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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Pharmacology and Toxicology of Antidepressants and Antipsychotics Prof Ian Whyte.

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Presentation on theme: "Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Pharmacology and Toxicology of Antidepressants and Antipsychotics Prof Ian Whyte."— Presentation transcript:

1 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Pharmacology and Toxicology of Antidepressants and Antipsychotics Prof Ian Whyte FRACP, FRCP Edin Hunter New England Toxicology Service

2 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

3 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)

4 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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

6 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Antipsychotics

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8 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

9 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

10 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

11 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Differences among Antipsychotic Drugs Chlorpromazine: α 1 = 5-HT 2 > D 2 > D 1 Haloperidol: D 2 > D 1 = D 4 > α 1 > 5-HT 2 Clozapine: D 4 = α 1 > 5-HT 2 > D 2 = D 1

12 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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14 Metabolic effects Weight gain over 1 year (kg) aripiprazole1 amisulpride1.5 quetiapine2 – 3 risperidone2 – 3 olanzapine> 6 clozapine> 6

15 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

16 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

17 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

18 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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)

19 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

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22 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)

23 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

24 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)

25 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Selectivity of antidepressants Nisoxetine Nomifensine Maprotiline (approx) Desipramine Imipramine Nortriptyline Amitriptyline Clomipramine Trazodone Zimelidine Fluoxetine Citalopram (approx) NA- selective Non- selective 5-HT- selective Ratio NA: 5-HT uptake inhibition

26 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital SSRINaRI RIMA NaSSA

27 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

28 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Sternbach criteria

29 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonin receptors 5–HT 1 –subtypes l 5–HT 1A, 5–HT 1B, 5–HT 1D, 5–HT 1E, 5–HT 1F 5–HT 2 –subtypes l 5–HT 2A, 5–HT 2B, 5–HT 2C

30 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonin receptors 5–HT 3 5–HT 4 (rat) 5–HT 5 (rat) l 5–HT 5A, 5–HT 5 5–HT 6 (rat) 5–HT 7 (rat and human)

31 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonin receptors 5–HT 1 –subtypes l 5–HT 1A, 5–HT 1B, 5–HT 1D, 5– HT 1E, 5–HT 1F –primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin 5–HT 2 –subtypes l 5–HT 2A, 5–HT 2B, 5–HT 2C –primarily responsible for the toxic effects of increased intrasynaptic serotonin

32 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Boyer EW, Shannon M The serotonin syndrome New England Journal of Medicine 2005 Mar 17;352(11): Isbister GK, Buckley NA The Pathophysiology of Serotonin Toxicity in Animals and Humans: Implications for Diagnosis and Treatment Clinical Neuropharmacology 2005;28(5):

33 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonergic drugs Serotonin precursors –S–adenyl–L–methionine –L–tryptophan –5–hydroxytryptophan –dopamine

34 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonergic drugs Serotonin re-uptake inhibitors –citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine –clomipramine, imipramine –nefazodone, trazodone –chlorpheniramine –cocaine, dextromethorphan, pentazocine, pethidine, tramadol

35 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonergic drugs Serotonin agonists –fenfluramine, p–chloramphetamine –bromocriptine, dihydroergotamine, gepirone –sumatriptan –buspirone, ipsapirone –eltoprazin, quipazine

36 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonergic drugs Monoamine oxidase inhibitors (MAOIs) –clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine –selegiline –furazolidone –procarbazine

37 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonergic drugs Reversible inhibitors of MAO (RIMAs) –brofaramine –befloxatone, toloxatone –moclobemide

38 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonergic drugs Miscellaneous/mixed –lithium –lysergic acid diethylamide (LSD) –3,4–methylenedioxymethamphetamine (MDMA, ecstasy) –methylenedioxyethamphetamine (eve) –propranolol, pindolol

39 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonin excess Primary neuroexcitation (5–HT 2A ) –mental status l agitation/delirium –motor system l clonus/myoclonus –inducible/spontaneous/ocular l tremor/shivering l hyperreflexia/hypertonia –autonomic system l diaphoresis/tachycardia/mydriasis

40 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonin excess Other responses to neuroexcitation –fever –rhabdomyolysis

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

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45 Treatment options Supportive care –symptom control –control of fever –ventilation 5–HT 2A antagonists –ideal l safe l effective l available

46 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist. American Journal of Psychiatry, 154, 884 Cyproheptadine Oral preparation Safe 20–30 mg required to achieve 90% blockade of brain 5–HT 2 receptors Affinity at 5-HT 2 = x 1/Kd

47 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Chlorpromazine 5–HT 2 antagonist –PET scans show avid 5–HT 2 binding Oral or parenteral medication –ventilated patients –impaired absorption l recent activated charcoal Sedating and a potent vasodilator

48 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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 > 39 o C –anaesthesia, muscle relaxation ± active cooling –chlorpromazine 100–400 mg IMI/IVI over first two hours

49 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Conclusions Serotonin toxicity is a spectrum disorder not a discrete syndrome The clinical manifestations of toxicity are 5– HT 2 mediated while the therapeutic effect is 5–HT 1 Newer agents with little or no risk of serotonin toxicity –Reboxetine and mirtazapine

50 Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Conclusions First line of treatment is to remove the offending agent(s) Specific inhibitors of 5–HT 2 have a role but paralysis and ventilation may be needed


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