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The Serotonin Syndrome

The Serotonin Syndrome. Hunter Area Toxicology Service. Serotonin. 5–hydroxytryptamine or 5–HT Discovered in 1948 Major role in multiple states aggression, pain, sleep, appetite anxiety, depression migraine, emesis. Serotonin metabolism. Dietary tryptophan

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The Serotonin Syndrome

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  1. The Serotonin Syndrome Hunter Area Toxicology Service

  2. Serotonin • 5–hydroxytryptamine or 5–HT • Discovered in 1948 • Major role in multiple states • aggression, pain, sleep, appetite • anxiety, depression • migraine, emesis Hunter Area Toxicology Service

  3. Serotonin metabolism • Dietary tryptophan • converted to 5–hydroxy– tryptophan by tryptophan hydroxylase • then to 5-HT by a non–specific decarboxylase • Specific transport system into cells • Degradation • mainly monoamine oxidase (MAO–A > MAO–B) • 5–hydroxyindoleacetic acid (5-HIAA) in urine Hunter Area Toxicology Service

  4. Serotonin actions • Serotonin causes the following effects • excitation/inhibition of CNS neurons • stimulation of peripheral nociceptive nerve endings • vascular effects • constriction (direct and via sympathetic innervation) • dilatation (endothelium dependent) • platelet aggregation • increased microvascular permeability Hunter Area Toxicology Service

  5. Serotonin actions • increased gastrointestinal motility • direct excitation of smooth muscle and indirect action via enteric neurons • contraction of other smooth muscle eg bronchi, uterus Hunter Area Toxicology Service

  6. Serotonin roles • Peripheral • peristalsis • vomiting • platelet aggregation and haemostasis • inflammatory mediator • sensitisation of nociceptors • microvascular control Hunter Area Toxicology Service

  7. Serotonin roles • Central • control of appetite • sleep • mood • hallucinations • stereotyped behaviour • pain perception • vomiting Hunter Area Toxicology Service

  8. Serotonin receptors • 5–HT1 • 7 trans–membrane domains • G protein linked • cAMP dependant • anxiolytic and antidepressant • subtypes • 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F Hunter Area Toxicology Service

  9. 5–HT1 • 5–HT1A • limbic system • regulation of emotions • neocortex • hypothalamus • substantia gelatinosa • proprioception • 5–HT1B (rat) Hunter Area Toxicology Service

  10. 5–HT1 • 5–HT1D • autoreceptors • inhibitory feedback • heteroreceptors • modulate release • acetylcholine • glutamate • anti–migraine effect of sumatriptan Hunter Area Toxicology Service

  11. 5–HT1 • 5–HT1E • ? functional role • 5–HT1F • ? functional role • distribution includes CNS, uterus, mesentery • inhibit cAMP • high affinity • sumatriptan, methysergide Hunter Area Toxicology Service

  12. Serotonin receptors • 5–HT2 • 7 trans–membrane domains • G protein linked • phospholipase C dependant • hallucinogens • subtypes • 5–HT2A, 5–HT2B, 5–HT2C Hunter Area Toxicology Service

  13. 5–HT2 • 5–HT2A • Periphery • contraction of vascular/non–vascular smooth muscle • platelet aggregation • increased capillary permeability • modulation of the release of other neurotransmitters and hormones • ACh, adrenaline, dopamine, excitatory amino acids, vasopressin Hunter Area Toxicology Service

  14. 5–HT2 • 5–HT2A • CNS • motor behaviour • head twitch • wet dog shakes • sleep regulation • nociception • neuroexcitation Hunter Area Toxicology Service

  15. 5–HT2 • 5–HT2B (rat) • stomach fundus • 5–HT2C • CSF production • locomotion • eating disorders • anxiety • migraine Hunter Area Toxicology Service

  16. Serotonin receptors • 5–HT3 • ligand gated cation channels • 5-HT4 (rat) • coupled to adenylate cyclase • 5-HT5 (rat) • coupled to adenylate cyclase • subtypes • 5–HT5A, 5–HT5B Hunter Area Toxicology Service

  17. 5–HT3 • Peripheral • located exclusively on neurons and mediate neurotransmitter release - parasympathetic, sympathetic, sensory and enteric • cardiac inhibition/activation, pain, initiation of the vomiting reflex • Central • facilitate dopamine and 5–HT release, inhibit ACh and noradrenaline release • anxiety, depression, memory, tolerance and dependence Hunter Area Toxicology Service

  18. Serotonin receptors • 5-HT6 (rat) • 5-HT7 (rat and human) • coupled to adenylate cyclase • significance unknown Hunter Area Toxicology Service

  19. Serotonin excess • Oates (1960) suggested excess serotonin as the cause of symptoms after MAOIs with tryptophan • Animal work (1980s) attributed MAOI/pethidine interaction to excess serotonin • Insel (1982) often quoted as describing the serotonin syndrome • Sternbach (1991) developed diagnostic criteria for serotonin syndrome Hunter Area Toxicology Service

  20. Sternbach criteria Hunter Area Toxicology Service

  21. Serotinergic drugs • Serotonin precursors • S–adenyl–L–methionine • L–tryptophan • 5–hydroxytryptophan • dopamine Hunter Area Toxicology Service

  22. Serotinergic drugs • Serotonin re–uptake inhibitors • citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine • clomipramine, imipramine • nefazodone, trazodone • chlorpheniramine • cocaine, dextromethorphan, pentazocine, pethidine Hunter Area Toxicology Service

  23. Serotinergic drugs • Serotonin agonists • fenfluramine, p–chloramphetamine • bromocriptine, dihydroergotamine, gepirone • sumatriptan • buspirone, ipsapirone • eltoprazin, quipazine Hunter Area Toxicology Service

  24. Serotinergic drugs • Monoamine oxidase inhibitors (MAOIs) • clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine • selegiline • furazolidone • procarbazine Hunter Area Toxicology Service

  25. Serotinergic drugs • Reversible inhibitors of MAO (RIMAs) • brofaramine • befloxatone, toloxatone • moclobemide Hunter Area Toxicology Service

  26. Serotinergic drugs • Miscellaneous/mixed • lithium • lysergic acid diethylamide (LSD) • 3,4–methylenedioxymethamphetamine (MDMA, ecstasy), methylenedioxyethamphetamine (eve) • propranolol, pindolol Hunter Area Toxicology Service

  27. Incidence • Over last 10 years • 4130 admissions for deliberate self poisoning • 267 admissions for serotinergic drug overdose • 41 admissions with serotonin syndrome Hunter Area Toxicology Service

  28. Incidence Hunter Area Toxicology Service

  29. Serotinergic drugs taken Hunter Area Toxicology Service

  30. Serotinergic drugs (Odds ratios) Hunter Area Toxicology Service

  31. Sternbach criteria (%) Hunter Area Toxicology Service

  32. Frequency of Sternbach criteria Hunter Area Toxicology Service

  33. Other clinical features (%) Hunter Area Toxicology Service

  34. Frequency of all clinical features Hunter Area Toxicology Service

  35. Sternbach criteria in HATS (%) Hunter Area Toxicology Service

  36. Sternbach criteria (Odds ratio) Hunter Area Toxicology Service

  37. Other clinical features in HATS (%) Hunter Area Toxicology Service

  38. Other clinical features (Odds ratio) Hunter Area Toxicology Service

  39. Major features Hunter Area Toxicology Service

  40. Minor features Hunter Area Toxicology Service

  41. Non–features Hunter Area Toxicology Service

  42. Suggested criteria • Agitation/confusion/hypomania • Clonus (inducible/spontaneous/ocular) • Tremor/shivering/myoclonus • Diaphoresis • Fever • Hyperreflexia • Hypertonia/rigidity Hunter Area Toxicology Service

  43. Suggested criteria Hunter Area Toxicology Service

  44. Signs suggestive of serotinergic drug overdose Hunter Area Toxicology Service

  45. Treatment of serotonin syndrome • Depends on severity • Many (if not most) do not require treatment • Many would benefit if a safe effective therapy was available Hunter Area Toxicology Service

  46. Severity of serotonin syndrome • Mild • three symptoms are present but they are not progressive and not significantly affecting the patient • no action is required • Moderate • four or more definite symptoms that between them cause significant impairment of functioning or distress to the patient • specific therapy may be indicated Hunter Area Toxicology Service

  47. Severity of serotonin syndrome • Severe • most symptoms are present and significant impairment of consciousness or functioning is also present • often progression of symptoms, particularly fever • rapidly rising temperature (>39oC) is an indication for urgent intervention • specific therapy may be very beneficial Hunter Area Toxicology Service

  48. Drugs used to treat serotonin syndrome • Non–specific blocking agents • methysergide • cyproheptadine • –blockers • propranolol • pindolol Hunter Area Toxicology Service

  49. Drugs used to treat serotonin syndrome • Benzodiazepines • lorazepam • diazepam • clonazepam • Neuroleptics • chlorprothixene • chlorpromazine • haloperidol Hunter Area Toxicology Service

  50. Drugs used to treat serotonin syndrome • Miscellaneous • chlormethiazole • nitroglycerine • Drugs used for neuroleptic malignant syndrome • dantrolene • bromocriptine Hunter Area Toxicology Service

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