1. Clinical Overview
A fixed-dose combination of two first-line anti-tubercular drugs used primarily as a component of multi-drug therapy for the treatment of pulmonary and extra-pulmonary tuberculosis. Sodium aminosalicylate (PAS) is a bacteriostatic agent that inhibits folic acid synthesis, while Isoniazid (INH) is a bactericidal agent that inhibits mycolic acid synthesis in actively dividing tubercle bacilli. This combination is used to prevent the emergence of INH resistance and is a key part of the Category II (re-treatment) regimen under the Revised National Tuberculosis Control Programme (RNTCP), now NTEP (National Tuberculosis Elimination Programme) in India.
| Onset | Duration | Bioavailability |
|---|---|---|
| Isoniazid: 1-2 hours for peak plasma concentration. Sodium aminosalicylate: 1-2 hours for peak plasma concentration. Clinical improvement (fever, cough) may be seen within 2-3 weeks. | Approximately 24 hours for both components, supporting once-daily dosing. | Isoniazid: ~90% (oral). Sodium aminosalicylate: ~70-80% (oral). Bioavailability of PAS is reduced when taken with food. |
2. Mechanism of Action
The combination exerts a synergistic anti-mycobacterial effect through two distinct pathways. Isoniazid is a prodrug activated by the bacterial catalase-peroxidase enzyme (KatG). The activated form inhibits the enzyme enoyl-acyl carrier protein reductase (InhA), which is crucial for the synthesis of mycolic acids—long-chain fatty acids essential for the mycobacterial cell wall. This leads to bactericidal activity against actively dividing organisms. Sodium aminosalicylate is a structural analog of para-aminobenzoic acid (PABA). It competitively inhibits the bacterial enzyme dihydropteroate synthase (DHPS), blocking the incorporation of PABA into dihydrofolic acid, a precursor of folic acid. This inhibition depletes folate cofactors required for nucleic acid synthesis, resulting in bacteriostatic activity.
3. Indications & Uses
- Pulmonary Tuberculosis (as part of multi-drug therapy, typically in re-treatment regimens)
- Extra-pulmonary Tuberculosis (as part of multi-drug therapy, typically in re-treatment regimens)
4. Dosage & Administration
Adult Dosage: Typical dosage is based on the Isoniazid component: 4-6 mg/kg/day (max 300 mg/day). In this combination, the standard adult dose is often one 4.5g sachet/granules (containing approx. 105 mg Isoniazid and 3.6g Sodium PAS) taken once daily. However, dosing MUST be calculated individually as per NTEP Category II regimen: INH 600 mg + PAS 12g per day in divided doses. The granular form is mixed with water or yogurt.
Administration: Take after food to minimize gastrointestinal irritation from PAS. The granules/powder should be mixed thoroughly in a glass of water, fruit juice, or yogurt immediately before consumption. Do not chew the granules. Administer once daily, preferably at the same time each day. For the full multi-drug regimen, other anti-TB drugs (Rifampicin, Pyrazinamide, Ethambutol) should be taken at their prescribed times, often separately to avoid interactions (especially with Rifampicin).
5. Side Effects
Common side effects may include:
- Nausea, Vomiting, Diarrhea, Abdominal pain (due to PAS)
- Anorexia
- Headache
- Dizziness
- Mild skin rash or itching
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Aluminum-containing Antacids | Decreased absorption of Isoniazid. Separate administration by at least 2 hours. | Moderate |
| Phenytoin, Carbamazepine | INH inhibits metabolism, increasing levels and risk of toxicity (ataxia, nystagmus). Monitor levels and reduce anticonvulsant dose. | Major |
| Warfarin | INH may potentiate anticoagulant effect. Monitor INR closely. | Major |
| Benzodiazepines (e.g., Diazepam) | INH may inhibit metabolism, increasing sedation. | Moderate |
| Theophylline | INH may increase Theophylline levels. Monitor for toxicity. | Moderate |
| Ketoconazole, Itraconazole | INH may reduce azole levels. Monitor efficacy. | Moderate |
| Rifampicin | Rifampicin induces INH metabolism, potentially lowering INH levels, but this is managed in standard TB regimens. Rifampicin also increases risk of hepatotoxicity. | Major |
| Corticosteroids | May decrease INH levels by increasing acetylation rate. | Moderate |
| Acetaminophen (Paracetamol) | Increased risk of hepatotoxicity, especially in malnourished patients. Avoid excessive doses. | Major |
| Tyramine-rich foods (with INH as MAO inhibitor) | Risk of hypertensive crisis (flushing, headache, palpitations). | Moderate |
7. Patient Counselling
- DO take the medication exactly as prescribed, at the same time each day, for the full duration (often 6-8 months or more).
- DO take it after food to reduce stomach upset.
- DO mix the granules completely in water, juice, or yogurt as instructed. Drink immediately.
- DO take Pyridoxine (Vitamin B6) supplement if prescribed by your doctor to prevent nerve problems.
- DO attend all follow-up appointments for sputum tests and monitoring.
- DON'T stop taking the medicine even if you feel better.
- DON'T consume ANY alcohol during treatment and for some time after.
- DON'T take any other medicines (including OTC, Ayurvedic, or home remedies) without consulting your doctor.
- DON'T share your medicine with anyone else.
8. Toxicology & Storage
Overdose: Isoniazid overdose is a medical emergency. Symptoms appear within 30 min to 3 hours: Severe nausea/vomiting, slurred speech, dizziness, visual hallucinations, seizures (often refractory), metabolic acidosis (high anion gap), hyperglycemia, coma, respiratory distress. PAS overdose: Severe nausea, vomiting, diarrhea, abdominal pain, electrolyte imbalance, metabolic acidosis, crystalluria, possible renal damage.
Storage: Store in a cool, dry place, protected from light and moisture. Keep the container tightly closed. Store at room temperature (15-30°C). Do not freeze. Keep out of reach of children. Do not use after the expiry date printed on the pack.