DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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, and cerebral hemorrhages
are the main pathological findings.
The toxic dose of amphetamine varies widely. Toxic manifestations
occasionally occur as an idiosyncratic reaction after as little as
2 mg, but are rare with doses of < 15 mg. Severe reactions have
occurred with 30 mg, yet doses of 400-500 mg are not uniformly
fatal. Larger doses can be tolerated after chronic use of the drug.
Treatment of acute amphetamine intoxication may include
acidification of the urine by administration of ammonium chloride;
this enhances the rate of elimination. Sedatives may be required for
the CNS symptoms. Severe hypertension may require administration
of sodium nitroprusside or an α adrenergic receptor antagonist.
Chronic intoxication with amphetamine causes symptoms
similar to those of acute overdosage, but abnormal mental conditions
are more common. Weight loss may be marked. A psychotic
reaction with vivid hallucinations and paranoid delusions, often mistaken
for schizophrenia, is the most common serious effect.
Recovery usually is rapid after withdrawal of the drug, but occasionally
the condition becomes chronic. In these persons, amphetamine
may act as a precipitating factor hastening the onset of incipient
schizophrenia.
The abuse of amphetamine as a means of overcoming
sleepiness and of increasing energy and alertness
should be discouraged. The drug should be used
only under medical supervision. The amphetamines are
schedule II drugs under federal regulations. The additional
contraindications and precautions for the use of
amphetamine generally are similar to those described
above for epinephrine. Its use is inadvisable in patients
with anorexia, insomnia, asthenia, psychopathic personality,
or a history of homicidal or suicidal tendencies.
Dependence and Tolerance. Psychological dependence often occurs
when amphetamine or dextroamphetamine is used chronically, as
discussed in Chapter 24. 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. Tolerance is striking in individuals who are dependent
on the drug; a daily intake of 1.7 g without apparent ill effects has
been reported. Development of tolerance is not invariable, and cases
of narcolepsy have been treated for years without requiring an
increase in the initially effective dose.
Therapeutic Uses. Amphetamine is used chiefly for its CNS effects.
Dextroamphetamine (DEXEDRINE, others), with greater CNS action
and less peripheral action, was used off-label for obesity (but no
longer is approved for this purpose because of the risk of abuse) and
is FDA-approved for the treatment of narcolepsy and attentiondeficit/hyperactivity
disorder (see below, “Therapeutic Uses of
Sympathomimetic Drugs”).
Methamphetamine
Methamphetamine (DESOXYN) is closely related chemically
to amphetamine and ephedrine (Table 12–1). In
the brain, methamphetamine releases DA and other biogenic
amines, and inhibits neuronal and vesicular
monoamine transporters as well as MAO.
Small doses have prominent central stimulant effects without
significant peripheral actions; somewhat larger doses produce a
sustained rise in systolic and diastolic blood pressures, due mainly
to cardiac stimulation. Cardiac output is increased, although the heart
rate may be reflexly slowed. Venous constriction causes peripheral
venous pressure to increase. These factors tend to increase the
venous return, and thus cardiac output. Pulmonary arterial pressure
is raised, probably owing to increased cardiac output.
Methamphetamine is a schedule II drug under federal regulations
and has high potential for abuse (Chapter 24). It is widely used as a
cheap, accessible recreational drug and its abuse is a widespread
phenomenon. Illegal production of methamphetamine in clandestine
laboratories throughout the U.S. is common. It is used principally
for its central effects, which are more pronounced than those of
amphetamine and are accompanied by less prominent peripheral
actions (see below, Therapeutic Uses of Sympathomimetic Drugs).
Methylphenidate
Methylphenidate is a piperidine derivative that is structurally
related to amphetamine. Methylphenidate
(RITALIN, others) is a mild CNS stimulant with more
prominent effects on mental than on motor activities.
However, large doses produce signs of generalized CNS
stimulation that may lead to convulsions.
Its pharmacological properties are essentially the same as
those of the amphetamines. Methylphenidate also shares the abuse
potential of the amphetamines and is listed as a schedule II controlled
substance in the U.S. Methylphenidate is effective in the treatment
of narcolepsy and attention-deficit/hyperactivity disorder, as
described in the subsequent paragraphs.
Methylphenidate is readily absorbed after oral administration
and reaches peak concentrations in plasma in ~2 hours. The drug
is a racemate; its more potent (+) enantiomer has a t 1/2
of ~6 hours,
and the less potent (–) enantiomer has a t 1/2
of ~4 hours.
Concentrations in the brain exceed those in plasma. The main urinary
metabolite is a de-esterified product, ritalinic acid, which accounts
for 80% of the dose. The use of methylphenidate is contraindicated
in patients with glaucoma.
Dexmethylphenidate. Dexmethylphenidate (FOCALIN) is the d-threo
enantiomer of racemic methylphenidate. It is FDA-approved for the
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS