This document summarizes antipsychotic drugs and lithium, which are used to treat schizophrenia and bipolar disorder. It discusses the classification, pharmacokinetics, mechanisms of action, clinical uses, and toxicities of antipsychotic agents. The major mechanisms involve blocking dopamine receptors, especially D2 receptors. Lithium is effective for treating mania and preventing recurrent episodes in bipolar disorder. It works by inhibiting enzymes involved in recycling neuronal membrane phosphoinositides. Common side effects of these drugs include extrapyramidal effects, tardive dyskinesia, and endocrine/metabolic issues.

1. M.Usman Khalid
DPT,MS-NMPT
Antipsychotic Agents
& Lithium

2. Antipsychotic drugs
• The antipsychotic drugs (neuroleptics) are
used in schizophrenia and are also
effective in the treatment of other
psychoses and agitated states.

3. Classification
• The major chemical subgroups of older
antipsychotic drugs are the
phenothiazines (eg, chlorpromazine,
thioridazine, fluphenazine), the
thioxanthenes (eg, thiothixene), and the
butyrophenones (eg, haloperidol).

4. Pharmacokinetics
• Orally
• Lipid soluble
• Require metabolism by liver enzymes
before elimination.
• Drugs that inhibit cytochrome P450
enzymes can prolong the half-lives of
antipsychotic agents.

5. Mechanism of Action
• 1. Dopamine hypothesis: caused by a relative excess of functional
activity of the neurotransmitter dopamine in specific neuronal tracts
in the brain.
• This hypothesis is based on several observations: First, many
antipsychotic drugs block brain dopamine receptors (especially D2
receptors).
• Second, dopamine agonist drugs (eg, amphetamine, levodopa)
exacerbate schizophrenia.
• Third, an increased density of dopamine receptors has been
detected in certain brain regions of untreated schizophrenics.

6. • 2. Dopamine receptors: Five different
dopamine receptors (D1–D5) have been
characterized.
• Each is G protein-coupled and contains 7
transmembrane domains.
• The D2 receptor, found in the caudate
putamen, nucleus accumbens, cerebral
cortex, and hypothalamus, is negatively
coupled to adenylyl cyclase.

7. • 3. Other receptors: Most of the newer
atypical antipsychotic agents have higher
affinities for other receptors than for the
D2 receptor.

8. Clinical Use
• 1. Treatment of schizophrenia:
• Antipsychotic drugs reduce some of the
positive symptoms of schizophrenia,
including hyperactivity, bizarre ideation,
hallucinations, and delusions.
• Consequently, they can facilitate
functioning in both inpatient and outpatient
environments

9. • 2. Other psychiatric and neurologic
indications: The newer antipsychotic drugs are
often used with lithium in the initial treatment of mania.
• The antipsychotic drugs are also used in the
management of psychotic symptoms of schizoaffective
disorders, in Gilles de la Tourette syndrome, and for
management of toxic psychoses caused by overdosage
of certain CNS stimulants.

10. Toxicity
• Reversible neurologic effects:
• Dose-dependent extrapyramidal effects
include a Parkinson-like syndrome with
bradykinesia, rigidity, and tremor.

11. • Tardive dyskinesias:
• This important toxicity includes
choreoathetoid movements of the muscles
of the lips and buccal cavity and may be
irreversible.

12. • Autonomic effects:
• Atropine-like effects (dry mouth, constipation,
urinary retention, and visual problems) are often
pronounced with the use of thioridazine and
phenothiazines with aliphatic side chains (eg,
chlorpromazine).
• Failure to ejaculate is common in men treated
with the phenothiazines.

13. • Endocrine and metabolic effects:
• Endocrine and metabolic effects include
hyperprolactinemia, gynecomastia, the
amenorrhea-galactorrhea syndrome, and
infertility.

14. • Neuroleptic malignant syndrome:
• The symptoms include muscle rigidity,
impairment of sweating, hyperpyrexia, and
autonomic instability, which may be life
threatening.
• Drug treatment involves the prompt use of
dantrolene, diazepam, and dopamine
agonists.

15. • Sedation
• Ventricular arrhythmias
• Visual impairment
• seizures

16. LITHIUM & OTHER DRUGS USED
IN BIPOLAR (MANIC-DEPRESSIVE)
DISORDER
• Lithium is effective in treatment of the
manic phase of bipolar disorder and
continues to be used for acute-phase
illness and for prevention of recurrent
manic and depressive episodes.

17. Pharmacokinetics
• The half-life of lithium is about 20 h.
• Lithium is absorbed rapidly and
completely from the gut.
• Caffeine and theophylline increase the
renal clearance of lithium.

18. Mechanism of Action
• The drug inhibits several enzymes involved in the
recycling ofneuronal membrane phosphoinositides.
• This action may result in depletion of the second
messenger source, phosphatidylinositol bisphosphate
(PIP2), which, in turn, would decrease generation of
inositol trisphosphate (IP3) and diacylglycerol (DAG).
• These second messengers are important in amine
neurotransmission, including that mediated by central
adrenoceptors and muscarinic receptors.

19. Effect of lithium on IP3 and DAG

20. Toxicity
• Tremor
• Sedation
• Ataxia
• Aphasia
• Thyroid enlargement
• Edema