tricyclic antidepressants poisoning
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DESCRIPTIONTricyclic Antidepressants Poisoning. Dr M.Moshiri MD & PhD Student of toxicology of Medical university of Mashhad; Iran. Tricyclic Antidepressants. Amitriptyline Amoxapine Clomipramine Desipramine Dothiepin Doxepin Imipramine Lofepramine Nortriptyline Protriptyline - PowerPoint PPT Presentation
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 15-20 mg/kg or more of a TCA is potentially fatal
TRICYCLIC ANTIDEPRESSANTSMECHANISMBlocking reuptake of noradrenaline and serotonin
These effects are probably unimportant in overdose except in combined overdose with selective serotonin reuptake inhibitors (SSRIs)
TRICYCLIC ANTIDEPRESSANTSMECHANISMthe 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 )
TRICYCLIC ANTIDEPRESSANTSMECHANISMThe 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 1Phase 2Phase 3
Phase 4Na+ca++ATPase mvCardiac Action PotentialResting membrane Potential
TRICYCLIC ANTIDEPRESSANTSMECHANISM 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.
TRICYCLIC ANTIDEPRESSANTSMECHANISMTCAs 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.
TRICYCLIC ANTIDEPRESSANTSMECHANISMOther 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
TRICYCLIC ANTIDEPRESSANTSKINETICSHighly lipid soluble weak basesRapidly absorbedAnticholinergic effects may prolong absorptionHigh volume of distributionDeath and toxicity mainly before redistribution (toxic compartment) (heart, brain) )Protein binding > 95%May saturate increasing free fractionpH dependent Toxicity increase with acidosis Prolonged clinical courseAlkalinisation causes significant decrease in the percentage of free amitriptyline; with a drop of 20% when pH rises from 7.0-7.4 and 42% over a pH range of 7.4-7.8.P450 Hepatic metabolismSaturable: long elimination half lifeActive metabolites
TRICYCLIC ANTIDEPRESSANTSCLINICAL EFFECTSSymptoms 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
TRICYCLIC ANTIDEPRESSANTSCLINICAL EFFECTSIn acute TCA overdose there a three major toxic syndromes. These areAnticholinergic effectsCardiac toxicityCNS toxicity (sedation and seizures)
Death in TCA overdose is usually due to CNS and cardiotoxic effects.
ANTICHOLINERGIC SYNDROMEAnticholinergic Syndrome:Hot as hellBlind as a batDry as a boneMad 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
There is a wide spectrum of toxic effects ranging from trivial to life threatening.Non-specific ST or T wave changesProlongation of QT intervalProlongation of PR intervalProlongation of QRS intervalRight bundle branch blockRight axis deviationAtrioventricular blockBrugada wave (ST elevation in V1-V3 and right bundle branch block)
PREDICTING MAJOR COMPLICATIONQRS > 100 milliseconds or more in a limb lead is as good as TCA concentrationVentricular arrhythmiaSensitivity 0.79 (95% CI 0.58- 0.91)Specificity 0.46 (95% CI 0.35- 0.59)SeizuresSensitivity 0.69 (95% CI 0.57- 0.78)Specificity 0.69 (95% CI 0.58- 0.78) Bailey et al J Tox ClinTox 2004R aVR > 3 mm Sensitivity 0.81R/S aVR > 0.7 Sensitivity 0.75
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 blockadeimpaired myocardial contractility and cardiac output
CENTRAL NERVOUS SYSTEM EFFECTSPatients will often have a rapid onset of decreasing level of consciousness and coma because of a very rapid absorption of the drugPatients should be assessed on admission to see if they are hyperreflexic or have myoclonic jerks or any evidence of seizure activityA 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.
TREATMENTSupportiveABC ECG monitoringGI Decontamination If patients are alert and co-operative and have ingested > 5 mg/kg, charcoal may be administered orallyIf the patient is unconscious and requires intubation to protect the airway insert an orogastric tube, aspirate stomach contents then give activated charcoal
TREATMENT OF SPECIFIC COMPLICATIONS
Seizuresdiazepam 5-20 mg IV phenobarbitone 15-18 mg/kg IVPhenytoin should be avoided ( sodium-channel blocking)Anticholinergic deliriumMild delirium can often be managed with reassurance plus or minus benzodiazepinesneuroleptics should be avoided (most of which have significant anticholinergic activity)
BICARBONATE 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 reports4 h later in case of suspected amitriptyline intoxication.
IFE decreased the frequency of recurrent ventricular arrhythmia in a case of suspected imipramine overdoseIntravenous Lipid emulsions A new antidote
Thus, blockade of the Na+ channel can be indirectly measured by estimating QRS width. Prolongation of the QRS is a reflection of TCA tissue concentrations and is predictive of both seizures and cardiac arrhythmias. *Thus, blockade of the Na+ channel can be indirectly measured by estimating QRS width. Prolongation of the QRS is a reflection of TCA tissue concentrations and is predictive of both seizures and cardiac arrhythmias. *Thus, blockade of the Na+ channel can be indirectly measured by estimating QRS width. Prolongation of the QRS is a reflection of TCA tissue concentrations and is predictive of both seizures and cardiac arrhythmias. *The drugs are highly lipid soluble and therefore rapidly absorbed. Peak drug levels occur early and this is the reason why most deaths occur outside of hospital. Because of the anticholinergic side effects associated with initial high levels patients may have delayed emptying of unabsorbed tablets from the stomach, which can cause late deterioration.
Approximately 95% of the drugs is bound to protein leaving 5% of the drug to be free to bind to receptors in tissues and to be metabolised. This protein binding is extremely sensitive to changes in the pH. A changed in the pH from 7.38 to 7.5 reduces the amount of free (unbound) tricyclic antidepressants by 21%. The classic anticholinergic syndrome is described as below:-
Hot as hellBlind as a batRed as a beetDry as a boneMad as a hatter
Patients may have:-
Elevated BP, red dry skin, dilated pupils, bowel sounds, urinary retention, delirium and convulsion
It can occur with any anticholinergic drugs e.g. cogentin, anticholinergic plants e.g. datura, as well as antihistamines, antidepressant drugs and antipsychotic drugs.The most accurate predictor for cardiac and CNS toxicity is a QRS duration of 100 milliseconds or more in a limb lead. This is due to TCA's quinidine like effect in binding to the fast sodium channels of the cardiac cell wall.
This decreases the rapid transit of sodium into the cell which is normally responsible for the zero phase of depolarisation which correlates with the duration of the QRS complex on the ECG. With increasing obstruction of sodium movement into the cell takes longer to depolarise and the QRS widens.
There may be an increase in the PR interval and dimpling of the T-waves.
VENTRICULAR TACHYCARDIAThe combination of tachycardia and increasing QRS width will lead to broad complex tachycardias, often ventricular tachycardias, but on some occasions supraventricular.