1. Antipsychotic agents & Lithium
Dr. Nadeem Akhtar
MBBS.M.Phil
Asst. Professor Pharmacology
Amna Inayat Medical College
Shaikhupura

2. Schizophrenia
• One of the most important psychiatric illness
• Affects about 1 % in population
• Strongly linked with hereditary
• Characterized by positive and negative
symptoms

3. • Positive symptoms
• Thought disorders
• Delusions
• Hallucinations
• Paranoia
• Negative symptoms
• Amotivation
• Social withdrawal
• Flat affect
• Poverty of speech

4. Hypotheses of schizophrenia
• Dopamine hypothesis
• Serotonin hypothesis
• Glutamate hypothesis

5. Dopaminergic systems
• Mesolimbic-mesocortical pathway:
• Projects from cell bodies in ventral
tegmentum in bundles of axons to limbic
system and neocortex
• Nigrostriatal pathway:
• project from substansia nigra to dorsal
striatum, caudate and putamen. involved in
coordination of voluntary movements

6. :
• Tuberoinfundibular system:
• Arises in arcuate nuclei and periventricular
neurons and releases dopamine in pituitary
portal circulation. Dopamine release by these
neurons inhibit prolactin secretion
• Incertohypothalamic:
• Forms connections from medial zona incerna
to hypothalamus and amygdala. Involved in
copulatory behavior in rats.

9. Classification
• Typical antipsychotics (classical)
• Chloropromazine
• Thioridazine
• Fluphenazine
• Haloperidol
• Atypical antipsychotics (newer generation)
• Clozapine
• Olanzopine
• Risperidone
• Aripiprazole
• Quitipine

10. Major antipsychotics
• Drug name Advantages Disavantages
• TYPICALS
• Chloropromazine inexpensive many adverse effects,esp. autonamic
•
• Thioridazine slight EPS cardiotoxic
•
• Fluphenazine available in depot form increase tardive dyskinesia
•
• Haloperidol available in parenteral form severe EPS
• ATYPICALS
• Clozapine treatment resistant patient may cause agranulocytosis
•
• Olanzopine no EPS,effective in –ve & +ve sympt wt gain
•
• Risperidone no EPS, effective –ve, +ve symptoms hypotension with high doses
•
• Airiprazole lower wt gain, parenteral form available QT prolongation
•
• Quetipine no EPS, effective in all symptoms short half life
•
•

11. Therapeutic indications of
antipsychotics
• A). Psychiatric indications:
• Schezophrenia
• Catatonic forms
• Schezoaffective disorders
• Bipolar affective disorders
• Tourettes syndrome
• Psychotic depression
• B).Nonpsychiatric indications
• As a antiemetic

12. Dosage
Minimum effective dose(mg) usual range of daily dose(mg)
• Minimum effective dose(mg) usual range of daily dose(mg)
• Chlropromazine 100 100-1000
•
• Thioridazine 100 100-800
•
• Fluphenazine 2 2-60
•
• Haloperidol 2 2-60
•
• Clozapine 50 300-600
•
• Olanzapine 5 10-30
•
• Quetiapine 150 150-800
•
• Risperidone 4 4-16
•

13. Absorption and distribution
• Oral doses of chloropromazine and thioriazine
have systemic bioavailability of 25-35 %
• Haloperidol has less first pass metabolism and
systemic availability about 65%
• Most antipsychotics have large volume of
distribution usually more than 7 L/kg
• Metabolites of chlorpromazine excreted
through urine weeks after the lost dose

14. • Long acting inject able formulations cause
blockade of D2 receptors for 3-6 months after
last injection.
• The average time for relapse in stable patients
who discontinue treatment is 6 months
• Without clozapine which has relapse usually
rapid and severe
• Thus clozapine should never be discontinued
abruptly

15. Metabolism
• Most antipsychotics are metabolized by
cytochrome 450 enzyme system
• At the typical clinical doses antipsychotic
drugs don’t interfere with the metabolism of
other drugs

16. Drug combinations
• Tricyclic antidepressants or SSRIs are often
used with antipsychotics for associated
symptoms of depression, complicating
schezophrenia.
• ECT is useful adjunct for antipsychotic drugs
• Lithium or valproic acid is added with
antipsychotic agents to resistant patients

17. Adverse reactions
• A). Behavioral effects:
• A pseudodepression may develop due to drug
induced akenesia with older antipsychotics
which usually relieve with antiparkinsonism
drugs
• B).Neurological effects:
• Extrapyrammidal reactions include Parkinsons
syndrome, akathisia and acute dystonic
reactions
• C).A.N.S:

18. • A.N.S: orthostatic hypotension , retention of
urine or impaired ejaculation are most common
adverse effects of chloropromazine or
mesoridazine.
• Metabolic & Endocrine: wait gain is common
with clozapine and olanzapine. Hyperglycemia
may develop secondary to wait gain.
Hyperprolactinemia in women results in
amenorrhea-galactorrhea syndrome and
infertility.

19. • In men loss of libido, impotency and infertility
may develop. Hyperprolactinemia may cause
osteoporosis in women. If such adverse affects
develop than drug should switch to atypical
agents that don’t raise prolactin e.g
airipiprazole

20. • Toxic or allergic reactions: clozapine causes
agranulocytosis in significant number of cases
approximately 1-2% who received treatment
• Cholestatic jaundice and skin eruptions occur
rarely with high potency antipsychotics.
• Ocular complications: deposits in cornea and
lens are common with chloropromazine.
Thioridazine may cause retinitis pigmentosa
with large doses

21. • Cardiac toxicity: larger doses of thioridazine
may produce ventricular arrythmias and
sudden death. Among atypical agents
ziprasidone may produce QT prolongation
• Clozapine is linked with myocarditis and
should be discontinued if observed.

22. Neuroleptic malignant syndrome
• This life threatening disorder is believed to be
due to excessively blockade of the dopamine
receptors usually due to treatment of older or
typical antipsychotics. Characterized with
extreme muscle rigidity, loss of sweating, high
grade fever, raised level of creatine kinase,
leukocytosis. Treatment: dopamine agonists
e.g bromocriptine, diazepam are often useful
with switch over to atypicals

23. Bipolar disorder
• Also known as manic disorder occurs 1-3% of
papulation, begin in early age but usually first
time diagnosed in 3rd or 4th decade.
• Symptoms
• Excitement . aggression
• Hyperactivity . diminished need for sleep
• Impulsivity . psychotic symptoms
• Disinhibition . may be with depression

24. Treatment
• A. LITHIUM
• B. Anticonvulsants
• Carbamezipine
• Valproic acid
• Lamotrigine
• Gabapentin
• Oxcarbezepine
• Topiramate
• And atypical antipsychotics are used

25. Lithium
• First used therapeutically in mid 19th century
for gout
• It was briefly used as a substitute to patients
of hypertension but was withdrawn
immediately
• In 1949, Cade discovered that it is effective for
the treatment of bipolar disorder

26. • Mode of action:
• Acting as second messenger for norepinephrine
and dopamine
• Enhances serotonin and cholinergic action
• Adverse effects:
• Tremors
• Dcreased thyroid functions
• Diabetes insipdus
• Edema
• Cardiac effects

27. THANK YOU VERY MUCH