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TOXICOLOGY: ANTIDEPRESSANTS & ANTIPSYCHOTICS

TOXICOLOGY: ANTIDEPRESSANTS & ANTIPSYCHOTICS . May 26, 2011 Jason Mitchell Joe McLellan Phil Ukrainetz. INTRODUCTION. 18 yo F 1/52 Fever, otalgia, chills, myalgia, arthralgia Tooth extraction 2/52 ago Meds: Percodan (ASA/Oxycodone) Chlorphenamine Erythromycin

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TOXICOLOGY: ANTIDEPRESSANTS & ANTIPSYCHOTICS

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  1. TOXICOLOGY: ANTIDEPRESSANTS &ANTIPSYCHOTICS May 26, 2011 Jason Mitchell Joe McLellan Phil Ukrainetz

  2. INTRODUCTION • 18 yo F • 1/52 Fever, otalgia, chills, myalgia, arthralgia • Tooth extraction 2/52 ago • Meds: Percodan (ASA/Oxycodone) Chlorphenamine Erythromycin “Something for stress” • Frequent marijuana, denies cocaine or other rec drugs

  3. INTRODUCTION • O/E: 39.7oC, 120, 110/75 supine 95/60 standing, 20, 4.7 • CNS: Appears distressed • Intermittent writhing/agitation/confusion ?volitional • “Strange jerking movements” and shivering noted • Hyper-reflexic, nystagmus • HEENT: Hyperemic R TM • CV: II/VI LLSB diastolic murmur • Resp: Clear to bases • Integument: Petechial rash to R thigh

  4. INTRODUCTION • Ix: • CBC/Lytes: WBC 18 • CXR: Normal • ECG: Sinus tach

  5. INTRODUCTION • Dx: Tentative diagnosis of “viral syndrome NYD with hysterical symptoms” • Admitted to hospital, routine vitals • Agitation persists • 25mg Demerol IM Rx for agitation and shivering

  6. INTRODUCTION • Agitation and confusion worsens • Pt thrashing in bed, ripped out IVs • Hypertense, tachycardic, ongoing fever • Resident notified by telephone • Physical restraints • 1 mg haloperidol

  7. Agitation initially resolves, but shortly returns • Axillary temp. 420C • Cold compresses and cooling blanket applied • Progresses to respiratory arrest and unable to resuscitate • Pt dies 7 hours after presentation to hospital

  8. ANTIDEPRESSANTS • Multiple Classes • SSRIs (Citalopram, Fluoxatine, Fluvoxamine, Paroxetine, Sertraline) • MAOIs (Isocarboxacid, Phenelzine, Moclobemide) • TCAs (Amitriptyline, Clomipramine, Imipramine, Desipramine) • SNRIs (Desvenlafaxine, Venlafaxine, Duloxetine) • NaSSAs (Mirtazapine) • NRIs (Strattera) • NDRIs (Bupropion) • SSREs (Tianeptine) • NDDIs (Agomelatine)

  9. ANTIDEPRESSANTS • Multiple Classes • SSRIs (Citalopram, Fluoxatine, Fluvoxamine, Paroxetine, Sertraline) • MAOIs (Isocarboxacid, Phenelzine, Moclobemide) • TCAs (Amitriptyline, Clomipramine, Imipramine, Desipramine) • SNRIs (Desvenlafaxine, Venlafaxine, Duloxetine) • NaSSAs (Mirtazapine) • NRIs (Strattera) • NDRIs (Bupropion) • SSREs (Tianeptine) • NDDIs (Agomelatine)

  10. ANTIDEPRESSANTS • PHYSIOLOGY • Mechanism of depression incompletely understood • Proposed consequence of low [monoamines]: • serotonin (5-HT), norepinephrine (NE), dopamine (DA)

  11. ANTIDEPRESSANTS • PHYSIOLOGY • SSRI: Prevents 5-HT reuptake • MAOI: Prevents 5-HT deamination • Increases synaptic [5-HT]

  12. MAOIs • PHARMACODYNAMICS • Peak plasma concentrations 0.5-2.5 hours • Hepatic metabolism • Minimal urinary excretion

  13. MAOIs • TOXICITY • MAOI Overdose • MAOI-food/beverage interactions • MAOI-drug interactions

  14. MAOIs • TOXICITY • MAOI Overdose Excessive • MAOI-food/beverage interactions Sympathetic Activity • MAOI-drug interactions

  15. MAOIs • MAOI OVERDOSE • Four phases • Asymptomatic/Latent • CV/CNS excitation with sympathetic hyperactivity • CNS depression and CV collapse • Secondary complications

  16. MAOIs • MAOI-FOOD/BEVERAGE INTERACTIONS • Foods high in tyramine • Tyramine leads to catecholamine release • May potentiate hypertensive crisis

  17. MAOIs • MAOI-FOOD/BEVERAGE INTERACTIONS

  18. MAOIs • MOAI-DRUG INTERACTIONS • Occur minutes to hours after co-ingestion • May cause sympathetic storm/serotonin syndrome • Production of excessive concentrations of monoamines • Examples: • SSRIs • TCAs • Sympathomimetics • Opiates • Lithium

  19. MAOIs • MANAGEMENT • Recall ABCDEFs of toxicology • ABCs primarily supportive • Sinus tachycardia does not usually require treatment • β Blockers and CCBs relatively contraindicated • Hypertension • Nitroprusside 0.3 mcg/kg/min titrated to effect (max 10 mcg/kg/min) • Nitroglycerine 20 mcg/min titrate q5min to effect • Phentolamine 5 mg bolus q5-10min

  20. MAOIs • MANAGEMENT • ABCs primarily supportive • Bradycardia • Compensatory response to hypertension • Treat if associated with hypotension • Hypotension • IV crystalloid • Atropine if associated with bradycardia • Vasopressors not contraindicated • Avoid dopamine

  21. MAOIs • MANAGEMENT • DEFs • May consider AC • Forced diuresis, hemoperfusion ineffective • No antidote available

  22. MAOIs • DISPOSITION • Onset of symptoms may be delayed • Recommended 24 hour observation for asymptomatic pts with MAOI overdose • Recommended 6 hour observation for food interaction • ICU/MTU admit depending on symptom severity

  23. SSRIs • PHARMACODYNAMICS • Peak plasma concentration: 3 – 10 hours • Liver metabolism: Elimination half-life 15hours – 4days • Small amount of urinary excretion

  24. SSRIs • TOXICITY • Not as pronounced as TCA toxicity • High ingested dosages required • Toxic Spectrum • Mild serotonin-related symptoms • Serotonin syndrome • Toxic states Radomski JW, Dursun SM, Reveley MA, Kutcher SP. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria Pages 218-224

  25. SSRIs • TOXICITY

  26. SSRIs • GI TOXICITY • Abdominal cramps • Nausea • Vomiting • Diarrhea • Salivation

  27. SSRIs • CV TOXICITIY • Cutaneous flushing • Hypertension/Hypotension • Tachycardia/Bradycardia • QT Prolongation (rare) • Fluoxetine, Citalopram • Ventricular tachycardia (rare)

  28. SSRIs • CNS TOXICITY (RARE) • Agitation • Akathisia • Anxiety • Clonus • Coma • Confusion • Delirium • Headache • Hyper-reflexia • Hyperthermia • Hypomania • Insomnia • Mania • Mydriasis • Myoclonus • Nystagmus • Rigidity • Seizures • Sedation

  29. SSRIs • CNS and CV TOXICITY Hoffman RS, Nelson LS, Howland MA, et al. Goldfrank's Manual of Toxicologic Emergencies. McGraw-Hill Companies, 2007.

  30. SSRIs • DIAGNOSIS • Primarily clinical • History important • SSRI dosage increase • Known ingestion • Co-ingestion of drugs that potentiate [synaptic serotonin] • Eg – Cocaine, DM, amphetamines, MAOIs, TCAs, Carbamazepine, Lithium, Sumatriptan • Urine/Blood tox screens not useful • Unless coingestion suspected.

  31. SSRIs • MANAGEMENT • Recall the ABCDEFs of toxicology • SSRI overdose is generally mild and rarely life-threatening • Treatment is largely supportive

  32. SSRIs • MANAGEMENT • ABCs – Mainly supportive • Hypertension • Not usually indicated • Consider sodium nitroprusside • Hypotension • IV crystalloid +/- norepinephrine or dopamine • VTach/Bradycardia • As per ACLS algorithms • Neurologic complications treated with benzodiazepines

  33. SSRIs • MANAGEMENT • Decontamination and Elimination • AC may be considered • Forced diuresis not indicated • Minimal amounts of SSRI excreted in urine • Hemodialysis not indicated • Large volumes of distribution, high protein-binding • Find an Antidote • No specific antidote exists for SSRIs

  34. SSRIs • DISPOSITION • 6-hour monitoring for asymptomatic patients • Psychiatric consultation if intentional ingestion • Citalopram OD warrants 12-24 hour observation

  35. DISCONTINUATION SYNDROME • Observed with cessation of TCAs, MAOIs, and SSRIs • Pts complain of: • Dizziness • Lethargy • Paresthesia • Nausea • Depressed mood • Occur ~5 days post-cessation; can last up to 3 weeks • Supportive treatment and re-initiation of stopped drug

  36. SEROTONIN SYNDROME • Clinically recognizable signs and symptoms • Pathophysiology incompletely understood, unpredictable • Severe disease manifested by • Hyperpyrexia • Hypertension • Tachycardia • Muscle rigidity • Clonus

  37. SEROTONIN SYNDROME • STERNBACH’S DIAGNOSTIC CRITERIA • Addition or increased dose of a serotinergic agent • 3 or more of: • A neuroleptic has not been given • Other etiologies ruled out Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148: 705-713

  38. SEROTONIN SYNDROME • HUNTER SEROTONIN TOXICITY CRITERIA Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003 Sep;96(9):635-42

  39. SEROTONIN SYNDROME • INVESTIGATIONS • Serum/Urine Tox Screen • Serum CK • Urine myoglobin • Blood gas (metabolic acidosis) • LFTs • Blood/CSF cultures • DIC Panel • βHCG • ECG

  40. SEROTONIN SYNDROME • MANAGEMENT • Primary supportive • Aggressive cooling • Aggressive use of benzodiazepines • Consider neuromuscular blockade and RSI • Consider cyproheptadine/chlorpromazine

  41. SEROTONIN SYNDROME • MANAGEMENT • Cyproheptadine 8mg followed by 4 mg q1-4g max 32mg/day • Non-specific antihistamine with anti-serotinergic properties • Case reports support use in mild symptoms • Efficacy not known in severe serotonin toxicity Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. NEJM 1994;13(15):1021-2. Graudins A, Stearman A and Betty Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 1998;16(4):615– 619

  42. SEROTONIN SYNDROME • DISPOSITION • Generally favourable prognosis • MTU/ICU admission for supportive management • Symptoms generally resolve after 24 hours • Delirium may persist

  43. ANTIPSYCHOTICS • PHARMACOLOGY • Three Classes: • Low Potency Typicals • Chlorpromazine, Hydroxyzine, Promethazine • High Potency Typicals • Droperidol, Haloperidol, Loxapine • Atypicals • Aripriprazole, Clozapine, Olanzepine • Quetiapine, Risperidone, Ziprazadole

  44. ANTIPSYCHOTICS • PHARMACOLOGY • Dopamine antagonists • Dopamine receptors found in the mesolimbic and nigrostriatal brain areas • Nigrostriatal dopamine blockade results in EPS and TD • Atypical antipsychotics more selective for mesolimbic dopamine antagonism

  45. ANTIPSYCHOTICS • TOXICITY • Exaggerated clinical effects • CNS depression universal • Mild sedation to coma (dose dependent) • Airway reflexes may be impaired • Concomitant respiratory depression • Low-potency typicals can cause anticholinergic delirium • Seizures rare • Exception: Clozapine

  46. ANTIPSYCHOTICS • TOXICITY • Cardiovascular Effects • Most commonly sinus tach • QRS prolongation rare? • QT prolongation • Clinical significance unknown • Risk of torsades development unknown

  47. ANTIPSYCHOTICS • TOXICITIY • Anticholinergic Effects • Tachycardia • Hyperthermia • Blurred vision • Dry mouth • Urinary retention • Ileus • Toxic psychosis

  48. ANTIPSYCHOTICS • ACUTE EXTRAPYRAMIDAL SYNDROMES • Acute Dystonia

  49. ANTIPSYCHOTICS • ACUTE EXTRAPYRAMIDAL SYNDROMES • Akasthisia

  50. ANTIPSYCHOTICS • ACUTE EXTRAPYRAMIDAL SYNDROMES • Parkinsonian syndrome

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