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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 23C 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   20.52.0  
       1984 
       Ciraulo et al.,   8   50    72   19.65.5  6.51.3 
       1982
       Gram et al.,      7  40-60  48    9.92.3  1.2     11.5
       1976
       Nagy & Johansson, 5   75    24    7.65.6  3.21.7 11.04.2
       1975
       Sutfin et al,     4   50    72    9.52.9  2.80.8 18.21.5
       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 43.64.6  21.22.0 0.80.1 21.02.1
       1984
       Abernethy et al.,14   12.5 42.03.0  16.51.3 0.80.1 18.11.9
       1985
       Brosen & Gram,        50            
       1988
       rapid metabol.    4        39.07.0  16.04.0 0.90.3 16.63.8
       slow metabol.     4        42.019.0 17.06.0 1.00.2 20.84.8
       poor metabol.     3        71.08.0  18.06.0 0.90.2 18.61.0
       DESIMIPRAMINE                 
       Brosen & Gram,        50            
       1988
       rapid metabol.    4        56.04.0  21.03.0 0.80.1 22.44.1
       slow metabol.     4        73.012.0 22.03.0 0.80.1 20.23.8
       poor metabol.     3        86.013.0 125.03  0.2     25.68.6
                                                  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



    See Also:
       Toxicological Abbreviations