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Transcript of Serotonin
The Serotonin SyndromeThe Serotonin Syndrome
Hunter Area Toxicology Service
Hunter Area Toxicology Service
SerotoninSerotonin
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
Serotonin metabolismSerotonin 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
Serotonin actionsSerotonin 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
Serotonin actionsSerotonin 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
Serotonin rolesSerotonin roles
Peripheral– peristalsis– vomiting– platelet aggregation and haemostasis– inflammatory mediator– sensitisation of nociceptors– microvascular control
Hunter Area Toxicology Service
Serotonin rolesSerotonin roles
Central– control of appetite– sleep– mood– hallucinations– stereotyped behaviour– pain perception– vomiting
Hunter Area Toxicology Service
Serotonin receptorsSerotonin 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
5–HT5–HT11
5–HT1A
– limbic system regulation of emotions
– neocortex– hypothalamus– substantia gelatinosa
proprioception
5–HT1B (rat)
Hunter Area Toxicology Service
5–HT5–HT11
5–HT1D
– autoreceptors inhibitory feedback
– heteroreceptors modulate release
– acetylcholine
– glutamate
– anti–migraine effect of sumatriptan
Hunter Area Toxicology Service
5–HT5–HT11
5–HT1E
– ? functional role
5–HT1F
– ? functional role– distribution includes CNS, uterus, mesentery– inhibit cAMP– high affinity
sumatriptan, methysergide
Hunter Area Toxicology Service
Serotonin receptorsSerotonin 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
5–HT5–HT22
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
5–HT5–HT22
5–HT2A
– CNS motor behaviour head twitch wet dog shakes sleep regulation nociception neuroexcitation
Hunter Area Toxicology Service
5–HT5–HT22
5–HT2B (rat)
– stomach fundus
5–HT2C
– CSF production– locomotion– eating disorders– anxiety– migraine
Hunter Area Toxicology Service
Serotonin receptorsSerotonin 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
5–HT5–HT33
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
Serotonin receptorsSerotonin receptors
5-HT6 (rat)
5-HT7 (rat and human)
– coupled to adenylate cyclase– significance unknown
Hunter Area Toxicology Service
Serotonin excessSerotonin 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
Sternbach criteriaSternbach criteriaMental status changes (confusion, hypomania)AgitationMyoclonusHyperreflexiaDiaphoresisShiveringTremorDiarrhoeaIncoordinationFever
Diarrhoea
Hunter Area Toxicology Service
Serotinergic drugsSerotinergic drugs
Serotonin precursors– S–adenyl–L–methionine– L–tryptophan– 5–hydroxytryptophan– dopamine
Hunter Area Toxicology Service
Serotinergic drugsSerotinergic drugs
Serotonin re–uptake inhibitors– citalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline, venlafaxine– clomipramine, imipramine– nefazodone, trazodone– chlorpheniramine– cocaine, dextromethorphan, pentazocine, pethidine
Hunter Area Toxicology Service
Serotinergic drugsSerotinergic drugs
Serotonin agonists– fenfluramine, p–chloramphetamine– bromocriptine, dihydroergotamine, gepirone– sumatriptan– buspirone, ipsapirone– eltoprazin, quipazine
Hunter Area Toxicology Service
Serotinergic drugsSerotinergic drugs
Monoamine oxidase inhibitors (MAOIs)– clorgyline, isocarboxazid, nialamide, pargyline,
phenelzine, tranylcypromine– selegiline– furazolidone– procarbazine
Hunter Area Toxicology Service
Serotinergic drugsSerotinergic drugs
Reversible inhibitors of MAO (RIMAs)– brofaramine– befloxatone, toloxatone– moclobemide
Hunter Area Toxicology Service
Serotinergic drugsSerotinergic drugs
Miscellaneous/mixed– lithium– lysergic acid diethylamide (LSD)– 3,4–methylenedioxymethamphetamine (MDMA,
ecstasy), methylenedioxyethamphetamine (eve)– propranolol, pindolol
Hunter Area Toxicology Service
IncidenceIncidence
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
IncidenceIncidence
0
5
10
15
20
Perc
en
t
87 88 89 90 91 92 93 94 95 96 97
Serotinergic drug Serotonin syndrome
Hunter Area Toxicology Service
Serotinergic drugs takenSerotinergic drugs takenAll serotinergic drugs
(n=267)Serotonin syndrome
(n=41)
Paroxetine 58 (22%) 11 (27%)Moclobemide 56 (21%) 10 (24%)Sertraline 51 (19%) 15 (37%)Fluoxetine 43 (16%) 3 (7%)Clomipramine 41 (15%) 1 (2%)Phenelzine 14 (5%) 3 (7%)Lithium 11 (4%) 1 (2%)Tranylcypromine 7 (3%) 3 (7%)Imipramine 2 (1%) 2 (5%)
Hunter Area Toxicology Service
Serotinergic drugs (Odds ratios)Serotinergic drugs (Odds ratios)
Single serotinergicdrug
Serotoninsyndrome (n=41)
No serotoninsyndrome (n=226)
Odds ratio(95% CI)
Sertraline 11 (26.8%) 33 (14.6%) 2.2 (0.98–4.7)Paroxetine 9 (22.0%) 44 (19.5%) 1.2 (0.5–2.6)Moclobemide 6 (14.6%) 43 (19.0%) 0.7 (0.3–1.9)Fluoxetine 2 (4.9%) 38 (16.8%) 0.3 (0.1–1.1)Phenelzine 2 (4.9%) 9 (4.0%) 1.2 (0.3–6.0)Tranylcypromine 1 (2.4%) 3 (1.3%) 1.9 (0.2–18.4)Lithium 1 (2.4%) 1 (0.4%) 5.7 (0.3–92.2)Clomipramine 0 39 (17.3%) 0.0 (0.0–0.4)Imipramine 0 0 Undefined
Total 32 (78.0%) 210 (92.9%) –
Hunter Area Toxicology Service
Sternbach criteria (%)Sternbach criteria (%)
Sternbach (n=38) Sporer (n=79) HATS (n=41)
Confusion/hypomania 42 45 42Agitation 45 NR 76Myoclonus 34 43 12Hyperreflexia 29 47 81Diaphoresis 26 31 10Shivering 26 21 15Tremor 26 NR 44Diarrhoea 16 10 15Ataxia/incoordination 13 38 15Fever NR 28 44
Hunter Area Toxicology Service
Frequency of Sternbach criteriaFrequency of Sternbach criteria
05
1015202530354045
Pati
en
ts (
%)
)
0 1 2 3 4 5 6 7 8 9 10
Serotinergic drug overdose with signs
Hunter Area Toxicology Service
Other clinical features (%)Other clinical features (%)Inducible clonus 56Tachycardia 51Mydriasis 39Spontaneous clonus 29Hypertonia/rigidity 24Coma 20Ocular clonus/oscillations 20Nystagmus 12Rhabdomyolysis 5Akathisia 2Seizures 2Lacrimation 0Oculogyric crisis 0Opisthotonus 0
Hunter Area Toxicology Service
Frequency of all clinical featuresFrequency of all clinical features
0
5
10
15
20
25
30
Pati
en
ts (
%)
)
0 2 4 6 8 10
12
14
16
18
20
22
24
Serotinergic drug overdose with signs
Hunter Area Toxicology Service
Sternbach criteria in HATS (%)Sternbach criteria in HATS (%)
Serotoninsyndrome (n=41)
Serotinergic drug,no SS (n=226)
Other drug(n=3863)
Hyperreflexia 80.5 28.3 8.3Agitation 75.6 5.3 naFever 43.9 5.3 3.0Tremor 43.9 2.2 naConfusion/hypomania 41.5 1.8 5.5Diarrhoea 14.6 10.2 naAtaxia/incoordination 14.6 3.5 naShivering 14.6 0.9 naMyoclonus 12.2 0.4 0.6Diaphoresis 9.8 0.4 na
Hunter Area Toxicology Service
Sternbach criteria (Odds ratio)Sternbach criteria (Odds ratio)Serotonin
syndrome vs no SSSerotinergic drug
vs other drug
Hyperreflexia 10.4 (4.6–23.8) 6.2 (4.7–8.2)Agitation 55.3 (22.0–138.7) naFever 14.0 (6.0–32.6) 2.9 (1.8–4.7)Tremor 34.6 (11.7–101.9) naConfusion/hypomania 39.3 (12.2–126.4) 1.5 (0.9–2.3)Diarrhoea 1.5 (0.6–4.2) naAtaxia/incoordination 4.7 (1.5–14.3) naShivering 19.2 (3.7–99.0) naMyoclonus 31.3 (3.5–275.4) 3.8 (1.5–9.5)Diaphoresis 28.8 (3.1–264.4) na
Hunter Area Toxicology Service
Other clinical features in HATS (%)Other clinical features in HATS (%)Serotonin syndrome
(n=41)Serotinergic drug,
no SS (n=226)Other drug(n=3863)
Inducible clonus 56.1 3.1 naTachycardia 51.2 23.9 30.8Mydriasis 39.0 29.2 13.9Spontaneous clonus 29.3 2.7 naHypertonia/rigidity 24.4 3.1 1.8Coma 19.5 8.4 9.5Ocular clonus/oscillations 19.5 1.8 naNystagmus 12.2 3.5 6.6Rhabdomyolysis 4.9 0 1.1Akathisia 2.4 0.4 naSeizures 2.4 1.4 2.3Lacrimation 0 0 naOculogyric crisis 0 0.4 naOpisthotonus 0 0 na
Hunter Area Toxicology Service
Other clinical features (Odds ratio)Other clinical features (Odds ratio)Serotonin syndrome
vs no SSSerotinergic drug
vs other drug
Inducible clonus 40.0 (25.1–105.8) naTachycardia 3.3 (1.7–6.6) 0.9 (0.7–1.2)Mydriasis 1.6 (0.8–3.1) 2.7 (2.1–3.6)Spontaneous clonus 15.7 (5.3–43.5) naHypertonia/rigidity 10.1 (3.6–28.5) 3.8 (2.2–6.6)Coma 2.6 (1.1–6.5) 1.1 (0.7–1.6)Ocular clonus/oscillations 13.5 (3.8–47.2) naNystagmus 3.8 (1.2–12.2) 0.7 (0.4–1.3)Rhabdomyolysis (1.6–) 0.7 (0.2–2.7)Akathisia 5.6 (0.3–91.8) naSeizures 1.9 (0.2–18.3) 0.7 (0.2–1.8)Lacrimation – naOculogyric crisis – naOpisthotonus – na
Hunter Area Toxicology Service
Major featuresMajor featuresAgitation 55.3 (22.0–138.7)Inducible clonus 40.0 (25.1–105.8)Confusion/hypomania 39.3 (12.2–126.4)Tremor 34.6 (11.7–101.9)Myoclonus 31.3 (3.5–275.4)Diaphoresis 28.8 (3.1–264.4)Shivering 19.2 (3.7–99.0)Spontaneous clonus 15.7 (5.3–43.5)Fever 14.0 (6.0–32.6)Ocular clonus/oscillations 13.5 (3.8–47.2)Hyperreflexia 10.4 (4.6–23.8)Hypertonia/rigidity 10.1 (3.6–28.5)
Hunter Area Toxicology Service
Minor featuresMinor features
Ataxia/incoordination 4.7 (1.5–14.3)Nystagmus 3.8 (1.2–12.2)Tachycardia 3.3 (1.7–6.6)Coma 2.6 (1.1–6.5)Rhabdomyolysis (1.6–)
Hunter Area Toxicology Service
Non–featuresNon–features
Akathisia 5.6 (0.3–91.8)Seizures 1.9 (0.2–18.3)Diarrhoea 1.5 (0.6–4.2)Mydriasis 1.6 (0.8–3.1)Lacrimation –Oculogyric crisis –Opisthotonus –
Hunter Area Toxicology Service
Suggested criteriaSuggested criteria
Agitation/confusion/hypomania Clonus (inducible/spontaneous/ocular) Tremor/shivering/myoclonus Diaphoresis Fever Hyperreflexia Hypertonia/rigidity
Hunter Area Toxicology Service
Suggested criteria Suggested criteria
0
10
20
30
40
50
60
Pati
en
ts (
%)
)
0 1 2 3 4 5 6 7
Serotinergic drug with serotonin syndrome
Serotinergic drug without serotonin syndrome
Hunter Area Toxicology Service
Signs suggestive of serotinergic Signs suggestive of serotinergic drug overdosedrug overdose
Hyperreflexia 6.2 (4.7–8.2)Hypertonia/rigidity 3.8 (2.2–6.6)Myoclonus 3.8 (1.5–9.5)Fever 2.9 (1.8–4.7)Mydriasis 2.7 (2.1–3.6)
Hunter Area Toxicology Service
Treatment of serotonin syndromeTreatment 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
Severity of serotonin syndromeSeverity 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
Severity of serotonin syndromeSeverity 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
Drugs used to treat serotonin Drugs used to treat serotonin syndromesyndrome
Non–specific blocking agents– methysergide– cyproheptadine
–blockers– propranolol– pindolol
Hunter Area Toxicology Service
Drugs used to treat serotonin Drugs used to treat serotonin syndromesyndrome
Benzodiazepines– lorazepam– diazepam– clonazepam
Neuroleptics– chlorprothixene– chlorpromazine– haloperidol
Hunter Area Toxicology Service
Drugs used to treat serotonin Drugs used to treat serotonin syndromesyndrome
Miscellaneous– chlormethiazole– nitroglycerine
Drugs used for neuroleptic malignant syndrome– dantrolene– bromocriptine
Hunter Area Toxicology Service
5–HT receptors in serotonin 5–HT receptors in serotonin syndromesyndrome
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
Hunter Area Toxicology Service
Antagonist potenciesAntagonist 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)
Hunter Area Toxicology Service
TherapyTherapy
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
Hunter Area Toxicology Service
TherapyTherapy 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