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Antidepressants Poisoning TCAs, SSRIs, MAOIs

Antidepressants Poisoning TCAs, SSRIs, MAOIs. Dr K.Naseri Pharm D, PhD of Pharmacology. Tricyclic Antidepressants Poisoning. Tricyclic Antidepressants. Amitriptyline Amoxapine Bupropion Clomipramine Desipramine Dothiepin Doxepin Imipramine Lofepramine. Maprotiline Mirtazapine

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Antidepressants Poisoning TCAs, SSRIs, MAOIs

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

  2. Tricyclic AntidepressantsPoisoning

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

  4. 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

  5. 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.

  6. 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.

  7. 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)

  8. 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 )

  9. 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

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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

  17. ‍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)

  18. ‍Cardiac effects

  19. 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

  20. ‍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

  21. ‍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

  22. ‍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

  23. ‍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

  24. ‍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

  25. 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

  26. Serotonin Re-Uptake Inhibitors

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

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

  29. 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

  30. 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

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

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

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

  34. 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)

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

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

  37. 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

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

  39. 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.

  40. 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

  41. 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

  42. 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

  43. 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)

  44. 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).

  45. Ferrous poisoining

  46. Arsenic poisoning

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