Risks of Psychotropics The Risks Antidepressants



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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.
    • 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.

  • 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







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