Therapeutic Uses of Sympathomimetic Drugs

THERAPEUTIC USES OF SYMPATHOMIMETIC DRUGS

Cardiovascular Applications

In keeping with the critical role of the sympathetic nervous system in the control of blood pressure, a major area of application of the sympathomimetics is in cardiovascular conditions.

A. Treatment of Acute Hypotension

Acute hypotension may occur in a variety of settings such as severe hemorrhage, decreased blood volume, cardiac arrhythmias, neuro-logic disease or accidents, adverse reactions or overdose of medica-tions such as antihypertensive drugs, and infection. If cerebral, renal, and cardiac perfusion is maintained, hypotension itself does not usually require vigorous direct treatment. Rather, placing the patient in the recumbent position and ensuring adequate fluid volume while the primary problem is determined and treated is usually the correct course of action. The use of sympathomimetic drugs merely to elevate a blood pressure that is not an immediate threat to the patient may increase morbidity. Sympathomimetic drugs may be used in a hypotensive emergency to preserve cerebral and coronary blood flow. The treatment is usually of short dura-tion while the appropriate intravenous fluid or blood is being administered. Direct-acting α agonists such as norepinephrine,phenylephrine, and methoxamine have been used in this settingwhen vasoconstriction is desired.

Shock is a complex acute cardiovascular syndrome that resultsin a critical reduction in perfusion of vital tissues and a wide range of systemic effects. Shock is usually associated with hypotension, an altered mental state, oliguria, and metabolic acidosis. If untreated, shock usually progresses to a refractory deteriorating state and death. The three major mechanisms responsible for shock are hypovolemia, cardiac insufficiency, and altered vascular resistance. Volume replacement and treatment of the underlying disease are the mainstays of the treatment of shock. Although sympathomimetic drugs have been used in the treatment of virtu-ally all forms of shock, their efficacy is unclear.

In most forms of shock, intense vasoconstriction, mediated by reflex sympathetic nervous system activation, is present. Indeed, efforts aimed at reducing rather than increasing peripheral resis-tance may be more fruitful to improve cerebral, coronary, and renal perfusion. A decision to use vasoconstrictors or vasodilators is best made on the basis of information about the underlying cause. Their use may require invasive monitoring.

Cardiogenic shock and acute heart failure, usually due to mas-sive myocardial infarction, has a poor prognosis. Mechanically assisted perfusion and emergency cardiac surgery have been utilized in some settings. Optimal fluid replacement requires monitoring of pulmonary capillary wedge pressure and other parameters of cardiacfunction. 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, compared with norepi-nephrine, cause relatively little peripheral vasoconstriction. Isoproterenol increases heart rate and work more than either dop-amine or dobutamine. Unfortunately, the patient with shock may not respond to any of these therapeutic maneuvers; the temptation is then to use vaso-constrictors to maintain blood pressure. Coronary perfusion may be improved, but this gain may be offset by increased myocardial oxygen demands as well as more severe vasoconstriction in blood vessels to the abdominal viscera. Therefore, the goal of therapy in shock should be to optimize tissue perfusion, not blood pressure.

B. Chronic Orthostatic Hypotension

On standing, gravitational forces induce venous pooling, resulting in decreased venous return. Normally, a decrease in blood pressure is prevented by reflex sympathetic activation with increased heart rate, and peripheral arterial and venous vasoconstriction. Impairment of autonomic reflexes that regulate blood pressure can lead to chronic orthostatic hypotension. This is more often due to medica-tions that can interfere with autonomic function (eg, imipramine and other tricyclic antidepressants, α blockers for the treatment of urinary retention, and diuretics) diabetes, and other diseases causing peripheral autonomic neuropathies, and less commonly, primary degenerative disorders of the autonomic nervous system.

Increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension, and drugs activating α receptors can be used for this purpose. Midodrine, an orally active α₁ ago-nist, is frequently used for this indication. Other sympathomimet-ics, such as oral ephedrine or phenylephrine, can be tried.

C. Cardiac Applications

Catecholamines such as isoproterenol and epinephrine have been used in the temporary emergency management of complete heart block and cardiac arrest. Epinephrine may be useful in cardiac arrest in part by redistributing blood flow during cardiopulmo-nary resuscitation to coronaries and to the brain. However, elec-tronic pacemakers are both safer and more effective in heart block and should be inserted as soon as possible if there is any indication of continued high-degree block.

Dobutamine injection is used as a pharmacologic cardiac stress test. Dobutamine augments myocardial contractility andpromotes coronary and systemic vasodilation. These actions lead to increased heart rate and increased myocardial work and can reveal areas of ischemia in the myocardium that are detected by echocardiogram or nuclear medicine techniques. Dobutamine is often used in patients unable to exercise during the stress test.

D. Inducing Local Vasoconstriction

Reduction of local or regional blood flow is desirable for achieving hemostasis in surgery, for reducing diffusion of local anesthetics away from the site of administration, and for reducing mucous membrane congestion. In each instance, α-receptor activation is desired, and the choice of agent depends on the maximal efficacy required, the desired duration of action, and the route of admin-istration.

Effective pharmacologic hemostasis, often necessary for facial, oral, and nasopharyngeal surgery, requires drugs of high efficacy that can be administered in high concentration by local application. Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). 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.

Combining α agonists with some local anesthetics greatly pro-longs 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 α ago-nists have also been used. Systemic effects on the heart and periph-eral vasculature may occur even with local drug administration but are usually minimal. Use of epinephrine with local anesthesia of acral vascular beds (digits, nose, and ears) has not been advised because of fear of ischemic necrosis. Recent studies suggest that it can be used (with caution) for this indication.

Mucous membrane decongestants are α agonists that reduce the discomfort of hay fever and, to a lesser extent, the common cold by decreasing the volume of the nasal mucosa. These effects are probably mediated by α₁ receptors. Unfortunately, rebound hyperemia may follow the use of these agents, and repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries. Constriction of these vessels may involve activa-tion of α₂ receptors, and phenylephrine is often used in nasal decongestant sprays. A longer duration of action—at the cost of much lower local concentrations and greater potential for cardiac and central nervous system effects—can be achieved by the oral administration of agents such as ephedrine or one of its isomers, pseudoephedrine. Long-acting topical decongestants include xylo-metazoline and oxymetazoline. Most of these mucous membrane decongestants are available as over-the-counter products.

Pulmonary Applications

One of the most important uses of sympathomimetic drugs is in the therapy of bronchial asthma. Beta₂-selective drugs (albuterol, metaproterenol, terbutaline) are used for this purpose. Short-acting preparations can be used only transiently for acute treat-ment of asthma symptoms. For chronic asthma treatment in adults, long-acting β₂ agonists should only be used as an addition to steroids because they may increase morbidity if used alone. There is less agreement about their benefit in children. Long-acting β₂ agonists are also used in patients with chronic obstruc-tive pulmonary disease (COPD). Nonselective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs.

Anaphylaxis

Anaphylactic shock and related immediate (type I) IgE-mediated reactions affect both the respiratory and the cardiovascular sys-tems. The syndrome of bronchospasm, mucous membrane con-gestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine, 0.3–0.5 mg (0.3–0.5 mL of a 1:1000 epinephrine solution). Intramuscular injection may be the preferred route of administration, since skin blood flow (and hence systemic drug absorption from subcutane-ous injection) is unpredictable in hypotensive patients. In some patients with impaired cardiovascular function, intravenous injec-tion of epinephrine may be required. Glucocorticoids and antihis-tamines (both H₁- and H₂-receptor antagonists) may be useful as secondary therapy in anaphylaxis. The use of these agents precedes the era of controlled clinical trials, but extensive experimental and clinical experience supports the use of epinephrine as the agent of choice in anaphylaxis, presumably because epinephrine activates α, β₁, and β₂receptors, all of which may be important in reversingthe pathophysiologic processes underlying anaphylaxis. It is rec-ommended that patients at risk for insect sting hypersensitivity, severe food allergies, or other types of anaphylaxis carry epineph-rine in an autoinjector (EpiPen) for self-administration.

Ophthalmic Applications

Phenylephrine is an effective 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 mem-branes. Sympathomimetics administered as ophthalmic drops are also useful in localizing the lesion in Horner’s syndrome. (See Box: An Application of Basic Pharmacology to a Clinical Problem.)

Glaucoma responds to a variety of sympathomimetic and sym-pathoplegic drugs. Epinephrine and its prodrug dipivefrin are now rarely used, but β-blocking agents are among the most important thera-pies. Apraclonidine and brimonidine are α₂-selective agonists that also lower intraocular pressure and are approved for use in glau-coma. The mechanism of action of these drugs in treating glaucoma is still uncertain; direct neuroprotective effects may be involved in addition to the benefits of lowering intraocular pressure.

Genitourinary Applications

As noted above, β₂-selective agents relax the pregnant uterus. Ritodrine, terbutaline, and similar drugs have been used to sup-press premature labor. The goal is to defer labor long enough to ensure adequate maturation of the fetus. These drugs may delay labor for several days. This may afford time to administer corticos-teroid drugs, which decrease the incidence of neonatal respiratory distress syndrome. However, meta-analysis of older trials and a randomized study suggest that β-agonist therapy may have no significant benefit on perinatal infant mortality and may increase maternal morbidity.

Oral sympathomimetic therapy is occasionally useful in the treatment of stress incontinence. Ephedrine or pseudoephedrine may be tried.

An Application of Basic Pharmacology to a Clinical Problem

Horner’s syndrome is a condition—usually unilateral—that results from interruption of the sympathetic nerves to the face. The effects include vasodilation, ptosis, miosis, and loss of sweat-ing on the affected side. The syndrome can be caused by either a preganglionic or a postganglionic lesion, such as a tumor. Knowledge of the location of the lesion (preganglionic or post-ganglionic) helps determine the optimal therapy.

A localized lesion in a nerve causes degeneration of the distal portion of that fiber and loss of transmitter contents from the degenerated nerve ending—without affecting neurons inner-vated by the fiber. Therefore, a preganglionic lesion leaves the postganglionic adrenergic neuron intact, whereas a postgangli-onic lesion results in degeneration of the adrenergic nerve end-ings and loss of stored catecholamines from them. Becauseindirectly acting sympathomimetics require normal stores of catecholamines, such drugs can be used to test for the presence of normal adrenergic nerve endings. The iris, because it is easily visible and responsive to topical sympathomimetics, is a conve-nient assay tissue in the patient.

If the lesion of Horner’s syndrome is postganglionic, indirectly acting sympathomimetics (eg, cocaine, hydroxyamphetamine) will not dilate the abnormally constricted pupil because cate-cholamines have been lost from the nerve endings in the iris. In contrast, the pupil dilates in response to phenylephrine, which acts directly on the α receptors on the smooth muscle of the iris. A patient with a preganglionic lesion, on the other hand, shows a normal response to both drugs, since the postganglionic fibers and their catecholamine stores remain intact in this situation.

Central Nervous System Applications

The amphetamines have a mood-elevating (euphoriant) effect; this effect is the basis for the widespread abuse of this drug group . The amphetamines also have an alerting, sleep-defer-ring action that is manifested by improved attention to repetitive tasks and by acceleration and desynchronization of the electroen-cephalogram. A therapeutic application of this effect is in the treat-ment of narcolepsy. Modafinil, a new amphetamine substitute, is approved for use in narcolepsy and is claimed to have fewer disad-vantages (excessive mood changes, insomnia, and abuse potential) than amphetamine in this condition. The appetite-suppressing effect of these agents is easily demonstrated in experimental ani-mals. In obese humans, an encouraging initial response may be observed, but there is no evidence that long-term improvement in weight control can be achieved with amphetamines alone, espe-cially when administered for a relatively short course. A final appli-cation of the central nervous system-active sympathomimetics is in the attention deficit hyperactivity disorder (ADHD), a behavioral syndrome consisting of short attention span, hyperkinetic physical behavior, and learning problems. Some patients with this syn-drome respond well to low doses of methylphenidate and related agents. Extended-release formulations of methylphenidate may simplify dosing regimens and increase adherence to therapy, espe-cially in school-age children. Slow or continuous-release preparations of the α₂agonists clonidine and guanfacine are also effective in children with ADHD. Clinical trials suggest that modafinil may also be useful in ADHD, but because the safety profile in children has not been defined, it has not gained approval by the FDA for this indication.

Additional Therapeutic Uses

Although the primary use of the α₂ agonist clonidine is in the treatment of hypertension , the drug has been found to have efficacy in the treatment of diarrhea in diabetics with autonomic neuropathy, perhaps because of its ability to enhance salt and water absorption from the intestine. In addition, clonidine has efficacy in diminishing craving for narcotics and alcohol during withdrawal and may facilitate cessation of cigarette smoking. Clonidine has also been used to diminish menopausal hot flushes and is being used experimentally to reduce hemody-namic instability during general anesthesia. Dexmedetomidine is anα₂ agonist used for sedation under intensive care circumstances and during anesthesia . It blunts the sympathetic response to surgery, which may be beneficial in some situations. It lowers opioid requirements for pain control and does not depress ventilation. Clonidine is also sometimes used as a premedication before anesthesia. Tizanidine is anα₂ agonist that is used as a muscle relaxant .