Antipsychotic agents & Lithium

Dr. Nadeem Akhtar MBBS.M.Phil

Asst. Professor PharmacologyAmna Inayat Medical College

Shaikhupura

Schizophrenia

• One of the most important psychiatric illness

• Affects about 1 % in population

• Strongly linked with hereditary

• Characterized by positive and negative symptoms

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

Hypotheses of schizophrenia

• Dopamine hypothesis

• Serotonin hypothesis

• Glutamate hypothesis

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

:

• 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.

Classification

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

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 • •

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

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 • • Airiprazole 10 10-30

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

• 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

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

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

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:

• 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.

• 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

• 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

• 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.

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

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

Treatment

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

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

• 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

THANK YOU VERY MUCH