Risks of Psychotropics The Risks Antidepressants

Risks of Psychotropics

The Risks

• Antidepressants

• Antipsychotics

• Adverse Effects

• Toxicity

• Significant Interactions

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.

TCAs: Pharmacokinetic Interactions

• Elevated [TCAs]

• Cimetidine

• Ethanal acute ingestion

• Haloperidol

• Phenothiazine

• Propoxyphene

• Fluoxetine

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.

Toxicity 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

• 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

• 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

• Toxicity

• Minimal toxicity in overdose
• CNS depression and confusion, nausea, hyperreflexia, hypotension and occasional hyperthermia.

Fluoxetine

• Mechanism

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

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.

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

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.

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.

Antipsychotics:Phenothiazines and butyrophenones

• Metabolism

• Predominantly Polymorphic hepatic P450 enzyme metabolism.
• Conjugation
• High volume of distribution, long half life

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

Antipsychotics:Phenothiazines and butyrophenones

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

Antipsychotics:Phenothiazines and butyrophenones

• Drug interactions

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

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)

Neuroleptic Malignant Syndrome

• MAJOR

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

Neuroleptic Malignant Syndrome

• MINOR CRITERIA

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

Neuroleptic Malignant Syndrome

• TREATMENT

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

Neuroleptic Malignant Syndrome

• Recommencement of Neuroleptics.

• with caution after complete recovery from NMS

Clozapine

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

• Indications

• Treatment Resistant Schizophrenia

Clozapine

• Pharmacokinetics

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

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

Clozapine

• Drug Interactions

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

Clozapine

• Overdose

• Delirium, Coma, Seizures
• Tachycardia, Hypotension
• Respiratory Depression
• Hypersalivation

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

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%

Risperidone - a benzisoxazole derivative

• Side effects

• postural hypotension
• weight gain
• hyperprolactinaemia asthaenia

• Drug interactions

• pharmacodynamic
• dopamine
• augmented affect of TCAs and phenothiazines

Selectivity of antidepressants