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Pharmacology and Toxicology of Antidepressants and Antipsychotics. Prof Ian Whyte FRACP, FRCP Edin Hunter New England Toxicology Service. Traditional Antipsychotics. Phenothiazines chlorpromazine (Chlorpromazine Mixture, Chlorpromazine Mixture Forte, Largactil)

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pharmacology and toxicology of antidepressants and antipsychotics

Pharmacology and Toxicology of Antidepressants and Antipsychotics

Prof Ian Whyte FRACP, FRCP Edin

Hunter New England Toxicology Service

traditional antipsychotics
Traditional Antipsychotics
  • Phenothiazines
    • chlorpromazine (Chlorpromazine Mixture, Chlorpromazine Mixture Forte, Largactil)
    • fluphenazine (Anatensol, Modecate)
    • flupenthixol (Fluanxol)
    • pericyazine (Neulactil)
    • pimozide (Orap)
    • thioridazine (Aldazine)
    • trifluoperazine (Stelazine)
    • zuclopenthixol (Clopixol)
  • Butyrophenones
    • droperidol (Droleptan Injection)
    • haloperidol (Haldol, Serenace)
newer antipsychotics
Newer Antipsychotics
  • Atypical agents
    • aripiprazole (Abilify)
    • clozapine (CloSyn, Clopine, Clozaril)
    • risperidone (Risperdal)
    • quetiapine (Seroquel)
    • amisulpride (Solian)
    • olanzapine (Zyprexa)
differences among antipsychotic drugs
Differences among Antipsychotic Drugs
  • All effective antipsychotic drugs block D2 receptors
  • Chlorpromazine and thioridazine
    • block α1 adrenoceptors more potently than D2 receptors
    • block serotonin 5-HT2 receptors relatively strongly
    • affinity for D1 receptors is relatively weak
  • Haloperidol
    • acts mainly on D2 receptors
    • some effect on 5-HT2 and α1 receptors
    • negligible effects on D1 receptors
  • Pimozide and amisulpride†
    • act almost exclusively on D2 receptors
differences among antipsychotic drugs9
Differences among Antipsychotic Drugs
  • Clozapine
    • binds more to D4, 5-HT2, α1, and histamine H1 receptors than to either D2 or D1 receptors
  • Risperidone
    • about equally potent in blocking D2 and 5-HT2 receptors
  • Olanzapine
    • more potent as an antagonist of 5-HT2 receptors
    • lesser potency at D1, D2, and α1 receptors
  • Quetiapine
    • lower-potency compound with relatively similar antagonism of 5-HT2, D2, α1, and α2 receptors
differences among antipsychotic drugs10
Differences among Antipsychotic Drugs
  • Clozapine, olanzapine and quetiapine
    • potent inhibitors of H1 histamine receptors
    • consistent with their sedative properties
  • Aripiprazole
    • partial agonist effects at D2 and 5-HT1A receptors
differences among antipsychotic drugs11
Differences among Antipsychotic Drugs
  • Chlorpromazine: α1 = 5-HT2 > D2 > D1
  • Haloperidol: D2 > D1 = D4 > α1 > 5-HT2
  • Clozapine: D4 = α1 > 5-HT2 > D2 = D1
insulin resistance
Insulin resistance
  • Prediabetes (impaired fasting glycaemia) has ~ 10% chance / year of converting to Type 2 diabetes
  • Prediabetes plus olanzapine has a 6-fold increased risk of conversion
  • If olanzapine is stopped 70% will revert back to prediabetes
stroke in the elderly
Stroke in the elderly
  • Risperidone and olanzapine associated with increased risk of stroke when used for behavioural control in dementia
  • Risperidone 3.3% vs 1.2% for placebo
  • Olanzapine 1.3% vs 0.4% for placebo
  • However, large observational database studies
    • Show no increased risk of stroke compared with typical antipsychotics or untreated dementia patients
conclusions
Conclusions
  • Atypical antipsychotics have serotonin blocking effects as well as dopamine blockade
  • As a group have less chance of extrapyramidal side effects
  • Most have weight gain and insulin resistance as a side effect (except perhaps aripiprazole and maybe amisulpride)
  • May be associated with stroke when used for behavioural control in dementia
  • Many have idiosyncratic toxicities
traditional antidepressants
Traditional Antidepressants
  • Tricyclic antidepressants
    • amitriptylline (Endep, Tryptanol)
    • clomipramine (Anafranil, Chem mart Clomipramine, GenRx Clomipramine, Placil, Terry White Chemists Clomipramine)
    • doxepin (Deptran, Sinequan)
    • dothiepin (Dothep, Prothiaden)
    • imipramine (Tofranil)
    • nortriptylline (Allegron)
    • trimipramine (Surmontil)
  • Tetracyclic antidepressants
    • Mianserin (Lumin, Tolvon)
  • MAOIs (monoamine oxidase inhibitors)
    • Phenelzine (Nardil)
    • Tranylcypromine (Parnate)
newer antidepressants
Newer antidepressants
  • SSRIs (specific serotonin reuptake inhibitors)
    • citalopram (Celapram, Chem mart Citalopram, Ciazil, Cipramil, GenRx Citalopram, Talam, Talohexal, Terry White Chemists Citalopram)
    • escitalopram (Lexapro)
    • fluoxetine (Auscap 20 mg Capsules, Chem mart Fluoxetine, Fluohexal, Fluoxebell, Fluoxetine-DP, GenRx Fluoxetine, Lovan, Prozac, Terry White Chemists Fluoxetine, Zactin)
    • fluvoxamine (Faverin, Luvox, Movox, Voxam)
    • paroxetine (Aropax, Chem mart Paroxetine, GenRx Paroxetine, Oxetine, Paxtine, Terry White Chemists Paroxetine)
    • sertraline (Chem mart Sertraline, Concorz, Eleva, GenRx Sertraline, Sertraline-DP, Terry White Chemists Sertraline, Xydep, Zoloft)
  • RIMA (reversible inhibitor of monoamine oxidase A)
    • moclobemide (Arima, Aurorix, Chem mart Moclobemide, Clobemix, GenRx Moclobemide, Maosig, Mohexal 150 mg, Terry White Chemists Moclobemide)
newest antidepressants
Newest antidepressants
  • SNRI (serotonin noradrenergic reuptake inhibitors)
    • venlafaxine (Efexor-XR)
  • NaSSA (noradrenergic and specific serotonergic antidepressant)
    • mirtazapine (Avanza, Avanza SolTab, Axit, Mirtazon, Remeron)
  • NaRI (selective noradrenaline reuptake inhibitor )
    • reboxetine (Edronax)
selectivity of antidepressants

Nisoxetine

1000

Nomifensine

Maprotiline (approx)

Selectivity of antidepressants

100

NA-

selective

Desipramine

10

Imipramine

Nortriptyline

Amitriptyline

Non-

selective

1

Ratio NA: 5-HT uptake inhibition

Clomipramine

Trazodone

Zimelidine

0.1

5-HT-

selective

0.01

Fluoxetine

Citalopram (approx)

0.001

slide26

RIMA

NaSSA

SSRI

NaRI

NaSSA

serotonin excess
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
serotonin receptors
Serotonin receptors
  • 5–HT1
    • subtypes
      • 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
  • 5–HT2
    • subtypes
      • 5–HT2A, 5–HT2B, 5–HT2C
serotonin receptors30
Serotonin receptors
  • 5–HT3
  • 5–HT4 (rat)
  • 5–HT5 (rat)
      • 5–HT5A, 5–HT5
  • 5–HT6 (rat)
  • 5–HT7 (rat and human)
serotonin receptors31
Serotonin receptors
  • 5–HT1
    • subtypes
      • 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
    • primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin
  • 5–HT2
    • subtypes
      • 5–HT2A, 5–HT2B, 5–HT2C
    • primarily responsible for the toxic effects of increased intrasynaptic serotonin
slide32

Boyer EW, Shannon M

  • The serotonin syndrome
  • New England Journal of Medicine
  • 2005 Mar 17;352(11):1112-20
  • Isbister GK, Buckley NA

The Pathophysiology of Serotonin Toxicity in Animals and Humans: Implications for Diagnosis and Treatment

  • Clinical Neuropharmacology 2005;28(5):205-214
serotonergic drugs
Serotonergic drugs
  • Serotonin precursors
    • S–adenyl–L–methionine
    • L–tryptophan
    • 5–hydroxytryptophan
    • dopamine
serotonergic drugs34
Serotonergic drugs
  • Serotonin re-uptake inhibitors
    • citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine
    • clomipramine, imipramine
    • nefazodone, trazodone
    • chlorpheniramine
    • cocaine, dextromethorphan, pentazocine, pethidine, tramadol
serotonergic drugs35
Serotonergic drugs
  • Serotonin agonists
    • fenfluramine, p–chloramphetamine
    • bromocriptine, dihydroergotamine, gepirone
    • sumatriptan
    • buspirone, ipsapirone
    • eltoprazin, quipazine
serotonergic drugs36
Serotonergic drugs
  • Monoamine oxidase inhibitors (MAOIs)
    • clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine
    • selegiline
    • furazolidone
    • procarbazine
serotonergic drugs37
Serotonergic drugs
  • Reversible inhibitors of MAO (RIMAs)
    • brofaramine
    • befloxatone, toloxatone
    • moclobemide
serotonergic drugs38
Serotonergic drugs
  • Miscellaneous/mixed
    • lithium
    • lysergic acid diethylamide (LSD)
    • 3,4–methylenedioxymethamphetamine (MDMA, ecstasy)
    • methylenedioxyethamphetamine (eve)
    • propranolol, pindolol
serotonin excess39
Serotonin excess
  • Primary neuroexcitation (5–HT2A)
    • mental status
      • agitation/delirium
    • motor system
      • clonus/myoclonus
        • inducible/spontaneous/ocular
      • tremor/shivering
      • hyperreflexia/hypertonia
    • autonomic system
      • diaphoresis/tachycardia/mydriasis
serotonin excess40
Serotonin excess
  • Other responses to neuroexcitation
    • fever
    • rhabdomyolysis
severe serotonin toxicity
Severe serotonin toxicity
  • Combination therapy
    • multiple different mechanisms of serotonin elevation
  • Rapidly rising temperature
  • Respiratory failure
    • hypertonia/rigidity
  • Spontaneous clonus
treatment options
Treatment options
  • Supportive care
    • symptom control
    • control of fever
    • ventilation
  • 5–HT2A antagonists
    • ideal
      • safe
      • effective
      • available
cyproheptadine
Cyproheptadine
  • Oral preparation
  • Safe
  • 20–30 mg required to achieve 90% blockade of brain 5–HT2 receptors

Affinity at 5-HT2 = 10-7 x 1/Kd

  • Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist. American Journal of Psychiatry, 154, 884
chlorpromazine
Chlorpromazine
  • 5–HT2 antagonist
    • PET scans show avid 5–HT2 binding
  • Oral or parenteral medication
    • ventilated patients
    • impaired absorption
      • recent activated charcoal
  • Sedating and a potent vasodilator
therapy
Therapy
  • Oral therapy
    • cyproheptadine 12 mg stat then 4–8 mg q 4–6h
  • Oral therapy unsuitable or fails
    • chlorpromazine 25–50 mg IVI stat then up to 50 mg orally or IVI q6h
  • Ventilation impaired and/or fever > 39oC
    • anaesthesia, muscle relaxation ± active cooling
    • chlorpromazine 100–400 mg IMI/IVI over first two hours
conclusions49
Conclusions
  • Serotonin toxicity is a spectrum disorder not a discrete syndrome
  • The clinical manifestations of toxicity are 5–HT2 mediated while the therapeutic effect is 5–HT1
  • Newer agents with little or no risk of serotonin toxicity
    • Reboxetine and mirtazapine
conclusions50
Conclusions
  • First line of treatment is to remove the offending agent(s)
  • Specific inhibitors of 5–HT2 have a role but paralysis and ventilation may be needed