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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Stimulants

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Amphetamines - Stimulant Neurotoxic Poisons

Amphetamines - Stimulant Neurotoxic Poisons
The original amphetamine, racemic beta-phenylisopropylamine was first synthesised in 1887, and was marketed in 1932 as a nasal decongestant (Benzedrine inhaler).

Amphetamines

The original amphetamine, racemic beta-phenylisopropylamine was first synthesised in 1887, and was marketed in 1932 as a nasal decongestant (Benzedrine inhaler). Widespread abuse led to its ban in 1959.

Source

·              Amphetamine belongs to the phenylethylamine family with a methyl group substitution in the alpha carbon position. Numerous substitutions of the phenylethylamine struc-ture are possible, resulting in several amphetamine-like compounds. These compounds have now collectively come to be known as “amphetamines”, and include ampheta- mine phosphate, amphetamine sulfate, benzphetamine, chlorphentermine, clobenzorex hydrochloride, dextroam- phetamine, diethylpropion, mazindol, methamphetamine, 4-methylthioamphetamine, methylphenidate, pemoline, phendimetrazine, phenmetrazine, and phentermine.

·              Methamphetamine abuse began in the 1950s and reached a peak in the 1970s. It used to be referred to as “speed” or “go” (Fig 16.1). In the late 1980s, a pure preparation of methamphetamine hydrochloride made its appearance for the first time in Hawaii where it was referred to as “batu”. It quickly made its way across to the United Kingdom, Australia, Western Europe, and USA, where it became popular by the slang name “ice” (or “glass”) (Fig 16.2). While ice is produced by the ephedrine reduction method and is very pure, occurring as large translucent crystals, a variant produced by an oil-based method is called “crystal” (or “crank”), and is a white to yellow crystal product.


·              Methamphetamine powder can be inhaled, smoked, ingested,or injected. Ice and crystal are almost always smoked.

Uses

Some amphetamines have therapeutic uses and are still available as prescription drugs in Western countries (Table 16.1). They are not available in India (except for mephentermine).



Mode of Action

·              The major mechanism of acion of amphetamines involves the release of monoamines from storage sites in axon termi-nals, which leads to increased monoamine concentration in the synaptic cleft. The release of dopamine in the nucleus accumbens and related structures is responsible for the reinforcing and mood elevating effects of amphetamines.

·              Methylphenidate has a different mechanism of action. Like cocaine, it produces CNS action by blocking the dopamine transporters responsible for the reuptake of dopamine from synapses following its release. The relatively low abuse potential of orally administered methylphenidate is due to slow occupation of dopamine transporters in the brain. Also, unlike cocaine, methylphenidate occupies the transporter sites for a much longer time.

·              The most prominent effects of amphetamines are the catecholamine effects as a result of stimulation of peripheral alpha and beta adrenergic receptors. Enhanced concentra- tion of noradrenaline at the locus coeruleus is responsible for the anorexic and stimulating effects, as well as to some extent, for the motor-stimulating effects.

·              Cardiovascular effects result from the stimulation of release of noradrenaline.

Toxicokinetics

·              In general, peak plasma levels are seen in about 30 minutes after intravenous or intramuscular injection, and about 2 to 3 hours after oral amphetamine ingestion.

·              Amphetamines are extensively metabolised in the liver, but much of what is ingested is excreted unchanged in the urine. The excretion of unchanged amphetamine is dependent on pH, and at urine pH less than 6.6, a range of 67 to 73% of unchanged drug is excreted in the urine. At urine pH greater than 6.7, the percent excreted unchanged in the urine is reported to be 17 to 43%.

Clinical Features

Acute Poisoning:

a. CNS:

·              Euphoria

·              Agitation

·               Headache

·               Paranoia

·               Anorexia

·               Hyperthermia: can be severe, and may result from hypothalamic dysfunction, metabolic and muscle hyperactivity, or prolonged seizures.

·                Hyperreflexia

·               Choreoathetoid movements

·               Convulsions: Seizures are associated with a high mortality rate

·              Intracerebral haemorrhage: Abuse of amphetamine and related drugs can increase the risk for cerebro-vascular incidents in young adults

·               Coma: If it occurs, is associated with a high mortality rate.

b. CVS

·              – Tachycardia: Tachycardia is common, however, reflex bradycardia secondary to hypertension can occur.

·              ––  Hypertension: Hypertension is common following amphetamine use and may result in end organ damage. Pulmonary hypertension has been associ-ated with methamphetamine use. Hypotension and cardiovascular collapse may result from severe toxicity, and is associated with a high fatality rate.

·              –– Arrhythmias.

·              –– Vasospasm.

·              –– Myocardial ischaemia: Infarction can occur (videinfra).

·              –– Cardiomyopathy: Acute and chronic cardiomyo-pathy can result from hypertension, necrosis, or ischaemia.

c. Sympathetic Effects:

·              Mydriasis     

·              Sweating

·              Tremor

·              Tachypnoea

·              Nausea.

d. Other Effects:

·              Muscle rigidity.

·              Pulmonary oedema.

·              Ischaemic colitis: More common in chronic poisoning.

·              Rhabdomyolysis: Develops in patients with severe agitation, muscular hyperactivity, hyperthermia, or seizures.

·              Metabolic acidosis: This occurs with severe poisoning, and has even been reported after smoking crystal methamphetamine.

e. Complications:

·              Psychosis with visual and tactile hallucinations.

·              Cerebral infarction.

·              Myocardial infarction.

·              Aortic dissection: Several cases of fatal aortic dissection associated with chronic amphetamine use have been reported.

·              Ventricular fibrillation.

·              Acute renal failure: Renal failure may develop secondary to dehydration or rhabdomyolysis in patients with severe amphetamine poisoning.

·              Use of “ice” is associated with unique neuropsy- chiatric toxicity. Auditory hallucinations, severe paranoia, and violent behaviour have been reported.

·              Amphetamines and methamphetamines can induce spontaneous recurrences of paranoid hallucinatory states known as “flashbacks”.

Chronic Poisoning:

·              Amphetamines can be taken orally, by injection, by absorption through nasal and buccal membranes; or by heating, inhalation of the vapours, and absorption through the pulmonary alveoli. Inhaled amphetamine is almost immediately absorbed with a rapid onset of effects. Unlike cocaine, amphetamines can be vapour- ised without much destruction of the molecule, thus obviating the need for preparing a free-base form for smoking. As with opiates, the rapid onset of effects from amphetamine injection or inhalation produces an intensely pleasurable sensation referred to as “rush”.

·              Manifestations of heavy chronic amphetamine use:

o     Hyperactivity, hyperexcitability.

o     Anorexia, loss of weight, emaciation: Weight loss is one of the most characteristic findings with chronic use of amphetamine or its derivatives, and is said to be the most striking effect in chronic “ice” smoking.

o     Vomiting and diarhoea are common. Ischaemic colitis may occur.

o     Stereotyped behaviour (skin picking, pacing, inter-

o     minable chattering).

o     Dyskinesias: bruxism, tics.

o     Paranoid psychosis, unpredictable violence: The most common symptoms in patients with meth- amphetamine-induced psychosis were auditory and visual hallucinations, persecutory delusions, and delusions of reference.

o     Heightened sexual activity initially, follo-wed by impotence and sexual dysfunction.

o     Occasionally, very rapid IV injection of a large dose produces a condition called “overamped”, charac- terised by inability to speak or move even though consciousness is fully retained. Blood pressure and temperature are usually elevated. There may be respiratory distress.

o     Deterioration of social (family problems), physical (slovenly, unkempt appearance), and economic (loss of job, bankruptcy) status.

o     Adverse psychological reactions—anxiety reactions, amphetamine psychosis, exhaustion syndrome, depression and hallucinosis.

·              Medical complications—cardiomyopathy, vasculitis, pulmonary hypertension, permanent neurological deficits, HIV infection, hepatitis, endocarditis, osteo- myelitis and pulmonary abscesses.

·              Obstetric complications (in pregnant users) — eclampsia, intrauterine growth retardation, prematurity,etc. Amphetamine use during pregnancy has also been associated with birth defects, increased risk of cardiac malformations and cleft palate.

·              Intravenous injection abusers may display skin lesions, such as “tracks”, abscesses, ulcers, cellulitis, or necro- tising angitis.

·              Withdrawal syndrome: Withdrawal after prolonged amphetamine abuse may precipitate severe depres- sion and suicide attempts. Anxiety, abdominal cramps, gastroenteritis, headache, diaphoresis, leth- argy and dyspnoea may result. Increased appetite is common.

Drug Interactions

·              Sympathomimetics, monoamine oxidase inhibitors, and tricyclic antidepressants cause potentiation of effects, while antihistamines cause diminution of effects.

·              Amphetamines may increase anticonvulsant levels.

Usual Fatal Dose

·              The fatal dose of amphetamines is highly variable, and while death can occur with as little as 1.5 mg/kg of metham- phetamine, survival has been recorded with 28 mg/kg. This in fact represents the usual range of amphetamine’s lethal dose—150 mg to 2 grams. However, because of tolerance, addicts can tolerate up to 5 grams (single IV dose), or 15 gm/day (smokable methamphetamine).

·              Lethal blood level is said to be around 0.2 mg per 100 ml, though addicts can tolerate much higher levels with hardly any toxic effects.

·              Death due to amphetamine toxicity most commonly results from arrhythmias, hyperthermia, or intracerebral haemorrhage. In cases of survival, symptoms gradually resolve as the drug is excreted over a period of 24 to 48 hours.

Diagnosis

·      Urine is the specimen of choice. Levels above 2 mg/100 ml indicate acute toxicity. Methods of analysis include TLC,

·              RIA, HPLC, and GC-MS. The first three methods often give false positive results, and hence confirmation of a positive test must always be done by GC-MS.

·      A new method (electron-impact mass fragmentography) enables detection and even quantitation of methampheta-mine in hair, nails, sweat, and saliva.

·      Hair analysis may provide documentation of methampheta-mine or other drug exposure for several months or longer. To obtain hair samples, a new disposable scissors should be used to cut a very small amount of hair (100 mg total, about the width of a pencil) from about 10 different places. The hair must be cut as close to the scalp as possible.

 

Treatment

Acute Poisoning:

Stabilisation:

·              i IV line, cardiac monitoring.

·              Oxygen.

·              Evaluate blood glucose, BUN, and electrolyte levels.

·              Consider the necessity of a CBC, urinalysis, coagu-lation profile, chest X-ray, CT scan of head, and lumbar puncture, depending on the presentation.

·              Measure core temperature.

·              Shock is a poor prognostic sign and needs to be managed effectively. Consider the need for right-sided heart catheterisation to measure right-sided filling pressure and cardiac output.

Supportive Measures:

·              Airway management, ventilatory support.

·              Rapid rehydration.

·              Mannitol diuresis promotes myoglobin clearance to prevent renal failure.

·              Assess psychological and neurological status.

·              v Gastric decontamination (in cases of ingestion) with appropriate tracheal protection. Activated charcoal is beneficial.

Specific Measures:

·              Anxiety, agitation, and hyperactivity can usually be controlled with benzodiazepines. Diazepam is the drug of choice, and is administered in a dose of 10 mg IV at intervals (up to a maximum of 100 mg). Much larger doses (hundreds of milligrams) may be required to obtain adequate sedation. Titrate dose to clinical response. Control of agitation is an important aspect to the treatment of amphetamine overdose, since it often leads to hyperthermia, a common cause of mortality in amphetamine overdose. Neuroleptics are generally not preferred since they may aggravate hyperthermia, convul-sions, and cardiac arrhythmias. Physical restraint is inadvisable, since resistance against such measures will aggravate rhabdomyolysis and hyperthermia. Extreme agitation and hallucinations may require the administration of IV droperidol (up to 0.1 mg/kg). Since haloperidol lowers the seizures threshold, and is associated with neuroleptic malig-nant syndrome, it is not advisable.

·              Convulsions can be managed with benzodiaz-epines (IV diazepam), phenytoin, or barbiturates. Refractory cases may require curarisation.

·              Hyperthermia should be tackled aggressively with hypothermic blankets, ice baths, and dantrolene infu-sions. Large IV doses of benzodiazepines can help.

·              Refractory cases must be subjected to neuromuscular paralysis and mechanical ventilation.

·              Tachycardia can be managed with beta blockers (atenolol). Labetolol which has combined alpha and beta blocking effects, may be preferable if tachycardia is associated with hypertension. Sedation with intra-venous benzodiazepines (diazepam 5 to 10 mg IV repeated every 5 to 10 minutes as needed) is usually sufficient for treating hypertension. A short acting, titratable agent such as sodium nitroprusside should be considered if unresponsive to benzodiazepines.

·              For ventricular arrhythmias: Lignocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia. Sotalol is a good alternative. Amiodarone and sotalol should be used with caution if the QT interval is prolonged, or if torsades de pointes is involved in the overdose.

·              Unstable rhythms require cardioversion. Atropine may be used when severe bradycardia is present, and PVCs are thought to represent an escape complex.

·              For rhabdomyolysis: Early aggressive fluid replacement is the mainstay of therapy, and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be needed to maintain urine output. Urinary alkalinisation is not routinely recommended.

·              Diazepam and chlorpromazine have been effective in treating amphetamine-induced chorea.

·              Although peritoneal dialysis and haemodialysis have been demonstrated to enhance elimination of amphetamine, the clinical efficacy of these procedures in human overdose has not been proven and they are rarely if ever clinically indicated. Acidification of urine enhances amphetamine excretion, but may precipitate acute renal failure in patients with myoglobinuria and is therefore contraindicated.

Chronic Poisoning:

·              Most casual users of amphetamines do not need treat-ment. Those with moderately severe dependence can be treated on an outpatient basis without using drugs.

·               Strategies range from residential and ambulatory detoxi-fication to day treatment, multistep activities, and case It is preferable to provide a structured and manualised cognitive behavioural treatment, making use of a combination of group and individual counselling.

·              A wide variety of pharmacological agents have been tried as adjuncts to (or major elements in) the treatment of amphetamine dependence. These include drugs such as imipramine and fluoxetine, but results have been disappointing.

 

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