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Phentermine

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)
    Phentermine

    International Programme on Chemical Safety
    Poison Information Monograph 415
    Pharmaceutical


    1.  NAME

        1.1  Substance

             Phentermine

        1.2  Group

             ATC Classification

             Antiobesity preparations, excl., diet products (A08A)
             Centrally acting antiobesity products (A08A A)

        1.3  Synonyms

             Duromine; Ionamin; Linyl;
             Lipopill;  Mirapront;
             Normephentermine; Omnibex;
             Wilpo

        1.4  Identification numbers

             1.4.1  CAS numbers

                    Phentermine  122-09-8

             1.4.2  Other numbers

                    Phentermine hydrochloride  CAS 1197-21-3

                    Phentermine RTECS/NIOSH     SH4025000

                    RCRA waste number P046

        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 g/L, chronic
             abusers of amphetamine have been known to have blood
             concentration of up to 3000 g/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

             Phentermine
    
             Chemical name:
    
             1,1-Dimethyl-2-phenylethylamine
    
             Other chemical names:
    
             2-Amino-2-methyl-1-phenylpropane
             2-Phenyl-tert-butylamine
             alpha,alpha-Dimethyl-beta-phenylethylamine
             alpha,alpha-Dimethylphenethylamine
             Benzeethanamine, alpha,alpha-dimethyl (9CI)
             1,1-Dimethyl-2-phenyl-ethanamine
    
             Molecular formula:  C10H15N
             Molecular weight:   149.2
    
             Phentermine hydrochloride
    
             Chemical name:
    
             Molecular formula: C10H15N,HCl
             Molecula weight:  185.7


        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

                    Antiobesity preparation (not diet product)
                    Centrally acting antiobesity product

             4.1.2  Description

                    Indications
    
                    Appetite suppressant (anorectic) for benzphetamine,
                    diethypropion, phendimetrazine, phenmetrazine and
                    phenteramine.
    
                    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 40C, 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 -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 40C)
             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 (38C), 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

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        Birkhahn HJ & Heifetz M (1973) Accidental intra-arterial injection
        of amphetamine: an unusual hazard of drug addiction. Brit. J
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        Briggs GG, Samson JH & Crawford DJ (1975) Lack of abnormalities in
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        Briggs G, Freeman J & Yaffe S (1990) Drugs in pregnancy and
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        Ellenhorn, M.J. (1997) Ellenhorn's Medical Toxicology, 2nd edition.
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        Soong WJ, Hwang BT, Tsai WJ & Deng JF (1991)  [Amphetamine
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        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)
    


    See Also:
       Toxicological Abbreviations