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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

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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)

    • fluphenazine (Anatensol, Modecate)

    • flupenthixol (Fluanxol)

    • pericyazine (Neulactil)

    • pimozide (Orap)

    • thioridazine (Aldazine)

    • trifluoperazine (Stelazine)

    • zuclopenthixol (Clopixol)

  • Butyrophenones

    • droperidol (Droleptan Injection)

    • haloperidol (Haldol, Serenace)


Newer Antipsychotics

  • Atypical agents

    • aripiprazole (Abilify)

    • clozapine (CloSyn, Clopine, Clozaril)

    • risperidone (Risperdal)

    • quetiapine (Seroquel)

    • amisulpride (Solian)

    • olanzapine (Zyprexa)


Antipsychotics


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 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 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 Drugs

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

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

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


Metabolic effects


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

  • 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

  • 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

  • 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

  • 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

  • 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)


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


RIMA

NaSSA

SSRI

NaRI

NaSSA


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


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 receptors

  • 5–HT3

  • 5–HT4 (rat)

  • 5–HT5 (rat)

    • 5–HT5A, 5–HT5

  • 5–HT6 (rat)

  • 5–HT7 (rat and human)


  • 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


    • 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

    • Serotonin precursors

      • S–adenyl–L–methionine

      • L–tryptophan

      • 5–hydroxytryptophan

      • dopamine


    Serotonergic drugs

    • Serotonin re-uptake inhibitors

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

      • clomipramine, imipramine

      • nefazodone, trazodone

      • chlorpheniramine

      • cocaine, dextromethorphan, pentazocine, pethidine, tramadol


    Serotonergic drugs

    • Serotonin agonists

      • fenfluramine, p–chloramphetamine

      • bromocriptine, dihydroergotamine, gepirone

      • sumatriptan

      • buspirone, ipsapirone

      • eltoprazin, quipazine


    Serotonergic drugs

    • Monoamine oxidase inhibitors (MAOIs)

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

      • selegiline

      • furazolidone

      • procarbazine


    Serotonergic drugs

    • Reversible inhibitors of MAO (RIMAs)

      • brofaramine

      • befloxatone, toloxatone

      • moclobemide


    Serotonergic drugs

    • Miscellaneous/mixed

      • lithium

      • lysergic acid diethylamide (LSD)

      • 3,4–methylenedioxymethamphetamine (MDMA, ecstasy)

      • methylenedioxyethamphetamine (eve)

      • propranolol, pindolol


    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 excess

    • Other responses to neuroexcitation

      • fever

      • rhabdomyolysis


    Severe serotonin toxicity

    • Combination therapy

      • multiple different mechanisms of serotonin elevation

    • Rapidly rising temperature

    • Respiratory failure

      • hypertonia/rigidity

    • Spontaneous clonus


    Treatment options

    • Supportive care

      • symptom control

      • control of fever

      • ventilation

    • 5–HT2A antagonists

      • ideal

        • safe

        • effective

        • available


    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

    • 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

    • 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


    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


    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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