Pharmacology and toxicology of antidepressants and antipsychotics l.jpg
Sponsored Links
This presentation is the property of its rightful owner.
1 / 50

Pharmacology and Toxicology of Antidepressants and Antipsychotics PowerPoint PPT Presentation

  • Updated On :
  • Presentation posted in: General

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)

Download Presentation

Pharmacology and Toxicology of Antidepressants and Antipsychotics

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript

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

  • 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 l.jpg

Newer Antipsychotics

  • Atypical agents

    • aripiprazole (Abilify)

    • clozapine (CloSyn, Clopine, Clozaril)

    • risperidone (Risperdal)

    • quetiapine (Seroquel)

    • amisulpride (Solian)

    • olanzapine (Zyprexa)

Antipsychotics l.jpg


Differences among antipsychotic drugs l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

Differences among Antipsychotic Drugs

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

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

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

Metabolic effects l.jpg

Metabolic effects

Insulin resistance l.jpg

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 l.jpg

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 l.jpg


  • 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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg




Maprotiline (approx)

Selectivity of antidepressants












Ratio NA: 5-HT uptake inhibition









Citalopram (approx)


Slide26 l.jpg






Serotonin excess l.jpg

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

Sternbach criteria l.jpg

Sternbach criteria

Serotonin receptors l.jpg

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 l.jpg

Serotonin receptors

  • 5–HT3

  • 5–HT4 (rat)

  • 5–HT5 (rat)

    • 5–HT5A, 5–HT5

  • 5–HT6 (rat)

  • 5–HT7 (rat and human)

  • Serotonin receptors31 l.jpg

    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 l.jpg

    • 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 l.jpg

    Serotonergic drugs

    • Serotonin precursors

      • S–adenyl–L–methionine

      • L–tryptophan

      • 5–hydroxytryptophan

      • dopamine

    Serotonergic drugs34 l.jpg

    Serotonergic drugs

    • Serotonin re-uptake inhibitors

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

      • clomipramine, imipramine

      • nefazodone, trazodone

      • chlorpheniramine

      • cocaine, dextromethorphan, pentazocine, pethidine, tramadol

    Serotonergic drugs35 l.jpg

    Serotonergic drugs

    • Serotonin agonists

      • fenfluramine, p–chloramphetamine

      • bromocriptine, dihydroergotamine, gepirone

      • sumatriptan

      • buspirone, ipsapirone

      • eltoprazin, quipazine

    Serotonergic drugs36 l.jpg

    Serotonergic drugs

    • Monoamine oxidase inhibitors (MAOIs)

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

      • selegiline

      • furazolidone

      • procarbazine

    Serotonergic drugs37 l.jpg

    Serotonergic drugs

    • Reversible inhibitors of MAO (RIMAs)

      • brofaramine

      • befloxatone, toloxatone

      • moclobemide

    Serotonergic drugs38 l.jpg

    Serotonergic drugs

    • Miscellaneous/mixed

      • lithium

      • lysergic acid diethylamide (LSD)

      • 3,4–methylenedioxymethamphetamine (MDMA, ecstasy)

      • methylenedioxyethamphetamine (eve)

      • propranolol, pindolol

    Serotonin excess39 l.jpg

    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 l.jpg

    Serotonin excess

    • Other responses to neuroexcitation

      • fever

      • rhabdomyolysis

    Severe serotonin toxicity l.jpg

    Severe serotonin toxicity

    • Combination therapy

      • multiple different mechanisms of serotonin elevation

    • Rapidly rising temperature

    • Respiratory failure

      • hypertonia/rigidity

    • Spontaneous clonus

    Treatment options l.jpg

    Treatment options

    • Supportive care

      • symptom control

      • control of fever

      • ventilation

    • 5–HT2A antagonists

      • ideal

        • safe

        • effective

        • available

    Cyproheptadine l.jpg


    • 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 l.jpg


    • 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 l.jpg


    • 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 l.jpg


    • 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 l.jpg


    • 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

  • Login