Quang Bui – May Contain Errors & Frustrating Abbrev. & Summative References – Page 1 of 1 – Serotonergic Syndrome – Filed As QS serotonin syndrome.doc – As of 04/2009

Serotonergic Syndrome: Pathophysiology S/Sx Tx

Risk Factors: - drug related (higher potency agents, higher total daily dose, rapid dose escalation, concomitant drugs) - patient related (older age, �, endogenous/acquired defects in MAOI activity, poor SSRI metabolizers)

Mechanisms1,2,3,4 Ex of central/peripheral 5HT receptors overstim thru meds/drugs of abuse ↑5HT production Dietary: tyramine, L-tryptophan & 5-hydroxytryptophan as 5HT precursor ↑5HT release Amphetamine & derivatives

- Methylenedioxymethamphetamine (MDMA, ecstasy) Cocaine, Fenfluramine, Levodopa MAOI, DM Meperidine, Mirtazapine, Reserpine

inhib of 5HT reuptake

Amphetamine & derivatives Bromopheniramine, Chorpheniramine, Dextromethorphan (DM) Cocaine, Fentanyl, Meperidine (Demerol), Propoxyphene Pentazocine (Talwin) SSRI, TCA, Venlafaxine, Bupropion Sibutramine (Meridia) SJW (Hypericum perforatum) Tramadol (Ultram), Trazodone, Nefazodone

inhib of 5HT metabolism

MAOi: - Linezolid - Isocarboxazid, Phenelzine, Tranylcypromine - Selegiline, - Pargylene

SJW Postsynaptic receptor stimulation

5-HT, receptor agonists Buspirone, Carbamazepine Lyseric acid diethylamid (LSD), Ecstacy Meperidine, Li, Triptans Metoclopramide (inc long half-life of Fluoxetine by 4-6 days) Dihydroergotamine (DHE 45)

Altered Rx elim SSRI inhibit Tramadol metabolism via CYP2D6 References

1. Pharmacist’s Letter. 2006; Vol 22, Number 220905. 9/06. 2. Taylor JJ, Wilson JW, and Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey.

CID 2006; 43: 180-187. 3. Birmes P, Coppin D, Schmitt L, and Lauque D. Serotonin syndrome: a brief review. JAMC 2003; 168(11):

1439-1442. (Canadian Medical Association Journal: www.jamc.ca) 4. Tisdale JE and Miller DA. Drug-induced diseases: prevention, detection, and management. ASHP 2005;

433-437.ISBN 1-58528-086-0.

Sternbach’s Criteria4: at least 3 of: AMS, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, in coordination Radomski et al3 revised the Dx criteria

AMS (altered mental status)

agitation, confusion, delirium, hallucinations, hyperactivity, hypervigilance, hypomania, & pressured speech, coma

Neuromuscular abnormalities

hyperreflexia, inc muscle tone, restlessness, rhabdomyolysis, rigidity, shivering, tremor; spontaneous/ inducible/ ocular clonus

Autonomic hyperactivity

diarrhea, mydriasis, fever, flushing, inc bowel sounds, resp rate & tearing; HTN or hypoTN

- Typically occur after inc dose, overdose, or addition of serotonergic Rx. Mostly 6 hrs after ingestion.

- Can occur up to 6 weeks after d/c of long-acting Rx (Fluoxetine) or MAOi - Mild 5HT Syndrome: more subacute or even chronic presentation. Sx might

be dismissed or not attributed to meds

Serotonin Syndrome VS. Neuroleptic Malignant Syndrome Sudden, w/in 24 hr after intro of serotonergic agent

Onset Slower, w/in 7 d following intro of neuroleptic agent

Agitation, diarrhea Sx Dysphagia, hypersalivation, incontinence

Dilated pupils, myoclonus, hyperreflexia

Signs Hyperthermia (>38C), akinesia, extrapyramidal “lead pipe” rigidity, rhabdomyolysis

23 deaths until 1999 Mortality 15-20%

Antipyretic therapy - not recommended b/c inc body temp d/t excessive muscular activity not change in hypothalamic temp set point Mild/ Moderate Sx - most resolves w/in 24-72 hrs - supportive care, Rx D/C, & Benzodiazepines Severe Sx - sedation, paralyzation & intubation - recommend admin of 5HT antagonists [Evidence Level D: anecdotal]

Cyprohepatadine (Periactin4) 4-8mg po q8h up to 48 h or 30mg x1dose

H1RA w/ antiCh & anti5HT charac SE: drowsiness

Chlorpromazine (Thorazine4) 12.5mg x1dose up to 1mg/kg po or IM; repeat if Sx returns

5HT1A & 5HT2 RA neuroleptic w/ antiCH effects SE: hypoTN, dystonic/NMS

Other Recommendations - IV electrolytes = maintain diuresis >50-100 mL/h to avoid myoglobinuria. Esp in diaphoretic pts. - BZD (Lora/diazepam) for anxiety. BB may benefit to block 5HT1A receptors(Propranolol). - Ziprasidone = most powerful blocker w/ moderate EPS. - Resuscitation (cool off, mech ventilation, antiepileptics, antiHTN agents) in serious cases. - Most pt completely resolves w/in 24 hr after admit (esp taking Cyproheptadine or CPZ). Sx persists longer in 40% of pts. - Neuromuscular blockers for sustained myoclonus or severe hyperthermia.