Risks of psychotropics
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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.

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Risks of Psychotropics

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Risks of psychotropics

Risks of Psychotropics


The risks

The Risks

  • Antidepressants

  • Antipsychotics

  • Adverse Effects

  • Toxicity

  • Significant Interactions


Tricyclic antidepressants

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

Lower [TCAs]

Chronic ethanol

Barbiturates

Carbamazepine

TCAs: Pharmacokinetic Interactions

Elevated

[Interacting Drugs]

Phenytoin

Warfarin


Tcas pharmacodynamic interactions

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

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

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 moclobemide1

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 moclobemide2

MAO-A inhibitors: Moclobemide

  • Toxicity

    • Minimal toxicity in overdose

    • CNS depression and confusion, nausea, hyperreflexia, hypotension and occasional hyperthermia.


Fluoxetine

Fluoxetine

  • Mechanism

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


Fluoxetine1

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.


Fluoxetine2

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


Fluoxetine3

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

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 butyrophenones1

Antipsychotics:Phenothiazines and butyrophenones

  • Metabolism

    • Predominantly Polymorphic hepatic P450 enzyme metabolism.

    • Conjugation

    • High volume of distribution, long half life


Antipsychotics phenothiazines and butyrophenones2

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 butyrophenones3

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 butyrophenones4

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

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 syndrome1

Neuroleptic Malignant Syndrome

  • MAJOR

    • Fever > 37.5OC (no other cause)

    • Autonomic dysfunction

    • Extrapyramidal syndrome


Neuroleptic malignant syndrome2

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 syndrome3

Neuroleptic Malignant Syndrome

  • TREATMENT

    • Withdrawal

    • Specific

    • Bromocriptine.

    • L-Dopa

    • Dantrolene.

    • Anticholinergics and benzodiazepines

    • ECT

    • Nifedipine


Neuroleptic malignant syndrome4

Neuroleptic Malignant Syndrome

  • Recommencement of Neuroleptics.

    • with caution after complete recovery from NMS


Clozapine

Clozapine

  • A Diebenzodizepine Antipsychotic

  • A Low Affinity Dopamine Antagonist

  • A High Affinity Serotonin Antagonist

  • Indications

    • Treatment Resistant Schizophrenia


  • Clozapine1

    Clozapine

    • Pharmacokinetics

      • Bioavailability 50%

      • Protein Binding 95%

      • Half Life 12 Hours

      • Hepatic Metabolism


    Clozapine2

    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


    Clozapine3

    Clozapine

    • Drug Interactions

      • Enhance Sedation With Other Sedatives

      • Metabolism Inhibited by Cimetidine Leading to Clozapine Toxicity

      • Clozapine Metabolism Induced by Phenytoin


    Clozapine4

    Clozapine

    • Overdose

      • Delirium, Coma, Seizures

      • Tachycardia, Hypotension

      • Respiratory Depression

      • Hypersalivation


    Risperidone a benzisoxazole derivative

    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 derivative1

    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 derivative2

    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

    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


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