Pharmacology and toxicology of antidepressants and antipsychotics
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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 l.jpg

Pharmacology and Toxicology of Antidepressants and Antipsychotics

Prof Ian Whyte FRACP, FRCP Edin

Hunter New England Toxicology Service


Traditional antipsychotics l.jpg
Traditional Antipsychotics 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)


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Newer Antipsychotics Antipsychotics

  • Atypical agents

    • aripiprazole (Abilify)

    • clozapine (CloSyn, Clopine, Clozaril)

    • risperidone (Risperdal)

    • quetiapine (Seroquel)

    • amisulpride (Solian)

    • olanzapine (Zyprexa)


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Antipsychotics Antipsychotics


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Differences among Antipsychotic Drugs Antipsychotics

  • 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


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Differences among Antipsychotic Drugs Antipsychotics

  • 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


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Differences among Antipsychotic Drugs Antipsychotics

  • 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


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Differences among Antipsychotic Drugs Antipsychotics

  • Chlorpromazine: α1 = 5-HT2 > D2 > D1

  • Haloperidol: D2 > D1 = D4 > α1 > 5-HT2

  • Clozapine: D4 = α1 > 5-HT2 > D2 = D1


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Metabolic effects Antipsychotics


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Insulin resistance Antipsychotics

  • 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


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Stroke in the elderly Antipsychotics

  • 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


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Conclusions Antipsychotics

  • 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


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Traditional Antidepressants Antipsychotics

  • 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)


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Newer antidepressants Antipsychotics

  • 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)


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Newest antidepressants Antipsychotics

  • 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)


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Nisoxetine Antipsychotics

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


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RIMA Antipsychotics

NaSSA

SSRI

NaRI

NaSSA


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Serotonin excess Antipsychotics

  • 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


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Sternbach criteria Antipsychotics


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Serotonin receptors Antipsychotics

  • 5–HT1

    • subtypes

      • 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F

  • 5–HT2

    • subtypes

      • 5–HT2A, 5–HT2B, 5–HT2C


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Serotonin receptors Antipsychotics

  • 5–HT3

  • 5–HT4 (rat)

  • 5–HT5 (rat)

    • 5–HT5A, 5–HT5

  • 5–HT6 (rat)

  • 5–HT7 (rat and human)


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    Serotonin receptors Antipsychotics

    • 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


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    • Boyer EW, Shannon M Antipsychotics

    • 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


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    Serotonergic drugs Antipsychotics

    • Serotonin precursors

      • S–adenyl–L–methionine

      • L–tryptophan

      • 5–hydroxytryptophan

      • dopamine


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    Serotonergic drugs Antipsychotics

    • Serotonin re-uptake inhibitors

      • citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine

      • clomipramine, imipramine

      • nefazodone, trazodone

      • chlorpheniramine

      • cocaine, dextromethorphan, pentazocine, pethidine, tramadol


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    Serotonergic drugs Antipsychotics

    • Serotonin agonists

      • fenfluramine, p–chloramphetamine

      • bromocriptine, dihydroergotamine, gepirone

      • sumatriptan

      • buspirone, ipsapirone

      • eltoprazin, quipazine


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    Serotonergic drugs Antipsychotics

    • Monoamine oxidase inhibitors (MAOIs)

      • clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine

      • selegiline

      • furazolidone

      • procarbazine


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    Serotonergic drugs Antipsychotics

    • Reversible inhibitors of MAO (RIMAs)

      • brofaramine

      • befloxatone, toloxatone

      • moclobemide


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    Serotonergic drugs Antipsychotics

    • Miscellaneous/mixed

      • lithium

      • lysergic acid diethylamide (LSD)

      • 3,4–methylenedioxymethamphetamine (MDMA, ecstasy)

      • methylenedioxyethamphetamine (eve)

      • propranolol, pindolol


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    Serotonin excess Antipsychotics

    • Primary neuroexcitation (5–HT2A)

      • mental status

        • agitation/delirium

      • motor system

        • clonus/myoclonus

          • inducible/spontaneous/ocular

        • tremor/shivering

        • hyperreflexia/hypertonia

      • autonomic system

        • diaphoresis/tachycardia/mydriasis


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    Serotonin excess Antipsychotics

    • Other responses to neuroexcitation

      • fever

      • rhabdomyolysis


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    Severe serotonin toxicity Antipsychotics

    • Combination therapy

      • multiple different mechanisms of serotonin elevation

    • Rapidly rising temperature

    • Respiratory failure

      • hypertonia/rigidity

    • Spontaneous clonus


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    Treatment options Antipsychotics

    • Supportive care

      • symptom control

      • control of fever

      • ventilation

    • 5–HT2A antagonists

      • ideal

        • safe

        • effective

        • available


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    Cyproheptadine Antipsychotics

    • 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


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    Chlorpromazine Antipsychotics

    • 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


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    Therapy Antipsychotics

    • 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


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    Conclusions Antipsychotics

    • 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


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    Conclusions Antipsychotics

    • 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


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