AMPHETAMINES

Timothy E. Albertson, MD, MPH, PhD

Dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) are used for the

treatment of narcolepsy and for attention-deficit disorders in children. Methamphetamine

(“crank,” “speed”), 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”),

paramethoxyamphetamine (PMA), and several other amphetamine derivatives

(see also “Lysergic Acid Diethylamide [LSD] and Other Hallucinogens,” p 263), as

well as a number of prescription drugs, are used as illicit stimulants and hallucinogens.

“Ice” is a smokable form of methamphetamine. Methamphetamine precursors such

as phenylpropanolamine, ephedrine, and other over-the-counter decongestants are

discussed on p 322. Several amphetamine-related drugs (benzphetamine, diethylpropion,

phendimetrazine, phenmetrazine, and phentermine) are marketed as prescription

anorectic medications for use in weight reduction (Table II–1). Fenfluramine and dexfenfluramine were
marketed as anorectic medications but were withdrawn from

the market in 1997 because of concerns about cardiopulmonary toxicity with long-term

use.

Cathinone (found in the shrub Catha edulis, or khat), methcathinone,

and mephedrone (4-methylmethcathinone) are chemically related drugs with

amphetamine-like effects. Newer synthetic analogs, such as 3,4-methylenedioxypyrovalerone

and various derivatives of methcathinone, are becoming popular drugs

of abuse, often sold on the Internet as “bath salts” with names such as “Ivory Wave,”

“Bounce,” “Bubbles,” “Mad Cow,” and “Meow Meow.” Atomoxetine is a specific norepinephrine

reuptake inhibitor approved as a nonstimulant alternative for the treatment of

attention-deficit/hyperactivity disorder (ADHD). Modafinil is a nonamphetamine stimulant

used in the treatment of narcolepsy, sleep disorders associated with shift work,

and sleep apnea.

I. Mechanism of toxicity

A. Amphetamine and related drugs activate the sympathetic nervous system via

CNS stimulation, peripheral release of catecholamines, inhibition of neuronal reuptake

of catecholamines, and inhibition of monoamine oxidase. Amphetamines,

particularly MDMA, PMA, fenfluramine, and dexfenfluramine, also cause serotonin

release and block neuronal serotonin uptake. The various drugs in this

group have different profiles of catecholamine and serotonin action, resulting in

different levels of CNS and peripheral stimulation.

B. Modafinil is a nonamphetamine stimulant. Its mechanism of action is unclear,

but CNS levels of dopamine, norepinephrine, serotonin, histamine, and glutamate

are increased while gamma-aminobutyric acid (GABA) is decreased.

Atomoxetine is a specific norepinephrine reuptake inhibitor.

C. Pharmacokinetics. All these drugs are well absorbed orally and have large

volumes of distribution (Vd = 3–33 L/kg), except for pemoline (Vd = 0.2–

0.6 L/kg), and they are generally extensively metabolized by the liver. Excretion

of most amphetamines is highly dependent on urine pH, with amphetamines

eliminated more rapidly in an acidic urine (see also Table II–61, p 412).

II. Toxic dose. These drugs generally have a low therapeutic index, with toxicity at levels

only slightly above usual doses.However, a high degree of tolerance can develop

after repeated use. Acute ingestion of more than 1 mg/kg of dextroamphetamine (or

an equivalent dose of other drugs; see Table II–1) should be considered potentially

life-threatening.

III. Clinical presentation

A. Acute CNS effects of intoxication include euphoria, talkativeness, anxiety, restlessness,

agitation, psychosis, seizures, and coma. Intracranial hemorrhage

may occur owing to hypertension or cerebral vasculitis.

B. Acute peripheral manifestations include sweating, tremor, muscle fasciculations

and rigidity, tachycardia, hypertension, acute myocardial ischemia, and

infarction (even with normal coronary arteries). Inadvertent intra-arterial injection

may cause vasospasm resulting in gangrene; this has also occurred with

oral use of DOB (2,5-dimethoxy-4-bromoamphetamine; see “Lysergic Acid Diethylamide

[LSD] and Other Hallucinogens,” p 263).

C. Death may be caused by ventricular arrhythmia, status epilepticus, intracranial

hemorrhage, or hyperthermia. Hyperthermia frequently results from seizures

and muscular hyperactivity and may cause brain damage, rhabdomyolysis, and

myoglobinuric renal failure (p 21).

D. Chronic effects of amphetamine abuse include weight loss, cardiomyopathy,

pulmonary hypertension, dental changes, stereotypic behavior (eg, picking at the

skin), paranoia, and paranoid psychosis. Psychiatric disturbances may persist

for days or weeks. After cessation of habitual use, patients may experience

fatigue, hypersomnia, hyperphagia, and depression lasting several days.

E. Prolonged use (usually 3 months or longer) of fenfluramine or dexfenfluramine

in combination with phentermine (“fen-phen”) has been associated with an increased risk for pulmonary
hypertension and fibrotic valvular heart disease

(primarily aortic, mitral, and tricuspid regurgitation). The pathology of the valvular

disease is identical to that seen with carcinoid syndrome.

F. Illicit manufacture of methamphetamine can expose the “chemist” and his or

her family to various toxic chemicals, including corrosive agents, solvents, and

heavy metals.
IV. Diagnosis is usually based on a history of amphetamine use and clinical features

of sympathomimetic drug intoxication.

A. Specific levels. Amphetamines and many related drugs can be detected in urine

and gastric samples, providing confirmation of exposure. However, quantitative

serum levels do not closely correlate with the severity of clinical effects and

are not generally available. Amphetamine derivatives and adrenergic amines

may cross-react in immunoassays (see Table I–33, p 43), and distinguishing the

specific drug requires confirmatory testing (eg, with thin-layer chromatography,

gas chromatography [GC], or GC/mass spectrometry). Selegiline (a drug used in

Parkinson disease) is metabolized to l-amphetamine and l-methamphetamine,

and Clobenzorex (an anorectic drug sold in Mexico) is metabolized to amphetamine;

these drugs can produce a positive result for amphetamines on urine

and blood tested with immunoassays (unless a specific monoclonal antibody

amphetamine assay is used) or GC/mass spectrometry (unless a special chiral

derivative or column is used). Amphetamine, methamphetamine, and MDMA

can be screened for by using hair and liquid chromatography–mass spectrometry.

B. Other useful laboratory studies include electrolytes, glucose, BUN and creatinine,

creatine kinase (CK), urinalysis, urine dipstick test for occult hemoglobin

(positive in patients with rhabdomyolysis with myoglobinuria), ECG and ECG

monitoring, and CT scan of the head (if hemorrhage is suspected). Echocardiography

and right heart catheterization may be useful for detecting valvular

disease or pulmonary hypertension.

V. Treatment

A. Emergency and supportive measures

1. Maintain an open airway and assist ventilation if necessary (pp 1–7).

2. Treat agitation (p 24), seizures (p 22), coma (p 18), and hyperthermia (p 21)

if they occur.

3. Continuously monitor the temperature, other vital signs, and the ECG for a

minimum of 6 hours.

B. Specific drugs and antidotes. There is no specific antidote.

1. Agitation. Benzodiazepines (p 454) are usually satisfactory, although antipsychotic

agents (p 443) may be added as needed.

2. Hypertension (p 17) is best treated with sedation and, if this is not effective,

a parenteral vasodilator such as phentolamine (p 535) or nitroprusside

(p 525).

3. Treat tachyarrhythmias (p 12) with propranolol (p 546) or esmolol (p 485).

Note: Paradoxical hypertension can occur owing to unopposed alphaadrenergic

effects when beta2-mediated vasodilation is blocked; be prepared

to give a vasodilator (see Item B.2 above) if needed.

4. Treat arterial vasospasm as described for ergots (p 202).

C. Decontamination. Administer activated charcoal orally if conditions are appropriate

(see Table I–38, p 51). Gastric lavage is not necessary after small to

moderate ingestions if activated charcoal can be given promptly. Consider wholebowel

irrigation and repeated doses of charcoal after ingestion of drug-filled

packets (“body stuffers”).

D. Enhanced elimination. Dialysis and hemoperfusion are not effective. Repeatdose

charcoal has not been studied. Renal elimination of dextroamphetamine

may be enhanced by acidification of the urine, but this is not recommended

because of the risk for aggravating the nephrotoxicity of myoglobinuria.