Risks of Psychotropics Clinical Toxicology Pharmacology Newcastle Mater

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

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

Tricyclic antidepressants N Mechanism of action – Block reuptake of noradrenaline seratonin. – Dose dependent increase in seratonin, noradrenaline and dopamine. – Also alpha blockade antihistamine actions and anticholinergic actions. N Pharmacokinetics – – Highly lipid soluble large volume of distribution rapid absorption Polymorphic hepatic metabolism. Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 3

TCAs: Pharmacokinetic Interactions Elevated [TCAs] Lower [TCAs] Elevated [Interacting Drugs] Cimetidine Ethanal acute ingestion Haloperidol Phenothiazine Propoxyphene Fluoxetine Chronic ethanol Barbiturates Carbamazepine Phenytoin Warfarin Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 4

TCAs: Pharmacodynamic Interactions N N 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. Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 5

Toxicity in overdose N N Not all are equipotent CNS – Sedation & coma – Seizures – Anticholinergic delirium N Cardiovascular – Supraventricular and ventricular arrhythmias – Conduction defects – Sinus tachycardia – Hypotension Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 6

MAO-A inhibitors: Moclobemide N Mechanism – reversible competitive blockade of monoamine oxidase A enzymes decreasing breakdown of monoamines. N Pharmacokinetics polymorphic P 450 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. l Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 7

MAO-A inhibitors: Moclobemide N Dosage – 300 to 600 mg per day. N Side effects – Nausea (for possibly 5%) N Drug interactions – No clear evidence for dietary restrictions. – Reduced clearance by cimetidine. Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 8

MAO-A inhibitors: Moclobemide N Toxicity – Minimal toxicity in overdose – CNS depression and confusion, nausea, hyperreflexia, hypotension and occasional hyperthermia. Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 9

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

Fluoxetine N Pharmacokinetics – High bioavailability and volume of distribution – High protein binding. – P 450 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. Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 11

Fluoxetine N Efficacy – In moderate depression similar to tricyclic antidepressants – some analgesic and anorectic effects, no sedative effects or alpha effects. N N Not proarrhythmic. No evidence of psychomotor changes subjectively or objectively Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 12

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

Antipsychotics: Phenothiazines and butyrophenones N Mechanism – Antipsychotic effect probably due to dopamine blockade. – Dirty drugs with alpha effects, antihistamine effects, anticholinergic effects (except haloperidol) direct membrane stabilising effects. Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 14

Antipsychotics: Phenothiazines and butyrophenones N Metabolism – Predominantly Polymorphic hepatic P 450 enzyme metabolism. – Conjugation – High volume of distribution, long half life Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 15

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

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

Antipsychotics: Phenothiazines and butyrophenones N Drug interactions – Enzyme inducers some self induction. – Heavy smoking may decrease levels. – Antipsychotics may inhibit antidepressant metabolism. – Inhibits phenytoin metabolism. Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 18

Neuroleptic Malignant Syndrome N 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) Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 19

Neuroleptic Malignant Syndrome N MAJOR – Fever > 37. 5 OC (no other cause) – Autonomic dysfunction – Extrapyramidal syndrome Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 20

Neuroleptic Malignant Syndrome N MINOR CRITERIA – CPK rise – Altered sensorium – Leucocytosis >15000 – Other possible cause for fever (delete leucocytosis) – Low serum iron – Therapeutic response (Sequence) Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 21

Neuroleptic Malignant Syndrome N TREATMENT – Withdrawal – Specific – Bromocriptine. – L-Dopa – Dantrolene. – Anticholinergics and benzodiazepines – ECT – Nifedipine Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 22

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

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

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

Clozapine N 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) l Increased Risk in the Elderly and Female l Increased Risk in Ashkenazi Jews l Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 26

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

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

Risperidone - a benzisoxazole derivative N Indications – schizophrenia Negative symptoms l Movement disorders on conventional therapy l N Mechanism – Low affinity D 2 antagonism – High affinity 5 H 2 antagonism – Some alpha 1 and antihistamine effect Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 29

Risperidone - a benzisoxazole derivative N Pharmacokinetics – rapid absorption and high bioavailability – risperidone metabolised to 9 hydroxy resperidone – P 450 to D 6 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% Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 30

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

Selectivity of antidepressants 1000 Nonselective 5 -HTselective 100 Ratio NA: 5 -HT uptake inhibition NAselective 10 Nisoxetine Nomifensine Maprotiline (approx) Desipramine Imipramine Nortriptyline Amitriptyline 1 Clomipramine Trazodone Zimelidine 0. 1 0. 001 Fluoxetine Citalopram (approx) Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital 32