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POISONING with ANTIDEPRESSANTS and DEPRIVATION (1999-2003) • Monoamine Oxidase Inhibitors

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POISONING with ANTIDEPRESSANTS and DEPRIVATION (1999-2003) • Monoamine Oxidase Inhibitors ADMISSION EPISODES TO POISONS TREATMENT POISONING WITH UNIT, CARDIFF 1997 ANTIDEPRESSANTS SIMPLE AND NARCOTIC ANALGESICS 57% HYPNOTICS/ANXIOLYTICS 33% ANTIDEPRESSANTS 22% NEUROLEPTIC DRUGS 7% ANTI-INFLAMMATORY DRUGS 6% Philip A Routledge Dept Pharmacology, Therapeutics and Toxicology 0 200 400 600 800 1000 Wales College of Medicine Number of admission episodes Cardiff University WALES, UK WHY ARE ANTIDEPRESSANTS MORTALITY FOR ANTIDEPRESSANT STILL USED? POISONING BY ENGLISH STRATEGIC HEALTH AUTHORITY, 2000-2003 • Depression is common • The morbidity and mortality is high • Non-drug treatments are often unsatisfactory Morgan O et al. Health Statistics Quarterly 2005; 27: 6-12 MORTALITY FOR ANTIDEPRESSANT POISONING POISONING WITH ANTIDEPRESSANTS AND DEPRIVATION (1999-2003) • Monoamine Oxidase Inhibitors • Tricyclic Antidepressants (TCAs) • Selective Serotonin Reuptake Inhibitors (SSRIs) • Others Morgan O et al. Health Statistics Quarterly 2005; 27: 6-12 1 MONOAMINE OXIDASE ENZYMES MONOAMINE OXIDASE (MAOs) INHIBITORS (MAOIs) Dopamine Phenylephrine Tyramine Serotonin (5HT) Norepinephrine Norepinephrine Tyramine • First generation MAOIs Dopamine – Phenelzine (Nardil) Phenylephrine – Tranylcypromine Tyramine – Isocarboxazid MAOI -A MAOI-B • Reversible inhibitors (RIMAs) – Moclobemide (Manerix) MAOI FIRST GENERATION MONOAMINE REVERSIBLE INHIBITORS OF OXIDASE INHIBITORS (MAOIs) RIMA MONOAMINE OXIDASE A (RIMAs) Dopamine Dopamine Phenylephrine Phenylephrine Tyramine Serotonin Serotonin (5HT) (5HT) Norepinephrine Norepinephrine Norepinephrine Norepinephrine Tyramine Phenylephrine Tyramine Tyramine Dopamine Dopamine Phenylephrine MAOI RIMA MAOI MAOI -A MAOI-B MAOI -A MAOI-B MONOAMINE OXIDASE INHIBITOR MONOAMINE OXIDASE INHIBITORS (MAOI) POISONING (MAOIs) • Clinical Features of poisoning (2) • Clinical Features of poisoning (1) – Often latent period 6-12 hours , prolonged features – Increased muscle tone, hypereflexia, myoclonus, pupillary dilatation – Agitation, restlessness, – Hyperpyrexia, rhabdomyolysis, acute renal failure – hallucinations, convulsions – Tachycardia, Hypertension, – Increased motor movements, nystagmus profuse sweating 2 MONOAMINE OXIDASE INHIBITORS (MAOIs) MOCLOBEMIDE • Management • Selective & reversible inhibitor of MOA type A (RIMA) • deaths have been reported in mixed overdoses involving – Gastric decontamination (when appropriate) moclobemide • Fatal serotonin syndrome has occurred after overdoses of moclobemide taken with other serotonergic agents, – Full supportive therapy (e.g. paroxetine, venlafaxine, citalopram or clomipramine) • In one study 55% of patients co-ingesting moclobemide with a serotonergic agent developed serotonin toxicity – Cooling measures, diazepam and dantrolene (Isbister et al, 2003) • Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done on all – Beta blockers moclobemide self-poisonings (Downes et al 2005) • Continuous cardiac monitoring can be considered in patients with a QTc > 500 ms or with known risks for QT – Paralysis and ventilation prolongation Isbister GK et al. Br J Clin Pharmacol. 2003; 56: 441-50 TOXBASE Downes MA et al. Intern Med J. 2005; 35: 388-91 POISONING WITH ANTIDEPRESSANTS POISONING WITH ANTIDEPRESSANTS • Monoamine oxidase inhibitors • Tricyclic antidepressants (TCAs) • Tricyclic antidepressants (TCAs) – Dosulepin [Dothiepin] (Prothiaden) – Amitryptiline (Tryptizol) Number of – Lofepramine (Gamanil) prescriptions • Selective serotonin Reuptake – Trazodone (Molipaxin) (South Inhibitors (SSRIs) – Clomipramine (Anafranil) Glamorgan 1995-1997) – Imipramine (Tofranil) • Others – Mianserin (Bolvidon) TRICYCLIC ANTIDEPRESSANT TRICYCLIC ANTIDEPRESSANT POISONING POISONING • Clinical Features (Mild-moderate) • Clinical Features (Severe) – Dry Mouth – Coma – Dilated pupils – Respiratory depression – Sinus tachycardia – Convulsions – Urinary retention – Hypotension – Drowsiness – Electrocardiographic changes – Hypereflexia – Arrhythmias 3 TRICYCLIC ANTIDEPRESSANT TRICYCLIC ANTIDEPRESSANT POISONING POISONING • Electrocardiographic changes Conscious Unconscious – Prolonged PR, QRS and QT intervals (corrected QTc) Pts.(%) Pts.(%) – Right axis deviation of the terminal 40 ms vector of the QRS complex in the frontal plane (T 40 ms axis) Strabismus 18 81 – Brugada pattern (down-sloping ST segment elevation in Urine retention 18 65 leads V1-V3 in association with right bundle branch block) Convulsions 1 10 – Non-specific ST segment and T wave changes – Atrioventricular block Pulse100-120 37 68 – Supraventricular and ventricular arrhythmias pulse>120 8 13 – “QRS duration >100 ms and a rightward T 40 ms axis predictors of cardiovascular toxicity but moderate Arrhythmias 0 12 sensitivity and specificity for predicting complications CNS toxicity 10 35 Thanacoody HK and Thomas SH. Tricyclic antidepressant poisoning : cardiovascular toxicity. Toxicol Rev. 2005; 24: 205-14 Drug induced Brugada ECG pattern TRICYCLIC ANTIDEPRESSANT Left anterior fascicular block POISONING and incomplete right bundle branch block. Apart from the saddle back ST segment • MANAGEMENT pattern without significant NHS Direct /NHS 24/Primary Care elevation in lead V2 (arrows), – Observation All children who have ingested this ST segment elevation or T tricyclic antidepressant should be wave abnormality is not seen reviewed by a physician in the right precordial leads – Supportive therapy Triangular (type I) Brugada ECG pattern after cibenzoline TOXBASE:The benefit of gastric (Type 1 antiarrhythmic agent). – Gut decontamination decontamination is uncertain J point elevation, descending ST elevation and negative T waves in lead V1 and V2 TOXBASE: Do not give flumazenil to – Specific therapy reverse benzodiazepine toxicity in Sarkozy A et al. Cibenzoline induced Brugada ECG pattern. Europace. 2005 ;7 :537-9. mixed overdoses. TRICYCLIC ANTIDEPRESSANT POISONING TRICYCLIC ANTIDEPRESSANT POISONING • Treatment – Gut decontamination 27 patients – Benefit gastric decontamination uncertain – Consider activated charcoal (50 g for adults) by 14 had TCA level > 1mg/l mouth or n.g. tube if patient presents within 1 hour of ingestion of more than 5 mg/kg, provided airway can be protected 3 had cardiac arrest at early stage – Second dose of charcoal (50 g) should be Often during gastric emptying considered after 1-2 hours in patients with features of toxicity who are able to swallow, or who have been intubated Bramble MG et.al. Q J Med 1985: 56; 357-66 TOXBASE 4 MODIFIED RELEASE TCAs TRICYCLIC ANTIDEPRESSANT POISONING MOLIPAXIN CR 150mg Roussel MOLIPAXIN 9.8 mm 3.9 mm • Treatment – (Supportive ) ANAFRANIL SR 75 mg Geigy GEIGY G D 8.1 mm 4.3 mm • Treat hypotension LENTIZOL • Treat Convulsions 50 mg Warner ENTIZO 17.5 mm 6.0 mm 5.8 mm LENTIZ O’Connor N et al. Prolonged clinical effects in modified-release • Cardiopulmonary resuscitation amitriptyline poisoning. Clin Toxicol (Phila). 2006;44:77-80 TRICYCLIC ANTIDEPRESSANT TRICYCLIC ANTIDEPRESSANT POISONING POISONING • Treatment • Treatment – Treatment of hypotension – Therapy of Hypotension – Administer colloid or crystalloid solutions, guided by central – Correct hypotension by raising foot of bed venous pressure monitoring – In severe cases administration of colloid to expand – Give Sodium bicarbonate (NaHCO3). If hypotension persists despite intravascular volume required (central venous pressure adequate filling pressure and NaHCO3, give inotropic support monitoring may be required) – In non-randomised controlled trial in rats, epinephrine resulted in higher survival rate and superior to norepinephrine both when the – Alkalinisation with sodium bicarbonate may correct drugs were used alone or when epinephrine used in combination hypotension. with NaHCO3 – If severe hypotension persists despite above measures – NaHCO3 alone resulted in modest increase in survival rate but this and adequate filling pressures, consider use of increased markedly when NaHCO3 used with epinephrine or inotropes with pure α agonist activity such as norepinephrine norepinephrine (Tran 1999) – Clinical studies suggest benefit from norepinephrine and dopamine; in an uncontrolled study the former appeared more – Glucagon has been used to correct myocardial effective. Glucagon has also been of benefit depression and hypotension (Sener 1995; Sensky 1999) – Experimental studies suggest extracorporeal circulation membrane – Glucagon 10 mg IV bolus may be given if patients are oxygenation is of potential value severely hypotensive. Bradberry SM et al. Management of the cardiovascular complications of tricyclic TOXBASE antidepressant poisoning : role of sodium bicarbonate. Toxicol Rev. 2005; 24: 195-204 TRICYCLIC ANTIDEPRESSANT TRICYCLIC ANTIDEPRESSANT POISONING POISONING • Treatment • Treatment of Convulsions • Prophylactic anticonvulsants not shown to be effective • Control convulsions with iv diazepam or lorazepam Prolonged resuscitation was successful • Give oxygen and correct acid base /metabolic disturb. in a patient after cardiac arrest due to • Do not give flumazenil to reverse benzodiazepine toxicity in mixed overdoses imipramine poisoning • Phenytoin best avoided in tricyclic overdosage TOXBASE: After cardiac arrest, prolonged (like TCAs it blocks sodium channels and may increase resuscitation may be successful and should risk of cardiac arrhythmias) be continued for at least 1 hour Bateman DN. Tricyclic antidepressant poisoning: central nervous system effects and management. Toxicol Rev. 2005; 24: 181-6. TOXBASE Orr DA & Bramble MG. Br Med J. 1981; 283; 1107-8 5
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