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 - 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
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
Serotonin actions - increased gastrointestinal motility
- direct excitation of smooth muscle and indirect action via enteric neurons
- contraction of other smooth muscle eg bronchi, uterus
Serotonin roles Peripheral - peristalsis
- vomiting
- platelet aggregation and haemostasis
- inflammatory mediator
- sensitisation of nociceptors
- microvascular control
Serotonin roles Central - control of appetite
- sleep
- mood
- hallucinations
- stereotyped behaviour
- pain perception
- vomiting
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
5–HT1 5–HT1A - limbic system
- neocortex
- hypothalamus
- substantia gelatinosa
5–HT1B (rat)
5–HT1 5–HT1D - autoreceptors
- heteroreceptors
- anti–migraine effect of sumatriptan
5–HT1 5–HT1E 5–HT1F - ? functional role
- distribution includes CNS, uterus, mesentery
- inhibit cAMP
- high affinity
- sumatriptan, methysergide
Serotonin receptors 5–HT2 - 7 trans–membrane domains
- G protein linked
- phospholipase C dependant
- hallucinogens
- subtypes
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
5–HT2 5–HT2A - CNS
- motor behaviour
- head twitch
- wet dog shakes
- sleep regulation
- nociception
- neuroexcitation
5–HT2 5–HT2B (rat) 5–HT2C - CSF production
- locomotion
- eating disorders
- anxiety
- migraine
Serotonin receptors 5–HT3 5-HT4 (rat) - coupled to adenylate cyclase
5-HT5 (rat) - coupled to adenylate cyclase
- subtypes
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
Serotonin receptors 5-HT6 (rat) 5-HT7 (rat and human) - coupled to adenylate cyclase
- significance unknown
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 Sternbach (1991) developed diagnostic criteria for serotonin syndrome
Sternbach criteria
Serotinergic drugs Serotonin precursors - S–adenyl–L–methionine
- L–tryptophan
- 5–hydroxytryptophan
- dopamine
Serotinergic drugs Serotonin re–uptake inhibitors - citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine
- clomipramine, imipramine
- nefazodone, trazodone
- chlorpheniramine
- cocaine, dextromethorphan, pentazocine, pethidine
Serotinergic drugs Serotonin agonists - fenfluramine, p–chloramphetamine
- bromocriptine, dihydroergotamine, gepirone
- sumatriptan
- buspirone, ipsapirone
- eltoprazin, quipazine
Serotinergic drugs Monoamine oxidase inhibitors (MAOIs) - clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine
- selegiline
- furazolidone
- procarbazine
Serotinergic drugs Reversible inhibitors of MAO (RIMAs) - brofaramine
- befloxatone, toloxatone
- moclobemide
Serotinergic drugs Miscellaneous/mixed - lithium
- lysergic acid diethylamide (LSD)
- 3,4–methylenedioxymethamphetamine (MDMA, ecstasy), methylenedioxyethamphetamine (eve)
- propranolol, pindolol
Incidence Over last 10 years 267 admissions for serotinergic drug overdose 41 admissions with serotonin syndrome
Incidence
Serotinergic drugs taken
Serotinergic drugs (Odds ratios)
Sternbach criteria (%)
Frequency of Sternbach criteria
Other clinical features (%)
Frequency of all clinical features
Sternbach criteria in HATS (%)
Sternbach criteria (Odds ratio)
Other clinical features in HATS (%)
Other clinical features (Odds ratio)
Major features
Minor features
Non–features
Suggested criteria Agitation/confusion/hypomania Clonus (inducible/spontaneous/ocular) Tremor/shivering/myoclonus Diaphoresis Fever Hyperreflexia Hypertonia/rigidity
Suggested criteria
Signs suggestive of serotinergic drug overdose
Treatment of serotonin syndrome Depends on severity Many (if not most) do not require treatment
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
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
Non–specific blocking agents - methysergide
- cyproheptadine
–blockers
Drugs used to treat serotonin syndrome Benzodiazepines - lorazepam
- diazepam
- clonazepam
Neuroleptics - chlorprothixene
- chlorpromazine
- haloperidol
Drugs used to treat serotonin syndrome Miscellaneous - chlormethiazole
- nitroglycerine
Drugs used for neuroleptic malignant syndrome
5–HT receptors in serotonin syndrome Originally thought to be 5–HT1 mediated (5–HT1A) - blocked in animals by non–specific 5–HT blockers
- methysergide
- cyproheptadine
- not blocked by ketanserin (5–HT2 blocker)
More recent evidence implicates 5–HT2 - failure of propranolol (5–HT1A blocker) in several cases
- cyproheptadine more potent at 5–HT2 than 5–HT1
Antagonist potencies Ki values (5–HT2) - chlorprothixene (0.43 nM) > chlorpromazine > cyproheptadine > haloperidol (36 nM)
- limited experience suggests haloperidol ineffective
Ki values (5–HT1) - chlorprothixene (230 nM) > haloperidol > chlorpromazine > cyproheptadine (3200 nM)
Therapy Moderate - when oral therapy suitable
- cyproheptadine 8 mg stat then 4 mg q4–6h
- when oral therapy unsuitable or cyproheptadine fails
- chlorpromazine 50 mg IMI/IVI stat then up to 50 mg orally or IMI/IVI q6h
Therapy Severe - when symptoms are not progressive and fever < 39oC
- chlorpromazine 50–100 mg IMI/IVI stat then 50–100 mg orally or IMI/IVI q6h
- when symptoms are progressive and fever < 39oC
- chlorpromazine 100–400 mg IMI/IVI over first two hours
- when symptoms are progressive and fever > 39oC
- barbiturate anaesthesia, muscle relaxation ± active cooling
- chlorpromazine 100–400 mg IMI/IVI over first two hours
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