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. Associated with 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 impairments.
• Extrapyramidal symptoms. Occur as a direct consequence of dopamine blockade in the nigrostriatal system, leading to motor disorders.
• Neuroendocrine shifts. Blockade of receptors in the tuberoinfundibular area (hypothalamus and pituitary gland) removes the inhibitory influence of dopamine on prolactin synthesis. Hyperprolactinemia develops, which manifests as galactorrhea and amenorrhea in women, and gynecomastia and impotence in men. Growth hormone secretion is also reduced.
• Antiemetic effect. Caused by the inhibition of dopamine receptors in the trigger zone of the vomiting center.
• Effect on thermoregulation and muscles. Muscle tone decreases due to the attenuation of descending influences from the reticular formation. Body temperature drops (hypothermia) due to the inhibition of the thermoregulation center and vasodilation of skin vessels.

Drug classification

Typical antipsychotics are divided into three main groups depending 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 reference standard of aliphatic phenothiazines. In addition to its antipsychotic effect, it has pronounced sedative and anxiolytic activity.

Its inhibitory effect on the ascending reticular formation of the brainstem leads to a decrease in motor activity, elimination of affective reactions, and general sedation. High doses cause superficial sleep (due to additional blockade of histamine and cholinergic structures). The drug actively potentiates the action of CNS depressants: general anesthetics, hypnotics, and narcotic analgesics.

Pharmacokinetics:

• Poorly absorbed upon oral administration.
• Highly bound to plasma proteins (about 90%).
• Metabolized in the liver to form more than 150 metabolites (half of which are active).
• The duration of the therapeutic effect is about 6 hours. Tolerance develops with prolonged use.

Used for schizophrenia, manic states, acute delirium, psychomotor agitation, aggression, as well as for intractable vomiting and hiccups, and premedication in anesthesiology.

Peripheral effects

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

• Anticholinergic (antimuscarinic) action: causes classic "atropine-like" effects — dry mouth (xerostomia), decreased bronchial and digestive gland secretion, urinary retention, constipation, and accommodation disorders.
• Alpha-adrenergic blocking action: provokes a decrease in blood pressure, the risk of orthostatic hypotension, and reflex tachycardia. Central depression of the vasomotor center also contributes to hypotension.
• Antihistamine action: blockade of $H_1$ receptors produces an antiallegic effect, but also contributes to lowered blood pressure and suppression of smooth muscle motility.

Extrapyramidal disorders and complications

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

1. Early (reversible):
2. Drug-induced parkinsonism (tremor, rigidity, motor retardation). Corrected by drug discontinuation or administration of central anticholinergics.
3. Spasmodic contractions of the facial, neck, and back muscles (occur after the first doses).
4. Akathisia (restlessness, motor agitation).
5. Late (irreversible):
6. Tardive dyskinesia. Manifests as involuntary excessive movements of the face and neck with long-term intake (years). It does not disappear after discontinuation and is untreatable.

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

Contraindications

Typical antipsychotics are contraindicated in:

• States of pronounced CNS depression (coma, depression).
• Severe liver and kidney diseases.
• Myxedema.
• Disorders of hematopoietic organ function (risk of agranulocytosis and hemolytic anemia).
• Pregnancy.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Pathogenesis and Treatment Principles of Neuroleptic Malignant Syndrome
• Pharmacodynamic Features of Butyrophenone Derivatives (Haloperidol, Droperidol)
• Use of Typical Antipsychotics in Anesthesiology (Neuroleptanalgesia)
• Mechanisms of Late Tardive Dyskinesia Development During Long-Term Therapy

Other topics in the section "Agents Used in Psychiatry and Neurology"

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