Risks of Psychotropics

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