Thioridazine

BRAND NAMES:

 Thioridazine, marketed under brand names such as Mellaril or Melleril, is a typical antipsychotic from the phenothiazine class. It was once commonly prescribed for managing schizophrenia and other psychotic disorders. 

MECHANISM OF ACTION:

 Thioridazine works by blocking postsynaptic D1 and D2 dopamine receptors in the mesolimbic pathway of the brain. It also inhibits alpha-adrenergic activity, reduces the secretion of hormones from the hypothalamus and pituitary gland, and is thought to suppress the reticular activating system. As a result, it influences functions such as basal metabolic rate, body temperature regulation, alertness, blood vessel tone, and the vomiting reflex. 

PHARMACOKINETICS

Absorption: 

Thioridazine is efficiently absorbed after oral intake. Being lipophilic, it disperses widely throughout body tissues. Like other drugs in the phenothiazine class, it undergoes extensive hepatic metabolism, resulting in the formation of numerous metabolites. 

Distribution: 

The drug and its active metabolites particularly mesoridazine are extensively distributed across the body, including the central nervous system, as they can cross the blood-brain barrier. Although thioridazine tends to have lower plasma concentrations compared to its metabolites, it accumulates in the brain at much higher levels.

Metabolism:

Thioridazine is extensively metabolized in the liver, with its main pathway involving oxidation by the cytochrome P450 (CYP450) enzyme system, particularly CYP2D6. This process produces several metabolites, some of which are pharmacologically active and more potent than the parent drug.

Excretion:

Thioridazine is extensively metabolized by the liver, primarily by the cytochrome P450 2D6 (CYP2D6) enzyme, before its metabolites are excreted mainly through the feces. Renal excretion plays a significantly smaller role in its elimination. 

PHARMACODYNAMICS 

Thioridazine is a first-generation antipsychotic and phenothiazine derivative with a complex mechanism of action involving multiple neurotransmitter systems in the central nervous system. Its activity is primarily based on blocking postsynaptic receptors, but it also causes a range of side effects due to its interactions with other receptors.

ADMINISTRATION 

Thioridazine is administered orally in tablet form, with the dosage tailored to the individual patient based on their condition and response to treatment. It is usually given in divided doses throughout the day and can be taken with or without food. Due to its potential for serious cardiac side effects, such as QTc prolongation, its use is limited to patients who have not responded to other antipsychotics. Close medical supervision and regular monitoring are essential during treatment. 

DOSAGE AND STRENGTH 

Thioridazine is available in oral tablet form with strengths typically including 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg. The dosage is individualized based on the patient's condition, age, and response to therapy. For adults with schizophrenia or psychotic disorders, initial doses usually range from 50 mg to 100 mg three times daily, with gradual adjustments as needed.

DRUG INTERACTIONS 

Medications that inhibit CYP450 2D6 should be used with caution when prescribing thioridazine. Medications that may affect thioridazine levels include but are not limited to fluoxetine, paroxetine, duloxetine, fluvoxamine, propranolol, citalopram, and pindolol.

FOOD INTERACTIONS 

Thioridazine has significant food interactions, requiring that you avoid alcohol because it can increase central nervous system depression and side effects like dizziness and falls. Caffeine intake should be limited, as it may raise blood pressure and affect the way the medication is metabolized in the body. Although not a food, patients should be cautious with vitamin A supplements, as thioridazine may elevate vitamin A levels, leading to potential toxicity. 

CONTRAINDICATIONS

 patients with long QT syndrome, QT intervals prolonged to more than 450, or taking concomitant medications known to prolong the QT interval should avoid thioridazine. Additionally, individuals with a history of heart arrhythmias or heart conditions related to low or high blood pressure should refrain from using this medication. 

SIDE EFFECTS

• drowsiness 

• blurred vision 

• dry mouth 

• nausea 

• vomiting 

• diarrhea 

• constipation 

• changes in appetite 

• weight gain 

• stuffed nose 

• pale skin 

• darkening of the skin or eyes 

• Swelling may occur in the arms, hands, feet, ankles, or lower legs. 

• blank facial expression 

• shuffling walk 

• Abnormal, slowed, or involuntary movements in any part of the body. 

• restlessness 

SERIOUS SIDE EFFECTS:

• fever 

• muscle stiffness 

• confusion

• sweating

• neck cramps

• tightness in the throat 

• difficulty breathing or swallowing 

• tongue that sticks out of the mouth 

• fine, worm-like tongue movements 

• uncontrollable, rhythmic face, mouth, or jaw movements 

• vision loss, especially at night 

• seeing everything with a brown tint 

• yellowing of the skin and eyes

• rash

OVER DOSE 

• Severe drowsiness or coma 

• Confusion or agitation 

• Seizures 

• Respiratory depression 

• Irregular heartbeat or arrhythmias, especially QTc prolongation and torsades de pointes

• Hypotension (low blood pressure) 

• Dry mouth, difficulty urinating, blurred vision, and constipation. 

TOXICITY 

Thioridazine toxicity primarily manifests as severe, vision-threatening pigmentary retinopathy, with symptoms including blurred vision, night blindness (nyctalopia), and dyschromatopsia (altered colour vision). Toxicity risk increases with higher daily doses, particularly above 800 mg/day, and can develop within weeks of starting therapy.