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is removed, plasma concentrations remain stable for ∼8 hours and then decline gradually over a period of several days; this decrease is associated with a rise in blood pressure.
ADVERSE EFFECTS
The major adverse effects of clonidine are dry mouth and sedation, which may diminish in inten-sity after several weeks of therapy. Sexual dysfunction and marked bradycardia may occur. These effects of clonidine frequently are dose-related; their incidence may be lower with transdermal administration of clonidine, which avoids the relatively high peak concentrations that occur after oral administration. About 15–20% of patients develop contact dermatitis when using clonidine in the transdermal system. Withdrawal reactions follow abrupt discontinuation of long-term therapy with clonidine in some hypertensive patients.
THERAPEUTIC USES
The major therapeutic use of clonidine (CATAPRES, others) is in the treatment of hypertension (see Chapter 32). Clonidine also has apparent efficacy in the off-label treatment of a range of other disorders: reducing diarrhea in some diabetic patients with autonomic neuropathy; treating and preparing addicted subjects for withdrawal (see Chapter 23); ameliorating some of the adverse sympathetic nervous activity associated with withdrawal, and decreasing craving for the drug.
Transdermal administration of clonidine (CATAPRES-TTS) may be useful in reducing the incidence of menopausal hot flashes.
The capacity of clonidine to activate postsynaptic a2receptors in vascular smooth muscle has been exploited in a limited number of patients whose autonomic failure is so severe that reflex sympathetic responses on standing are absent; postural hypotension is thus marked. Since the cen-tral effect of clonidine on blood pressure is unimportant in these patients, the drug can elevate blood pressure and improve the symptoms of postural hypotension. Among the other off-label uses of clonidine are atrial fibrillation, attention-deficit/hyperactivity disorder (ADHD), constitutional growth delay in children, cyclosporine-associated nephrotoxicity, Tourette’s syndrome, hyper-hidrosis, mania, posthepatic neuralgia, psychosis, restless leg syndrome, ulcerative colitis, and allergy-induced inflammatory reactions in patients with extrinsic asthma.
Apraclonidine
Apraclonidine (IOPIDINE) is a relatively selective a2 agonist that is used topically to reduce intraocular pressure with minimal systemic effects; apraclonidine seems not to cross the blood–brain barrier and is more useful than clonidine for ophthalmic therapy. The drug is useful as short-term adjunctive therapy in glaucoma patients whose intraocular pressure is not well con-trolled by other pharmacological agents and to control or prevent elevations in intraocular pres-sure that occur in patients after laser trabeculoplasty or iridotomy (see Chapter 63).
Brimonidine
Brimonidine (ALPHAGAN), a clonidine derivative and a2agonist, is administered topically to lower intraocular pressure in patients with ocular hypertension or open-angle glaucoma; brimonidine both decreases aqueous humor production and increases outflow (see Chapter 63). Unlike apra-clonidine, brimonidine crosses the blood–brain barrier and can produce hypotension and sedation, although these effects are slight compared to those of clonidine.
Dexmedetomidine (PRECEDEX), a relatively selective a2agonist with sedative properties, pro-duces preoperative sedation and anxiolysis, drying of secretions, and analgesia; the drug is used as an anesthetic adjunct.
Guanfacine
Guanfacine (TENEX), an a2agonist, is more selective for a2receptors than is clonidine. Guanfacine lowers blood pressure by activation of brainstem receptors with resultant suppression of sympa-thetic activity. The drug is well absorbed after oral administration. About 50% of guanfacine appears unchanged in the urine; the rest is metabolized. The t1/2for elimination ranges from 12–24 hours. Guanfacine and clonidine appear to have similar efficacy for the treatment of hyper-tension and a similar pattern of adverse effects. A withdrawal syndrome may occur after abrupt discontinuation, but it is less frequent and milder than the syndrome that follows clonidine with-drawal, perhaps reflecting the longer t1/2of guanfacine.
Guanabenz
Guanabenz (WYTENSIN, others) and guanfacine are closely related chemically and pharmacologi-cally. Guanabenz is a centrally acting a2agonist that decreases blood pressure. Guanabenz has a t1/2of 4–6 hours and is extensively metabolized by the liver. Dosage adjustment may be necessary
in patients with hepatic cirrhosis. The adverse effects of guanabenz (e.g., dry mouth and sedation) are similar to those of clonidine.
Methyldopa
In the brain, methyldopa (a-methyl-3,4-dihydroxyphenylalanine) is metabolized to a-methylNE , and this compound is thought to activate central a2receptors and lower blood pressure in a manner similar to that of clonidine (see Chapter 32).
Tizanidine
Tizanidine (ZANAFLEX, others) is an a2agonist with some properties similar to those of clonidine.
The drug is also a muscle relaxant used for the treatment of spasticity associated with cerebral and spinal disorders.
MISCELLANEOUS SYMPATHOMIMETIC AGONISTS
Amphetamine
Amphetamine (racemic b-phenylisopropylamine; see Table 10–1) acts indirectly to produce pow-erful stimulant actions in the CNS and a and b receptor stimulation in the periphery. Unlike Epi, amphetamine is effective after oral administration, and its effects last for several hours.
CARDIOVASCULAR RESPONSES
Amphetamine given orally raises systolic and diastolic blood pressure. Heart rate often is reflexly slowed; with large doses, cardiac arrhythmias may occur.
OTHER SMOOTH MUSCLES
In general, smooth muscles respond to amphetamine as they do to other sympathomimetic amines.
The contractile effect on the sphincter of the urinary bladder is particularly marked, and for this reason amphetamine has been used in treating enuresis and incontinence. Pain and difficulty in micturition occasionally occur. GI effects are unpredictable: relaxation if enteric activity is pro-nounced, stimulation if the gut already is relaxed. The response of the human uterus varies, but there usually is an increase in tone.
CNS
Amphetamine is one of the most potent sympathomimetic amines in stimulating the CNS. It stim-ulates the medullary respiratory center, lessens the degree of central depression caused by vari-ous drugs, and produces other signs of CNS stimulation; the d-isomer (dextroamphetamine) is three to four times more potent than the l-isomer. Psychic effects depend on the dose and the mental state and personality of the individual. The main results of an oral dose of 10–30 mg include wakefulness, alertness, and a decreased sense of fatigue; elevation of mood, with increased initiative, self-confidence, and ability to concentrate; often, elation and euphoria; and increase in motor and speech activities. Performance of simple mental tasks is improved; although more work may be accomplished, the number of errors may increase. Physical performance—in athletes, for example—is often improved, and the drug often is abused for this purpose. Prolonged use or large doses are nearly always followed by depression and fatigue. Many individuals given amphetamine experience headache, palpitation, dizziness, vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, or fatigue (see Chapter 23).
FATIGUE AND SLEEP
In general, amphetamine prolongs the duration of adequate performance before fatigue appears, and partly reverses the effects of fatigue, most noticeably when performance has been reduced by fatigue and lack of sleep. The need for sleep may be postponed, but it cannot be avoided indefi-nitely. When the drug is discontinued after long use, the pattern of sleep may take as long as 2 months to return to normal.
Analgesia
Amphetamine and some other sympathomimetic amines have a small analgesic effect that is not sufficiently pronounced to be therapeutically useful. Amphetamine can enhance the analgesia produced by opiates.
Respiration
Amphetamine stimulates the respiratory center, increasing the rate and depth of respiration. In normal individuals, usual doses of the drug do not appreciably increase respiratory rate or minute volume. Nevertheless, when respiration is depressed by centrally acting drugs, amphetamine may stimulate respiration.
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Appetite
Weight loss in obese humans treated with amphetamine is almost entirely due to reduced food intake and only in small measure to increased metabolism. In humans, tolerance to the appetite suppression develops rapidly.
Mechanisms of Action in the CNS
Amphetamine appears to exert most or all of its CNS effects indirectly by releasing biogenic amines from storage sites in nerve terminals. The alerting effect of amphetamine, its anorectic effect, and at least a component of its locomotor-stimulating action presumably are mediated by release of NE from central noradrenergic neurons. Some aspects of locomotor activity and the stereotyped behavior induced by amphetamine probably result from the release of DA from dopaminergic nerve terminals in the neostriatum. Higher doses are required to produce these behavioral effects. With still higher doses of amphetamine, disturbances of perception and overt psychosis occur, possibly due to release of 5-HT from serotonergic neurons and of DA in the mesolimbic system.
TOXICITY AND ADVERSE EFFECTS The acute toxic effects of amphetamine usually are extensions of its therapeutic actions and as a rule result from overdosage. CNS effects commonly include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, tenseness, irritability, weakness, insomnia, fever, and sometimes euphoria. Confusion, aggressiveness, changes in libido, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies occur, especially in mentally ill patients. However, these psychotic effects can be elicited in any individ-ual if sufficient quantities of amphetamine are ingested for a prolonged period. Fatigue and depres-sion usually follow central stimulation. Cardiovascular effects are common and include headache, chilliness, pallor or flushing, palpitation, cardiac arrhythmias, anginal pain, hypertension or hypotension, and circulatory collapse. Excessive sweating occurs. GI symptoms include dry mouth, metallic taste, anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma; cerebral hemorrhages are the main pathological findings.
Toxicity shows great biological variability, occasionally occurring after as little as 2 mg, but rare with<15 mg. Severe reactions have occurred with 30 mg, yet doses of 400–500 mg are not uni-formly fatal. Larger doses can be tolerated after chronic use of the drug. Treatment of acute amphetamine intoxication may include acidification of the urine with ammonium chloride to enhance the rate of elimination. Sedatives may be required for the CNS symptoms. Severe hyper-tension may require administration of sodium nitroprusside or an a adrenergic receptor antago-nist. Chronic amphetamine intoxication causes symptoms similar to those of acute overdosage, but abnormal mental conditions are more common. Weight loss may be marked. A psychotic reac-tion with vivid hallucinareac-tions and paranoid delusions, often mistaken for schizophrenia, is the most common serious effect. Recovery usually is rapid after withdrawal of the drug, but the con-dition can become chronic, with amphetamine hastening the onset of incipient schizophrenia.
Amphetamines are schedule II drugs and should be used only under medical supervision.
Amphetamine use is inadvisable in patients with anorexia, insomnia, asthenia, psychopathic per-sonality, or a history of homicidal or suicidal tendencies.
DEPENDENCE AND TOLERANCE
Psychological dependence often occurs when amphetamine or dextroamphetamine is used chron-ically, as discussed in Chapter 23. Tolerance almost invariably develops to the anorexigenic effect of amphetamines, and often is seen also in the need for increasing doses to maintain improvement of mood in psychiatric patients, yet cases of narcolepsy have been treated for years without requiring an increase in the initially effective dose.
THERAPEUTIC USES
Dextroamphetamine (DEXEDRINE, others), with greater CNS action and less peripheral action, is FDA approved for the treatment of narcolepsy and attention-deficit/hyperactivity disorder (see below).