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Risks of Psychotropics
Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital
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The Risks





Antidepressants
Antipsychotics
Adverse Effects
Toxicity
Significant Interactions
Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital
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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 [TCAs]
Lower [TCAs]
Elevated
[Interacting Drugs]
Cimetidine
Ethanal acute
ingestion
Haloperidol
Phenothiazine
Propoxyphene
Fluoxetine
Chronic ethanol
Barbiturates
Carbamazepine
Phenytoin
Warfarin
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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.
Clinical Toxicology & Pharmacology Newcastle Mater Misericordiae Hospital
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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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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.
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Antipsychotics:Phenothiazines and
butyrophenones

Metabolism
– Predominantly Polymorphic hepatic P450 enzyme
metabolism.
– Conjugation
– High volume of distribution, long half life
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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

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Antipsychotics:Phenothiazines and
butyrophenones
–
–
–
–
–
–
Lowered seizure threshold
Hypersensitivity reactions
Hyperpigmentation
Retinal toxicity (especially thioridazine >800mg/day)
Lowered seizure threshold for phenothiazines
Endocrine
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Antipsychotics:Phenothiazines 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 > 37.5OC (no other cause)
– Autonomic dysfunction
– Extrapyramidal syndrome
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Neuroleptic Malignant Syndrome

MINOR CRITERIA
–
–
–
–
–
–
CPK rise
Altered sensorium
Leucocytosis >15000
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 > 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
1000
Nisoxetine
Nomifensine
Maprotiline (approx)
Nonselective
5-HTselective
Ratio NA: 5-HT uptake inhibition
100
NAselective
10
1
0.1
Desipramine
Imipramine
Nortriptyline
Amitriptyline
Clomipramine
Trazodone
Zimelidine
0.01
Fluoxetine
0.001
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Citalopram (approx)
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