T RICYCLIC A NTIDEPRESSANTS P OISONING

T RICYCLIC A NTIDEPRESSANTS Amitriptyline Amoxapine Clomipramine Desipramine Dothiepin Doxepin Imipramine Lofepramine Nortriptyline Protriptyline Trimipramine

T RICYCLIC A NTIDEPRESSANTS TCAs are one of the most common causes of death from poisoning In developed countries, accounting for 20-25% of fatal drug poisoning in the United Kingdom and United States. Deaths normally occur outside of hospital The ingestion of mg/kg or more of a TCA is potentially fatal

T RICYCLIC A NTIDEPRESSANTS MECHANISM Blocking reuptake of noradrenaline and serotonin These effects are probably unimportant in overdose except in combined overdose with selective serotonin reuptake inhibitors (SSRIs)

T RICYCLIC A NTIDEPRESSANTS MECHANISM the drugs are pharmacologically "dirty" and bind to many other receptors:  including histamine(H1 & H2) ( sedation)  Alpha 1 & 2 (vasodilatation)  GABA-A (seizures )  muscarinic receptors ( anticholinergic effects )

T RICYCLIC A NTIDEPRESSANTS MECHANISM The drugs block sodium and other membrane ion channels. The influx of sodium is the major event responsible for the zero phase of depolarisation in cardiac muscle and Purkinje fibres.

Phase 0 Phase 1 Phase 2 Phase 3 Phase 4 Na + ca ++ ATPase mv Cardiac Action Potential Resting membrane Potential Na + m h K+K+ ca ++ K+K+ K+K+ K+K+ (Plateau Phase) K+K+ K+K+ K+K+ Na + K+K+ Depolarization

T RICYCLIC A NTIDEPRESSANTS MECHANISM The duration of phase 0 in the heart as a whole is measured indirectly as the duration of the QRS complex on the ECG. Thus, blockade of the Na+ channel can be indirectly measured by estimating QRS width.

T RICYCLIC A NTIDEPRESSANTS MECHANISM TCAs block voltage gated Na+ channels in a use dependent manner (i.e. block increases with heart rate). As the degree of Na+ channel block increases with use, the QRS width will increase with increasing heart rates.

T RICYCLIC A NTIDEPRESSANTS MECHANISM Other cardiac channel effects include reversible inhibition of the outward potassium channels responsible for repolarisation giving a mechanism for QT prolongation and arrhythmia generation TCAs demonstrate a dose dependent direct depressant effect on myocardial contractility that is independent of impaired conduction  alter mitochondrial function and uncouple oxidative phosphorylation

T RICYCLIC A NTIDEPRESSANTS KINETICS Highly lipid soluble weak bases Rapidly absorbed  Anticholinergic effects may prolong absorption High volume of distribution Death and toxicity mainly before redistribution (toxic compartment) (heart, brain) ) Protein binding > 95% May saturate increasing free fraction pH dependent  Toxicity increase with acidosis  Prolonged clinical course  Alkalinisation causes significant decrease in the percentage of free amitriptyline; with a drop of 20% when pH rises from and 42% over a pH range of P 450 Hepatic metabolism Saturable: long elimination half life Active metabolites

T RICYCLIC A NTIDEPRESSANTS ‍ CLINICAL EFFECTS Symptoms and signs at presentation depend upon the dose and the time since ingestion. Patients who are asymptomatic at three hours post ingestion of normal release medication do not normally develop major toxicity

T RICYCLIC A NTIDEPRESSANTS ‍ CLINICAL EFFECTS In acute TCA overdose there a three major toxic syndromes. These are  Anticholinergic effects  Cardiac toxicity  CNS toxicity (sedation and seizures ) Death in TCA overdose is usually due to CNS and cardiotoxic effects.

A NTICHOLINERGIC S YNDROME Anticholinergic Syndrome: Hot as hell Blind as a bat Dry as a bone Mad as a hatter  (Thus, it is often useful to ask patients when they regain consciousness whether they're hearing or seeing anything strange and reassure them that this is a drug effect) A sensitive indicator for ingestion, but poor predictor for toxicity. Full syndrome is rare

‍ C ARDIAC EFFECTS There is a wide spectrum of toxic effects ranging from trivial to life threatening. Non-specific ST or T wave changes Prolongation of QT interval Prolongation of PR interval Prolongation of QRS interval Right bundle branch block Right axis deviation Atrioventricular block Brugada wave (ST elevation in V1-V3 and right bundle branch block)

‍ C ARDIAC EFFECTS

P REDICTING M AJOR C OMPLICATION QRS > 100 milliseconds or more in a limb lead is as good as TCA concentration Ventricular arrhythmia Sensitivity 0.79 (95% CI ) Specificity 0.46 (95% CI ) Seizures Sensitivity 0.69 (95% CI ) Specificity 0.69 (95% CI ) Bailey et al J Tox ClinTox 2004 R aVR > 3 mm Sensitivity 0.81 R/S aVR > 0.7 Sensitivity 0.75

‍ C ARDIAC EFFECTS Arrhythmias The most common arrhythmia is sinus tachycardia which is due to anticholinergic activity and/or inhibition of norepinephrine uptake by tricyclic antidepressants. Hypotension : The blood pressure may be elevated in the early stages after overdose, presumably due to the inhibition of norepinephrine uptake. hypovolaemia, decreased peripheral resistance due to alpha-adrenergic blockade impaired myocardial contractility and cardiac output

‍ C ENTRAL NERVOUS SYSTEM EFFECTS Patients will often have a rapid onset of decreasing level of consciousness and coma because of a very rapid absorption of the drug Patients should be assessed on admission to see if they are hyperreflexic or have myoclonic jerks or any evidence of seizure activity A number of TCAs (dothiepin, desipramine, and amoxapine) cause seizures more frequently. Thus, they may cause seizure at lower drug ingestions Convulsions may lead to haemodynamic compromise.

‍ TREATMENT ‍ Supportive  ABC  ECG monitoring ‍ GI Decontamination  If patients are alert and co-operative and have ingested < 5 mg/kg, charcoal may be administered orally  If the patient is unconscious and requires intubation to protect the airway insert an orogastric tube, aspirate stomach contents then give activated charcoal

‍ T REATMENT OF SPECIFIC COMPLICATIONS Seizures  diazepam 5-20 mg IV  phenobarbitone mg/kg IV  Phenytoin should be avoided ( sodium-channel blocking) Anticholinergic delirium  Mild delirium can often be managed with reassurance plus or minus benzodiazepines  neuroleptics should be avoided (most of which have significant anticholinergic activity)

B ICARBONATE Both sodium loading and alkalinisation have been show to be effective in reversing TCA induced conduction defects and hypotension Sodium bicarbonate is the drug of choice for the treatment of ventricular dysrhythmias and/or hypotension due to TCA poisoning

IFE decreased mortality from clomipramine toxicity by 80% when compared to placebo. Yoav G, Odelia G, Shaltiel C. A lipid emulsion reduces mortality from clomipramine overdose in rats. Vet Hum Toxicol 2002; 44(1):30 ) EKG Case reports  4 h later in case of suspected amitriptyline intoxication.  IFE decreased the frequency of recurrent ventricular arrhythmia in a case of suspected imipramine overdose Intravenous Lipid emulsions A new antidote

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