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 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) • Inhibitors

• Antidepressants (TCAs)

• Selective Inhibitors (SSRIs)

• Others

Morgan O et al. Health Statistics Quarterly 2005; 27: 6-12

1 MONOAMINE OXIDASE ENZYMES MONOAMINE OXIDASE (MAOs)

INHIBITORS (MAOIs) Phenylephrine Serotonin (5HT)

Norepinephrine Tyramine

• First generation MAOIs Dopamine – (Nardil) Phenylephrine – Tyramine – MAOI -A MAOI-B • Reversible inhibitors (RIMAs) – Moclobemide (Manerix)

MAOI FIRST GENERATION MONOAMINE REVERSIBLE INHIBITORS OF OXIDASE INHIBITORS (MAOIs) RIMA (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, , – 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 has occurred after overdoses of moclobemide taken with other serotonergic agents, – Full supportive therapy (e.g. , , or ) • 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) – [Dothiepin] (Prothiaden) – Amitryptiline (Tryptizol) Number of – (Gamanil) prescriptions • Selective serotonin Reuptake – (Molipaxin) (South Inhibitors (SSRIs) – Clomipramine (Anafranil) Glamorgan 1995-1997) – (Tofranil) • Others – (Bolvidon)

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 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 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 TRICYCLIC ANTIDEPRESSANT TRICYCLIC ANTIDEPRESSANT POISONING POISONING • Treatment • Treatment – Therapy of Arrhythmias (1) – 12 lead ECG and assess QRS duration – Specific therapy – QRS duration of > 120 ms may indicate cardiotoxicity • Bicarbonate therapy – QRS duration of > 160 ms suggests severe cardiotoxicity with very high risk of • (Hyperventilation) arrhythmia – Seek urgent senior medical attention and • Antiarrhythmic therapy consider immediate administration of bicarbonate TOXBASE

TRICYCLIC ANTIDEPRESSANT TRICYCLIC ANTIDEPRESSANT • Treatment POISONING POISONING • Treatment – Therapy of Arrhythmias (2) – Correct metabolic acidosis using iv sodium bicarbonate – Therapy of Arrhythmias (3) (CAUTION: if given by a peripheral venous line, irritant to veins and can • Resist temptation to treat arrhythmias with drugs. cause skin necrosis in cases of extravasation) – 1.26% sodium bicarbonate alternative for patients who are Best treated by correction / acidosis haemodynamically stable • Magnesium sulphate and lidocaine may be used for – Even in absence of acidosis, consider alkalinisation with iv sodium VT/VF. bicarbonate (50 mL 8.4%) in patients with: - QRS duration > 120 msec • Class Ia (e.g. quinidine, disopyramide, - arrhythmias procainamide) and class Ic antiarrhythmic drugs - hypotension resistant to fluid resuscitation (e.g. flecainide, propafenone) contraindicated as - Further doses of sodium bicarbonate may be given cautiously depending on clinical response, to achieve arterial pH 7.5-7.55 they may worsen sodium channel blockade and (Hoffman et al 1993) but care needed as alkalosis to pH>7.65 is exacerbate arrhythmias. potentially fatal. (Wrenn 1992) • Class ii agents (beta-blockers) may also induce - Resist temptation to treat arrhythmias with drugs, best treated by correction of hypoxia and acidosis hypotension TOXBASE TOXBASE

TORSADES DE POINTES TRICYCLIC ANTIDEPRESSANT (TdeP) • Treatment POISONING – Therapy of Arrhythmias (4) – Prolongation of QRS and QTc may be associated with risk TdeP – TdeP may be treated with magnesium sulphate 8-10 mmol iv over 30-120 seconds, repeated twice at intervals of 5-15 minutes if necessary Torsades de Points Torsardes des Pontes – Hypoxia, electrolyte abnormalities and acid base disturbance should be corrected (NB These rapid infusion rates of magnesium (which are needed if the patient is having frequent or continuous torsade) usually cause Torsardes de Points Torsade de Pointes flushing) – Alternatively, or if these measures fail, TdeP may be abolished by Torsardes de Pointes Torsades de Point increasing underlying heart rate e.g. by atrial or ventricular pacing or by isoprenaline (isoproterenol) infusion to achieve heart rate 90- Torsades des Pointes Torsaad de Ponts 110 beats/minute – TdeP usually not helped by antiarrhythmic drugs. Those which Torsades des Points Torsades des Point prolong the QT interval (e.g. amiodarone, quinidine) make it worse (use only after specialist advice) TOXBASE

6 TRICYCLIC ANTIDEPRESSANT POISONING POISONING WITH ANTIDEPRESSANTS

• Treatment – Enhancement of Elimination? • Monoamine Oxidase Inhibitors – NO (sadly) – Forced diuresis, haemodialysis and haemoperfusion • Tricyclic Antidepressants (TCAs) of no value due to large volumes of distribution of TCAs – ANTIDOTES? • Selective Serotonin Reuptake Inhibitors – Extremely large amounts required and at present the (SSRIs) use of Fab fragments limited by cost and possibility of renal toxic effects • Others TOXBASE

SELECTIVE SEROTONIN SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) REUPTAKE INHIBITORS (SSRIs) • Clinical Features of poisoning (mild- moderate) • Clinical Features of poisoning (severe) – Often minimal – May be latent period – May be latent period, – GIT- severe nausea, , – GIT- nausea, vomiting, abdominal pain abdominal pain – CNS- Agitation, tremor, dizziness, – CNS- drowsiness, coma, convulsions sweating, – CVS- bradycardia, hypertension, – CVS- sinus tachycardia, hypertension junctional rhythm

TOXBASE TOXBASE

SELECTIVE SEROTONIN SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) REUPTAKE INHIBITORS (SSRIs)

• Treatment • Clinical Features of poisoning (severe) –Supportive therapy –SEROTONIN SYNDROME – has been reported following overdose of SSRIs alone or in combination with other –Gastric decontamination serotinergic drugs. • Alteration of mental status • Neuromuscular hyperactivity –Treat complications • Autonomic instability.

TOXBASE

7 SEROTONIN SYNDROME SEROTONIN SYNDROME • Alteration of mental status • TREATMENT (1) – Occur in 40% of patients and may range from agitation, • Monitor urea, electrolytes, and creatine kinase. confusion, delirium, and hallucinations to drowsiness Send urine for myoglobin analysis and coma • Commence intravenous fluids to correct • Neuromuscular features hypotension and to replace insensible fluid loss if – Occur in around 50% and include profound shivering, temperature raised tremor, teeth grinding, myoclonus and hyperreflexia • Fitting should be controlled with benzo’s such as • Autonomic instability diazepam. Myoclonic jerking said to be helped by clonazepam – occurs in around 50% and includes tachycardia, fever, hypertension / hypotension, flushing, diarrhoea and • In serious cases: propranolol may help reduce vomiting autonomic dysregulatory effects, but role controversial TOXBASE TOXBASE

SEROTONIN SYNDROME SEROTONIN SYNDROME • TREATMENT (2) • TREATMENT (3) • Cyproheptadine has been used • If the CK is raised or rhabdomyolysis suspected, • Cooled IV fluid to replace insensible losses and volume replacement and urine alkalinization may correct hyperthermia be helpful in preventing or reducing the severity • Tepid sponging and use of fans of rhabdomyolysis-induced renal failure • Dantrolene may be of benefit if above measure fail • Give volume replacement and 225 mmol of 8.4% to reduce temperature and evidence of muscle sodium bicarbonate over two hours to increase rigidity urine pH to >7 • If all measures fail consider paralysing and • Haemodialysis or haemofiltration may be ventilating patient for management of malignant required for acute renal failure or severe hyperthermia hyperkalaemia

TOXBASE TOXBASE

POISONING WITH ANTIDEPRESSANTS POISONING WITH ANTIDEPRESSANTS

• Monoamine oxidase inhibitors • Other antidepressants

• Tricyclic antidepressants (TCAs) – Venlafaxine (Efexor) – (Dutonin) • Selective serotonin Reuptake – (optimax) Inhibitors (SSRIs) – Mirtazipine (Zispin) – Citalopram • Other antidepressants

8 VENLAFAXINE CITALOPRAM • Nausea, vomiting, sweating, tachycardia, • Drowsiness, sinus tachycardia, hypotension or drowsiness, coma, dystonia, convulsions, hypertension, convulsions, sweating and dizziness hyperventilation and hyperpyrexia • Coma, prolongation of the QT and QRS duration and • Rarely features of the "serotonin syndrome" may ventricular arrhythmias occur in severe poisoning. • rise in plasma creatine kinase and rhabdomyolysis • Nodal rhythm, prolonged QT intervals and wide possible (Pascale et al. 2005) QRS complexes • Effects may be enhanced by simultaneous ingestion • “Prolonged bradycardia with severe hypotension of other drugs acting on monoamine mechanisms and syncope have been reported” (Rothenhausler [e.g. other antidepressants, monoamine oxidase et al 2000) inhibitors, (Adam-Manes et al. 2006) and ecstasy] • “Associated with QTc prolongation. Consider cardiac monitoring with large ingestions and • Risk of serotonin syndrome (alone or in combination) patients with associated cardiac disease” (Isbister et al 2004) Adam-Manes J et al. J Clin Pharm Ther. 2006; 31: 397-400 Pascale P et al. Ther Drug Monit. 2005; 27: 562-4. Rothenhausler HB et al. Pharmacopsychiatry 2000; 33: 150-152 Isbister GK et al. J Toxicol Clin Toxicol. 2004; 42: 277-85

DEATHS ASSOCIATED WITH POISONING WITH ANTIDEPRESSANTS ANTIDEPRESSANT POISONING 1989-1994 Bialas MC, Ryles C, Hutchings A, Scorer RC and Routledge PA • Monoamine Oxidase Inhibitors Trends in antidepressant poisoning 1989-1994. Clin Toxicol 35: 499 (1997)

• Tricyclic Antidepressants (TCAs) • Twenty-three deaths were recorded, 15 associated with dothiepin, 4 with amitryptyline, 2 with imipramine, 1 with amitryptyline and • Selective Serotonin Reuptake imipramine and 1 with Inhibitors (SSRIs) • All the deaths occurred before admission to the unit, indicating that preventive strategies • Others are more likely to have an impact on mortality than improvements in treatment.

“An ounce of prevention is worth a pound of cure.” Henry de Bracton c.1240

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