Methylphenidate hydrochloride
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS numbers |
| 1.4.2 Other numbers |
| 1.5 Main brand names, main trade names |
| 1.6 Main manufacturers, main importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/Form |
| 3.3.3 Description |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Storage conditions |
| 4. USES |
| 4.1 Indications |
| 4.1.1 Indications |
| 4.1.2 Description |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF EXPOSURE |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination and excretion |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological analyses and their interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple qualitative test(s) |
| 8.2.1.2 Advanced qualitative test(s) |
| 8.2.1.3 Simple qualitative method(s) |
| 8.2.1.4 Advanced quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple qualitative test(s) |
| 8.2.2.2 Advanced qualitative test(s) |
| 8.2.2.3 Simple qualitative method(s) |
| 8.2.2.4 Advanced quantitative Method(s) |
| 8.2.2.5 Other dedicated method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central nervous system (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbance |
| 9.4.12.2 Fluid and electrolyte disturbance |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Life supportive procedures and symptomatic/specific treatment |
| 10.3 Decontamination |
| 10.4 Enhanced elimination |
| 10.5 Antidote treatment |
| 10.5.1 Adults |
| 10.5.2 Children |
| 10.6 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 12. ADDITIONAL INFORMATION |
| 12.1 Specific preventive measures |
| 12.2 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
Methylphenidate hydrochloride
International Programme on Chemical Safety
Poison Information Monograph 344
Pharmaceutical
1. NAME
1.1 Substance
Methylphenidate hydrochloride
1.2 Group
ATC Classification
Psychostimulants (N06B)
Phenylethylamine derivatives (N06B A)
1.3 Synonyms
Centedrin; Meridil;
Ritalin hydrochloride
1.4 Identification numbers
1.4.1 CAS numbers
Methylphenidate hydrochloride 298-59-9
1.4.2 Other numbers
Methylphenidate CAS 113-45-1
Methylphenidate NIOSH/RTECS TM3675000
Methylphenidate hydrochloride NIOSH/RTECS TM3850000
1.5 Main brand names, main trade names
1.6 Main manufacturers, main importers
2. SUMMARY
2.1 Main risks and target organs
Acute central nervous system stimulation, cardiotoxicity
causing tachycardia, arrhythmias, hypertension and
cardiovascular collapse. High risk of dependency and abuse.
2.2 Summary of clinical effects
Cardiovascular - Palpitation, chest pain, tachycardia,
arrhythmias and hypertension are common; cardiovascular
collapse can occur in severe poisoning. Myocardial ischaemia,
infarction and ventricular dysfunction are described.
Central Nervous System (CNS) - Stimulation of CNS, tremor,
restlessness, agitation, insomnia, increased motor activity,
headache, convulsions, coma and hyperreflexia are described.
Stroke and cerebral vasculitis have been observed.
Gastrointestinal - Vomiting, diarrhoea and cramps may occur.
Acute transient ischaemic colitis has occurred with chronic
methamphetamine abuse.
Genitourinary - Increased bladder sphincter tone may cause
dysuria, hesitancy and acute urinary retention. Renal failure
can occur secondary to dehydration or rhabdomyolysis. Renal
ischaemia may be noted.
Dermatologic - Skin is usually pale and diaphoretic, but
mucous membranes appear dry.
Endocrine - Transient hyperthyroxinaemia may be noted.
Metabolism - Increased metabolic and muscular activity may
result in hyperventilation and hyperthermia. Weight loss is
common with chronic use.
Fluid/Electrolyte - Hypo- and hyperkalaemia have been
reported. Dehydration is common.
Musculoskeletal - Fasciculations and rigidity may be noted.
Rhabdomyolysis is an important consequence of severe
amphetamine poisoning.
Psychiatric - Agitation, confusion, mood elevation, increased
wakefulness, talkativeness, irritability and panic attacks
are typical. Chronic abuse can cause delusions and paranoia.
A withdrawal syndrome occurs after abrupt cessation following
chronic use.
2.3 Diagnosis
The diagnosis of acute amphetamine poisoning is made on
the history of exposure or abuse, and the characteristic
features of CNS and cardiovascular stimulation. The presence
of amphetamines in urine or blood can support the diagnosis
but is not helpful in management. Whilst some patients show
signs of toxicity at blood concentrations of 20 µg/L, chronic
abusers of amphetamine have been known to have blood
concentration of up to 3000 µg/L.
2.4 First aid measures and management principles
Management of amphetamine and its complications is
essentially supportive.
The initial priority is stabilisation of the airway,
breathing and circulation. Monitoring of pulse, blood
pressure, oxygenation, core temperature and cardiac rhythm
should instituted. Supplemental oxygen should be
administered. Specific supportive care measures that may be
necessary include: maintenance of hydration, control of
seizures, relief of agitation, control of hyperthermia,
control of hypertension, management of rhabdomyolysis.
Decontamination with oral activated charcoal is appropriate
if the patient is conscious.
There are no suitable methods of enhancing elimination of
amphetamine and no specific antidotes.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic
3.2 Chemical structure
Methylphenidate hydrochloride
Chemical Name:
2-Piperidineacetic acid, alpha-phenyl-, methyl ester,
hydrochloride
Other chemical names:
Methyl alpha-phenyl-2-piperidineacetate hydrochloride
Molecular formula: C14H19NO2, HCL
Molecular weight: 269.8
3.3 Physical properties
3.3.1 Colour
3.3.2 State/Form
3.3.3 Description
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Storage conditions
Store in airtight containers. Refrigeration
unnecessary.
4. USES
4.1 Indications
4.1.1 Indications
Psychostimulant
Phenylethylamine derivative; psychostimulant
4.1.2 Description
Indications
Narcolepsy & Hyperkinetic states in children (as an
adjunct to psychological, educational and social
measures) for amphetamine, dextroamphetamine and
ethylphenidate.
Misuse:
Performance enhancement
Relief of fatigue
Abuse:
Abuse either orally or by injection is extremely
common.
(Dollery, 1991; Reynolds, 1996)
4.2 Therapeutic dosage
4.2.1 Adults
4.2.2 Children
4.3 Contraindications
Anorexia, insomnia, psychopathic personality disorders,
suicidal tendencies, Gilles de la Tourette syndrome and other
disorders, hyperthyroidism, narrow angle glaucoma, diabetes
mellitis and cardiovascular diseases such as angina,
hypertension and arrythmias (Dollery, 1991; Reynolds, 1996).
Amphetamine interacts with several other drugs (see 7.6).
5. ROUTES OF EXPOSURE
5.1 Oral
Readily absorbed from the gastro-intestinal tract and
buccal mucosa. It Is resistant to metabolism by monoamine
oxidase.
5.2 Inhalation
Amphetamine is rapidly absorbed by inhalation and is
abused by this route (Brust, 1993).
5.3 Dermal
No data available.
5.4 Eye
No data available.
5.5 Parenteral
Frequent route of entry in abuse situations.
5.6 Other
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Amphetamine is rapidly absorbed after oral ingestion.
Peak plasma levels occur within 1 to 3 hours, varying with
the degree of physical activity and the amount of food in the
stomach. Absorption is usually complete by 4 to 6 hours.
Sustained release preparations are available as resin-bound,
rather than soluble, salts. These compounds display reduced
peak blood levels compared with standard amphetamine
preparations, but total amount absorbed and time to peak
levels remain similar (Dollery, 1991).
6.2 Distribution by route of exposure
Amphetamines are concentrated in the kidney, lungs,
cerebrospinal fluid and brain. They are highly lipid soluble
and readily cross the blood-brain barrier. Protein binding
and volume of distribution varies widely, but the average
volume of distribution is 5 L/kg body weight (Dollery, 1991).
6.3 Biological half-life by route of exposure
Under normal conditions, about 30% of amphetamine is
excreted unchanged in the urine but this excretion is highly
variable and is dependent on urinary pH. When the urinary pH
is acidic (pH 5.5 to 6.0), elimination is predominantly by
urinary excretion with approximately 60% of a dose of
amphetamine being excreted unchanged by the kidney within 48
hours. When the urinary pH is alkaline (pH 7.5 to 8.0),
elimination is predominantly by deamination (less than 7%
excreted unchanged in the urine); the half-life ranging from
16 to 31 hours (Ellenhorn, 1997).
6.4 Metabolism
The major metabolic pathway for amphetamine involves
deamination by cytochrome P450 to para-hydroxyamphetamine and
phenylacetone; this latter compound is subsequently oxidised
to benzoic acid and excreted as glucuronide or glycine
(hippuric acid) conjugate. Smaller amounts of amphetamine are
converted to norephedrine by oxidation. Hydroxylation
produces an active metabolite, O-hyroxynorephedrine, which
acts as a false neurotransmitter and may account for some
drug effect, especially in chronic users (Dollery, 1991).
6.5 Elimination and excretion
Normally 5 to 30% of a therapeutic dose of amphetamine
is excreted unchanged in the urine by 24 hours, but the
actual amount of urinary excretion and metabolism is highly
pH dependent (Dollery, 1991).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
Amphetamine appears to exert most or all of its effect
in the CNS by causing release of biogenic amines, especialy
norepinephrine and dopamine, from storage sites in nerve
terminals. It may also slow down catecholamine metabolism by
inhibiting monoamine oxidase (Hardman, et al., 1997).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
The toxic dose varies considerably
due to individual variations and the
development of tolerance. Fatalities have
been reported following ingestion of doses as
low as 1.3 mg/kg, while tolerance has been
developed to 1,000 mg at a time and up to 5 g
in a day.
7.2.1.2 Children
Children appear to be more
susceptible than adults and are less likely
to have developed tolerance.
7.2.2 Relevant animal data
Adult monkeys have an LD50 of 15 to 20 mg/kg,
whereas for young monkeys the LD50 is only 5 mg/kg.
7.2.3 Relevant in vitro data
Not relevant
7.3 Carcinogenicity
To be completed
7.4 Teratogenicity
The use of amphetamine for medical indications does not
pose a significant risk to the fetus for congenital anomalies
(Briggs, 1990). Amphetamines generally do not appear to be
human teratogens. Mild withdrawal symptoms may be observed in
the newborn, but the few studies of infant follow-up have not
shown long-term sequelae, although more studies of this
nature are needed.
Illicit maternal use or abuse of amphetamine presents a
significant risk to the foetus and newborn, including
intrauterine growth retardation, premature delivery and the
potential for increased maternal, fetal and neonatal
morbidity.
These poor outcomes are probably multifactorial in origin,
involving multiple drug use, life-styles and poor maternal
health. However, cerebral injuries occurring in newborns
exposed in utero appear to be directly related to the
vasoconstrictive properties of amphetamines. Ericksson et al.
(1989) followed 65 children whose mothers were addicted to
amphetamine during pregnancy, at least during the first
trimester. Intelligence, psychological function, growth, and
physical health were all within the normal range at eight
years, but those children exposed throughout pregnancy tended
to be more aggressive.
7.5 Mutagenicity
No relevant data
7.6 Interactions
Acetazolamide - administration may increase serum
concentration of amphetamine.
Alcohol - may increase serum concentration of amphetamine.
Ascorbic acid -lowering urinary pH, may enhance amphetamine
excretion
Furazolidone - amphetamines may induce a hypertensive
response in patients taking furazolidone.
Guanethidine - amphetamine inhibits the antihypertensive
response to guanethidine.
Haloperidol - limited evidence indicates that haloperidol may
inhibit the effects of amphetamine but the clinical
importance of this interaction is not established.
Lithium carbonate - isolated case reports indicate that
lithium may inhibit the effects of amphetamine.
Monoamine oxidase inhibitor - severe hypertensive reactions
have followed the administration of amphetamines to patients
taking monoamine oxidase inhibitors.
Noradrenaline - amphetamine abuse may enhance the pressor
response to noradrenaline.
Phenothiazines - amphetamine may inhibit the antipsychotic
effect of phenothiazines, and phenothiazines may inhibit the
anorectic effect of amphetamines.
Sodium bicarbonate - large doses of sodium bicarbonate
inhibit the elimination of amphetamine, thus increasing the
amphetamine effect.
Tobacco smoking - amphetamine appears to induce dose-related
increases in cigarette smoking.
Tricyclic antidepressants - theoretically increases the
effect of amphetamine, but clinical evidence is lacking.
(Stockley, 1994; Dollery, 1991)
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological analyses and their interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple qualitative test(s)
8.2.1.2 Advanced qualitative test(s)
8.2.1.3 Simple qualitative method(s)
8.2.1.4 Advanced quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple qualitative test(s)
8.2.2.2 Advanced qualitative test(s)
8.2.2.3 Simple qualitative method(s)
8.2.2.4 Advanced quantitative Method(s)
8.2.2.5 Other dedicated method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.1.1 Basic analyses
8.3.1.1.2 Dedicated analyses
8.3.1.1.3 Optional analyses
8.3.1.2 Urine
8.3.1.2.1 Basic analyses
8.3.1.2.2 Dedicated analyses
8.3.1.2.3 Optional analyses
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.3.1.1 Basic analyses
8.3.3.1.2 Dedicated analyses
8.3.3.1.3 Optional analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall interpretation of all toxicological analyses and
toxicological investigations
Sample collection
Creatinine, urea, and electrolyte measurement are important
to establish whether renal impairment or hyperkalaemia is
present. Measurements of serum creatine kinase, aspartate
transaminase and myoglobin can help to establish if there is
rhabdomyolysis, and myoglobin can be detected in urine.
Liver function tests are relevant, since hepatitis can occur.
A full blood count and coagulation studies can be helpful,
with measurement of fibrinogen and of fibrin degradation
products, in establishing a diagnosis of disseminated
intravascular coagulation.
Biomedical analysis
Temperature, blood pressure, and pulse rate should be
monitored frequently. A temperature above 40°C, and marked
hypertension and tachycardia are seen in severe poisoning.
An electrocardiogram can be useful in detecting myocardial
ischaemia or arrhythmia. Electrocardiographic monitoring can
be helpful in patients with arrhythmia.
Toxicological analysis
Urine or serum analysis for amphetamine can help to confirm
exposure, but cannot be used to establish poisoning, because
of difference in individual tolerance to amphetamines.
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Effects are most marked on the central nervous
system, cardiovascular system, and muscles. The triad
of hyperactivity, hyperpyrexia, and hypertension is
characteristic of acute amphetamine overdosage.
Agitation, confusion, headache, delirium, and
hallucination, can be followed by coma, intracranial
haemorrhage, stroke, and death.
Chest pain, palpitation, hypertension, tachycardia,
atrial and ventricular arrhythmia, and myocardial
infarction can occur.
Muscle contraction, bruxism (jaw-grinding), trismus
(jaw clenching), fasciculation, rhabdomyolysis, are
seen leading to renal failure; and flushing, sweating,
and hyperpyrexia can all occur. Hyperpyrexia can cause
disseminated intravascular coagulation.
(Brust, 1993; Derlet et al., 1989)
9.1.2 Inhalation
The clinical effects are similar to those after
ingestion, but occur more rapidly (Brust, 1993).
9.1.3 Skin exposure
No data available
9.1.4 Eye contact
No data available
9.1.5 Parenteral exposure
Intravenous injection is a common mode of
administration of amphetamine by abusers. The euphoria
produced is more intense, leading to a "rush" or
"flash" which is compared to sexual orgasm (Brust,
1993). Other clinical effects are similar to those
observed after ingestion, but occur more rapidly.
9.1.6 Other
No data available
9.2 Chronic poisoning
9.2.1 Ingestion
Tolerance to the euphoric effects and CNS
stimulation induced by amphetamine develops rapidly,
leading abusers to use larger and larger amounts to
attain and sustain the desired affect.
Habitual use or chronic abuse usually results in toxic
psychosis classically characterised by paranoia,
delusions and hallucinations, which are usually
visual, tactile or olfactory in nature, in contrast to
the typical auditory hallucinations of schizophrenia.
The individual may act on the delusions, resulting in
bizarre violent behaviour, hostility and aggression,
sometimes leading to suicidal or homicidal actions.
Dyskinesia, compulsive behaviour and impaired
performance are common in chronic abusers. The chronic
abuser presents as a restless, garrulous, tremulous
individual who is suspicious and anxious.
9.2.2 Inhalation
As for 9.2.1.
9.2.3 Skin exposure
No relevant data.
9.2.4 Eye contact
No relevant data.
9.2.5 Parenteral exposure
As for 9.2.1.
9.2.6 Other
Vaginal exposure, as for 9.2.1.
9.3 Course, prognosis, cause of death
Symptoms and signs give a clinical guide to the severity
of intoxication as follows (Espelin and Done, 1968):
Mild toxicity - restlessness, irritability, insomnia, tremor,
hyperreflexia, sweating, dilated pupils, flushing;
Moderate toxicity - hyperactivity, confusion, hypertension,
tachypnoea, tachycardia, mild fever, sweating;
Severe toxicity - delirium, mania, self-injury, marked
hypertension, tachycardia, arrhythmia, hyperpyrexia,
convulsion, coma, circulatory collapse.
Death can be due to intracranial haemorrhage, acute heart
failure or arrhythmia, hyperpyrexia, rhabdomyolysis and
consequent hyperkalaemia or renal failure, and to violence
related to the psychiatric effects (Kalant & Kalant,
1975).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Cardiovascular symptoms of acute poisoning
include palpitation and chest pain. Tachycardia and
hypertension are common. One third of patients
reported by Derlet et al. (1989) had a blood pressure
greater than 140/90 mmHg, and nearly two-thirds had a
pulse rate above 100 beats per minute.
Severe poisoning can cause acute myocardial ischaemia,
myocardial infarction (Carson et al., 1987; Packe et
al., 1990), and left ventricular failure (Kalant &
Kalant, 1975). These probably result from vasospasm,
perhaps at sites of existing atherosclerosis. In at
least one case, thrombus was demonstrated initially
(Bashour, 1994).
Chronic oral amphetamine abuse can cause a chronic
cardiomyopathy; an acute cardiomyopathy has also been
described (Call et al., 1982).
Hypertensive stroke is a well-recognised complication
of amphetamine poisoning (see 9.4.3).
Intra-arterial injection of amphetamine can cause
severe burning pain, vasospasm, and gangrene (Birkhahn
& Heifetz, 1973).
9.4.2 Respiratory
Pulmonary fibrosis, right ventricular
hypertrophy and pulmonary hypertension are frequently
found at post-mortem examination.
Pulmonary function tests usually are normal except for
the carbon monoxide diffusing capacity. Respiratory
complications are sometimes caused by fillers or
adulterants used in injections by chronic users. These
can cause multiple microemboli to the lung, which can
lead to restrictive lung disease.
Pneumomediastinum has been reported after amphetamine
inhalation (Brust, 1993).
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Main symptoms include agitation,
confusion, delirium, hallucinations,
dizziness, dyskinesia, hyperactivity, muscle
fasciculation and rigidity, rigors, tics,
tremors, seizures and coma.
Both occlusive and haemorrhagic strokes have
been reported after abuse of amphetamines.
Twenty-one of 73 drug-using young persons
with stroke had taken amphetamine (Kaku &
Lowenstein, 1990), of whom six had documented
intracerebral haemorrhage and two had
subarachnoid haemorrhage. Patients with
underlying arteriovenous malformations may be
at particular risk (Selmi et al., 1995).
Stroke can occur after oral, intravenous, or
nasal administration. Severe headache
beginning within minutes of ingestion of
amphetamine is usually the first symptom. In
more than half the cases, hypertension which
is sometimes extreme, accompanies other
symptoms. A Cerebral vasculitis has also been
observed (Brust, 1993).
Dystonia and dyskinesia can occur, even with
therapeutic dosages (Mattson & Calverley,
1968).
Psychiatric effects, particularly euphoria
and excitement, are the motives for abuse.
Paranoia and a psychiatric syndrome
indistinguishable from schizophrenia are
sequelae of chronic use ( Hall et al., 1988;
Flaum & Schultz, 1996; Johnson & Milner,
1966).
9.4.3.2 Peripheral nervous system
No relevant data
9.4.3.3 Autonomic nervous system
Stimulation of alpha-adrenergic
receptors produces mydriasis, increased
metabolic rate, diaphoresis, increased
sphincter tone, peripheral vasoconstriction
and decreased gastrointestinal motility.
Stimulation of ß-adrenergic receptors
produces increased heart rate and
contractility, increased automaticity and
dilatation of bronchioles.
9.4.3.4 Skeletal and smooth muscle
Myalgia, muscle tenderness, muscle
contractions, and rhabdomyolysis, leading to
fever, circulatory collapse, and
myoglobinuric renal failure, can occur with
amphetamines (Kendrick et al., 1977).
9.4.4 Gastrointestinal
Most common symptoms are nausea, vomiting,
diarrhoea, and abdominal cramps. Anorexia may be
severe. Epigastric pain and haematemesis have been
described after intravenous amphetamine use. A case of
ischaemic colitis with normal mesenteric arteriography
in a patient taking dexamphetamine has been described
(Beyer et al., 1991).
9.4.5 Hepatic
Hepatitis and fatal acute hepatic necrosis have
been described (Kalant & Kalant, 1975).
9.4.6 Urinary
9.4.6.1 Renal
Renal failure, secondary to dehydration
or rhabdomyolysis may be observed.
9.4.6.2 Other
Increased bladder sphincter tone may
cause dysuria, hesitancy and acute urinary
retention. This effect may be a direct result
of peripheral alpha-agonist activity.
Spontaneous rupture of the bladder has been
described in a young woman who took alcohol
and an amphetamine-containing diet tablet
(Schwartz, 1981).
9.4.7 Endocrine and reproductive systems
Transient hyperthyroxinaemia may result from
heavy amphetamine use (Morley et al., 1980).
9.4.8 Dermatological
Skin is usually pale and diaphoretic, but
mucous membranes appear dry. Chronic users may display
skin lesion, abscesses, ulcers, cellulitis or
necrotising angiitis due to physical insult to skin,
or dermatologic signs of dietary deficiencies, e.g.
cheilosis, purpura.
9.4.9 Eye, ear, nose, throat: local effects
Mydriasis may be noted.
Diffuse hair loss may be noted.
Chronic users may display signs of dietary
deficiencies.
9.4.10 Haematological
Disseminated intravascular coagulation is an
important consequence of severe poisoning ( Kendrick
et al., 1980).
Idiopathic thrombocytopenic purpura may occur.
9.4.11 Immunological
No relevant data.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbance
No relevant data
9.4.12.2 Fluid and electrolyte disturbance
Increase metabolic and muscular activity
may result in dehydration.
9.4.12.3 Others
No data available
9.4.13 Allergic reactions
No relevant data
9.4.14 Other clinical effects
No relevant data
9.4.15 Special risks
Pregnancy: Eriksson et al. (1989) followed 65
children whose mother were addicted to amphetamine
during pregnancy, at least during the first trimester.
Intelligence, psychological function, growth, and
physical health were all within the normal range at
eight years, but those exposed throughout pregnancy
tended to be more aggressive.
A case report describes a normal female infant born to
mother who took up to 180 mg/day of dexamphetamine for
narcolepsy throughout pregnancy (Briggs et al., 1975).
Breast-feeding: Amphetamine is passed into breast
milk and measurable amounts can be detected in
breast-fed infant's urine. Therefore lactating mothers
are advised not to take or use amphetamine.
9.5 Other
Amphetamine withdrawal syndrome: Abrupt discontinuance
following chronic use is characterised by apathy, depression,
lethargy, anxiety and sleep disturbances. Myalgias, abdominal
pain, voracious appetite and a profound depression with
suicidal tendencies may complicate the immediate
post-withdrawal period and peak in 2 to 3 days. To relieve
these symptoms, the user will often return to use more
amphetamine, often at increasing doses due to the tolerance
which is readily established. Thus a cycle of
use-withdrawal-use is established (Kramer et al., 1967; Hart
& Wallace, 1975). Physical effects are not life threatening
but can lead to a stuporose state (Tuma, 1993); the
associated depression can lead to suicide. It may take up to
eight weeks for suppressed REM (rapid eye movement) sleep to
return to normal (Brust 1993).
"Overamped": When the intravenous dosage is increased too
rapidly the individual develops a peculiar condition referred
to as "overamped: in which he or she is conscious but unable
to speak or move. Elevated blood pressure, temperature and
pulse as well as chest distress occurs in this setting. Death
from overdose in tolerant individuals is infrequent.
9.6 Summary
10. MANAGEMENT
10.1 General principles
General supportive measures should be used. These
should include stabilisation of the airway, breathing, and
circulation; relief of agitation, adequate hydration, and
control of core temperature. Convulsions, hyperthermia, and
rhabdomyolysis may require specific treatment. Activated
charcoal may be helpful for decontamination after oral
ingestion. Ipecacuanha is contra-indicated because of its
stimulant properties. There are no effective methods of
enhancing elimination and no antidote.
Agitation and convulsion can be treated with diazepam. If
agitation is severe, then chlorpromazine may have specific
advantages over other major tranquillisers ( Espelin & Done,
1968; Klawans, 1968). Parenteral dosages of 0.5 to 2
milligrams per kilogram have been used in Infants (Espelin &
Done, 1968).
Severe hyperthermia (core temperature greater than 40°C)
requires forced cooling by fans, tepid sponging or other
means, and may also require the administration of diazepam or
dantrolene or both agents in order to eliminate muscle
activity.
Rhabdomyolysis associated with muscle overactivity can cause
hyperkalaemia or renal failure, and should be treated
conventionally. Dialysis may be needed if renal failure
supervenes.
Acute severe hypertension (diastolic blood pressure greater
than 100 mmHg) can be controlled by infusion of sodium
nitroprusside by continuous intravenous infusion at an
initial rate of 3 mcg/kg/min, titrated to achieve the desired
response.
Patients who are addicted to amphetamines may develop the
withdrawal syndrome described in 9.5.
10.2 Life supportive procedures and symptomatic/specific
treatment
Treatment is supportive. Administration of
supplemental oxygen, establishment of intravenous access and
monitoring of vital signs including core temperature, and
cardiac rhythm are recommended. The following may be
necessary according to clinical indication:
-Maintenance adequate airway and ventilation
-Rehydration with intravenous fluids
-Control of seizures
-Control of agitation with benzodiazepines
-Control of severe hypertension (diastolic blood pressure
greater than 110 mmHg)
-Control of hyperthermia
-Treatment of hyperkalaemia
-Cardiac intensive care for ischaemia or arrhythmia
10.3 Decontamination
No regime of oral decontamination has been demonstrated
to improve outcome. Ipecacuanha is contra-indicated. Oral
activated charcoal may be helpful following oral overdosage.
10.4 Enhanced elimination
No regime of decontamination has been demonstrated to
improve outcome. Forced acid diuresis has been abandoned as a
decontamination procedure. Neither haemodialysis nor charcoal
haemoperfusion is likely to be of benefit.
10.5 Antidote treatment
10.5.1 Adults
There is no antidote to amphetamine poisoning.
10.5.2 Children
There is no antidote to amphetamine poisoning.
10.6 Management discussion
There are differences between dexamphetamine and
related compounds such as 3,4-methylenedeoxymetamphetamine
("ecstacy"); for example, hyperthermia appears to be more of
a problem with the latter, and this may be because of the
association between use and frenetic physical activity
("rave" dancing) (Henry et al., 1992).
In the past, energetic gastric decontamination procedures
were suggested (Espelin & Done, 1968). There is no evidence
that such procedures improve outcome in amphetamine
poisoning, and they are potentially hazardous.
Oral activated charcoal is probably the safest option for
decontamination, but is only likely to bind drug in the
stomach if a substantial oral dose of amphetamine has been
taken, and the charcoal is given within an hour or two of
ingestion. If should only administered to patients in whom
swallowing and gag reflexes are intact. In drug smugglers who
have swallowed supposedly inert packages of amphetamines
("stuffers" or "packers"), and who develop symptoms because
of leakage from the packages, then repeated doses of oral
activated charcoal with a cathartic are likely to be
worthwhile.
Forced acid diuresis has now been abandoned as an elimination
treatment, because it is intrinsically difficult and
potentially dangerous.
Treatment of agitation in amphetamine poisoning is required
when a patient is a danger to himself or herself, or to
others. Because poisoning is associated with sympathetic
overactivity, and chlorpromazine has alpha-adrenoreceptor
antagonist actions, chlorpromazine has been recommended as
the sedative treatment of choice (see 10.1). There is no
study to demonstrate that chlorpromazine is in fact superior
to benzodiazepine.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Ingestion of 2.2g (28mg/kg) in a 21 year old man
resulted in severe toxicity (Ginsberg et.al., 1970).
An 18 month old male infant ingested an unknown amount of
amphetamine, subsequently detected in the urine. He had a
history of restlessness and vomiting for 10 hours and was
admitted to hospital with mild fever (38°C), pulse rate of
140 per minute and respiratory rate of 34 per minute. He
looked acutely unwell, hyperactive and combative and had
normal pupils with a bi-lateral light reflex. Some irregular
flushing was found over the skin of the trunk. He was given
diazepam 10mg intravenously, 10% chloral hydrate 10ml
rectally and haloperidol 20mg intravenously. After a sleep of
20 hours normal activity resumed and the patient was
clinically well and discharged (Soong et.al., 1991).
A 20-month-old male infant was admitted to hospital with a
history of being too restless, hyperactive and agitated to be
manageable for several hours, and had not responded to 10mg
diazepam given intravenously in a local medical clinic. He
had dilated pupils, doll's eyes and normal discs. Generalised
hypperreflexia and a mild clonus were noted, but no focal
neurological abnormalities could be found. His vital signs
were - blood pressure 130/90 mmHg, pulse rate 150/min,
respiratory rate 46/min and normal temperature. The clinical
status remained unchanged for a further 18 hours and the
patient then calmed down to sleep for 20 hours. Subsequently
the parents found amphetamine powder spread near the infant's
bed (Soong, et.al., 1991).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
When prescribing amphetamines, due regard must be given
to its potential for misuse and addiction.
12.2 Other
No data available.
13. REFERENCES
Bashour TT (1994) Acute myocardial infarction resulting from
amphetamine abuse: a spasm-thrombus interplay? Am Heart J, 128:
1237-1239.
Beyer K., Bickel JT & Butt JH (1991) Ischemic colitis associated
with dextroamphetamine use. J Clin Gastroenterol, 13: 198-201.
Birkhahn HJ & Heifetz M (1973) Accidental intra-arterial injection
of amphetamine: an unusual hazard of drug addiction. Brit. J
Anaesthesia, 45: 761-763.
Briggs GG, Samson JH & Crawford DJ (1975) Lack of abnormalities in
a newborn exposed to amphetamine during gestation. Am J Dis Child,
129: 249-250.
Briggs G, Freeman J & Yaffe S (1990) Drugs in pregnancy and
lactation: a reference guide to fetal and neonatal risk, ed 3.
Baltimore, Williams & Wilkins.
Brust JCM (1993) Neurological aspects of substance abuse.
Stoneham, Butterworth-Heineman.
Budavari S ed. (1996) The Merck Index: an encyclopedia of
chemical, drugs, and biological, 12th ed. Rahway, New Jersey, Merck
and Co., Inc.
Call TD, Hartneck J, Dickinson WW, Hartman CW & Bartel AG (1982)
Acute cardiomyopathy secondary to amphetamine abuse. Ann Int Med,
97: 559-560.
Carson P, Oldroyd K & Phadkle K (1987) Myocardial infarction due
to amphetamine. Brit Med J, 294: 1525-1526.
Derlet RW, Price P, Horowitz BZ & Lord RV (1989) Amphetamine
toxicity: experience with 127 cases. J Emerg Med, 7: 157-161.
Dollery CT (1991) Therapeutic drugs. Edinburgh Churchill,
Livingstone.
Ellenhorn, M.J. (1997) Ellenhorn's Medical Toxicology, 2nd edition.
Baltimore, Williams and Wilkins.
Eriksson M, Billing L, Steneroth G & Zetterstrom R (1989) Health
and development of 8-year-old children whose mothers abused
amphetamine during pregnancy. Acta Paediatrica Scandinavica, 78:
944-949.
Espelin DE, Done AK (1968) Amphetamine poisoning. Effectiveness of
chlorpromazine. New Eng J Med, 278:1361-1365.
Flaum M & Schultz SK (1996) When does amphetamine-induced
psychosis become schizophrenia? Am J Psych, 153: 812-815.
Ginsberg MD Hertzman M & Schmidt-Nowara WW (1970) Amphetamine
intoxication with coagulopathy, hyperthermia and reversible renal
failure. A syndrome resembling heatstroke. Ann Intern Med, 73:
81-85.
Hall RCW, Popkin MK, Beresford TP & Hall AK (1988) Amphetamine
psychosis: clinical presentation and differential diagnosis.
Psychiatric Med, 6: 73-79.
Hardman JG, Limbird LE, Molinoff PB, Ruddon RW & Goodman Gilman A
(1996) Goodman & Gilman's the pharmacological basis of
therapeutics, 9th ed. New York, McGraw Hill.
Hart JB & Wallace J (1975) The adverse effects of amphetamines.
Clin Toxicol, 8: 179-190.
Henry JA, Jeffreys KS & Dawling S (1992) Toxicity and deaths from
3,4-methylenedeoxymetamphetamine ("ecstasy"). Lancet, 340:
384-387.
Johnson J & Milner G (1966) Psychiatric complications of
amphetamine abuse. Acta Psychiatrica Scandinavica, 42:
252-263.
Kalant H & Kalant OJ (1975) Death in amphetamine users: causes and
rates. Canad Med Assoc J, 112: 299-304.
Kaku DA & Lowenstein DH (1990) Emergence of recreational drug
abuse as a major risk factor for stroke in young adults. Ann Int
Med, 113: 821-827.
Kendrick WC, Hull AR & Knochel JP (1977) Rhabdomyolysis and shock
after intravenous amphetamine administration. Ann Int Med, 86:
381-387.
Klawans HL (1968) Chlorpromazine vs. amphetamine. New Engl J Med,
279:329.
Kramer JC, Fischman VS & Littlefield DC (1967) Amphetamine abuse.
Pattern and effects of high doses taken intravenously. JAMA, 201:
305-304.
Mattson RH & Calverly JR (1968) Dextroamphetamine-sulphate-induced
dyskinesias. JAMA, 204: 400-402.
Morley JE, Schafer RB, Elson MK, Slag MF, Raleigh MJ, Brammer GL,
Yuwiler A & Herschman JM (1980) Amphetamine-induced
hyperthyroxinemia. Ann Int Med, 93: 707-709.
Packe GE, Garton MJ & Jenning K (1990) Acute myocardial infarction
caused by intravenous amphetamine abuse. Brit Med J, 64:
23-24.
Reynolds JEF (1996) Martindale; The extra pharmacopoeia, 31st ed.
London, Pharmaceutical Press.
Schwartz DT (1981) Idiopathic rupture of the bladder. J Urol, 125:
602.
Selmi F, Davies KG, Sharma RR & Neal JW (1995) Intracerebral
haemorrhage due to amphetamine abuse; report of two cases with
underlying arteriovenous malformation. Brit J Neruosurg, 9:
93-96.
Soong WJ, Hwang BT, Tsai WJ & Deng JF (1991) [Amphetamine
poisoning in infants: report of 2 cases]. Chung-Hua-I-Hsueh-Tsa-
Chih, 48: 228-231.
Stockley IH (1994) Drug interactions, 3rd ed. Oxford, Blackwell
Science.
Tuma TA (1993) Depressive stupor following amphetamine withdrawal.
Brit J Hosp Med, 49: 361-363.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Authors: Miss Glady Heedes
Senior Pharmacist-in-Charge
Mr John Ailakis
Clinical Pharmacist
Western Australian Poisons Information Centre
Princess Margaret Hospital for Children
GPO Box D184
Perth, WA 6001
Australia
June 1992
Revised by: Dr Robin Ferner
West Midlands Centre for Adverse Drug Reaction
Reporting
City Hospital
Birmingham B18 7Q
United Kingdom
August 1997
Peer Review: INTOX 5 Meeting, September 1992: J-F Deng, R
Ferner, Landoni, Maramba, E Wickstrom
INTOX 10 Meeting, Rio, Brazil, September
1997: N Ben-Salah, A Borges, M Mathieu-Nolf,
L Murray, M-O Rambourg, R Ferner
Editor: Michael Ruse, IPCS (June, 1998)