Typical Antipsychotics

Mechanisms of Action and Main Effects

The pharmacodynamics of typical antipsychotics largely depends on the specific brain structures where they block dopamine receptors (predominantly $D_2$ type).

• Antipsychotic effect. Mediated by the blockade of $D_2$ receptors in the mesolimbic system. The drugs successfully eliminate positive symptoms (hallucinations, delusions) but have virtually no effect on negative and cognitive symptoms.
• Extrapyramidal symptoms. Occur as a direct consequence of dopamine blockade in the nigrostriatal system, leading to motor disturbances.
• Neuroendocrine changes. Blockade of receptors in the tuberoinfundibular pathway (hypothalamus and pituitary gland) removes the inhibitory effect of dopamine on prolactin synthesis. Hyperprolactinemia develops, manifested as galactorrhea and amenorrhea in women, and gynecomastia and impotence in men. Growth hormone secretion is also decreased.
• Antiemetic effect. Caused by the inhibition of dopamine receptors in the chemoreceptor trigger zone of the vomiting center.
• Effect on thermoregulation and muscles. Muscle tone is decreased due to attenuation of descending influences from the reticular formation. Body temperature drops (hypothermia) due to depression of the thermoregulatory center and cutaneous vasodilation.

Drug Classification

Typical antipsychotics are divided into three main groups based on their chemical structure:

1. Phenothiazine derivatives (classified by side chain):
2. Aliphatic: Chlorpromazine, Levomepromazine.
3. Piperazine: Perphenazine, Trifluoperazine, Fluphenazine.
4. Piperidine: Thioridazine, Pipotiazine.
5. Butyrophenone derivatives: Haloperidol, Droperidol.
6. Thioxanthene derivatives: Chlorprothixene.

Pharmacological Profile of Chlorpromazine

Chlorpromazine is the prototype aliphatic phenothiazine. In addition to its antipsychotic properties, it exhibits pronounced sedative and anxiolytic effects.

Its inhibitory effect on the ascending reticular activating system of the brainstem leads to decreased motor activity, elimination of affective reactions, and general calming. High doses induce superficial sleep (due to additional blockade of histamine and cholinergic structures). The drug actively potentiates the effects of CNS depressants: general anesthetics, sedatives, hypnotics, and opioid analgesics.

Pharmacokinetics:

• Poorly absorbed orally.
• High plasma protein binding (approximately 90%).
• Metabolized in the liver to form over 150 metabolites (half of which are active).
• The duration of the therapeutic effect is about 6 hours. Tolerance develops with prolonged use.

Indicated for schizophrenia, manic states, acute delirium, psychomotor agitation, aggression, as well as for intractable vomiting and hiccups, and preoperative sedation in anesthesiology.

Peripheral Effects

The action of antipsychotics is not limited to the central nervous system; they also affect autonomic regulation:

• Anticholinergic (antimuscarinic) effect: causes classic "atropine-like" effects—dry mouth (xerostomia), decreased bronchial and digestive secretions, urinary retention, constipation, and accommodation disturbance (blurred vision).
• Alpha-adrenergic blocking effect: provokes blood pressure reduction, risk of orthostatic hypotension, and reflex tachycardia. Central depression of the vasomotor center also contributes to hypotension.
• Antihistamine effect: blockade of $H_1$ receptors provides an allergic effect, but also contributes to lower blood pressure and suppression of smooth muscle motility.

Extrapyramidal Symptoms and Complications

Motor complications are the most frequent and severe problem associated with typical antipsychotics. They are divided into two groups:

1. Early (reversible):
2. Drug-induced parkinsonism (tremor, rigidity, motor retardation). Corrected by drug withdrawal or administration of central anticholinergics.
3. Acute dystonia (spasmodic contractions of facial, neck, and back muscles; occur after initial doses).
4. Akathisia (restlessness, motor agitation).
5. Late (irreversible):
6. Tardive dyskinesia. Manifested by involuntary, choreoathetoid movements of the face and neck with long-term therapy (years). Does not disappear after discontinuation and is refractory to treatment.

A life-threatening complication is neuroleptic malignant syndrome (NMS), characterized by muscle rigidity, hyperthermia, and autonomic instability (blood pressure fluctuations, tachycardia).

Contraindications

Typical antipsychotics are contraindicated in:

• States of marked CNS depression (coma, severe depression).
• Severe hepatic and renal diseases.
• Myxedema.
• Hematopoietic disorders (risk of agranulocytosis and hemolytic anemia).
• Pregnancy.