Imipramine
| 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 |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, 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 Properties of the substance |
| 3.3.2 Properties of the locally available formulation |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulation |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indications |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 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 by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 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 |
| 7.7 Main adverse effects |
| 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 Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative 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 Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative 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 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 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. Additional information |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
PHARMACEUTICALS
1. NAME
1.1 Substance
Imipramine
1.2 Group
Tricyclic Antidepressants (B.P., E.P.P, U.S.P.)
1.3 Synonyms
Imipramine Hydrochloride
Imipramine Hydrochlorum
Imipramini Chloridum
Imipraminum
Imizine
Imizinum
1.4 Identification numbers
1.4.1 CAS number
Imipramine: 50-49-7
1.4.2 Other numbers
No data available.
1.5 Brand names, Trade names
Berkomine (Berk Pharmaceuticals, UK) Imipramine hydrochloride
available as tablets of 10 mg.
Praminil (DDSA Pharmaceuticals). Imipramine hydrochloride,
available as tablets of 10 and 25 mg.
Tofranil (Geigy, UK). Imipramine hydrochloride, available as
tablets of 10 and 25 mg. Tofranil Syrup, contains in each 5 ml
imipramine (as a resin complex) equivalent to 25 mg imipramine
hydrochloride.
1.6 Manufacturers, Importers
To be completed by each centre.
It is important to include the number of unit doses, as well
as the vehicle or solvent in the formulation.
2. SUMMARY
2.1 Main risks and target organs
Affects the parasympathetic nervous system, central nervous
system, and cardiovascular system.
2.2 Summary of clinical effects
Early symptoms: mydriasis, blurred vision, dry mouth,
tachycardia, hyperpyrexia, urinary retention, decreased
intestinal peristalsis, and CNS excitation. Extrapyramidal
symptoms may occur.
Later more serious features: convulsions, coma, hypotension,
arrhythmias, and cardiorespiratory arrest.
The progression from being alert with mild symptoms to life-
threatening toxic effects may be extremely rapid.
2.3 Diagnosis
Frequent control of arterial blood gases is indicated.
Metabolic acidosis is a common feature and may exacerbate
toxicity.
As with all drugs which have a large volume of distribution
the value of monitoring the serum concentration is
controversial.
2.4 First aid measures and management principles
Every patient with a history of significant imipramine
ingestion or having symptoms, signs or ECG changes consistent
with imipramine poisoning, should be admitted to an intensive
care department, with immediate monitoring (for 24 hours) of
ventilation and circulation, independent of the clinical
condition of the patient.
Gastric lavage, administration of activated charcoal and
cathartics.
Seizure activity must be prevented or minimized by treatment
with diazepam or, if unsuccessful, with phenytoin.
Severe hypotension should be treated with norepinephrine.
Treat ventricular arrhythmias with intravenous magnesium;
atrial or ventricular pacing; or isoproterenol infusion.
Bradycardia or heart block treated by isoproterenol or
antibradycardia pacing.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic
3.2 Chemical structure
Imipramine
3-(10,11-Dihydro-5H-dibenz[bf]-azepin-5-yl)-NN-dimethyl-
propylamine.
C19H24N2
Molecular weight 280.4.
Imipramine Hydrochloride
C19H24N2HCl
Molecular weight 316.9.
3.3 Physical properties
3.3.1 Properties of the substance
Imipramine Hydrochloride
A white or slightly yellow, odourless or almost
odourless, crystalline powder with a burning
taste, followed by a sensation of numbness.
Soluble 1 in 2 of water, 1 in 1.5 of alcohol, 1
in 1.5 of chloroform, and 1 in 15 of acetone;
practically insoluble in ether. A 10% solution
in water has a pH of 3.6 to 5.0. pKa = 9.4
(Martindale, 1982).
3.3.2 Properties of the locally available formulation
To be completed by each centre.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
Aqueous solutions are stable when protected from oxygen
and light.
3.4.2 Shelf-life of the locally available formulation
To be completed by each centre.
3.4.3 Storage conditions
In airtight containers. Protect from light. The powder
absorbs insignificant amounts of moisture at 23°C at
relative humidities up to 60%; under more humid
conditions significant absorption occurs (Martindale
1982).
3.4.4 Bioavailability
To be added by each centre.
3.4.5 Specific properties and composition
To be added by each centre.
4. USES
4.1 Indications
Treatment of depression; nocturnal enuresis in children
4.2 Therapeutic dosage
4.2.1 Adults
Orally: Initially, 25 to 75 mg/day, increasing in
increments of 25 mg/day to the usual maintenance dose
of 150-200 mg/day; maximum 300 mg/day.
Elderly: Initially, 10 mg/day, increasing in increments
of 20 to 40 mg/day, to a maximum of 100 mg/day.
4.2.2 Children
Orally: not for children younger than 6 years old
6 to 7 years old: 25 mg at night.
8 to 11 years old: 25 to 50 mg at night.
over 11 years old: 50 75 mg at night
After 2 months, the dose should be gradually reduced and
treatment withdrawn. Treatment should not continue for
more than 3 months. (Reynolds, 1993)
Intramuscular: Initially, 25 mg three times a day,
increasing in increments of 25 mg/day to a maximum of
100 mg/day. Intramuscular administration should be
gradually replaced by oral administration as soon as
possible (Informatorium Medicamentorium, 1986; Reynolds,
1993).
4.3 Contraindications
Epilepsy, organic brain damage, urine retention, heart
diseases, acute glaucoma. Hyperthyroidism and liver diseases
are a relative contraindication.
5. ROUTES OF ENTRY
5.1 Oral
Preferred route of administration.
5.2 Inhalation
Not relevant.
5.3 Dermal
Not relevant.
5.4 Eye
Not relevant.
5.5 Parenteral
In the initial stages of treatment, if administration by mouth
is impracticable or inadvisable imipramine may be given by
intramuscular injection.
5.6 Other
Not relevant.
6. KINETICS
6.1 Absorption by route of exposure
Oral: absorption occurs in the small intestine with little or
no absorption in the stomach (Crammer et al., 1969; Gramm &
Christiansen, 1975). Absorption is virtually complete (95%).
The peak plasma concentration occurs 2 to 6 hours after
administration (Christiansen et al., 1967; Dencker et al.,
1976; Gram & Christiansen, 1975). Food does not affect
absorption, peak concentration or time to peak concentration
(Abernethy et al., 1984).
Large doses may be absorbed more slowly due to delayed gastric
emptying and reduced peristalsis. Large amounts of imipramine,
including intact pill fragments, have been recovered at
autopsy (Hanzlick, 1984).
Parenteral: absorption appears to be complete since recovery
of urinary metabolites is the same after either oral or
parenteral administration (Sallee & Pollock, 1990).
6.2 Distribution by route of exposure
Imipramine is lipophilic and therefore widely distributed in
the body. The apparent volume of distribution is 10 to 20 L/kg
though Dollery (1991) quotes a figure of 28 to 61 L/kg.
Distribution is influenced by the degree of binding to plasma
proteins. Plasma protein binding of imipramine ranges from 60
to 96% (Devane, 1980).
6.3 Biological half-life by route of exposure
The half-life of imipramine is approximately 20 hours. Its
active metabolite desipramine has a half-life of up to 125
hours.
Table 1: Mean pharmacokinetics parameters after single oral
doses
Reference No. Dose Sampling t´ Cl Vd
(mg) interval (h) (L/h/kg) (L/kg)
(h)
Abernathy et al.,12 50 96 20.5±2.0
1984
Ciraulo et al., 8 50 72 19.6±5.5 6.5±1.3
1982
Gram et al., 7 40-60 48 9.9±2.3 1.2 11.5
1976
Nagy & Johansson, 5 75 24 7.6±5.6 3.2±1.7 11.0±4.2
1975
Sutfin et al, 4 50 72 9.5±2.9 2.8±0.8 18.2±1.5
1988
Table 2: Mean pharmacokinetic parameters after single
parenteral doses
Reference No Dose Bioavail- t´ Cl Vd
(mg) ability (h) (L/h/kg) (L/kg)
%
IMIPRAMINE
Abernethy et al.,12 12.5 43.6±4.6 21.2±2.0 0.8±0.1 21.0±2.1
1984
Abernethy et al.,14 12.5 42.0±3.0 16.5±1.3 0.8±0.1 18.1±1.9
1985
Brosen & Gram, 50
1988
rapid metabol. 4 39.0±7.0 16.0±4.0 0.9±0.3 16.6±3.8
slow metabol. 4 42.0±19.0 17.0±6.0 1.0±0.2 20.8±4.8
poor metabol. 3 71.0±8.0 18.0±6.0 0.9±0.2 18.6±1.0
DESIMIPRAMINE
Brosen & Gram, 50
1988
rapid metabol. 4 56.0±4.0 21.0±3.0 0.8±0.1 22.4±4.1
slow metabol. 4 73.0±12.0 22.0±3.0 0.8±0.1 20.2±3.8
poor metabol. 3 86.0±13.0 125.0±3 0.2 25.6±8.6
3
6.4 Metabolism
Imipramine is metabolised almost exclusively in the liver,
undergoing oxidation by microsomal enzymes, followed by
conjugation with glucuronic acid.
Imipramine is mainly metabolised by demethylation to an active
metabolite desipramine, and to a lesser extent by aromatic 2-
hydroxylation to 2-hydroxyimipramine. Desipramine is
metabolised by aromatic 2-hydroxylation to 2-
hydroxydesimipramine. Quantitively, hydroxylation is the most
important intermediate metabolic pathway and it is the rate-
limiting step for the elimination of imipramine and
desimipramine (Rubinstein et al., 1983).
The greater plasma elimination half-life for desimipramine
compared with imipramine may be due to a lower rate of
hydroxylation (Kruger et al., 1986).
Both imipramine and desimipramine undergo substantial and
highly variable first-pass metabolism (Gram & Christiansen,
1975; Nagy & Johansson, 1975), the extent of which is
determined by oxidative phenotype. In Caucasians, there are
slow and fast metabolisres: at least 6.5 to 10% of the
population are slow metabolisers (Eichelbaum, 1982; Peart et
al., 1986; Price-Evans et al., 1980; Vinks et al., 1982).
First-pass metabolism of imipramine and desimipramine is
reduced in slow metabolisers (Brosen & Gram, 1988) (see fig.
2).
Smoking, alcohol ingestion and other drugs may influence
imipramine and desimipramine metabolism by altering the mixed
function oxidase system:
Smokers have lower steady-state levels of imipramine than non-
smokers (Perel et al., 1978).
Alcoholics were found to have a 3-fold greater intrinsic
clearance of imipramine (Ciraulo et al., 1982).
Cimetidine increases the bioavailability of imipramine by 40
to 75% (Abernethy et al., 1984b; Amsterdam et al., 1984; Spina
& Koike, 1986).
Some drugs, such as haloperidol, disulfiram, and morphine, may
prolong toxicity by inhibiting hydroxylation (Van Brunt,
1983).
6.5 Elimination by route of exposure
Less than 5% of an oral dose of imipramine is excreted
unchanged in the urine (Sjoqvist et al., 1969).
The rate of renal clearance of 2-hydroxydesimipramine is 2.1
to 16 L/h (Sutfin et al., 1988). In patients with chronic
renal failure, disproportionate increases in hydroxymetabolite
concentration may occur (Lieberman et al., 1985).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Anticholinergic effects: increased heart rate.
"Quinidine-like" effects on the heart due to slowing of
sodium influx and potassium efflux, resulting in slowing
of conduction and repolarization. Slowing of conduction
notably occurs at the His-Purkinje portion of the
atrioventricular conduction system (Vohra et al 1975)
resulting in prolongation of the PR- and QRS- intervals.
Prolonged depolarization results in lengthening of the
QT-interval.
Peripheral -receptor blockade may cause orthostatic
hypotension (Glassman, 1984).
7.1.2 Pharmacodynamics
The probable mechanism of antidepressant activity is
central inhibition of biogenic amine reuptake,
predominantly affecting norepinephrine and serotonin.
(Frommer et al., 1987).
In addition to its central effects, imipramine is also a
competitive antagonist at histamine H1 and H2 receptors
(Richelson, 1982).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Dose range for serious acute poisoning (oral): 7
to 127 mg/kg
Fatal dose: 10 to 210 mg/kg (Bickel, 1975)
7.2.1.2 Children
Toxicity occurs after ingestion of 10 mg/kg.
Fatalities have occurred in children at doses as
low as 15 mg/kg (Saraf et al., 1974).
7.2.2 Relevant animal data
No data available.
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
No data available.
7.5 Mutagenicity
No data available.
7.6 Interactions
Effect on imipramine itself:
potentiation due to reduced hepatic metabolism by: neuroleptic
drugs, methylphenidate, and certain steroids, including oral
contraceptives.
reduced effect due to enhanced hepatic metabolism by
barbiturates, certain other sedatives, and cigarette smoking.
Effect of imipramine on other substances:
potentiates the effect of alcohol and probably other CNS
depressants.
potentiates the anticholinergic effects of anticholinergic
drugs used in the treatment of Parkinson's disease.
potentiates the effect of biogenic amines, such as
norepinephrine, which are normally removed from their site of
action by neuronal reuptake.
blocks the effects of indirectly acting amines, such as
tyramine.
prevents the action of adrenergic neurone blocking agents such
as guanethidine.
potentiates central nervous stimulation by amphetamine but
blocks its peripheral effects.
A particularly severe interaction occurs with concurrent
administration of an MAO inhibitor and a tricyclic
antidepressant. The resultant syndrome can include severe CNS
toxicity, marked by hyperpyrexia, convulsions and coma
(Baldessarini, 1990).
7.7 Main adverse effects
Antimuscarinic effects include dry mouth, a sour or metallic
taste, epigastric distress, constipation, dizziness,
tachycardia, palpitations, blurred vision and urinary
retention. Paradoxically, excessive sweating. Weakness and
fatigue. Older patients suffer more from dizziness, postural
hypotension, constipation, delayed micturition, oedema, and
muscle tremors. In approximately 10% of treated patients and
in over 30% of patients over age 50, manic reactions,
confusion, or delirium may occur. Extrapyramidal reactions are
rare, though tremor is not unusual. A withdrawal syndrome, my
occur in children, who experience gastrointestinal symptoms.
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 Confirmation Test(s)
8.2.1.3 Simple Quantitative 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 Confirmation Test(s)
8.2.2.3 Simple Quantitative 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
Myoglobinuria occurs in patients with protracted
seizures.
8.3.1.3 Other fluids
No data available
8.3.2 Arterial blood gas analyses
Seizures may cause significant metabolic acidosis,
thereby unbound imipramine in the circulation and
contributing to the development of dysrhythmias. However
the thue clinical relevance of increases in "free"
imipramine is uncertain in th context of its very large
distribution. Even large displacements of imipramine
from plasma protein binding sites would have little
effect on the amount of "free" drug because of rapid
redistribution (Greenblatt et al., 1982).
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
Electrocardiogram changes are very important for
diagnosis of drug toxicity, prognosis and management.
ECG changes may occur at therapeutic doses within weeks
of beginning therapy. These may include increased heart
rate, increased PR-interval, and flattened T waves.
Occasionally, slight QRS- or QT-interval prolongation
may be seen. Little clinical significance can be
ascribed to these isolated ECG changes (Glassman, 1984).
Sinus tachycardia (>100 beats/min) is a sensitive
indicator for the anticholinergic effects of imipramine
but is an insensitive marker for the development of
serious toxicity. The most accurate predictor of
subsequent life-threatening complications is overt
prolongation of QRS duration and QT-interval. Syncope or
sudden death due to torsade de pointes ventricular
fibrillation is particularly associated with marked
prolongation of the QT-interval (QTc >450 ms).
Conduction delays commonly display a rightward axis
(Bessen et al., 1986) or a right bundle branch block
pattern (Nicotra et al., 1981; Biggs et al., 1977) and
may evolve into varying degrees of AV block. Other ECG
changes may include PR- and QRS-interval prolongation,
ST- T- wave abnormalities and QT-prolongation.
Isolated premature ventricular contractions,
supraventricular tachycardia, atrial fibrillation, or
nodal rhythms occur infrequently. Since ventricular
tachycardia and fibrillation can be exceptionally
difficult to control, any abnormal ventricular activity
should be viewed as significant in this setting (Nicotra
et al., 1981; Pentel & Sioris, 1981).
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
Monitor cardiac function to detect conduction abnormalities
and abnormallities of rhythm; monitor blood gases for
acidosis.
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Mild early symptoms and signs are predominantly
anticholinergic, and may include mydryasis, blurred
vision, dry mouth, tachycardia, hyperpyrexia, urinary
retention, decreased intestinal activity, and CNS
excitation.
More serious features may include convulsions, coma,
hypotension, arrhythmias, and cardiorespiratory arrest
(Frommer et al., 1987).
The progression from being alert with mild symptoms to
life-threatening toxic effects may be extremely rapid
(Herson et al., 1979).
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 available.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
No data available.
9.2.2 Inhalation
No relevant.
9.2.3 Skin exposure
Not relevant.
9.2.4 Eye contact
Not relevant.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
9.3 Course, prognosis, cause of death
The progression from being alert with mild symptoms to life-
threatening toxic effects may be rapid (Herson et al.1979).
The most accurate predictor of subsequent life-threatening
ventricular arrhythmias is marked QT-prolongation.
Hypotension precede cardiac arrest (Callaham & Kassel, 1985).
The cause of death is cardiovascular toxicity with intractable
myocardial depression, ventricular tachycardia, or ventricular
fibrillation. Malignant ventricular arrhythmias have occured
without prior sinus tachycardia (Crome & Newman, 1979).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
There are four specific effects on the cardiovascular
system:
(i) an anticholinergic (atropine-like) effect leading
to sinus tachycardia.
(ii) block of norepinephrine reuptake in adrenergic
neurons, increases serum and cardiac concentrations of
this catecholamine, which contributes to sinus
tachycardia and to the hypertension that may occur
occasionally after an overdose.
(iii) a quinidine-like action resulting in
myocardial depression and impairment of cardiac
conduction.
(iv) a blockade of -adrenegic discharge at postsynaptic
sympathetic neurons leading to vasodilation and
resulting in hypotension. (Marshall & Forker, 1982;
Walsh, 1986; Rosen, 1983).
Sinus tachycardia (>100 beats/min) is a sensitive
indicator of an anticholinergic effect but an
insensitive indicator for development of serious
toxicity. The most accurate predictor of subsequent life-
threatening complications is the QT-duration (QTc>450
ms).
Conduction delays commonly manifest as a rightward axis
(Bessen et al., 1985) or a right bundle branch block
(Nicotra et al., 1981; Biggs et al., 1977) and may
evolve into varying degrees of AV block. Further PR-
and QT-interval prolongation, and ST-T-wave
abnormalities may be observed.
Hypotension due to vasodilatation, central or peripheral
-receptor blockade, and cardiac depression is a serious
effect of imipramine overdose (Nicotra et al., 1981;
Pentel & Benowitz, 1986; Callaham, 1979).
At therapeutic levels ECG changes can be seen within
weeks of beginning therapy. These may include increased
heart rate increased PR interval, and flattened T waves
(Glassman, 1984).
Occasionally, slight QRS or QT-interval prolongation may
be seen during therapeutic dosing. Little clinical
significance can be attributed to this isolated ECG
changes, and each is reversible with discontinuation of
therapy (Glassman, 1984).
9.4.2 Respiratory
Hyperventilation due to acidosis has been reported
(Sunderajan et al., 1985)
9.4.3 Neurological
9.4.3.1 CNS
Confusion, agitation, hallucinations, coma,
myoclonus, and seizures are common features
(Noble & Matthew, 1969; Crome, 1982).
If hypoxic encephalopathy does not occur, about
one third of comatose patients will awake within
12 hours, and two thirds within 24 hours
(Thorstrand, 1976).
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
The effects on the function of the autonomic
nervous system are believed to result from
inhibition of norepinephrine transport into
adrenergic nerve terminals and from antagonism
of muscarinic cholinergic and 1-adrenergic
responses to autonomic neurotransmitters.
Blurred vision, dry mouth, constipation, and
urinary retention are due to anticholinergic
activity.
9.4.3.4 Skeletal and smooth muscle
Rhabdomyolysis may occur due to protracted
seizures.
9.4.4 Gastrointestinal
Large does of imipramine may be absorbed more slowly due
to delayed gastric emptying and reduced peristalsis.
9.4.5 Hepatic
Jaundice has been observed infrequently in overdose with
tricyclic antidepressants (Baldessarini, 1990).
Hepatic failure associated with imipramine therapy has
been reported (Shaefer et al., 1990).
9.4.6 Urinary
9.4.6.1 Renal
Acute renal failure may be associated with
rhabdomyolysis due to protracted seizures.
9.4.6.2 Other
Urinary retention due to antimuscarinic activity
of imipramine.
9.4.7 Endocrine and reproductive systems
Delay of orgasm and orgasmic impotence have been
described in men and women (Baldessarini 1990)
9.4.8 Dermatological
Rash (Baldessarini, 1990) and alopecia areata-like
lesions may occur (Baral & Deakins, 1987).
A slate-grey hyperpigmentation has been reported after
long-term treatment with imipramine (Hashimoto et al.,
1991).
9.4.9 Eye, ear, nose, throat: local effects
No data available.
9.4.10 Haematological
Agranulocytosis has been reported as a toxic effect
(Baldessarini, 1990).
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
The majority of overdose patients exhibit
either metabolic acidosis or combined
respiratory and metabolic acidosis. A pure
respiratory acidosis or alkalosis occurs less
often (Ellenhorn and Barceloux, 1984).
9.4.12.2 Fluid and electrolyte disturbances
No data available.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
No data available.
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Regardless of their clinical condition, every patient with a
history of significant imipramine ingestion, or having
symptoms, signs, or ECG changes consistent with imipramine
poisoning, should be admitted in an intensive care
department, with immediate monitoring (for 24 hours) of
ventilation and circulation.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
10.2.2 Biomedical analysis
Determination of acid-base balance is important to
control metabolic acidosis.
10.2.3 Toxicological analysis
10.2.4 Other investigations
Not relevant
10.3 Life supportive procedures and symptomatic/specific
treatment
Ventilation and cardiac monitoring, and stabilizing vital
signs. Patients with no symptoms or signs of toxic reactions
to imipramine should be monitored for a minimum of six hours
(Callaham, 1982).
Patients with continued evidence of tachycardia, conduction
abnormalities, or other symptoms of toxicity should be
monitired for at least 24 hours (Callaham & Kassel, 1985;
Pentel & Sioris, 1981; Goldberg et al., 1985)
Norepinephrine may be preferred to reverse hypotension
because of its predominant - stimulating effect. The use of
dopamine may be less effective in combination with
alkalinization.
If cardiac arrest occurs, external cardiac massage should be
continued for a long time. A case of full recovery with
five hours of external cardiac massage following tricyclic
antidepressant poisoning has been reported (Orr & Bramble,
1981).
To prevent or minimize seizure activity diazepam in
combination with a longer-acting anticonvulsant, such as
phenytoin, should be considered, provided the seizures are
not provoked by cardiac arrhythmias causing cerebral
hypoxia.
In the treatment of prolonged QRS complex (>100
milliseconds) alkalinization has been reported to be
effective in narrowing QRS complexes, correcting hypotension,
and controlling arrhythmias (Hoffman & McAlroy, 1981;
Molloy et al., 1984). In experimental animals ventricular
arrythmias have been reversed by alkalinizing above pH
>7.45 (Nattel et al., 1984) but this is hardly attainable
in patients. The beneficial therapeutic effects may be due
to the blood pH and/or change in plasma sodium concentration
(Hoffman & McAlroy, 1981).
As an initial therapy of polymorph ventricular tachycardias
the recommended therapy may be:
1. magnesium chloride i.v. (Tzivoni et al.1984)
2. overdrive pacing of the ventricle or atrium
3. in anticipation of pacing: isoproterenol i.v. (provoke
an overdrive suppression and QT-narrowing).
Lidocaine and phenytoin are no longer recommended, although
they can be useful when no altenative is available.
Bretylium tosylate has prominent anti-fibrillatory
properties, but it blocks sympathetic ganglion activity,
resulting in hypotension. Bretylium also causes a QT-
prolongation and may intensify the effect of imipramine. It
therefore seems to be contraindicated.
Procainamide, dysopyramide, and quinidine are
contraindicated because their membrane-stabilizing effects
synergistically enhance tricyclic antidepressant toxicity
(Ellenhorn & Barceloux, 1984), and may promote ventricular
arrhythmies due to QT-prolongation.
The use of atropine sulphate to improve conduction through
the AV-node is ineffective since AV-conduction disturbances
in antidepressant overdose are largely distal to the AV-node
(Bigger et al., 1978).
Beta-blockers such as propranolol have been reported to
narrow QRS-complexes and convert ventricular tachycardia to
sinus rhythm (Roberts et al., 1973). However intravenous
administration of propranolol may exacerbate hypotension and
increase the risk of cardiac arrest (Freeman et al., 1973).
10.4 Decontamination
Consider gastric lavage, even 24 hours after ingestion is
indicated, because gastric emptying may be delayed.
Activated charcoal plus a cathartic is indicated in every
patient with a history of significant imipramine ingestion
or having symptoms, signs, or ECG changes. Administration
should be repeated to interrupt enterohepatic recirculation
(Swarz & Sherman, 1984).
Syrup of ipecac should be avoided since decreased mental
status or seizures may occur abruptly, increasing the risk
of aspiration (Frommer et al., 1987).
10.5 Elimination
Since only a small amount of total imipramine body burden is
in the serum, enhancing elimination from the vascular
compartment by haemoperfusion or other extracorporeal
methods may not be effective. Amberlite XAD-4 resin columns
effectively remove tricyclic antidepressants from plasma but
a rebound increase in blood concentration is common (Heath
et al., 1982).
10.6 Antidote treatment
10.6.1 Adults
The anticholinergic effects of imipramine, such as
the extrapyramidal effects, myoclonus and perhaps
coma, can be reversed by physostigmine (Burks et al.,
1974). However, this may be associated with serious
complications, including bradycardia, asystole and
death, have been reported (Pentel & Peterson, 1981).
Furthermore, life-threatening cardiotoxicity is not
due to anticholinergic activity.
10.6.2 Children
No data available.
10.7 Management discussion
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
11.2 Internally extracted data on cases
11.3 Internal cases
12. Additional information
12.1 Availability of antidotes
12.2 Specific preventive measures
Must include limiting the issue of nonrefillable
prescriptions; encouraging safe packaging; and limiting
access to medication by promoting safe storage of drugs in
the home (Frommer et al.1987).
12.3 Other
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author: Dr A.N.P. van Heijst
Baarnse weg 42A
3735 MJ Bosch en Duin
Netherlands
Tel: (31) 30 287178
Date: 17-06-1992
Aknowledgment to Prof. Dr E.O. Robles de Medina (cardiologist) of
the State University Hospital in Utrecht (The Netherlands) for
his important contributions to all the cardiological aspects in
this monograph.
Reviewer: Dr T.J. Meredith
Department of Health
Hannibal House
Elephant and Castle
London SE1 6TE
United Kingdom
Tel: (44) 71 9722449
Fax: (44) 71 7039565
Peer Review: 10 September 1992 - London, United Kingdom
Drs Van Heijst, Meredith, Borges, Danel, Jouglard,
Sener, Merad, Karzazi