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Monoamine-oxidase inhibitors

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
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
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.6 Interactions
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 disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         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 Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    MONOAMINE-OXIDASE INHIBITORS (MAOIs)

    International Programme on Chemical Safety
    Poisons Information Monograph G025
    Pharmaceutical

    This monograph contains the following sections: 1 (Name), 2 (Summary),
    3 (Physico-chemical properties), 4 (Uses), 7 (Pharmacology and
    Toxicology), 9 (Clinical effects) and 10 (Management).

    1.  NAME

        1.1  Substance

             Monoamine oxidase inhibitors

        1.2  Group

             Psychoanaleptics/antidepressants/monoamine oxidase
             inhibitors non-selective
             Psychoanaleptics/antidepressants/monoamine oxidase type
             A inhibitors

             The members of these groups are:

             - Non-selective monoamine oxidase inhibitors:

             Iproniazid
             Isocarboxazid
             Nialamide
             Phenelzine
             Tranylcypromine

             - Monoamine oxidase type A inhibitors:

             Clorgyline
             Moclobemide
             Toloxatone

        1.3  Synonyms

             MAOI

        1.4  Identification numbers

             1.4.1  CAS number

                    Clorgyline                    17780-72-2
                    Clorgyline hydrochloride      17780-75-5
                    Iproniazid                    54-92-2
                    Iproniazid phosphate          305-33-9
                    Isocarboxazid                 59-63-2
                    Moclobemide                   71320-77-9
                    Nialamide                     51-12-7

                    Phenelzine                    51-71-8
                    Phenelzine sulphate           156-51-4
                    Toloxatone                    29218-27-7
                    Tranylcypromine               155-09-9
                    Tranylcypromine sulphate      13492-01-8

             1.4.2  Other numbers

                    ATC codes: N06AF (non selective MAOI)
                               N06AG (MAO type A inhibitor)
    

    2.  SUMMARY

        2.1  Main risks and target organs

             MAOIs cause an increase in the concentration of
             norepinephrine, dopamine, and 5HT in the brain and other
             tissues accompanied by a variety of effects.
             MAOIs overdose or concurrent ingestion of thyramine-rich
             foods or medications which increase the availability of
             biogenic amines with MAOIs may cause a life-threatening
             serotonin syndrome resulting in severe cardiovascular and/or
             CNS reactions. Because of the late onset (4 hours) of these
             reactions, hospitalisation is necessary even though no or
             minor symptoms are observed.
    
             In severe cases the main risk is coma, rigidity and
             opisthotonus leading to metabolic acidosis and hyperpyrexia.
             Further complications include hypotension, cardiovascular
             collapse and cardiac arrest. Death may result from
             hyperthermia which may peak as late as 24 hours after
             presentation.
    
             Deaths have more commonly followed interaction of therapeutic
             MAOIs with thyramine rich food, tricyclic antidepressants or
             sympathomimetic amines and selective serotonin reuptake
             inhibitors (SSRIs).
    
             Some MAOIs have been abused by patients having a history of
             prior substance abuse. Withdrawal symptoms include anxiety,
             confusion, depression, hallucinations, nausea, vomiting,
             rigor.
    
             Short acting selective and reversible monoamine oxidase type
             A inhibitors are generally well tolerated in overdose when
             taken alone. As for non selective MAOIs, the serotonergic
             effects may be enhanced by combination with tricyclic
             antidepressants, other MAOIs, selective serotonin reuptake
             inhibitors (SSRIs), or lithium, causing a life-threatening
             serotonin syndrome.

        2.2  Summary of clinical effects

             In overdose the clinical effects may be delayed for 6 to
             24 hours. Initially there may be vomiting, headache, dilated
             pupils, drowsiness, confusion, agitation, nystagmus, sweating
             and muscle tremors. Then, hallucinations, hyperventilation,
             hypertension and ventricular tachycardia may occur. In severe
             cases there is a risk of coma, muscle twitching, rigidity and
             opisthotonus leading to metabolic acidosis and hyperpyrexia.
             Complications include rhabdomyolysis, acute renal failure,
             disseminated intravascular coagulation (DIC), hypotension,
             cardiovascular collapse and arrest.

        2.3  Diagnosis

             Diagnosis of MAOIs poisoning is clinical and based on
             history of overdose and/or access to MAOI drugs and the
             presence of agitation, hypertension, sweating, hyperthermia
             and muscle tremor. Co-ingestion of other medications
             enhancing the availability of biogenic amines should be
             suspected and the diagnosis of the serotonin syndrome should
             be considered in the presence of three or more of the
             following symptoms: behavioural change (confusion or
             hypomania), agitation, myoclonus, hyperreflexia, sweating,
             shivering, tremor, diarrhoea, motor incoordination, muscle
             rigidity, fever. The differential diagnoses include
             neuroleptic malignant syndrome, acute poisoning with strychnine,
             acute sepsis, or severe metabolic disturbances.

        2.4  First aid measures and management principles

             In adults a gastric lavage followed by activated
             charcoal should be carried out within 1 hour of ingestion.
             Cardiac monitoring should be instituted for 24 hours, even in
             the absence of initial symptoms. Diazepam can be given for
             sedation if necessary.
    
             Treatment of the serotonin syndrome may require aggressive
             supportive care including diazepam, mechanical ventilation,
             external cooling and if necessary paralysis with a
             neuromuscular blocking agent.
    

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Clorgyline
    
             Chemical name:
             3-(2,4-dichlorophenoxy) propyl (methyl) prop-2-ynylamine
             Molecular formula Clorgyline Hydrochloride: C13 H15 Cl2 NO,
             HCl
             Molecular weight Clorgyline Hydrochloride: 308.6
    
             Iproniazid
    
             Chemical name:
             2'-isopropylisonicotinohydrazide phosphate
    
             Molecular formula Iproniazid Phosphate: C9 H13 N3 O, H3
             PO4
             Molecular weight Iproniazid Phosphate: 277.2
    
             Isocarboxazid
    
             Chemical name:
             2'-benzyl-5-methylisoxazole-3-carbohydrazide
    
             Molecular formula: C12 H13 N3 O2
             Molecular weight: 231.3
    
             Moclobemide
             See individual Monograph
    
             Nialamide
    
             Chemical name:
             N'-(2-benzylcarbamoylethyl)isonicotinohydrazide
             Molecular formula: C16 H18 N4 O2
             Molecular weight: 298.3
    
             Phenelzine
    
             Chemical name:
             Phenethylhydrazine hydrogen sulphate
    
             Molecular formula Phenelzine Sulphate: C8 H12 N2, H2 SO4
             Molecular weight Phenelzine Sulphate: 234.3
    
             Toloxatone
    

             Chemical name:
             5-(hydroxymethyl)-3- m-tolyl-2-oxazolidinone
    
             Molecular formula: C11 H13 N O3
             Molecular weight: 207.2
    
             Tranylcypromine
    
             Chemical name:
             (+-)- trans-2-phenylcyclopropylamine sulphate
    
             Molecular formula Tranylcypromine Sulphate: (C9 H11 N)2,
             H2 SO4
             Molecular weight Tranylcypromine Sulphate: 364.5

        3.3  Physical properties

             3.3.1  Colour

             3.3.2  State/Form

             3.3.3  Description

                    Iproniazid 
                    Melting point: 112.5 to 113.5C
    
                    Isocarboxazid
                    Melting point: 105 to 106C
    
                    Moclobemide
                    See individual Monograph
    
                    Nialamide
                    Melting point: 152 to 153C
    
                    Phenelzine Hydrochloride
                    Melting point: 174C
    
                    Toloxatone
                    See individual Monograph
    
                    Tranylcypromine Hydrochloride
                    Melting point: 164 to 166C
    
                    (Budavari, 1996)

        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

                    MAOIs are used in the treatment of severe depression.

    

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Mono amine oxidase inhibitors (MAOIs) exert
                    their toxic effects by inhibiting the metabolism of
                    sympathomimetic amines and serotonin, and by
                    decreasing norepinephrine stores in post-ganglionic
                    sympathetic neurons. They do not inhibit MAO
                    synthesis. MAOIs also inhibit enzymes other than MAO,
                    including dopamine-B-oxidase, diamine-oxidase,
                    amino-acid decarboxylase and choline dehydrogenase.
                    Inhibition of these enzymes occurs only with very high
                    doses of MAOIs and may be responsible for some of the
                    toxic effects of MAOIs.
                    Drugs that enhance serotonin production or release
                    (tricyclic antidepressants, selective serotonin
                    reuptake inhibitors) may cause the serotonin syndrome
                    when they are administered concurrently with the
                    MAOIs, even at therapeutic doses.
                    A toxic reaction to MAOIs may be caused by pressor
                    amines such as tyramine, resulting in hypertensive
                    crisis. When the protective role of intestinal and
                    hepatic MAO is eliminated, increased absorption of
                    tyramine from certain foods occurs and can cause a
                    significant increase in blood pressure ("cheese
                    reaction") through the release of noradrenaline from
                    pre-synaptic vesicles.
                    Two isoforms of the MAO enzyme have been discovered:
                    MAO-A and MAO-B. These isoforms differ in anatomical
                    distribution and preferred substrates. The
                    isoform-selective MAOIs reversibly inhibit MAO-A, and
                    thus have a lower potential for interactions than non
                    selective MAOIs at therapeutic doses. However
                    selectivity is lost in overdoses and in extreme
                    situations such as high-dose combination therapies and
                    mixed drug overdoses, severe toxic reactions may
                    occur.

             7.1.2  Pharmacodynamics

                    The MAOs are a group of enzymes that
                    metabolise, and therefore inactivate endogenous
                    pressor amines (such as noradrenaline, adrenaline,
                    dopamine, serotonin) as well as ingested pressor
                    amines (such as tyramine). MAOIs inhibit the
                    degradation of these amines by MAO. The increased
                    availability of biogenic amines (such as noradrenaline
                    and serotonin) is thought to be linked with the
                    improvement in depression accounted for by IMAO
                    treatment.

                    Two isoforms of the MAO enzyme have been discovered:
                    MAO-A and MAO-B, which differ in anatomical
                    distribution and preferred substrates. The MAO type A
                    enzymes preferentially metabolize serotonin and
                    noradrenaline and are located primarily in the
                    placenta, gut and liver. The MAO type B enzymes are
                    predominant in brain, liver and platelets, and
                    phenylethylamine, methylhistamine and tryptamine are
                    their primary substrates. Both MAO-A and MAO-B
                    metabolize tyramine.
                    The isoforme-selective MAOIs reversibly inhibit MAO-A
                    and have a lower potential for interactions than non
                    selective MAOIs at therapeutic doses. The duration of
                    MAO-A inhibition by selective MAOIs is shorter (16 to
                    24 h) than the inhibition induced by conventional
                    MAOIs (> 10 days).
                    MAOIs significantly reduces REM (rapid eye movement),
                    sleep density, REM time and the REM percentage of
                    total sleep time in patients with major
                    depression.

        7.6  Interactions

             Drug interactions:
             Most common with sympathomimetic agents such as amphetamines,
             dopamine, ephedrine, levodopa, phenylpropanolamine and
             pseudoephedrine. The MAOIs cause accumulation of
             noradrenaline in the brain and within the sympathetic nerve
             endings in the arterial blood vessels. Stimulation of these
             nerve endings by the sympathomimetic amine causes exaggerated
             blood vessel constriction and therefore hypertension,
             increasing the risk of intracranial haemorrhage.
             MAOIs inhibit other drug-metabolising enzymes and may enhance
             the effects of barbiturates and possibly of other hypnotics,
             hypoglycaemic agents, antimuscarinic agents, beta blockers
             and thiazide diuretics.
             Severe reactions have also been reported in patients
             receiving opioid analgesics while being treated with a
             MAOI.
             There is a possibility of serious interactions when agents
             that increase serotonin availability have been taken
             concomitantly with MAOIs: eg. tricyclic antidepressants,
             SSRIs. This may cause a serotonin syndrome (Feighner et al.,
             1990; Sternbach, 1991; Spigset et al., 1993; Liebenberg et
             al., 1996).
             Because of this risk, there should be a minimum 2 week
             wash-out period between stopping a MAOI and starting a
             tricyclic antidepressant or a SSRI (Lane & Fischler,
             1995).
    
             (Livingston & Livingston, 1996; Reynolds, 1996)
    

             Food interactions:
             The concomitant ingestion of tyramine rich foods in patients
             being treated with non-selective and irreversible MAOIs can
             cause hypertensive crises (cheese reaction). Tyramine rich
             foods which should be avoided include cheese, pickled
             herring, meat/yeast extracts and fermented soya bean extract.
             Effects occur very quickly (usually within 3 hours) and are
             usually self-limiting and short lived (Blackwell et al.,
             1967).

    

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    After a latent period of some hours patients
                    may progressively develop motor uneasiness, agitation,
                    violent motor activity with moaning and grimacing,
                    profuse sweating, and hallucinations. In severe cases,
                    hyperthermia, coma, rigidity and opisthotonus,
                    metabolic acidosis, hypotension, cardiovascular
                    collapse and cardiac arrest can occur.
                    (Henry, 1986; Myrenfors et al., 1993).

             9.1.2  Inhalation

                    Not relevant

             9.1.3  Skin exposure

                    Not relevant

             9.1.4  Eye contact

                    Not relevant

             9.1.5  Parenteral exposure

                    No data

             9.1.6  Other

                    No data

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Some MAOIs have been abused by patients having
                    a history of prior substance abuse (Livingston &
                    Livingston, 1996).

             9.2.2  Inhalation

                    Not relevant

             9.2.3  Skin exposure

                    Not relevant

             9.2.4  Eye contact

                    Not relevant

             9.2.5  Parenteral exposure

                    No data

             9.2.6  Other

                    No data

        9.3  Course, prognosis, cause of death

             Short acting selective and reversible monoamine oxidase
             type A inhibitors are generally well tolerated in overdose
             when taken alone, and the clinical course is usually benign
             (Iwersen & Schmoldt, 1996).
             Deaths have more commonly followed interaction of MAOIs with
             thyramine rich food, tricyclic antidepressants or
             sympathomimetic amines and selective serotonin reuptake
             inhibitors (SSRIs). The clinical course consisted of
             agitation, then extreme tremor, followed by convulsions and
             hyperthermia. Death occured within 3 to 16 hours after
             ingestion, after intractable seizure and/or hyperthermia and
             its subsequent complications: disseminated intravascular
             coagulation and multiple organ failure (Henry, 1986; Neuvonen
             et al., 1993; Kuisma, 1995; Power et al., 1995).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Vascular: vasoconstriction followed by a
                    hypertensive crisis may be observed.
                    Cardiac: ventricular tachycardia has been observed in
                    severe cases.

             9.4.2  Respiratory

                    Hyperventilation.

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Headache, drowsiness, confusion,
                             agitation, hallucinations, hypomania,
                             nystagmus; muscle tremor, convulsions, muscle
                             rigidity, trismus and opisthotonus;
                             hyperthermia. Coma.

                    9.4.3.2  Peripheral nervous system

                    9.4.3.3  Autonomic nervous system

                             Dilated pupils, sweating.

                    9.4.3.4  Skeletal and smooth muscle

             9.4.4  Gastrointestinal

                    Vomiting and diarrhoea.

             9.4.5  Hepatic

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Acute renal failure due to
                             rhabdomyolysis may be observed.

                    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 disturbances

                             Severe metabolic acidosis may be found.

                    9.4.12.2 Fluid and electrolyte disturbances

                    9.4.12.3 Others

             9.4.13 Allergic reactions

             9.4.14 Other clinical effects

             9.4.15 Special risks

                    Abuse potential does exist with MAOIs. It is
                    wise to be cautious when prescribing these drugs for
                    individuals who have a substance misuse problem,
                    including alcohol dependence, or for personality
                    disorders patients with poor impulse control.
                    Withdrawal symptoms include anxiety, confusion,
                    depression, hallucinations, nausea, vomiting, rigor.

        9.5  Other

        9.6  Summary

    

    10. MANAGEMENT

        10.1 General principles

             The primary management of MAOIs overdose consists of
             the institution of careful observation of vital signs (even
             in cases of no or minor symptoms within the first 4 hours
             because of the delayed onset of MAOI action), and
             neurological status and supportive care until signs and
             symptoms resolve. Intravenous access should be established as
             soon as practical.
             In more severe intoxications or where there are other
             substances ingested, more aggressive measures such as
             establishment of an airway, ventilation, administration of
             intravenous fluids, control of seizures, and control of
             hyperthermia may be necessary.
             In patients with MAOI abuse tapering of doses rather than
             abrupt discontinuation appears to reduce withdrawal symptoms.

        10.2 Life supportive procedures and symptomatic/specific treatment

             In severe cases or when a serotonin syndrome occurs,
             measures that may be required include: endotracheal
             intubation and assisted ventilation if coma is present,
             intravenous fluid resuscitation if hypotension is present,
             pharmacological control of seizures (diazepam), external
             cooling and administration of dantrolene if hyperthermia is
             present (1 mg/kg intravenously over 10 to 15 minutes, if no
             response, repeat dose to a maximum of 10 mg/kg in 24 hours).

        10.3 Decontamination

             Gastric lavage followed by activated charcoal should be
             advocated in patients who have ingested large doses and/or
             when there has been a co-ingestion.

        10.4 Elimination

             There are no effective methods known to enhance the
             elimination of MAOIs.

        10.5 Antidote treatment

             10.5.1 Adults

                    No data

             10.5.2 Children

                    No data

        10.6 Management discussion

             Although dantrolene has been used successfully, its
             role in the management of the serotonin syndrome has yet to
             be evaluated.

    

    13. REFERENCES

        Blackwell B, Marley E, Price J, Taylor D (1967) Hypertensive
        interactions between monoamine oxidase inhibitors and foodstuffs.
        Brit J Psychiatry, 113: 348-365
    
        Budavari S ed. (1996) The Merck Index: an encyclopedia of
        chemicals, drugs and biologicals, 12th ed. Rahway, New Jersey,
        Merck and Co., Inc.
    
        Feighner JP, Boyer WF, Tyler DL, Neborsky RJ (1990) Adverse
        consequences of fluoxetine-MAOI combination therapy. J Clin
        Psychiatry, 148: 705-713
    
        Henry JA (1986) Specific problems of drug intoxication. Brit
        Anaesth, 58: 223-233
    
        Iwersen S & Schmoldt A (1996) Three suicide attempts with
        moclobemide. Clin Toxicol, 34: 223-225
    
        Kuisma MJ (1995) Fatal serotonin syndrome with trismus. Ann Emerg
        Med, 26, 1: 108
    
        Lane R & Fischler B (1995) The serotonin syndrome: co-
        administration, discontinuation and washout periods for the
        selective serotonin reuptake inhibitors (SSRIs). J Serotonin
        Research, 3: 171-180
    
        Liebenberg R, Berk M & Winkler G (1996) Serotonergic syndrome
        after concomitant use of moclobemide and fluoxetine. Human
        Psychopharmacol: Clin and Experiment, 11: 146-147

        Livingston M & Livingston H (1996) Monoamine oxidase inhibitors.
        An update on drug interactions. Drug Safety, 14, 4: 219-227
    
        Myrenfors PG, Eriksson T, Sansdtedt CS & Sjoberg G (1993)
        Moclobemide overdose. J Intern Med, 233: 113-115
    
        Neuvonen P, Pohjola-Sintonen S, Tacke U & Vuori E (1993) Five
        fatal cases of serotonin syndrome after moclobemide-citalopram or
        moclobemide-clomipramine overdoses. Lancet, 342: 1419
    
        Power BM, Pinder M, Hackett LP & Ilett KF (1995) Fatal serotonin
        syndrome following a combined overdose of moclobemide,
        clomipramine and fluoxetine. Anaesth Intens Care, 23: 499-502
    
        Reynolds JEF ed (1996) Martindale: the extra pharmacopoeia, 31st
        ed. London, The Pharmaceutical Press
    

        Spigset O, Mjorndal T & Lovheim O (1993) Serotonin syndrome caused
        by a moclobemide-clomipramine interaction. Br Med J, 306, 6872:
        248
    
        Sternbach H (1991) The serotonin syndrome. Am J Psychiatry, 148:
        705-713

    

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:           Medical Toxicology Unit,
                          Guy's and St Thomas' Trust
                          Avonley Road, London SE14 5ER, UK
    
                          October, 1997
    
        Reviewers:        Drs R. Ferner, M. Mathieu-Nolf, M.O. Rambourg
                          Schepens (coordinator)
    
                          London, March, 1998
    
        Editing and
        Finalisation:     M.O. Rambourg Schepens, March 2000
    


    See Also:
       Toxicological Abbreviations