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

1Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital

Risks of PsychotropicsRisks of Psychotropics


The RisksThe Risks

Antidepressants Antipsychotics Adverse Effects Toxicity Significant Interactions


Tricyclic antidepressantsTricyclic 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.


TCAs: Pharmacokinetic InteractionsTCAs: Pharmacokinetic Interactions

Elevated [TCAs]

Cimetidine

Ethanal acute ingestion

Haloperidol

Phenothiazine

Propoxyphene

Fluoxetine

Lower [TCAs]

Chronic ethanol

Barbiturates

Carbamazepine

Elevated

[Interacting Drugs]

Phenytoin

Warfarin


TCAs: Pharmacodynamic InteractionsTCAs: 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.


Toxicity in overdoseToxicity in overdose Not all are equipotent CNS

– Sedation & coma– Seizures– Anticholinergic delirium

Cardiovascular– Supraventricular and ventricular arrhythmias– Conduction defects– Sinus tachycardia– Hypotension


MAO-A inhibitors: Moclobemide 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.


MAO-A inhibitors: Moclobemide 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.


MAO-A inhibitors: Moclobemide MAO-A inhibitors: Moclobemide

Toxicity

– Minimal toxicity in overdose– CNS depression and confusion, nausea, hyperreflexia,

hypotension and occasional hyperthermia.


FluoxetineFluoxetine

Mechanism – Inhibition of presynaptic seratonin reuptake plus

probably altering sensitivity to serotonin.



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.



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


FluoxetineFluoxetine 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.


Antipsychotics:Phenothiazines and Antipsychotics:Phenothiazines and butyrophenonesbutyrophenones

Mechanism– Antipsychotic effect probably due to dopamine

blockade.– Dirty drugs with alpha effects, antihistamine effects,

anticholinergic effects (except haloperidol) direct membrane stabilising effects.



Metabolism– Predominantly Polymorphic hepatic P450 enzyme

metabolism.– Conjugation– High volume of distribution, long half life



Side effects– Similar to those of tricyclic antidepressants– Attributed to dopamine blockade

Parkinsonian states Tardive dyskinesia Neuroleptic malignant syndrome Acute dystonia (early) Akathesia



– Lowered seizure threshold– Hypersensitivity reactions– Hyperpigmentation– Retinal toxicity (especially thioridazine >800mg/day)– Lowered seizure threshold for phenothiazines– Endocrine



Drug interactions– Enzyme inducers some self induction. – Heavy smoking may decrease levels.– Antipsychotics may inhibit antidepressant metabolism.– Inhibits phenytoin metabolism.


Neuroleptic Malignant SyndromeNeuroleptic 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)



MAJOR– Fever > 37.5OC (no other cause)– Autonomic dysfunction– Extrapyramidal syndrome



MINOR CRITERIA– CPK rise– Altered sensorium– Leucocytosis >15000– Other possible cause for fever (delete leucocytosis)– Low serum iron– Therapeutic response (Sequence)



TREATMENT– Withdrawal– Specific– Bromocriptine. – L-Dopa– Dantrolene. – Anticholinergics and benzodiazepines – ECT – Nifedipine



Recommencement of Neuroleptics.– with caution after complete recovery from NMS


ClozapineClozapine

– A Diebenzodizepine Antipsychotic– A Low Affinity Dopamine Antagonist– A High Affinity Serotonin Antagonist

Indications– Treatment Resistant Schizophrenia


ClozapineClozapine

Pharmacokinetics– Bioavailability 50%– Protein Binding 95%– Half Life 12 Hours– Hepatic Metabolism


ClozapineClozapine

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


ClozapineClozapine

Drug Interactions– Enhance Sedation With Other Sedatives– Metabolism Inhibited by Cimetidine Leading to

Clozapine Toxicity– Clozapine Metabolism Induced by Phenytoin


ClozapineClozapine

Overdose– Delirium, Coma, Seizures– Tachycardia, Hypotension– Respiratory Depression– Hypersalivation


Risperidone - a benzisoxazole derivativeRisperidone - 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



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%



Side effects– postural hypotension– weight gain– hyperprolactinaemia asthaenia

Drug interactions– pharmacodynamic

dopamine augmented affect of TCAs and phenothiazines


Selectivity of antidepressantsSelectivity of antidepressants

0.001

0.01

0.1

1

10

100

1000 Nisoxetine

NomifensineMaprotiline (approx)

Desipramine

Imipramine Nortriptyline Amitriptyline

Clomipramine Trazodone Zimelidine

Fluoxetine

Citalopram (approx)

NA-selective

Non-selective

5-HT-selective Rat

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5-H

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

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