Antipsychotic Drugs-1

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ANTIPSYCHOTIC DRUGS
Antipsychotic drugs are drugs used to control manifestations of Psychosis. Psychosis is a
mental illness in which the mind is separated from reality.
Manifestations of Psychosis:
I- Hallucinations: - Perception without an external stimulus. Patient sees or
hears things that don’t exist.
II- Delusions: - False beliefs. They may be paranoid (suspicion), persecutory
(Patient believes people are against him) or Grandiose (Patient believes he is a
genius or a messenger from God).
III- Incoherent (meaningless) speech.
IV- Abnormal behavior: - Aggression and Agitation.
Schizophrenia: - It is the most common and most classic example of Psychosis.

At first, Patient presents with positive symptoms (e.g. Hallucinations and Delusions)
which show good response to drug treatment. After several years, patient may present
with negative symptoms (Flat emotions, social withdrawal and intellectual dysfunction)
due to brain atrophy. Negative symptoms show poor response to drug treatment.
Dopamine theory of Psychosis

According to this theory, Psychosis is caused by increased dopaminergic activity in the
brain mesolimbic system.
Mechanism of action of Antipsychotics

All Antipsychotics block Dopamine D2 receptors in the mesolimbic system.
Classification of Antipsychotics
I- Typical Antipsychotics: - They are Dopamine antagonists. They include:
1- Phenothiazines e.g. Chlorpromazine.
2- Butyrophenones e.g. Haloperidol.
II- Atypical Antipsychotics: - They are 5-HT and Dopamine antagonists:
1- Resperidone.
2- Clozapine.
3- Olanzepine.
Pharmacological Actions, Uses and Side effects of Typical Antipsychotics

I- Blockade of Central D2 receptors:
1- Blockade of D2 in the mesolimbic system producing Antipsychotic
action.
Uses: - Antipsychotic action. It calms violent patients in a few hours.
Primary Psychosis (Decreases Hallucinations and Delusions in a few weeks)

- Schizophrenia.
- Manic phase of bipolar Manic-depressive disorder.
- Psychotic depression.
Secondary Psychosis:
- Brain tumors.
- Cocaine.
- Hypoglycemia.
2- Blockade of D2 receptors in the Chemo-receptor trigger zone (CTZ).
Uses: - Anti-emetic.
3- Blockade of D2 in the Hypothalamus and Pituitary gland leading to the
following side effects:
- Increased body weight.
- Gynaecomastia.
- Galactorrhea.
- Amenorrhea.
- Infertility.
4- Blockade of D2 receptors in the basal ganglia leading to extrapyramidal
side effects:
a) Akathisia (motor restlessness).
b) Dystonia (Muscle spasm).
c) Parkinsonism (muscle rigidity, hypokinesia and tremors).
v Anticholinergic drugs (e.g. Benzhexol or Benztropine) are given routinely with
Antipsychotics as prophylaxis against Extrapyramidal side effects. However,
Anticholinergic drugs may aggravate Tardive dyskinesia.
d) Tardive dyskinesia: - Abnormal involuntary movements e.g. chewing,
sucking or tongue protrusion. Tardive dyskinesia is due to increased
sensitivity of Dopamine receptors following chronic blockade.
Anticholinergic drugs aggravate Tardive dyskinesia.
Preventive measures:
1) Use the least possible dose of Antipsychotics.
2) Minimal duration.
3) Avoid routine use of Antipsychotics.
4) Switch to Atypical Antipsychotics.
e) Neurolept malignant syndrome:
Features: - Muscle rigidity + Fever.
Mechanism: - Idiosyncrasy. It is an acute severe form of Parkinsonism
due to rapid blockade of D2 receptors.
Treatment:
- Dantrolene to decrease muscle rigidity.
- Anti-Parkinsonian drugs.
II- Blockade of Autonomic receptors:
1) Blockade of H1 receptors.
Uses: - Antipruritic.
Side effects: - Sedation and Fatigue.
2) Blockade of M-receptors.
Side effects: - Dry mouth, blurred vision, retention of urine, constipation.
3) Blockade of Alpha-receptors.
Side effects: - Postural hypotension and reflex tachycardia.
III- Miscellaneous effects:
- Cardiotoxicity, Leucopenia.
- Convulsions.
- Corneal and lens opacities.
- Cholestatic jaundice.
Members of Typical Antipsychotics

1) Chlorpromazine: - Prototype.
2) Other members resemble Chlorpromazine but differ in potency and side effects.
According to potency, Typical Antipsychotics are classified into:
I- Low Potency; e.g. Chlorpromazine. It has: -
- More autonomic side effects.
- More miscellaneous side effects.
- Less central side effects.
II- High Potency; e.g. Haloperidol and Trifluperazone. They have:
- Less autonomic side effects.
- Less miscellaneous side effects.
- More central side effects.
- Suitable for elderly and cardiac patients.
Advantages of Typical Antipsychotics:

1) Cheap.
2) Sustained release preparations (e.g. Haloperidol decanoate in oil) are available
for I.M injections every 3 weeks leading to increased patient compliance.
Atypical Antipsychotics
They have the following advantages:
I- Less central side effects (more selective on the Mesolimbic system), less
Parkinsonism, less Akathisia, less Dystonia, and less Tardive dyskinesia.
II- More efficacy (due to 5-HT antagonism):
- Effective in resistant cases of Schizophrenia.
- Effective against negative symptoms (typical Antipsychotics are only
effective against positive symptoms).
Atypical Antipsychotics include:
- Resperidone.
- Clozapine; reserved for refractory cases due to high incidence of fetal
agranulocytosis (requires weekly monitoring of white blood cells).
- Olanzepine; similar to Clozapine but no agranulocytosis.
Lithium carbonate
- Lithium (Li) is a monovalent cation similar to Na+.
- It is mainly used as a prophylactic maintenance therapy for Manic-depressive
disorder.
Manic-Depressive disorder:
- It is a chronic disorder characterized by attacks of Mania alternating with attacks of
Depression.
- During the Manic phase, there are euphoric and psychotic symptoms
(Hallucinations, Delusions, Agitation).
- Increased catecholamine activity has been shown to be associated with mania.
The beneficial effects of Lithium in Bipolar Manic-depression are:
- Mood stabilizer: - Reduces mood swings.
- Anti-Manic effect: - Decreases the Manic behavior during the manic
phase (Antipsychotics are added to Lithium for rapid control of acute
mania).
Mania
Mood stabilizers Lithium + Antipsychotics
Depression Lithium
Antidepressants Valpraote Alternative mood stabilizers
Carbamazepine in cases of Li+ toxicity or
Ineffectiveness.
Fig: Manic-depressive disorder.
Lithium side effects, Toxicity and Precautions:

CNS: - Fine tremors.
GIT: - Nausea, vomiting and diarrhea.
v Coarse tremors and increased GIT symptoms are early signs of Lithium toxicity.
Kidney:
- Antagonizes ADH leading to polyuria and thirst.
- Nephrogenic diabetes insipidus.
- Renal tubular damage (Monitor kidney damage).
Thyroid: - Benign thyroid enlargement with or without hypothyroidism (Monitor thyroid
function).
v Lithium is a toxic drug with narrow therapeutic index (0.5 – 1.5 mEq/l). Li+ has
long half-life. Lithium is an accumulative drug.
v Monitor the serum level of Lithium.
v Adjust the dose in cases of decreased renal excretion of Li+:
- Na+ depletion.
- Diuretics.
- Renal dysfunction.
- Old age (Renal dysfunction).
Acute Lithium toxicity: - Lithium serum level >2.5 mEq/l.

Manifestations of acute Lithium toxicity:
- Nausea, vomiting, coarse tremors (early signs of toxicity).
- Ataxia.
- Arrhythmias.
- Confusion, Convulsions and Coma.
Treatment of acute Lithium toxicity:

- Sodium carbonate + Fluids (for dehydration).
v Li+ is excreted unchanged by the kidney.
v Li+ competes with Na+ for renal tubular reabsorption.
v In cases of Na+ depletion (e.g. by Diuretics). Li+ reabsorption is increased
leading to increased Li+ serum level leading to Li+ toxicity.
v Na+ loading decreases the renal reabsorption of Li+, therefore, useful in treatment
of Lithium toxicity.

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Schizophrenia: - It is the most common and most classic example of Psychosis.

Dopamine theory of Psychosis

Mechanism of action of Antipsychotics

Pharmacological Actions, Uses and Side effects of Typical Antipsychotics

Primary Psychosis (Decreases Hallucinations and Delusions in a few weeks)

Members of Typical Antipsychotics

Advantages of Typical Antipsychotics:

Lithium side effects, Toxicity and Precautions:

Acute Lithium toxicity: - Lithium serum level >2.5 mEq/l.

Treatment of acute Lithium toxicity:

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