Risks of Psychotropics

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Risks of Psychotropics
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The Risks

• Antidepressants
• Antipsychotics
• Adverse Effects
• Toxicity
• Significant Interactions

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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.

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TCAs Pharmacokinetic Interactions
Elevated Interacting Drugs Phenytoin Warfarin

• Elevated TCAs
• Cimetidine
• Ethanal acute ingestion
• Haloperidol
• Phenothiazine
• Propoxyphene
• Fluoxetine

• Lower TCAs
• Chronic ethanol
• Barbiturates
• Carbamazepine

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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.

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Toxicity in overdose

• Not all are equipotent
• CNS
• Sedation coma
• Seizures
• Anticholinergic delirium
• Cardiovascular
• Supraventricular and ventricular arrhythmias
• Conduction defects
• Sinus tachycardia
• Hypotension

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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.

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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.

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MAO-A inhibitors Moclobemide

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

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Fluoxetine

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

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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.

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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

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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.

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AntipsychoticsPhenothiazines 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.

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AntipsychoticsPhenothiazines and butyrophenones

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

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AntipsychoticsPhenothiazines 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

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AntipsychoticsPhenothiazines and butyrophenones

• Lowered seizure threshold
• Hypersensitivity reactions
• Hyperpigmentation
• Retinal toxicity (especially thioridazine
  gt800mg/day)
• Lowered seizure threshold for phenothiazines
• Endocrine

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AntipsychoticsPhenothiazines and butyrophenones

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

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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)

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Neuroleptic Malignant Syndrome

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

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Neuroleptic Malignant Syndrome

• MINOR CRITERIA
• CPK rise
• Altered sensorium
• Leucocytosis gt15000
• Other possible cause for fever (delete
  leucocytosis)
• Low serum iron
• Therapeutic response (Sequence)

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Neuroleptic Malignant Syndrome

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

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Neuroleptic Malignant Syndrome

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

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Clozapine

• A Diebenzodizepine Antipsychotic
• A Low Affinity Dopamine Antagonist
• A High Affinity Serotonin Antagonist
• Indications
• Treatment Resistant Schizophrenia

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Clozapine

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

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Clozapine

• Adverse Effects
• Neuroleptic Malignanct Syndrome
• Seizures 5 of Patients gt 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

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Clozapine

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

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Clozapine

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

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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

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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

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Risperidone - a benzisoxazole derivative

• Side effects
• postural hypotension
• weight gain
• hyperprolactinaemia asthaenia
• Drug interactions
• pharmacodynamic
• dopamine
• augmented affect of TCAs and phenothiazines

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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