1 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Risks of Psychotropics

2 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital The Risks  Antidepressants  Antipsychotics  Adverse Effects  Toxicity  Significant Interactions

3 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital TCAs: Pharmacokinetic Interactions Elevated [TCAs] Cimetidine Ethanal acute ingestion Haloperidol Phenothiazine Propoxyphene Fluoxetine Lower [TCAs] Chronic ethanol Barbiturates Carbamazepine Elevated [Interacting Drugs] Phenytoin Warfarin

5 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Toxicity in overdose  Not all are equipotent  CNS –Sedation & coma –Seizures –Anticholinergic delirium  Cardiovascular –Supraventricular and ventricular arrhythmias –Conduction defects –Sinus tachycardia –Hypotension

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

8 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital MAO-A inhibitors: Moclobemide  Toxicity –Minimal toxicity in overdose –CNS depression and confusion, nausea, hyperreflexia, hypotension and occasional hyperthermia.

10 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Fluoxetine  Mechanism –Inhibition of presynaptic seratonin reuptake plus probably altering sensitivity to serotonin.

11 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Antipsychotics:Phenothiazines and butyrophenones  Metabolism –Predominantly Polymorphic hepatic P450 enzyme metabolism. –Conjugation –High volume of distribution, long half life

16 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Antipsychotics:Phenothiazines and butyrophenones  Side effects –Similar to those of tricyclic antidepressants –Attributed to dopamine blockade l Parkinsonian states l Tardive dyskinesia l Neuroleptic malignant syndrome l Acute dystonia (early) l Akathesia

17 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Antipsychotics:Phenothiazines and butyrophenones –Lowered seizure threshold –Hypersensitivity reactions –Hyperpigmentation –Retinal toxicity (especially thioridazine >800mg/day) –Lowered seizure threshold for phenothiazines –Endocrine

18 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Neuroleptic Malignant Syndrome  MAJOR –Fever > 37.5OC (no other cause) –Autonomic dysfunction –Extrapyramidal syndrome

21 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Neuroleptic Malignant Syndrome  TREATMENT –Withdrawal –Specific –Bromocriptine. –L-Dopa –Dantrolene. –Anticholinergics and benzodiazepines –ECT –Nifedipine

23 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Neuroleptic Malignant Syndrome  Recommencement of Neuroleptics. – with caution after complete recovery from NMS

24 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Clozapine –A Diebenzodizepine Antipsychotic –A Low Affinity Dopamine Antagonist –A High Affinity Serotonin Antagonist  Indications –Treatment Resistant Schizophrenia

25 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Clozapine  Pharmacokinetics –Bioavailability 50% –Protein Binding 95% –Half Life 12 Hours –Hepatic Metabolism

26 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Clozapine  Adverse Effects –Neuroleptic Malignanct Syndrome –Seizures 5% of Patients > 600 Mg a Day –Hypersalivation –Agranulocytosis l 0.8% In One Year (95% in First Six Months) l Increased Risk in the Elderly and Female l Increased Risk in Ashkenazi Jews

27 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Clozapine  Drug Interactions –Enhance Sedation With Other Sedatives –Metabolism Inhibited by Cimetidine Leading to Clozapine Toxicity –Clozapine Metabolism Induced by Phenytoin

28 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Clozapine  Overdose –Delirium, Coma, Seizures –Tachycardia, Hypotension –Respiratory Depression –Hypersalivation

29 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Risperidone - a benzisoxazole derivative  Indications –schizophrenia l Negative symptoms l Movement disorders on conventional therapy  Mechanism –Low affinity D2 antagonism –High affinity 5H2 antagonism –Some alpha 1 and antihistamine effect

30 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 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) l risperidone 88%, 9 hydroxyrisperidone 77%

31 Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital Risperidone - a benzisoxazole derivative  Side effects –postural hypotension –weight gain –hyperprolactinaemia asthaenia  Drug interactions –pharmacodynamic l dopamine l augmented affect of TCAs and phenothiazines

32 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