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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. Phenothiazines chlorpromazine (Chlorpromazine Mixture, Chlorpromazine Mixture Forte, Largactil)

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Pharmacology and Toxicology of Antidepressants and Antipsychotics

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  1. Pharmacology and Toxicology of Antidepressants and Antipsychotics Prof Ian Whyte FRACP, FRCP Edin Hunter New England Toxicology Service

  2. 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)

  3. Newer Antipsychotics • Atypical agents • aripiprazole (Abilify) • clozapine (CloSyn, Clopine, Clozaril) • risperidone (Risperdal) • quetiapine (Seroquel) • amisulpride (Solian) • olanzapine (Zyprexa)

  4. Antipsychotics

  5. 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

  6. 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

  7. 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

  8. Differences among Antipsychotic Drugs • Chlorpromazine: α1 = 5-HT2 > D2 > D1 • Haloperidol: D2 > D1 = D4 > α1 > 5-HT2 • Clozapine: D4 = α1 > 5-HT2 > D2 = D1

  9. Metabolic effects

  10. 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

  11. 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

  12. 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

  13. 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)

  14. 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)

  15. 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)

  16. 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

  17. RIMA NaSSA SSRI NaRI NaSSA

  18. 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

  19. Sternbach criteria

  20. Serotonin receptors • 5–HT1 • subtypes • 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F • 5–HT2 • subtypes • 5–HT2A, 5–HT2B, 5–HT2C

  21. Serotonin receptors • 5–HT3 • 5–HT4 (rat) • 5–HT5 (rat) • 5–HT5A, 5–HT5 • 5–HT6 (rat) • 5–HT7 (rat and human)

  22. 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

  23. 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

  24. Serotonergic drugs • Serotonin precursors • S–adenyl–L–methionine • L–tryptophan • 5–hydroxytryptophan • dopamine

  25. Serotonergic drugs • Serotonin re-uptake inhibitors • citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine • clomipramine, imipramine • nefazodone, trazodone • chlorpheniramine • cocaine, dextromethorphan, pentazocine, pethidine, tramadol

  26. Serotonergic drugs • Serotonin agonists • fenfluramine, p–chloramphetamine • bromocriptine, dihydroergotamine, gepirone • sumatriptan • buspirone, ipsapirone • eltoprazin, quipazine

  27. Serotonergic drugs • Monoamine oxidase inhibitors (MAOIs) • clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine • selegiline • furazolidone • procarbazine

  28. Serotonergic drugs • Reversible inhibitors of MAO (RIMAs) • brofaramine • befloxatone, toloxatone • moclobemide

  29. Serotonergic drugs • Miscellaneous/mixed • lithium • lysergic acid diethylamide (LSD) • 3,4–methylenedioxymethamphetamine (MDMA, ecstasy) • methylenedioxyethamphetamine (eve) • propranolol, pindolol

  30. 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

  31. Serotonin excess • Other responses to neuroexcitation • fever • rhabdomyolysis

  32. Severe serotonin toxicity • Combination therapy • multiple different mechanisms of serotonin elevation • Rapidly rising temperature • Respiratory failure • hypertonia/rigidity • Spontaneous clonus

  33. Treatment options • Supportive care • symptom control • control of fever • ventilation • 5–HT2A antagonists • ideal • safe • effective • available

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

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