Antidepressants Poisoning TCAs, SSRIs, MAOIs

2. AntidepressantsPoisoningTCAs, SSRIs, MAOIs Dr K.Naseri Pharm D, PhD of Pharmacology

3. Tricyclic AntidepressantsPoisoning

4. Tricyclic Antidepressants • Amitriptyline • Amoxapine • Bupropion • Clomipramine • Desipramine • Dothiepin • Doxepin • Imipramine • Lofepramine • Maprotiline • Mirtazapine • Nefazodone • Nortriptyline • Protriptyline • Trazodone • Trimipramine • Venlafaxine

5. Tricyclic Antidepressants • 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

6. Toxic Dose • For all TCAs except desipramine, nortriptyline,trimipramine, and protriptyline, this dose is >5 mg/kg. • Despiramine , Nortriptyline, trimipramine>2.5 mg/kg • Protriptyline>1 mg/kg.

7. Tricyclic Antidepressants • Narrow therapeutic index • Therapeutic plasma Conc.< 300ng/ml • Toxic plasma Conc.> 1000ng/ml • Toxic Dose ≤10times of therapeutic dose • 1gr Amitriptyline was fatal in 1year child • 1.5gr Desipramine was fatal in 4years old child.

8. Tricyclic Antidepressantsmechanism • Blocking reuptake of noradrenaline and serotonin • These effects are probably unimportant in overdose except in combined overdose with selective serotonin reuptake inhibitors (SSRIs)

9. Tricyclic Antidepressantsmechanism • The drugs are pharmacologically "dirty" and bind to many other receptors: • including histamine(H1 & H2) ( sedation) • Alpha 1 & 2 (vasodilatation, iBP) • GABA-A (seizures ) • muscarinic receptors (anticholinergic effects )

10. TCA Toxicity In overdose, the tricyclics produce rapid onset (within 1-2 hours) of: • Sedation and coma • Seizures • Hypotension • Tachycardia, midriasis • Broad complex dysrhythmias • Anticholinergic syndrome

11. Tricyclic Antidepressantsmechanism • The drugs block sodiumand 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.

12. 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. • Prolongation of the QRS is a reflection of TCA tissue concentrations and is predictive of both seizures and cardiac arrhythmias.

13. Tricyclic Antidepressantsmechanism • Other cardiac channel effects include reversible inhibition of the outward K+ 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

14. Tricyclic AntidepressantsKINETICS • 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 7.0-7.4 and 42% over a pH range of 7.4-7.8. • P450 Hepatic metabolism • Saturable: long elimination half life • Active metabolites

15. Tricyclic Antidepressants‍CLINICAL EFFECTS • Symptoms and signs 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

16. Tricyclic Antidepressants‍CLINICAL EFFECTS • In acute TCA overdose there are 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.

17. Anticholinergic Syndrome • Anticholinergic Syndrome: • Hot as hell • Blind as a bat • Red as a beet • 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 sensitiveindicator for ingestion, but poor predictor for toxicity. • Full syndrome is rare

18. ‍Cardiac 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 • Atrioventricular block • Brugada wave (ST elevation in V1-V3 and right bundle branch block)

19. ‍Cardiac effects

20. Predicting Major Complication • QRS > 100 milliseconds or more in a limb lead is as good as TCA concentration • Ventricular arrhythmia • Seizures • R aVR > 3 mm • R/S aVR > 0.7

21. ‍Cardiac effects • ArrhythmiasThe 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

22. ‍Central nervous system effects • Low consciousness and coma because of a very rapid absorption of the drug • Hyperreflexicor have myoclonic jerks or any evidence of seizure activity • A number of TCAs (dothiepin, desipramine, maprotiline, bupropion and amoxapine) cause seizures more frequently. Thus, they may cause seizure at lower drug ingestions

23. ‍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

24. ‍TREATMENT • IV fluids (control BP) • Acidosis control with sodium bicarbonate (hypotensive patients, wide QRS, metabolic acidosisa dysrrhythmia) • NaHCO3: drug of choice for the treatment of ventricular dysrhythmias and/or hypotension due to TCA poisoning

25. ‍Treatment of specific complications Seizures Contraindication: • Diazepam 5-20 mg IV: 1mg/min(.01-0.2mg/kg) • Phenobarbitone 15-18 mg/kg IV • Succinylcholine chloride 10-20mg IV slowly and maintain adequate oxygenation/ventilation) • Phenytoin should be avoided ( sodium-channel blocking) • Kinidine • Procainamide • Disopyramide • Propranolol • Atropine • Physostigmine • Flumazenil (hseizure risk) • Ipecac

26. IntravenousLipid emulsions A new antidote • 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

27. Serotonin Re-Uptake Inhibitors

28. SSRIs • Citalopram • Fluoxetine • Fluvoxamine • Paroxetine • Serteraline

29. Serotonin Syndrome • Excessive serotonergic tone 5HT1A, 5HT2 • Continuum of neuropsychiatric manifestations Serotonin

30. Serotonin Syndrome: Major Criteria* • Confusion • Elevated mood • Coma • Fever • Diaphoresis • Chills • Rigidity • Hyperreflexia • Myclonus • Tremor 4 major, or 3 major and 2 minor Birmes P CMAJ 2003;168:1439-1442

31. Minor Criteria: Serotonin Syndrome • Agitation • Nervousness • Insomnia • Tachypnea • Dyspnea • Tachycardia • High or low BP • Akathisia • Incoordination • Mydriasis • Diarrhea 4 major, or 3 major and 2 minor Birmes P CMAJ 2003;168:1439-1442

32. Fatal Serotonin Syndrome • Abrupt onset • Autonomic instability • Hyperthermia, diaphoresis • Neuromuscular rigidity, movement disorder • Altered mental status • Absence of a neuroleptic or other cause

33. Serotonin Syndrome • Most often iatrogenic • Resolution in 48-96 hours • Death from uncontrolled hyperthermia

34. Serotonin Syndrome: Therapeutic Goals • Rapid identification of Hyperthermia • Continuous core temperature monitoring, aggressive cooling, benzodiazepines for sedation • Rule out other potential etiologies

35. Serotonin Syndrome • Identification of serotonergic factors, particularly the presence of monoamine oxidase inhibitors • ?Role of serotonin antagonists (cyproheptadine 0.1mg/kg, max 0.25mg/kg/d)

36. Drugs Implicated in Serotonin Syndrome • MAO-Inhibitors • SSRIs • Clomipramine • Venlafaxine • Lithium • MDMA* • L-Tryptophan* • Meperidine* • Dextromethorphan* • Cocaine*

37. Citalopram • SSRI with toxic metabolite • In overdose can prolong QRS, QTc, • Seizures • Delay in onset Catalano G. Clin Neuropharmacol 2001;24:158-62

38. Citalopram Overdose • Immediate cardiac monitoring for QTc, IV lines • Assess and correct electrolytes, especially K+, Ca2+, Mg2+ • Decontamination • Use of Mg2+ for torsade • Admission of minimum 24 hours of cardiac monitoring

39. Mono Amine Oxides InhibitorsMAOIs Tranylcypromine (parnate) Phenelzine (nardil) Isocarboxazide Selegiline (MAO –B inhibitor) moclobemide

40. Kinetics • MAOIs are orally absorbed well • peak plasma conc. within 2-3 hours. • large volume of distribution (1-5 L/kg) • highly protein bound. • They are metabolized by oxidation and acetylation in the liver • excreted in the urine.

41. MAOI toxicity MAOI poisoning is classified into the following 3 subtypes: • Actual poisoning from an overdose is uncommon. Symptoms of intentional overdose may be delayed up to 32 hours post ingestion (hmorbidity) • Drug-food interaction is so-called tyramine reaction or cheese reaction. • rapid in onset(15-90 min after ingestion). • Most symptoms resolve in 6 hours • Drug-drug interaction

42. symptoms and signs • The symptoms and signs of all 3 categories are quite similar and represent the effects of excessive catecholamine neurotransmitters. • MAOIs inhibit breakdown of the neurotransmitters norepinephrine, dopamine, and serotonin, resulting in • hypertension • tachycardia • tremors • seizures • hyperthermia

43. Prehospital Care Prehospital care for MAOI toxicity may include the following: • Stabilization of vital signs - IV fluids • Treatment of seizure activity - Benzodiazepines • Attention to airway maintenance • Attention to temperature control

44. Emergency Department Care • Decontamination • Because of the potential for severe toxicity and lack of antidotes, an aggressive decontamination is very important. • Consider gastric lavage, particularly in patients with recent ingestion (within an hour). • Administer charcoal • Because of its pharmacokinetics, extracorporeal removal, such as hemodialysis or repeat dosed of activated charcoal, is likely less effective to reduce its level. • Control hyperthermic, rapidly (within 20-30 min)

45. Emergency Department Care • Fluid therapy (control dehydration from hyperthermia). • Treating the associated hypertension is usually not necessary. • It may actually be dangerous because of the eventual hypotensive phase (avoid beta-blockers because they leave unopposed alpha-stimulation), which may exacerbate the clinical picture. • If deemed necessary, use of a short-acting antihypertensive agent, such as nitroprusside, nitroglycerine or phentolamine, is advisable. • IV benzodiazepines (useful for agitation and seizure control; they also may help control the hypertension).

47. Ferrous poisoining

48. Arsenic poisoning