Monoamine-oxidase inhibitors
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 113.5°C
Isocarboxazid
Melting point: 105 to 106°C
Moclobemide
See individual Monograph
Nialamide
Melting point: 152 to 153°C
Phenelzine Hydrochloride
Melting point: 174°C
Toloxatone
See individual Monograph
Tranylcypromine Hydrochloride
Melting point: 164 to 166°C
(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