Clinical pharmacology of antipsychotic drugs: adverse effects, drug interactions, poisoning

1. Adverse effects of
antipsychotic drugs
Domina Petric, MD

2. Behavioral effects
• The older typical antipsychotic drugs
are unpleasant to take.
• This can be mitigated by giving small
doses during the day and the major
portion at bedtime.
• Pseudodepression may be due to
drug-induced akinesia: usually
responds to treatment with
antiparkinsonism drugs.

3. Behavioral effects
• Other pseudodepressions may be due
to higher doses than needed in a
partially remitted patient: decreasing
the dose may relieve the symptoms.
• Toxic-confusional states may occur with
very high doses of drugs that have
prominent antimuscarinic actions.

4. Neurologic effects
Extrapyramidal reactions occurring
early during treatment with older
agents include:
• typical Parkinson´s syndrome
• akathisia (uncontrollable
restlessness)
• acute dystonic reactions (spastic
retrocollis or torticollis)

5. Neurologic effects
• Parkinsonism can be treated with
conventional antiparkinsonism drugs of
the antimuscarinic type or with
amantadine (rarely).
• Levodopa should never be used in
these patients!
• Parkinsonism may be self-limiting.
• An attempt to withdraw antiparkinsonism
drugs should be made every 3-4 months.

6. Neurologic effects
Akathisia and dystonic
reactions are best treated in
many cases with sedative
antihistamine with
anticholinergic properties
parenterally or orally:
diphenhydramine.

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8. Neurologic effects
Tardive dyskinesia
• It is a late-occurring syndrome of
abnormal choreoathetoid movements.
• It is the most important unwanted effect
of antipsychotic drugs.
• It is probably caused by a relative
cholinergic deficiency secondary to
supersensitivity of dopamine receptors in
the caudate-putamen.

9. Tardive dyskinesia
• Tardive dyskinesia is estimated to have
occurred in 20-40% of chronically treated
patients before the introduction of the
newer atypical antipsychotics.
• Early recognition is important!
• Advanced cases may be difficult to
reverse.
• Quetiapine and clozapine have the least
likelihood of causing tardive dyskinesia.

10. Tardive dyskinesia
• Any patient with tardive dyskinesia treated
with a typical antipsychotic drug or possibly
risperidone or paliperidone should be
switched to quetiapine or clozapine.
• The course of the disorder is variable and
sometimes self-limited.
• First step should be to discontinue or
reduce the dose of the current
antipsychotic agent or switch to
quetiapine or clozapine.

11. Tardive dyskinesia
• Second step would be to eliminate
the drugs with central
anticholinergic action, particularly
antiparkinsonism drugs and tricyclic
antidepressants.
• The addition of diazepam in doses of
30-40 mg/day may add to the
improvement by enhancing
GABAergic activity.

12. Extrapyramidal syndrome (EPS)
Akathisia
Can occur early during
treatment.
Tardive dyskinesia
Most important
unwanted effect!
Parkinson´s syndrome
Should not be treated
with levodopa!
Acute dystonic reactions
Can occur early during
treatment.
EPS

13. Neurologic effects
Seizures
• De novo seizures may occur in 2-5%
of patients treated with clozapine.
• Use of an anticonvulsant is able to
control seizures in most cases.
• Seizures can also be a complication
of chlorpromazine treatment.

14. Autonomic nervous system effects
• Most patients are able to tolerate
the antimuscarinic adverse effects of
antipsychotic drugs.
• Those patients who develop urinary
retention or other severe symptoms
can be switched to an agent without
significant antimuscarinic action.

15. Autonomic nervous system effects
• Orthostatic hypotension and
impaired ejaculation are common
complications of therapy with
chlorpromazine or mesoridazine.
• These patients should be switched
to drugs with less marked
adrenoreceptor-blocking actions.

16. Metabolic and endocrine effects
• Weight gain is very common, especially with
clozapine and olanzapine.
• This requires monitoring of food intake,
especially carbohydrates.
• Hyperglycemia may also develop, as well as
hyperlipidemia.
• The management of weight gain, insulin
resistance and increased lipids should include
monitoring of weight at each visit and
measurement of fasting blood sugar and
lipids at 3-6 month intervals.

17. Metabolic and endocrine effects
Measurement of hemoglobin A1C
may be useful.
Diabetic ketoacidosis has been
reported in a few cases.
The triglyceride:HDL ratio should
be less than 3,5 in fasting samples.

18. Metabolic and endocrine effects
• Hyperprolactinemia in women results in
the amenorrhea-galactorrhea syndrome,
which leads to infertility.
• HyperPRL in men causes loss of libido,
impotence and infertility.
• HyperPRL may cause osteoporosis,
particularly in women.
• Aripiprazole does not raise PRL
levels!

19. Toxic/allergic reactions
• Agranulocytosis, cholestatic jaundice and
skin eruptions…
• Clozapine causes agranulocytosis in a small,
but significant number of patients: 1-2%.
• Agranulocytosis can develop rapidly, usually
between the 6th and 18th weeks of therapy.
• Patients receiving clozapine must have
weekly blood counts for the first 6
months of treatment and every 3 weeks
thereafter.

20. Ocular complications
Deposits in the anterior portions of the
eye (cornea, lens) are a common
complication of chlorpromazine therapy.
These deposits may accentuate the
normal process of aging of the lens.

21. Ocular complications
Thioridazine is the only antipsychotic drug that
causes retinal deposits.
These deposits may resemble in advanced cases
retinitis pigmentosa.
The deposits are usually associated with
browning of vision.
The maximum daily dose of thioridazine is
limited to 800 mg/day.

22. Cardiac toxicity
• Thioridazine in doses exceeding 300 mg
daily is almost always associated with
minor abnormalities of T waves that
are easily reversible.
• Overdoses of thioridazine are
associated with major ventricular
arrhythmias: torsades de pointes,
cardiac conduction block and sudden
death.

23. Cardiac toxicity
• Ziprasidone carries the greatest risk of
QT prolongation and should not be
combined with other drugs that prolong
the QT interval: thioridazine, pimozide,
antiarrhythmic drugs 1A and 3.
• Clozapine is sometimes associated with
myocarditis and must be discontinued
if myocarditis manifests.

24. Pregnancy
If a pregnant woman could
manage to be free of
antipsychotic drugs during
pregnancy, this would be
desirable because of their effects
on the neurotransmitters
involved in neurodevelopment.

25. Neuroleptic malignant syndrome
(NMS)
• This life-threatening disorder occurs in
patients who are extremely sensitive to
the extrapyramidal effects of
antipsychotic agents.
• The initial symptom is marked muscle
rigidity.
• If sweating is impaired, fever may ensue,
reaching dangerous levels: often with
anticholinergic drugs.

26. Neuroleptic malignant syndrome
(NMS)
• The stress leukocytosis may erroneously
suggest an infectious process.
• Autonomic instability, with altered blood
pressure and pulse rate, is often present.
• Muscle-type creatine kinase levels are
usually elevated, reflecting muscle
damage.
• Pathophysiology: excessively rapid
blockade of postsynaptic dopamine
receptors.

27. Treatment
Muscle relaxants: diazepam, dantrolene…
Dopamine agonists, such as bromocriptine
Cooling measures
Switching to an atypical drug after
recovery!

28. Drug interactions
II.

29. Drug interactions
• Antipsychotics produce more important
pharmacodynamic than pharmacokinetic
interactions!
• Additive effects may occur when these drugs
are combined with others that have sedative
effects, α-adrenoreceptor blocking action
and anticholinergic effects.
• In the case of thioridazine and ziprasidone it
is important not to combine these drugs with
those that have quinidine-like action.

30. Overdose
III.

31. Overdose
• Poisonings with antipsychotic agents are
rarely fatal, except with MESORIDAZINE
and THIORIDAZINE.
• Drowsiness proceeds to coma with an
intervening period of agitation.
• Neuromuscular excitability may be
increased and proceed to convulsions.
• Pupils are miotic.
• Deep tendon reflexes are decreased.

32. Overdose
• Hypotension and hypothermia are the
rule, although fever may be present
later in the course.
• The lethal effects of mesoridazine and
thioridazine are related to induction of
ventricular tachyarrhythmias.
• ABCD treatment for poisonings
and supportive care!

33. Overdose
Hypotension, hypothermia
FEVER later in the course
Drowsiness
COMA with an intervening
period of AGITATION
Neuromuscular excitability
CONVULSIONS
MIOSIS
Decreased deep tendon
reflexes
Mesoridazine,
thioridazine
Other
agents
rarely
Ventricular
tachyarrhythmias
ABCD!

34. Psychosocial treatment and
cognitive remediation
are very important part of the therapy.

35. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
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