the organs of the body. Causes of shock include hypovolemia (due to dehydration or blood loss), cardiac failure (extensive myocardial infarction, severe arrhythmia, or cardiac mechanical defects such as ventricular septal defect), obstruction to cardiac output (due to pulmonary embolism, pericardial tamponade, or aortic dissection), and peripheral circulatory dysfunction (sepsis or anaphylaxis). Recent research on shock has focused on the accompanying increased permeability of the GI mucosa to pancreatic proteases, and on the role of these degradative enzymes on microvascular inflammation and multi-organ failure (Schmid-Schoenbein and Hugli, 2005). The 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 vasoconstriction 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. It is essential to maintain blood volume, which often requires monitoring of hemodynamic parameters. Specific therapy (e.g., antibiotics for patients in septic shock) should be initiated immediately. 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 therapy generally is empirically based on response to hemodynamic measurements. Many of these pharmacological approaches, while apparently clinically 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, β receptor agonists increase heart rate and force of contraction, α receptor agonists increase peripheral vascular resistance, and DA promotes dilation of renal and splanchnic vascular beds, in addition to activating β and α receptors (Breslow and Ligier, 1991).
Cardiogenic shock due to myocardial infarction has a poor prognosis; therapy is aimed at improving peripheral blood flow. Definitive therapy, such as emergency cardiac catheterization followed by surgical revascularization or angioplasty, may be very important. Mechanical left ventricular assist devices also may help to maintain cardiac output and coronary perfusion in critically ill patients. In the setting of severely impaired cardiac output, falling blood pressure leads to intense sympathetic outflow and vasoconstriction. This may further decrease cardiac output as the damaged heart pumps against a higher peripheral resistance. Medical intervention is designed to optimize cardiac filling pressure (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. A number of 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 O2 demand; NE intensifies peripheral vasoconstriction; and epinephrine 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. DA also promotes renal arterial dilation; this may be useful in preserving renal function. When given in high doses (> 10-20 μg/kg per minute), DA activates α receptors, causing peripheral and renal vasoconstriction. Dobutamine has complex pharmacological actions that are mediated by its stereoisomers; the clinical effects of the drug are to increase myocardial contractility with little increase in heart rate or peripheral resistance.
In some patients in shock, hypotension is so severe that vasoconstricting drugs are required to maintain a blood pressure that is adequate for CNS perfusion. Alpha agonists such as NE, phenylephrine, metaraminol, mephentermine, midodrine, ephedrine, epinephrine, DA, and methoxamine all have been used for this purpose. This approach may be advantageous in patients with hypotension due to failure of the sympathetic nervous system (e.g., after spinal anesthesia or injury). However, in patients with other forms of shock, such as cardiogenic shock, reflex vasoconstriction generally is intense, and α 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 barely normal peripheral vascular resistance, possibly owing to excessive effects of endogenously produced NO as well as normal or increased cardiac output. If the syndrome progresses, myocardial depression, increased peripheral resistance, and impaired tissue oxygenation occur. The primary treatment of septic shock is antibiotics. Data on the comparative value of various adrenergic agents in the treatment of septic shock are limited. Therapy with drugs such as DA or dobutamine is guided by hemodynamic monitoring, with individualization of therapy depending on the patient's overall clinical condition.
Hypotension. Drugs with predominantly α agonist activity can be used to raise blood pressure in patients with decreased peripheral resistance in conditions such as spinal anesthesia or intoxication with antihypertensive 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. In patients with spinal anesthesia that interrupts sympathetic activation of the heart, injections of ephedrine increase heart rate as well as peripheral vascular resistance; tachyphylaxis may occur with repetitive injections, necessitating the use of a directly acting drug.
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, somatostatin analogs, caffeine, vasopressin analogs, and DA antagonists). A number of sympathomimetic drugs also have been used in treating this disorder. 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 in this disorder to activate α1 receptors include both direct- and indirect-acting agents. Midodrine shows promise in treating this challenging disorder.
Hypertension. Centrally acting α2 receptor agonists such as clonidine are useful in the treatment of hypertension. Drug therapy of hypertension is discussed in Chapter 27.
Cardiac Arrhythmias. Cardiopulmonary resuscitation in patients with cardiac arrest due to ventricular fibrillation, electromechanical dissociation, or asystole may be facilitated by drug treatment. Epinephrine is an important therapeutic agent in patients with cardiac arrest; epinephrine and other α agonists increase diastolic pressure and improve coronary blood flow. Alpha agonists also help to preserve cerebral blood flow during resuscitation. Cerebral blood vessels are relatively insensitive to the vasoconstricting effects of catecholamines, and perfusion pressure is increased. Consequently, during external cardiac massage, epinephrine facilitates distribution of the limited cardiac output to the cerebral and coronary circulations. Although it had been thought that the β adrenergic effects of epinephrine on the heart made ventricular fibrillation more susceptible to conversion with electrical countershock, tests in animal models have not confirmed this hypothesis. 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.
In patients with paroxysmal supraventricular tachycardias, particularly those associated with mild hypotension, careful infusion of an α agonist (e.g., phenylephrine) to raise blood pressure to ~160 mm Hg may end the arrhythmia by increasing vagal tone. However, this method of treatment has been replaced largely by Ca2+ channel blockers with clinically significant effects on the AV node,β antagonists, adenosine, and electrical cardioversion (Chapter 29). Beta agonists such as isoproterenol may be used as adjunctive or temporizing therapy with atropine in patients with marked bradycardia who are compromised hemodynamically; if long-term therapy is required, a cardiac pacemaker usually is the treatment of choice.
Congestive Heart Failure. Sympathetic stimulation of β receptors in the heart is an important compensatory mechanism for maintenance of cardiac function in patients with congestive heart failure. Responses mediated by β receptors are blunted in the failing human heart. While β agonists may increase cardiac output in acute emergency settings such as shock, long-term therapy with β agonists as inotropic agents is not efficacious. Indeed, interest has grown in the use of β receptor antagonists in the treatment of patients with congestive heart failure (Chapter 28).
Local Vascular Effects of α Adrenergic Receptor Agonists. Epinephrine 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 epinephrine with local anesthetics retards the absorption of the anesthetic and increases the duration of anesthesia (Chapter 20). Injection of α agonists into the penis may be useful in reversing priapism, a complication of the use of α receptor antagonists or PDE5 inhibitors (e.g., sildenafil) in the treatment of erectile dysfunction. Both phenylephrine and oxymetazoline are efficacious vasoconstrictors when applied locally during sinus surgery.
Nasal Decongestion. α Receptor agonists are used extensively as nasal decongestants in patients with allergic or vasomotor rhinitis and in acute rhinitis in patients with upper respiratory infections. These drugs probably decrease resistance to airflow by decreasing the volume of the nasal mucosa; this may occur by activation of α receptors in venous capacitance vessels in nasal tissues that have erectile characteristics. The receptors that mediate this effect appear to be α1 receptors. Interestingly, α2 receptors may mediate contraction of arterioles that supply nutrition to the nasal mucosa. Intense constriction of these vessels may cause structural damage to the mucosa. A major limitation of therapy with nasal decongestants is loss of efficacy, "rebound" hyperemia, and worsening of symptoms with chronic use or when the drug is stopped. Although mechanisms are uncertain, possibilities include receptor desensitization and damage to the mucosa. Agonists that are selective for α1 receptors may be less likely to induce mucosal damage.
For decongestion, α agonists may be administered either orally or topically. Oral ephedrine often causes CNS adverse effects. Pseudoephedrine is a stereoisomer of ephedrine that is less potent than ephedrine in producing tachycardia, increased blood pressure, and CNS stimulation. Sympathomimetic decongestants should be used with great caution in patients with hypertension and in men with prostatic enlargement, and they are contraindicated in patients who are taking MAO inhibitors. A variety of compounds (see under Ephedrine, earlier) are available for topical use in patients with rhinitis. Topical decongestants are particularly useful in acute rhinitis because of their more selective site of action, but they are apt to be used excessively by patients, leading to rebound congestion. Oral decongestants are much less likely to cause rebound congestion but carry a greater risk of inducing adverse systemic effects. Indeed, patients with uncontrolled hypertension or ischemic heart disease generally should carefully avoid the oral consumption of over-the-counter products or herbal preparations containing sympathomimetic drugs.
Asthma. Use of β adrenergic agonists in the treatment of asthma and chronic obstructive pulmonary disease (COPD) is discussed in Chapter 36.
Allergic Reactions. Epinephrine 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 epinephrine rapidly relieves itching, hives, and swelling of lips, eyelids, and tongue. In some patients, careful intravenous infusion of epinephrine 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, epinephrine is thought to activate β 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, epinephrine remains the mainstay. Epinephrine auto-injectors (epipen, others) are employed widely for the emergency self-treatment of anaphylaxis.
Ophthalmic Uses. Application of various sympathomimetic amines for diagnostic and therapeutic ophthalmic use is discussed in Chapter 64.
Narcolepsy and Related Syndromes. Narcolepsy is characterized by hypersomnia, including attacks of sleep that may occur suddenly under conditions that are not normally conducive to sleep. Some patients respond to treatment with tricyclic antidepressants or MAO inhibitors. Alternatively, CNS stimulants such as amphetamine, dextroamphetamine, or methamphetamine may be useful. Modafinil (provigil), a CNS stimulant, may have benefit in narcolepsy. In the U.S., it is a schedule IV controlled substance. Its mechanism of action in narcolepsy is unclear and may not involve adrenergic receptors. Therapy with amphetamines is complicated by the risk of abuse and the likelihood of the development of tolerance. Depression, irritability, and paranoia also may occur. Amphetamines may disturb nocturnal sleep, which increases the difficulty of avoiding daytime attacks of sleep in these patients. Armodafinil (nuvigil), the R-enantiomer of modafinil (a mixture of R- and S-enantiomers) is also indicated for narcolepsy, to improve wakefulness in shift workers, and to combat excessive sleepiness in patients with obstructive sleep apnea-hypopnea syndrome.
Narcolepsy in rare individuals is caused by mutations in the related orexin neuropeptides (also called hypocretins), which are expressed in the lateral hypothalamus, or in their G protein–coupled receptors (Mignot, 2004). Although such mutations are not present in most subjects with narcolepsy, the levels of orexins in the CSF are markedly 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. Obesity arises as a consequence of positive caloric balance. Optimally, weight loss is achieved by a gradual increase in energy expenditure from exercise combined with dieting to decrease the caloric intake. However, this obvious approach has a relatively low success rate. Consequently, alternative forms of treatment, including surgery or medications, have been developed in an effort to increase the likelihood of achieving and maintaining weight loss. Amphetamine was found to produce weight loss in early studies of patients with narcolepsy and was subsequently used in the treatment of obesity. The drug promotes weight loss by suppressing appetite rather than by increasing energy expenditure. Other anorexic drugs include methamphetamine, dextroamphetamine (and a prodrug form, lisdexamfetamine), phentermine, benzphetamine, phendimetrazine, phenmetrazine, diethylpropion, mazindol, phenylpropanolamine, and sibutramine (a mixed adrenergic/serotonergic drug). Phenmetrazine, mazindol, and phenylpropanolamine have been discontinued in the U.S. In short-term (up to 20 weeks), double-blind controlled studies, amphetamine-like drugs have been shown to be more effective than placebo in promoting weight loss; the rate of weight loss typically is increased by ~ 0.5 pound per week with these drugs. There is little to choose among these drugs in terms of efficacy. However, long-term weight loss has not been demonstrated unless these drugs are taken continuously. In addition, other important issues have not yet been resolved, including the selection of patients who might benefit from these drugs, whether the drugs should be administered continuously or intermittently, and the duration of treatment. Adverse effects of treatment include the potential for drug abuse and habituation, serious worsening of hypertension (although in some patients blood pressure actually may fall, presumably as a consequence of weight loss), sleep disturbances, palpitations, and dry mouth. These agents may be effective adjuncts in the treatment of obesity. However, available evidence does not support the isolated use of these drugs in the absence of a more comprehensive program that stresses exercise and modification of diet. β3 Receptor agonists have remarkable anti-obesity and anti-diabetic effects in rodents. However, pharmaceutical companies have not yet succeeded in developing β3 receptor agonists for the treatment of these conditions in humans, perhaps because of important differences in β3 receptors between humans and rodents. With the cloning of the human β3 receptor, compounds with favorable metabolic effects have been developed. The use of β3 agonists in the treatment of obesity remains a possibility for the future (Fernandez-Lopez et al., 2002; Robidoux et al., 2004).
Attention-Deficit/Hyperactivity Disorder (ADHD). This syndrome, usually first evident in childhood, is characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness. Children with this disorder frequently are troubled by difficulties in school, impaired interpersonal relationships, and excitability. Academic underachievement is an important characteristic. A substantial number of children with this syndrome have characteristics that persist into adulthood, although in modified form. Behavioral therapy may be helpful in some patients. Catecholamines may be involved in the control of attention at the level of the cerebral cortex. A variety of stimulant drugs have been utilized in the treatment of ADHD, and they are particularly indicated in moderate-to-severe cases. Dextroamphetamine has been demonstrated to be more effective than placebo. Methylphenidate is effective in children with ADHD and is the most common intervention (Swanson and Volkow, 2003). Treatment may start with a dose of 5 mg of methylphenidate in the morning and at lunch; the dose is increased 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; because of its short duration of action, most children require two or three doses of methylphenidate each day. The timing of doses is adjusted individually in accordance with rapidity of onset of effect and duration of action. Methylphenidate, dextroamphetamine, and amphetamine probably have similar efficacy in ADHD and are the preferred drugs in this disorder. Sustained-release preparations of dextroamphaetamine, methylphenidate (ritalin sr, concerta, meta-date), dexmethylphenidate (focalin xr), and amphetamine (adderal xr) may be used once daily in children and adults. Lisdexamfetamine (vyvanse) can be administered once daily and a transdermal formulation of methylphenidate (daytrana) is marketed for daytime use. 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. Other drugs that have been utilized include tricyclic antidepressants, antipsychotic agents, and clonidine. A sustained release formulation of guanfacine (intuniv), an α2A receptor agonist, has recently been approved for use in children (ages 6-17 years) in treating ADHD.