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Risks of Psychotropics

Learn about the risks associated with psychotropic medications like antidepressants and antipsychotics. Understand their adverse effects, toxicity, and potential interactions. Explore the mechanisms of action, pharmacokinetics, and common drug interactions that can impact treatment outcomes. Stay informed about the dangers of overdose and potential toxicities that may arise.

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Risks of Psychotropics

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  1. Risks of Psychotropics

  2. The Risks • Antidepressants • Antipsychotics • Adverse Effects • Toxicity • Significant Interactions

  3. Tricyclic antidepressants • Mechanism of action • Block reuptake of noradrenaline seratonin. • Dose dependent increase in seratonin, noradrenaline and dopamine. • Also alpha blockade antihistamine actions and anticholinergic actions. • Pharmacokinetics • Highly lipid soluble • large volume of distribution • rapid absorption • Polymorphic hepatic metabolism.

  4. Elevated [TCAs] Cimetidine Ethanal acute ingestion Haloperidol Phenothiazine Propoxyphene Fluoxetine Lower [TCAs] Chronic ethanol Barbiturates Carbamazepine TCAs: Pharmacokinetic Interactions Elevated [Interacting Drugs] Phenytoin Warfarin

  5. TCAs: Pharmacodynamic Interactions • Decreased antihypertensive effect. • Methyldopa Clonidine • Disulfiram - acute organic brain syndrome • Classic monoamine oxidase inhibitors increase therapeutic and toxic effects of both drugs. Hypertension, delirium, seizures.

  6. Toxicity in overdose • Not all are equipotent • CNS • Sedation & coma • Seizures • Anticholinergic delirium • Cardiovascular • Supraventricular and ventricular arrhythmias • Conduction defects • Sinus tachycardia • Hypotension

  7. MAO-A inhibitors: Moclobemide • Mechanism • reversible competitive blockade of monoamine oxidase A enzymes decreasing breakdown of monoamines. • Pharmacokinetics • polymorphic P450 hepatic metabolism - active metabolites • half life 1 - 1½ hours • low volume of distribution • 50% protein bound • high bioavailabilty 90% with repeated doses • Inhibition of monoamine oxidase 12 to 16 hours.

  8. MAO-A inhibitors: Moclobemide • Dosage • 300 to 600mg per day. • Side effects • Nausea (for possibly 5%) • Drug interactions • No clear evidence for dietary restrictions. • Reduced clearance by cimetidine.

  9. MAO-A inhibitors: Moclobemide • Toxicity • Minimal toxicity in overdose • CNS depression and confusion, nausea, hyperreflexia, hypotension and occasional hyperthermia.

  10. Fluoxetine • Mechanism • Inhibition of presynaptic seratonin reuptake plus probably altering sensitivity to serotonin.

  11. Fluoxetine • Pharmacokinetics • High bioavailability and volume of distribution • High protein binding. • P450 hepatic metabolism, less than 5% renal metabolism. • Half life of fluoxetine approximately 70 hours. • Half life of active metabolite desmethylfluoxetine 330 hours, therefore steady state concentrations take 2 to 4 weeks.

  12. Fluoxetine • Efficacy • In moderate depression similar to tricyclic antidepressants • some analgesic and anorectic effects, no sedative effects or alpha effects. • Not proarrhythmic. • No evidence of psychomotor changes subjectively or objectively

  13. Fluoxetine • Side effects • Approximately 20% of patients experience nervousness, insomnia or nausea. Treatment failure due to side effects approximately 5%. • Drug interaction • Kinetic: Increased concentration of TCA, carbamazepine, haloperidol, metoprolol & terfenadine • Toxicity • Minimal cardiotoxicity, ataxia, CNS depression, occasional seizures.

  14. Antipsychotics:Phenothiazines and butyrophenones • Mechanism • Antipsychotic effect probably due to dopamine blockade. • Dirty drugs with alpha effects, antihistamine effects, anticholinergic effects (except haloperidol) direct membrane stabilising effects.

  15. Antipsychotics:Phenothiazines and butyrophenones • Metabolism • Predominantly Polymorphic hepatic P450 enzyme metabolism. • Conjugation • High volume of distribution, long half life

  16. Antipsychotics:Phenothiazines and butyrophenones • Side effects • Similar to those of tricyclic antidepressants • Attributed to dopamine blockade • Parkinsonian states • Tardive dyskinesia • Neuroleptic malignant syndrome • Acute dystonia (early) • Akathesia

  17. Antipsychotics:Phenothiazines and butyrophenones • Lowered seizure threshold • Hypersensitivity reactions • Hyperpigmentation • Retinal toxicity (especially thioridazine >800mg/day) • Lowered seizure threshold for phenothiazines • Endocrine

  18. Antipsychotics:Phenothiazines and butyrophenones • Drug interactions • Enzyme inducers some self induction. • Heavy smoking may decrease levels. • Antipsychotics may inhibit antidepressant metabolism. • Inhibits phenytoin metabolism.

  19. Neuroleptic Malignant Syndrome • ESSENTIAL CRITERIA (need 1 of the following) • Receiving or recently received a neuroleptic drug • Receiving other dopamine antagonist (eg metoclopramide) • Recently stopped therapy with a dopamine agonist (eg levodopa)

  20. Neuroleptic Malignant Syndrome • MAJOR • Fever > 37.5OC (no other cause) • Autonomic dysfunction • Extrapyramidal syndrome

  21. Neuroleptic Malignant Syndrome • MINOR CRITERIA • CPK rise • Altered sensorium • Leucocytosis >15000 • Other possible cause for fever (delete leucocytosis) • Low serum iron • Therapeutic response (Sequence)

  22. Neuroleptic Malignant Syndrome • TREATMENT • Withdrawal • Specific • Bromocriptine. • L-Dopa • Dantrolene. • Anticholinergics and benzodiazepines • ECT • Nifedipine

  23. Neuroleptic Malignant Syndrome • Recommencement of Neuroleptics. • with caution after complete recovery from NMS

  24. Clozapine • A Diebenzodizepine Antipsychotic • A Low Affinity Dopamine Antagonist • A High Affinity Serotonin Antagonist • Indications • Treatment Resistant Schizophrenia

  25. Clozapine • Pharmacokinetics • Bioavailability 50% • Protein Binding 95% • Half Life 12 Hours • Hepatic Metabolism

  26. Clozapine • Adverse Effects • Neuroleptic Malignanct Syndrome • Seizures 5% of Patients > 600 Mg a Day • Hypersalivation • Agranulocytosis • 0.8% In One Year (95% in First Six Months) • Increased Risk in the Elderly and Female • Increased Risk in Ashkenazi Jews

  27. Clozapine • Drug Interactions • Enhance Sedation With Other Sedatives • Metabolism Inhibited by Cimetidine Leading to Clozapine Toxicity • Clozapine Metabolism Induced by Phenytoin

  28. Clozapine • Overdose • Delirium, Coma, Seizures • Tachycardia, Hypotension • Respiratory Depression • Hypersalivation

  29. Risperidone - a benzisoxazole derivative • Indications • schizophrenia • Negative symptoms • Movement disorders on conventional therapy • Mechanism • Low affinity D2 antagonism • High affinity 5H2 antagonism • Some alpha 1 and antihistamine effect

  30. Risperidone - a benzisoxazole derivative • Pharmacokinetics • rapid absorption and high bioavailability • risperidone metabolised to 9 hydroxy resperidone • P450 to D6 half life of risperidone (fast acetylators 2-4 hours) • Half life hydroxyrisperidone (fast acetylators 27 hours) • Protein binding (albumin and alpha glycoprotein) • risperidone 88%, 9 hydroxyrisperidone 77%

  31. Risperidone - a benzisoxazole derivative • Side effects • postural hypotension • weight gain • hyperprolactinaemia asthaenia • Drug interactions • pharmacodynamic • dopamine • augmented affect of TCAs and phenothiazines

  32. Selectivity of antidepressants Nisoxetine 1000 Nomifensine Maprotiline (approx) 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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