The Serotonin Syndrome

Hunter Area Toxicology Service
Serotonin
 5–hydroxytryptamine or 5–HT
 Discovered in 1948
 Major role in multiple states
– aggression, pain, sleep, ap...
Serotonin metabolism
 Dietary tryptophan
– converted to 5–hydroxy– tryptophan by tryptophan
hydroxylase
– then to 5-HT by...
Serotonin actions
 Serotonin causes the following effects
– excitation/inhibition of CNS neurons
– stimulation of periphe...
Serotonin actions
– increased gastrointestinal motility
direct excitation of smooth muscle and indirect action via
enteric...
Serotonin roles
 Peripheral
–
–
–
–
–
–

peristalsis
vomiting
platelet aggregation and haemostasis
inflammatory mediator
...
Serotonin roles
 Central
–
–
–
–
–
–
–

control of appetite
sleep
mood
hallucinations
stereotyped behaviour
pain percepti...
Serotonin receptors
 5–HT1
–
–
–
–
–

7 trans–membrane domains
G protein linked
cAMP dependant
anxiolytic and antidepress...
5–HT1
 5–HT1A
– limbic system
regulation of emotions

– neocortex
– hypothalamus
– substantia gelatinosa
proprioception

...
5–HT1
 5–HT1D
– autoreceptors
inhibitory feedback

– heteroreceptors
modulate release
– acetylcholine
– glutamate

– anti...
5–HT1
 5–HT1E
– ? functional role

 5–HT1F
–
–
–
–

? functional role
distribution includes CNS, uterus, mesentery
inhib...
Serotonin receptors
 5–HT2
–
–
–
–
–

7 trans–membrane domains
G protein linked
phospholipase C dependant
hallucinogens
s...
5–HT2
 5–HT2A
– Periphery
contraction of vascular/non–vascular smooth muscle
platelet aggregation
increased capillary per...
5–HT2
 5–HT2A
– CNS
motor behaviour
head twitch
wet dog shakes
sleep regulation
nociception
neuroexcitation
Hunter Area T...
5–HT2
 5–HT2B (rat)
– stomach fundus

 5–HT2C
–
–
–
–
–

CSF production
locomotion
eating disorders
anxiety
migraine

Hu...
Serotonin receptors
 5–HT3
– ligand gated cation channels

 5-HT4 (rat)
– coupled to adenylate cyclase

 5-HT5 (rat)
– ...
5–HT3
 Peripheral
– located exclusively on neurons and mediate
neurotransmitter release - parasympathetic,
sympathetic, s...
Serotonin receptors
 5-HT6 (rat)
 5-HT7 (rat and human)
– coupled to adenylate cyclase
– significance unknown

Hunter Ar...
Serotonin excess
 Oates (1960) suggested excess serotonin as the
cause of symptoms after MAOIs with tryptophan
 Animal w...
Sternbach criteria
Mental status changes (confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tr...
Serotinergic drugs
 Serotonin precursors
–
–
–
–

S–adenyl–L–methionine
L–tryptophan
5–hydroxytryptophan
dopamine

Hunter...
Serotinergic drugs
 Serotonin re–uptake inhibitors
– citalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline, venlafa...
Serotinergic drugs
 Serotonin agonists
–
–
–
–
–

fenfluramine, p–chloramphetamine
bromocriptine, dihydroergotamine, gepi...
Serotinergic drugs
 Monoamine oxidase inhibitors (MAOIs)
– clorgyline, isocarboxazid, nialamide, pargyline,
phenelzine, t...
Serotinergic drugs
 Reversible inhibitors of MAO (RIMAs)
– brofaramine
– befloxatone, toloxatone
– moclobemide

Hunter Ar...
Serotinergic drugs
 Miscellaneous/mixed
– lithium
– lysergic acid diethylamide (LSD)
– 3,4–methylenedioxymethamphetamine ...
Incidence
 Over last 10 years
 4130 admissions for deliberate self poisoning
 267 admissions for serotinergic drug over...
Incidence
Serotinergic drug

Serotonin syndrome

20

Percent

15
10
5
0

87

88

Hunter Area Toxicology Service

89

90

9...
Serotinergic drugs taken
All serotinergic drugs
(n=267)
Paroxetine
Moclobemide
Sertraline
Fluoxetine
Clomipramine
Phenelzi...
Serotinergic drugs (Odds ratios)
Single serotinergic
drug

Serotonin
syndrome (n=41)

No serotonin
syndrome (n=226)

Odds ...
Sternbach criteria (%)
Sternbach (n=38)
Confusion/hypomania
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor...
Frequency of Sternbach criteria

Patients (%) )

Serotinergic drug overdose with signs
45
40
35
30
25
20
15
10
5
0

0

1

...
Other clinical features (%)
Inducible clonus
Tachycardia
Mydriasis
Spontaneous clonus
Hypertonia/rigidity
Coma
Ocular clon...
Frequency of all clinical features
Serotinergic drug overdose with signs

Patients (%) )

30
25
20
15
10

Hunter Area Toxi...
Sternbach criteria in HATS (%)
Serotonin
syndrome (n=41)
Hyperreflexia
Agitation
Fever
Tremor
Confusion/hypomania
Diarrhoe...
Sternbach criteria (Odds ratio)
Serotonin
syndrome vs no SS
Hyperreflexia
Agitation
Fever
Tremor
Confusion/hypomania
Diarr...
Other clinical features in HATS (%)
Serotonin syndrome
(n=41)
Inducible clonus
Tachycardia
Mydriasis
Spontaneous clonus
Hy...
Other clinical features (Odds ratio)
Serotonin syndrome
vs no SS

Inducible clonus
Tachycardia
Mydriasis
Spontaneous clonu...
Major features
Agitation
Inducible clonus
Confusion/hypomania
Tremor
Myoclonus
Diaphoresis
Shivering
Spontaneous clonus
Fe...
Minor features
Ataxia/incoordination
Nystagmus
Tachycardia
Coma
Rhabdomyolysis

Hunter Area Toxicology Service

4.7 (1.5–1...
Non–features
Akathisia
Seizures
Diarrhoea
Mydriasis
Lacrimation
Oculogyric crisis
Opisthotonus
Hunter Area Toxicology Serv...
Suggested criteria
 Agitation/confusion/hypomania
 Clonus (inducible/spontaneous/ocular)
 Tremor/shivering/myoclonus
 ...
Suggested criteria
Serotinergic drug with serotonin syndrome
Serotinergic drug without serotonin syndrome

Patients (%) )
...
Signs suggestive of serotinergic
drug overdose
Hyperreflexia
Hypertonia/rigidity
Myoclonus
Fever
Mydriasis

Hunter Area To...
Treatment of serotonin syndrome
 Depends on severity
 Many (if not most) do not require treatment
 Many would benefit i...
Severity of serotonin syndrome
 Mild
– three symptoms are present but they are not
progressive and not significantly affe...
Severity of serotonin syndrome
 Severe
– most symptoms are present and significant impairment
of consciousness or functio...
Drugs used to treat serotonin
syndrome
 Non–specific blocking agents
– methysergide
– cyproheptadine

 β–blockers
– prop...
Drugs used to treat serotonin
syndrome
 Benzodiazepines
– lorazepam
– diazepam
– clonazepam

 Neuroleptics
– chlorprothi...
Drugs used to treat serotonin
syndrome
 Miscellaneous
– chlormethiazole
– nitroglycerine

 Drugs used for neuroleptic ma...
5–HT receptors in serotonin
syndrome
 Originally thought to be 5–HT1 mediated (5–HT1A)
– blocked in animals by non–specif...
Antagonist potencies
 Ki values (5–HT2)
– chlorprothixene (0.43 nM) > chlorpromazine >
cyproheptadine > haloperidol (36 n...
Therapy
 Moderate
– when oral therapy suitable
cyproheptadine 8 mg stat then 4 mg q4–6h

– when oral therapy unsuitable o...
Therapy
 Severe
– when symptoms are not progressive and fever < 39oC
chlorpromazine 50–100 mg IMI/IVI stat then 50–100 mg...
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Serotonin

  1. 1. The Serotonin Syndrome Hunter Area Toxicology Service
  2. 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. 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. 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. 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. 6. Serotonin roles  Peripheral – – – – – – peristalsis vomiting platelet aggregation and haemostasis inflammatory mediator sensitisation of nociceptors microvascular control Hunter Area Toxicology Service
  7. 7. Serotonin roles  Central – – – – – – – control of appetite sleep mood hallucinations stereotyped behaviour pain perception vomiting Hunter Area Toxicology Service
  8. 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. 9. 5–HT1  5–HT1A – limbic system regulation of emotions – neocortex – hypothalamus – substantia gelatinosa proprioception  5–HT1B (rat) Hunter Area Toxicology Service
  10. 10. 5–HT1  5–HT1D – autoreceptors inhibitory feedback – heteroreceptors modulate release – acetylcholine – glutamate – anti–migraine effect of sumatriptan Hunter Area Toxicology Service
  11. 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. 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. 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. 14. 5–HT2  5–HT2A – CNS motor behaviour head twitch wet dog shakes sleep regulation nociception neuroexcitation Hunter Area Toxicology Service
  15. 15. 5–HT2  5–HT2B (rat) – stomach fundus  5–HT2C – – – – – CSF production locomotion eating disorders anxiety migraine Hunter Area Toxicology Service
  16. 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. 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. 18. Serotonin receptors  5-HT6 (rat)  5-HT7 (rat and human) – coupled to adenylate cyclase – significance unknown Hunter Area Toxicology Service
  19. 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. 20. Sternbach criteria Mental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever Hunter Area Toxicology Service Diar rhoea
  21. 21. Serotinergic drugs  Serotonin precursors – – – – S–adenyl–L–methionine L–tryptophan 5–hydroxytryptophan dopamine Hunter Area Toxicology Service
  22. 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. 23. Serotinergic drugs  Serotonin agonists – – – – – fenfluramine, p–chloramphetamine bromocriptine, dihydroergotamine, gepirone sumatriptan buspirone, ipsapirone eltoprazin, quipazine Hunter Area Toxicology Service
  24. 24. Serotinergic drugs  Monoamine oxidase inhibitors (MAOIs) – clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine – selegiline – furazolidone – procarbazine Hunter Area Toxicology Service
  25. 25. Serotinergic drugs  Reversible inhibitors of MAO (RIMAs) – brofaramine – befloxatone, toloxatone – moclobemide Hunter Area Toxicology Service
  26. 26. Serotinergic drugs  Miscellaneous/mixed – lithium – lysergic acid diethylamide (LSD) – 3,4–methylenedioxymethamphetamine (MDMA, ecstasy), methylenedioxyethamphetamine (eve) – propranolol, pindolol Hunter Area Toxicology Service
  27. 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. 28. Incidence Serotinergic drug Serotonin syndrome 20 Percent 15 10 5 0 87 88 Hunter Area Toxicology Service 89 90 91 92 93 94 95 96 97
  29. 29. Serotinergic drugs taken All serotinergic drugs (n=267) Paroxetine Moclobemide Sertraline Fluoxetine Clomipramine Phenelzine Lithium Tranylcypromine Imipramine Hunter Area Toxicology Service Serotonin syndrome (n=41) 58 (22%) 56 (21%) 51 (19%) 43 (16%) 41 (15%) 14 (5%) 11 (4%) 7 (3%) 2 (1%) 11 (27%) 10 (24%) 15 (37%) 3 (7%) 1 (2%) 3 (7%) 1 (2%) 3 (7%) 2 (5%)
  30. 30. Serotinergic drugs (Odds ratios) Single serotinergic drug Serotonin syndrome (n=41) No serotonin syndrome (n=226) Odds ratio (95% CI) Sertraline Paroxetine Moclobemide Fluoxetine Phenelzine Tranylcypromine Lithium Clomipramine Imipramine 11 (26.8%) 9 (22.0%) 6 (14.6%) 2 (4.9%) 2 (4.9%) 1 (2.4%) 1 (2.4%) 0 0 33 (14.6%) 44 (19.5%) 43 (19.0%) 38 (16.8%) 9 (4.0%) 3 (1.3%) 1 (0.4%) 39 (17.3%) 0 2.2 (0.98–4.7) 1.2 (0.5–2.6) 0.7 (0.3–1.9) 0.3 (0.1–1.1) 1.2 (0.3–6.0) 1.9 (0.2–18.4) 5.7 (0.3–92.2) 0.0 (0.0–0.4) Undefined Total 32 (78.0%) 210 (92.9%) – Hunter Area Toxicology Service
  31. 31. Sternbach criteria (%) Sternbach (n=38) Confusion/hypomania Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Ataxia/incoordination Fever Hunter Area Toxicology Service 42 45 34 29 26 26 26 16 13 NR Sporer (n=79) 45 NR 43 47 31 21 NR 10 38 28 HATS (n=41) 42 76 12 81 10 15 44 15 15 44
  32. 32. Frequency of Sternbach criteria Patients (%) ) Serotinergic drug overdose with signs 45 40 35 30 25 20 15 10 5 0 0 1 Hunter Area Toxicology Service 2 3 4 5 6 7 8 9 10
  33. 33. Other clinical features (%) Inducible clonus Tachycardia Mydriasis Spontaneous clonus Hypertonia/rigidity Coma Ocular clonus/oscillations Nystagmus Rhabdomyolysis Akathisia Seizures Lacrimation Oculogyric crisis Opisthotonus Hunter Area Toxicology Service 56 51 39 29 24 20 20 12 5 2 2 0 0 0
  34. 34. Frequency of all clinical features Serotinergic drug overdose with signs Patients (%) ) 30 25 20 15 10 Hunter Area Toxicology Service 24 22 20 18 16 14 12 10 8 6 4 2 0 0 5
  35. 35. Sternbach criteria in HATS (%) Serotonin syndrome (n=41) Hyperreflexia Agitation Fever Tremor Confusion/hypomania Diarrhoea Ataxia/incoordination Shivering Myoclonus Diaphoresis Hunter Area Toxicology Service 80.5 75.6 43.9 43.9 41.5 14.6 14.6 14.6 12.2 9.8 Serotinergic drug, Other drug no SS (n=226) (n=3863) 28.3 5.3 5.3 2.2 1.8 10.2 3.5 0.9 0.4 0.4 8.3 na 3.0 na 5.5 na na na 0.6 na
  36. 36. Sternbach criteria (Odds ratio) Serotonin syndrome vs no SS Hyperreflexia Agitation Fever Tremor Confusion/hypomania Diarrhoea Ataxia/incoordination Shivering Myoclonus Diaphoresis Hunter Area Toxicology Service Serotinergic drug vs other drug 10.4 (4.6–23.8) 55.3 (22.0–138.7) 14.0 (6.0–32.6) 34.6 (11.7–101.9) 39.3 (12.2–126.4) 1.5 (0.6–4.2) 4.7 (1.5–14.3) 19.2 (3.7–99.0) 31.3 (3.5–275.4) 28.8 (3.1–264.4) 6.2 (4.7–8.2) na 2.9 (1.8–4.7) na 1.5 (0.9–2.3) na na na 3.8 (1.5–9.5) na
  37. 37. Other clinical features in HATS (%) Serotonin syndrome (n=41) Inducible clonus Tachycardia Mydriasis Spontaneous clonus Hypertonia/rigidity Coma Ocular clonus/oscillations Nystagmus Rhabdomyolysis Akathisia Seizures Lacrimation Oculogyric crisis Opisthotonus Hunter Area Toxicology Service Serotinergic drug, no SS (n=226) Other drug (n=3863) 56.1 51.2 39.0 29.3 24.4 19.5 19.5 12.2 4.9 2.4 2.4 0 0 0 3.1 23.9 29.2 2.7 3.1 8.4 1.8 3.5 0 0.4 1.4 0 0.4 0 na 30.8 13.9 na 1.8 9.5 na 6.6 1.1 na 2.3 na na na
  38. 38. Other clinical features (Odds ratio) Serotonin syndrome vs no SS Inducible clonus Tachycardia Mydriasis Spontaneous clonus Hypertonia/rigidity Coma Ocular clonus/oscillations Nystagmus Rhabdomyolysis Akathisia Seizures Lacrimation Oculogyric crisis Opisthotonus Hunter Area Toxicology Service Serotinergic drug vs other drug 40.0 (25.1–105.8) 3.3 (1.7–6.6) 1.6 (0.8–3.1) 15.7 (5.3–43.5) 10.1 (3.6–28.5) 2.6 (1.1–6.5) 13.5 (3.8–47.2) 3.8 (1.2–12.2) ) ∞(1.6–∞ 5.6 (0.3–91.8) 1.9 (0.2–18.3) – – – na 0.9 (0.7–1.2) 2.7 (2.1–3.6) na 3.8 (2.2–6.6) 1.1 (0.7–1.6) na 0.7 (0.4–1.3) 0.7 (0.2–2.7) na 0.7 (0.2–1.8) na na na
  39. 39. Major features Agitation Inducible clonus Confusion/hypomania Tremor Myoclonus Diaphoresis Shivering Spontaneous clonus Fever Ocular clonus/oscillations Hyperreflexia Hypertonia/rigidity Hunter Area Toxicology Service 55.3 (22.0–138.7) 40.0 (25.1–105.8) 39.3 (12.2–126.4) 34.6 (11.7–101.9) 31.3 (3.5–275.4) 28.8 (3.1–264.4) 19.2 (3.7–99.0) 15.7 (5.3–43.5) 14.0 (6.0–32.6) 13.5 (3.8–47.2) 10.4 (4.6–23.8) 10.1 (3.6–28.5)
  40. 40. Minor features Ataxia/incoordination Nystagmus Tachycardia Coma Rhabdomyolysis Hunter Area Toxicology Service 4.7 (1.5–14.3) 3.8 (1.2–12.2) 3.3 (1.7–6.6) 2.6 (1.1–6.5) (1.6–∞ ) ∞
  41. 41. Non–features Akathisia Seizures Diarrhoea Mydriasis Lacrimation Oculogyric crisis Opisthotonus Hunter Area Toxicology Service 5.6 (0.3–91.8) 1.9 (0.2–18.3) 1.5 (0.6–4.2) 1.6 (0.8–3.1) – – –
  42. 42. Suggested criteria  Agitation/confusion/hypomania  Clonus (inducible/spontaneous/ocular)  Tremor/shivering/myoclonus  Diaphoresis  Fever  Hyperreflexia  Hypertonia/rigidity Hunter Area Toxicology Service
  43. 43. Suggested criteria Serotinergic drug with serotonin syndrome Serotinergic drug without serotonin syndrome Patients (%) ) 60 50 40 30 20 10 0 0 Hunter Area Toxicology Service 1 2 3 4 5 6 7
  44. 44. Signs suggestive of serotinergic drug overdose Hyperreflexia Hypertonia/rigidity Myoclonus Fever Mydriasis Hunter Area Toxicology Service 6.2 (4.7–8.2) 3.8 (2.2–6.6) 3.8 (1.5–9.5) 2.9 (1.8–4.7) 2.7 (2.1–3.6)
  45. 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. 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. 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. 48. Drugs used to treat serotonin syndrome  Non–specific blocking agents – methysergide – cyproheptadine  β–blockers – propranolol – pindolol Hunter Area Toxicology Service
  49. 49. Drugs used to treat serotonin syndrome  Benzodiazepines – lorazepam – diazepam – clonazepam  Neuroleptics – chlorprothixene – chlorpromazine – haloperidol Hunter Area Toxicology Service
  50. 50. Drugs used to treat serotonin syndrome  Miscellaneous – chlormethiazole – nitroglycerine  Drugs used for neuroleptic malignant syndrome – dantrolene – bromocriptine Hunter Area Toxicology Service
  51. 51. 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–HT 2 – failure of propranolol (5–HT1A blocker) in several cases – cyproheptadine more potent at 5–HT2 than 5–HT1 Hunter Area Toxicology Service
  52. 52. 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) Hunter Area Toxicology Service
  53. 53. 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 Hunter Area Toxicology Service
  54. 54. 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 Hunter Area Toxicology Service

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