MONOGRAPH FOR UKPID AMITRIPTYLINE HYDROCHLORIDE HY Allen ZM Everitt AT Judd National Poisons Information Service (Leeds Centre) Leeds Poisons Information Centre Leeds General Infirmary Leeds LS1 3EX UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. MONOGRAPH FOR UKPID Drug name Amitriptyline hydrochloride. Chemical group Tricyclic antidepressant. Origin of substance Synthetic. Name UK Brand name(s) e.g. Lentizol(R), Tryptizol(R), Domical(R), Elavil(R). Also available in compound preparations with perphenazine as Triptafen(R) and Triptafen-M(R). Synonyms Common names/street names Pharmacotherapeutic group Drug acting upon CNS; antidepressant; tricyclic. Reference number Product licence Lentizol(R) 25 mg capsules: 0018/0173R Lentizol(R) 50 mg capsules: 0018/0174R Tryptizol(R) 10 mg tablets: 0025/0093 Tryptizol(R) 25 mg tablets: 0025/0094 Tryptizol(R) 50 mg tablets: 0025/0095 Tryptizol(R) injection: 0025/5036 Tryptizol(R) syrup: 0025/5037 Other CAS 549-18-8 Manufacturer of Lentizol(R) Name Parke-Davis Medical Address Lambert Court, Chestnut Avenue, Eastleigh, Hampshire SO53 3ZQ Telephone 01703 620500 Fax 01703 629812 of Tryptizol(R) Name Thomas Morson Pharmaceuticals (a subsidiary of Merck Sharp & Dohme Ltd) Address Hertford Road, Hoddesdon, Hertfordshire EN11 9BU Telephone 01992 467272 Fax 01992 451006 of Domical(R) Name Berk Pharmaceuticals (a subsidiary of Approved Prescription Services Ltd) Address Brampton Road, Hampden Park, Eastbourne, East Sussex BN22 9AG Telephone 01323 501111 Fax 01232 520306 of Elavil(R) Name DDSA Pharmaceuticals Ltd Address 310 Old Brompton Road, London SW5 9JQ Telephone 0171 373 7884 Fax 0171 370 4321 Supplier/importer In addition to the branded products listed above, non-proprietary products are available from Antigen, APS and Cox. Name Antigen Pharmaceuticals Ltd Address Antigen House, 82 Waterloo Rd, Hillside, Southport, Merseyside, PR8 4QW Telephone 01704 562777 Fax 01704 562888 Name APS (Approved Prescription Services Ltd) Address Brampton Road, Hampden Park, Eastbourne, East Sussex BN22 9AG Telephone 01323 501111 Fax 01323 520306 Name AH Cox & Co Ltd Address Whiddon Valley, Barnstaple, Devon EX32 8NS Telephone 01271 311257 Fax 01271 321326 Presentation Form Oral tablets, modified release capsules, and mixture. Injection for intramuscular or intravenous administration. Formulation details Tablets of 10 mg, 25 mg, and 50 mg. Modified release capsules of 25 mg and 50 mg. Mixture (as amitriptyline embonate) equivalent to 10mg/5ml. Injection of 10mg/ml. Pack size(s) Lentizol(R) 25 mg and 50 mg modified release capsules: blister packs of 56 or 100. Tryptizol(R) 10 mg tablets: blister packs of 30, 25 mg tablets: blister packs of 30, 50 mg tablets: blister packs of 30, mixture: bottle of 200 ml, injection: vials of 10 ml. Packaging Lentizol(R) 25 mg: pink capsules of 25 mg amitriptyline hydrochloride in a modified release form, marked 'LENTIZOL 25', Lentizol(R) 50 mg: pink/red capsules of 50 mg amitriptyline hydrochloride in a modified release form, marked 'LENTIZOL 50'. Tryptizol(R) 10 mg: blue tablets of 10 mg amitriptyline hydrochloride marked 'MSD23', Tryptizol(R) 25 mg: yellow tablets of 25 mg amitriptyline hydrochloride marked' MSD 45', Tryptizol(R) 50 mg: brown tablets of 50 mg amitriptyline hydrochloride marked 'MSD 102', Tryptizol(R) syrup: pink suspension of amitriptyline embonate equivalent to 10 mg/5 ml amitriptyline, Tryptizol(R) injection: colourless solution for injection containing 10mg/ml amitriptyline hydrochloride. Compound preparations Triptafen(R): pink tablets of 25 mg amitriptyline hydrochloride and 2 mg perphenazine. Triptafen-M(R): pink tablets of 10 mg amitriptyline hydrochloride and 2 mg perphenazine. Amitriptyline is also available in generic and branded-generic formulations, the appearance of which will differ from the branded products listed. Physico-chemical properties Solubility in water Freely soluble (Martindale 1996). Solubility in ether Practically insoluble (Martindale 1996). Solubility in other solvents Freely soluble in alcohol, chloroform, methyl alcohol and methylene chloride (Martindale 1996). Chemical structure 3-(10,11-Dihydro- 5H-dibenz-[ a,d]cyclohepten-5- ylidene)propyldimethylamine hydrochoride C20H23N,HCl = 313.9 Uses Indication Symptomatic treatment of depressive illness especially where sedation is required. Nocturnal enuresis in children. Therapeutic dosage in adults In depression by mouth: 75-150 mg daily in single or divided doses (lower doses in elderly and adolescents). by IM or IV injection: 10-20 mg four times daily. in children For nocturnal enuresis: 6-10 years: 10-20 mg daily by mouth. 11-16 years: 25-50 mg daily by mouth. Modified release preparations are not licensed for use in children. Contra-indications Recent myocardial infarction or coronary artery insufficiency. Heart block or other cardiac arrhythmia. Mania. Severe liver disease. Co-administration with monoamine oxidase inhibitors. Hypersensitivity to amitriptyline. Lactation. Children under 6 years of age. Abuses Pharmacokinetics Absorption Amitriptyline is well absorbed orally with maximum plasma concentrations being reached after approximately 3 hours (Schulz et al. 1985). It undergoes extensive first-pass metabolism, the systemic bioavailability being in the region of 45%(Schulz et al. 1985). Little information is available on the disposition of amitriptyline following parenteral administration. Distribution Amitriptyline is widely distributed throughout the body with an apparent volume of distribution of about 19 L/kg (Schulz et al. 1985). Approximately 95% of amitriptyline in the plasma is bound to proteins (Schulz et al. 1985). The plasma protein binding of tricyclic antidepressants is pH sensitive, with a small reduction in plasma pH being associated with large increases in unbound (pharmacologically active) drug (Nyberg & Martensson 1984). Metabolism There is wide individual variation in the pharmacokinetic profile of amitriptyline. Amitriptyline is metabolised in the liver, the primary routes of metabolism being demethylation, hydroxylation and conjugation. It is considered that the metabolic pathways are mediated by the enzymes CYP2D6 and CYP2C19, although other enzymes are probably also involved (Schmider et al. 1995). The major active metabolites formed are nortriptyline, 10-hydroxyamitriptyline, and 10-hydroxynortriptyline. Both nortriptyline and 10-hydroxynortriptyline contribute significantly to the antidepressant effect (Bertilsson et al. 1979). Elimination Amitriptyline is excreted mainly in the urine as conjugated and unconjugated metabolites. Less than 5% is excreted as unchanged drug (Dollery 1991). Significant gastric and biliary secretion of amitriptyline and its metabolites occurs, resulting in enteroenteric and enterohepatic circulations (Gard et al. 1973). Dialysis as a means of promoting drug and metabolite elimination is ineffective (Dawling et al. 1982). Half-life substance Amitriptyline: 21 hours (range 13-36 hours)(Schulz et al. 1985). metabolite(s) Nortriptyline: 25 hours (Dawling et al. 1982). 10-hydroxynortriptyline: 26 hours (Dawling et al. 1982). Special populations Elderly: metabolic changes in the elderly result in higher plasma amitriptyline concentrations than in younger populations (Schmider et al. 1995). Renal impairment: reduced metabolite clearance in renal impairment results in accumulation, particularly of the hydroxymetabolites (Dawling et al. 1982). Hepatic impairment: reduced metabolic capacity in liver impairment results in accumulation of amitriptyline (Hrdina et al. 1985). Gender: there is some evidence to suggest that higher plasma concentrations of amitriptyline occur in females over the age of 50 than in males of a similar age, but factors other than gender complicate the picture (Preskorn & Mac 1985, Schmider et al. 1995). Breast milk Amitriptyline and its metabolites are secreted into breast milk. In one patient the amounts of amitriptyline and nortriptyline in the breast milk and serum were approximately equal (Bader & Newman 1980). In a second patient the concentrations of amitriptyline, nortriptyline and 10-hydroxynortriptyline in breast milk were about 50%, 75%, and 70% of the maternal serum concentrations respectively (Breyer-Pfaff et al. 1995). The doses to the infants in these two cases are approximately 3% and 1% of the maternal doses respectively. Toxicokinetics Absorption In a study of 27 tricyclic overdose patients, peak plasma concentrations occurred within 3 hours of the overdose (Bramble et al. 1985). There was no evidence of prolonged absorption from the gut following amitriptyline overdose in 9 patients (Hulten et al. 1992). Distribution Amitriptyline is rapidly distributed into body tissues with plasma drug concentrations beginning to fall within 3 hours of overdose (Bramble et al. 1985). The value for protein binding remains within the range observed with therapeutic doses and is likewise pH sensitive (Hulten et al. 1992). Metabolism A comparison of half-life values for amitriptyline following overdose with values after therapeutic dosing suggests that saturation of metabolic process may occur. Insufficient data are available to draw firm conclusions. Elimination There is evidence to show that enterohepatic or enteroenteral circulation of the metabolite nortriptyline occurs (Hulten et al. 1992). Less than 5% of a dose is excreted in urine during the first 24 hours after overdose (Gard et al. 1973). Half-life substance Following overdose, half-life values between 15 hours and 81 hours have been reported (Hulten et al. 1992, Spiker & Biggs 1976). metabolite(s) Special populations Breast milk Adverse effects Antimuscarinic effects, sedation, ECG changes, arrhythmias, postural hypotension, tachycardia, syncope, sweating, tremor, rashes, hypersensitivity reactions, behavioral disturbances, hypomania or mania, confusion, interference with sexual function, blood sugar changes, weight gain, convulsions, movement disorders and dyskinesias, fever, hepatic and haematological reactions. Interactions Pharmacodynamic a) A potentially hazardous interaction may occur between a tricyclic antidepressant and a monoamine oxidase inhibitor (including moclobemide and selegiline) resulting in increased amounts of noradrenaline and serotonin at the synapse. Coma, hyperthermia, convulsions, delirium, or death may result (White & Simpson 1984). b) There is an increased risk of cardiotoxicity when administered with other drugs which prolong the QT interval e.g. anti-arrhythmics, astemizole, halofantrine, terfenadine. c) The pharmacology of amitriptyline suggests that concomitant ingestions of selective serotonin reuptake inhibitors, phenothiazines, sympathomimetics, or other tricyclic antidepressants will enhance its toxicity. Pharmacokinetic a) The metabolism of tricyclic antidepressants is inhibited by most selective serotonin reuptake inhibitors resulting in elevated tricyclic plasma concentrations. Fluoxetine, fluvoxamine, and paroxetine appear to exert a greater effect than sertraline. Limited data suggest that citalopram does not inhibit tricyclic metabolism (Baettig et al. 1993, Taylor 1995). b) As the metabolism of amitriptyline is mediated by cytochrome P450 microsomal enzymes, particularly CYP2D6 and CYP2C19, the potential exists for interactions with drugs which are substrates of these pathways. c) Cimetidine reduces the metabolic clearance of amitriptyline by inhibition of liver enzymes, resulting in higher plasma amitriptyline concentrations (Stockley 1996). Ethanol Plasma concentrations of amitriptyline are higher when ingested with ethanol, probably as a result of reduced first-pass metabolism (Shoaf & Linnoila 1991). Summary Type of product A tricyclic antidepressant. Ingredients Amitriptyline tablets: 10 mg, 25 mg, 50 mg. Amitriptyline in a modified release capsule: 25 mg, 50 mg. Amitriptyline mixture: equivalent to 10mg/5ml. Amitriptyline injection: 10mg/ml. Summary of toxicity Patients with only mild signs of toxicity may rapidly develop life- threatening complications. Where major toxic events occur these usually develop within 6 hours of overdose, the risk of toxicity being greatest 2-4 hours after ingestion. Amitriptyline overdose must be managed on a clinical basis rather than on the amount ingested, but as a guide, doses of 750 mg in adults have been associated with severe toxicity. Ingestions of tricyclic antidepressants in children indicate that doses of 15 mg/kg may prove fatal to a child, although recovery has followed reported ingestions of over 100 mg/kg. Sinus tachycardia, hypotension, and anticholinergic symptoms are common features. Cardiotoxicity, impaired consciousness, seizures, acidosis, and respiratory insufficiency are associated with severe toxicity. The occurrence of seizures may precipitate the onset of cardiac arrhythmias and hypotension. Delirium may be a complication on recovery. Common features Dry mouth, blurred vision, dilated pupils, urinary retention, sinus tachycardia, drowsiness, hypothermia, and confusion. Hypoxia, acidosis, hypotension, convulsions, cardiac arrhythmias, and coma. Uncommon features Skin blisters, rhabdomyolysis, disseminated intravascular coagulation, adult respiratory distress syndrome, and absent brain stem reflexes. Summary of management SUPPORTIVE 1. Maintain a clear airway and adequate ventilation if consciousness is impaired. 2. If within 1 hour of the ingestion and more than 300 mg has been taken by an adult or more than 1mg/kg by a child, give activated charcoal. 3. Carry out arterial blood gas analysis, and correct any acidosis and hypoxia. 4. Monitor the cardiac rhythm and blood pressure. 5. Single, brief convulsions do not require treatment but if they are prolonged or recurrent, they should be controlled with intravenous diazepam. 6. Other measures as indicated by the patient's clinical condition. Epidemiology Over an 11 year period between 1975 and 1985, more than 1,200 deaths were attributable to amitriptyline poisoning in the UK, or 47 deaths per million prescriptions dispensed (Montgomery et al. 1989). Fatalities tend to occur in older rather than younger patients. In both fatal and non-fatal overdose, there are a greater number of ingestions in females than in males (Crome 1986). The overall incidence of serious cardiac complications in patients who are admitted to hospital following tricyclic overdose is reported to be less than 10%. Some degree of coma occurs in about 50% of cases, but is only unresponsive to painful stimuli in about 10-15% of cases (Crome 1986). Convulsions occur in approximately 6% of patients (Taboulet 1995). The death rate in patients admitted to hospital is estimated to be 2%-3% (Dziukas & Vohra 1991). Mechanism of action/toxicity Mechanism of action The precise mechanism of antidepressant action is unclear, but results from the potent inhibition of noradrenaline and serotonin reuptake into presynaptic neurones, and adaptive changes in receptor sensitivity (Richelson 1994). Amitriptyline inhibits the reuptake of noradrenaline and serotonin with similar potency, whilst the metabolite nortriptyline inhibits the reuptake of noradrenaline to a greater degree than serotonin. The hydroxy metabolites of amitriptyline and nortriptyline inhibit noradrenaline reuptake, but to a lesser degree than the parent drugs. They do not have any significant effect on serotonin reuptake (Bertilsson et al. 1979). Amitriptyline is a potent antagonist of both peripheral and central muscarinic cholinergic receptors. It has also relatively potent antagonist activity at H1 histamine and a1 adrenergic receptors. These antagonist actions account for its anticholinergic, sedative, and hypotensive properties (Richelson 1994). Mechanism of toxicity Toxicity is due to depression of myocardial function (a quinidine-like effect), central and peripheral muscarininic receptor blockade, a1 adrenergic receptor blockade, and respiratory insufficiency. The risk of toxicity is greatest 2-4 hours after ingestion when plasma levels are maximal. Features of poisoning Acute Ingestion Mild to moderate toxicity: dilated pupils, sinus tachycardia, drowsiness, dry mouth, blurred vision, urinary retention, absent bowel sounds, confusion, agitation, body temperature disturbances, twitching, delirium, hallucinations, nystagmus, and ataxia. Increased tone and hyperreflexia may be present with extensor plantar responses (Callaham 1979, Crome 1986, Dziukias & Vohra 1991). Severe toxicity: coma, hypotension, convulsions, supraventricular and ventricular arrhythmias, hypoxia, metabolic/respiratory acidosis, and cardiac arrest (Crome 1986, Dziukias & Vohra 1991). ECG changes (in the usual order of appearance) include non-specific ST or T wave changes, prolongation of the QT, PR, and QRS intervals, right bundle branch block, and atrioventricular block. The terminal 0.04 second frontal plane QRS axis often shows a right axis deviation (Dziukas & Vohra 1991). Delayed features: adult respiratory distress syndrome (Varnell et al. 1989). Uncommon features: skin blisters, rhabdomyolysis, disseminated intravascular coagulation, gaze paralysis, and absent brain reflexes (Dziukias & Vohra 1991, White 1988, Yang & Dantzker 1991). See case report 1. Inhalation Dermal Ocular Other routes Chronic Ingestion Inhalation Dermal Ocular Other routes At risk groups Elderly There is an increased risk of toxicity resulting from impaired drug metabolism (Schmider et al. 1995). Pregnancy There is relatively wide experience with the therapeutic use of amitriptyline during pregnancy. Although a few birth defects have been reported, the number is insufficient to support an association with amitriptyline administration (Briggs 1994). Children Ingestions in children result in features similar to those following adult ingestion (Crome & Braithwaite 1978, Goel & Shanks 1974, James & Kearns 1995). See case report 2. Enzyme deficiencies The metabolism of amitriptyline is in part mediated by the microsomal enzymes CYP2D6 and CYP2C19 which are subject to genetic polymorphism (Schmider et al. 1995). Metabolic processes will differ in individuals deficient in these enzymes and there is a risk of amitriptyline accumulation. Enzyme induced The metabolism of amitriptyline is increased in the presence of enzyme inducing drugs, but is of doubtful clinical relevance as the metabolites formed also have pharmacological activity. Others Renal impairment: increased risk of toxicity due to accumulation of metabolites. Hepatic impairment: increased risk of toxicity due to impaired amitriptyline metabolism. Cardiac disease: increased risk of cardiotoxicity due to underlying disease. Epilepsy: increased risk of seizures. Management Decontamination In cases where more than 300 mg has been taken by an adult or more than 1mg/kg by a child, activated charcoal should be given to reduce the absorption if administered within one hour of the drug ingestion. Adult dose; 50 g, child dose; 1 g/kg. If the patient is drowsy this should be administered via a nasogastric tube, and if there is no gag reflex present, using a cuffed endotracheal tube to protect the airway. Supportive care General Clear and maintain the airway, and give cardiopulmonary resuscitation where necessary. Evaluate the patient's condition and provide support for vital functions. Management of the symptomatic patient 1. Administer intravenous sodium bicarbonate to correct any acidosis. Adult dose: 50 ml of 8.4%sodium bicarbonate by slow intravenous injection; child dose: 1 ml/kg of 8.4% sodium bicarbonate by slow intravenous injection. Subsequent bicarbonate therapy should be guided by arterial blood pH which should be monitored frequently. 2. Maintain adequate ventilation to prevent hypoxia with supplemental oxygen or artificial ventilation as appropriate. 3. Carefully maintain plasma potassium levels to prevent hypokalaemia. In mixed overdoses where a benzodiazepine has also been ingested, the use of the competitive benzodiazepine antagonist flumazenil is contraindicated (Mordel et al. 1992). Where symptoms develop following mild to moderate overdose, they may persist for 24 hours. Prolonged or delayed complications following severe toxicity may require the patient to be hospitalised for several days. Specific Management of cardiotoxicity. GENERAL NOTE: in practice it is seldom necessary or advisable to use specific drug treatment for arrhythmias. If hypoxia and acidosis are reversed and adequate serum potassium levels maintained, then the majority of patients show improvement with supportive measures. SINUS and SUPRAVENTRICULAR TACHYCARDIAS: no specific treatment required (Pimentel & Trommer 1994). VENTRICULAR ARRHYTHMIAS: give sodium bicarbonate (even in the absence of acidosis) before considering antiarrhythmic drug therapy. Where an antiarrhythmic is considered necessary, lignocaine is the preferred drug (Pimentel & Trommer 1994). ADULT DOSE: 50-100 mg given by IV bolus over a few minutes, followed by an intravenous infusion of 4 mg/minute for 30 minutes, 2 mg/minute for 2 hours, then 1 mg/minute (BNF 1998). The use of quinidine, disopyramide, procainamide, and flecainide are all contra-indicated as they depress cardiac conduction and contractility. The use of beta-blockers should also be avoided as they decrease cardiac output and exacerbate hypotension. The efficacy of other antiarrhythmic agents (e.g bretylium, amiodarone, calcium channel blockers) has not been studied in tricyclic antidepressant poisoning (Pimentel & Trommer 1994). BRADYARRHYTHMIAS and HEART BLOCK: cardiac pacing may have only limited success as the cardiotoxicity of amitriptyline results from depression of contractility rather than failure of cardiac pacemakers. CARDIAC ARREST: manage in the standard manner but with continuing resuscitative measures as some patients have recovered after receiving several hours of external cardiac massage (Orr & Bramble 1981). Management of coma Good supportive care is essential. Management of hypotension Hypotension should be managed by the administration of intravenous fluids and by physical means. The majority of patients ingesting amitriptyline have otherwise healthy cardiovascular systems and providing cardiac output is good it is unnecessary to use specific drug therapy. If there is evidence of poor cardiac output (after correction of acidosis, hypovolaemia, and hypoxia) then the use of a vasoactive agent may need to be considered. Noradrenaline has been shown to be helpful in a number of studies (including cases where dopamine therapy has failed) (Pimentel & Trommer 1994, Teba et al. 1988, Yang & Dantzker 1991). ADULT DOSE: IV infusion of noradrenaline acid tartrate 80 micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute adjusted according to response (BNF 1998). CHILD DOSE (unlicensed indication): IV infusion of noradrenaline acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1 microgram/kg/minute of noradrenaline base) in glucose 5% or glucose/saline via a central venous catheter (Guy's, Lewisham & St Thomas Paediatric Formulary, 1997). Management of seizures Administer intravenous diazepam to control frequent or prolonged convulsions. ADULT DOSE: 10 mg, CHILD DOSE: 0.25-0.4 mg/kg, Both by slow IV injection preferably in emulsion form. Where seizure activity proves difficult to manage, paralyse and ventilate the patient. Continue to monitor the cerebral function to ensure the cessation of seizure activity. Other management Catheterisation may be required to relieve distressing urinary retention and to allow continuous monitoring of urine output as a means of assessing cardiac output (Crome 1986). Respiratory complications should be managed conventionally with early respiratory support. Control delirium with oral diazepam. Large doses may be required (20- 30 mg two-hourly in adults). Monitoring Monitor the cardiac rhythm, arterial blood gases, serum electrolytes, blood pressure, respiratory rate and depth, and urinary output. Observe for a minimum of 6 hours post-ingestion where: i) more than 1 mg/kg has been ingested by a child, ii) more than 300 mg has been ingested by an adult, iii) the patient is symptomatic. Antidotes None available. Elimination techniques Due to the large volume of distribution and high lipid solubility of amitriptyline, haemodialysis and haemoperfusion do not significantly increase drug elimination (Lieberman et al. 1985). Investigations Following severe toxicity: i) a chest X-ray will be needed to exclude pulmonary complications, ii) measure serum creatine kinase and other skeletal muscle enzyme activity (e.g. AST, ALT, and lactic dehydrogenase), iii) assess renal function, iv) assess haematological status. Management controversies Gastric lavage is not recommended as the procedure may be associated with significant morbidity, and there is no evidence that it is of any greater benefit than activated charcoal used alone (Bosse et al. 1995). If the procedure is used (i.e. in cases where activated charcoal cannot be administered), a cuffed endotracheal tube should be used to protect the airway if the patient is drowsy, and activated charcoal left in the stomach following the lavage. Repeat doses of oral activated charcoal may prevent the reabsorption of tricyclic antidepressants and their metabolites secreted in gastric juices and bile (Swartz & Sherman 1984). However, it would not be expected from the large volume of distribution of amitriptyline that clinically significant increases in body clearance would result. Physostigmine salicylate is a short acting reversible cholinesterase inhibitor which has been used historically in the management of tricyclic overdoses to reverse coma and antimuscarinic effects. Reports of serious complications from its use include severe cholinergic activity, convulsions, bradycardia, and asystole (Newton 1975, Pentel & Peterson 1980). The use of physostigmine is no longer recommended. The use of dopamine in the management of hypotension has been advocated, but the pressor effect of this indirect acting inotrope may be diminished in tricyclic overdosed patients due to depleted levels of noradrenaline (Buchman et al. 1990, Pimentel & Trommer 1994, Teba et al. 1988). The use of intravenous glucagon has been proposed in cases where hypotension is unresponsive to volume expansion and sodium bicarbonate administration, because of its positive inotropic effect and possible antiarrhythmic property. Its place in therapy has not been established (Senner et al. 1995). Adult dose: 10 mg by IV bolus followed by an infusion of 10 mg over 6 hours (unlicensed indication and dose). There are a number of reports of severe arrhythmias or sudden death occurring up to 1 week after tricyclic overdose, but a review of the cases show that the patients had continuing toxicity, underlying disease, or abnormalities (Stern et al. 1985). See case report 3. Several predictors of clinical severity in tricyclic overdoses have been suggested, including: 1. a maximal limb-lead QRS duration of 0.1 second or longer as a predictor of the risk of seizure (Boehnert & Lovejoy 1985), 2. a maximal limb-lead QRS duration of 0.16 second or longer as a predictor of the risk of ventricular arrhythmias (Boehnert & Lovejoy 1985), 3. plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart 1991), 4. the ECG terminal 40-ms frontal plane QRS axis of more than 120° (Wolfe et al. 1989). 5. plasma drug concentrations in excess of 2 mg/L as a predictor of the development of lung injury (Roy et al. 1989). Whilst none of these features in isolation are predictive of life-threatening toxicity, they may be helpful in assessing patient risk. Case data Case report 1 Massive ingestion of amitriptyline in an adult. A 46 year old woman took an estimated 9 g of amitriptyline. One hour later she suffered a grand mal seizure. Diazepam, phenobarbitone and physostigmine were administered. Her blood pressure was 98/66 mm Hg, and the pulse was 94 beats per minute. Arterial blood gas values showed a pH of 7.16, PaCO2 of 31 mm Hg, and PaO2 of 373 mm Hg on 100 percent oxygen. The ECG revealed a widened QRS complex of 160 ms. She had metabolic acidosis and an anion gap of 24. Dopamine and adrenaline were given to maintain blood pressure. At this time the woman was transferred to intensive care facilities as she failed to respond to pressor therapy. She was comatose with no response to painful stimuli, without spontaneous respiration, and corneal and oculocephalic reflexes were absent. The serum amitriptyline level was 2.35 mg/L. Her blood pressure remained low (75/50) despite an infusion of 30 micrograms/kg/min of dopamine, but rose to 130/70 when noradrenaline was substituted for dopamine. Spontaneous respiration returned after 24 hours, and during the next 3 days corneal, pupillary, and oculocephalic reflexes also returned. The patient regained full consciousness five days after the ingestion (Yang & Dantzker 1991). Case report 2 Ingestion of 1.15 g amitriptyline in a young child. A 20-month-old girl reportedly ingested 23 tablets of amitriptyline 50 mg. She was cyanotic, comatose, and had continuous clonic-tonic seizures. Her rectal temperature was 34.7°C, the heart rate was 115 beats/min, and her blood pressure was 59/27 mm Hg. The ECG tracing was consistent with ventricular tachycardia. After extensive resuscitative measures, including mechanical ventilation, the girl recovered and was discharged home one week later (Beal & May 1989). Case Report 3 Unexpected death 7 days after overdose in adult. A 34 year old woman was admitted to hospital following an intentional overdose of amitriptyline and diazepam. She was comatose, had a sinus tachycardia, nonspecific ST and T wave changes, and was normotensive. Her electrolyte levels were normal except for a potassium value of 3.3 mmmol/L. During 44 hours of monitoring no arrhythmias occurred and her mental status returned to normal. On the second day her usual hydrochlorothiazide diuretic therapy was restarted, the potassium level being 4 mmmol/L at this time. Five days after admission her potassium level was 3.2 mmmol/L. Seven days after recovery from overdose the patient was found unresponsive and in refractory ventricular fibrillation. Venous blood samples during unsuccessful resuscitative efforts showed a potassium level of 2.6 mmmol/L. Post-mortem plasma amitriptyline and nortriptyline levels were both 0.2 mg/L. An autopsy did not reveal an anatomic cause of death (Babb & Dunlop 1985). Analysis Agent/toxin/metabolite There is no clear relationship between plasma amitriptyline concentration and clinical response or toxicity. Consequently the measurement of plasma drug concentration following overdose is not routinely advised, although it may have diagnostic value. Sample container Storage conditions Transport Interpretation of data There is considerable variation in plasma concentrations of amitriptyline and its metabolites between individuals. As a guide, a therapeutic range for amitriptyline of 0.15-0.25 mg/L has been proposed, whilst moderate to severe toxicity is associated with combined amitriptyline and nortriptyline concentrations of 1 mg/L or greater (Bramble et al. 1985, Preskorn & Mac 1985). Conversion factors 1 mg/L = 3.186 micromoles/L 1 micromole/L = 0.314 mg/L Other The molecular weight of amitriptyline hydrochloride is 313.9 Other toxicological data Carcinogenicity Tumour-inducing effects have not been reported (Dollery 1991). Reprotoxicity Teratogenicity There are occasional reports suggesting an association between amitriptyline and congenital abnormalities (particularly limb reductions), but analysis of over 500,000 births failed to confirm such an association. A surveillance study between 1985 and 1992 involving over 200,000 completed pregnancies exposed to amitriptyline (of which 467 were during the first trimester) observed 25 major birth defects (20 expected in a control population). These data do not support an association between amitriptyline and congenital defects (Briggs 1994). Relevant animal data There is evidence of amitriptyline-induced teratogenicity in some animals. Encephaloceles and bent tails in hamsters, and skeletal malformations in rats have been reported (Briggs 1994). Relevant in vitro data Authors HY Allen ZM Everitt AT Judd National Poisons Information Service (Leeds Centre) Leeds Poisons Information Centre Leeds General Infirmary Leeds LS1 3EX UK This monograph was produced by the staff of the Leeds Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review was undertaken by the Directors of the UK National Poisons Information Service. Prepared September 1996 Updated May 1998 References Babb SV, Dunlop SR. Case report of sudden and unexpected death after tricyclic overdose (letter). Am J Psychiatry 1985; 142: 275-276. Bader TF, Newman K. Amitriptyline in human breast milk and the nursing infant's serum. Am J Psychiatry 1980; 137: 855-856. Baettig D, Bondolfi G, Montaldi S, Amey M, Baumann P. 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