Isoniazid + Sodium aminosalicylate

Usage

• Medical Conditions: Isoniazid + Sodium aminosalicylate is prescribed for the treatment of active tuberculosis (TB) infections caused by susceptible strains of Mycobacterium tuberculosis. Sodium aminosalicylate is specifically used as part of a combination regimen for drug-resistant tuberculosis, especially when resistance to other first-line drugs like isoniazid and rifampicin is present. It is also used to treat latent TB infection.
• Pharmacological Classification: Antituberculosis agents (Sodium aminosalicylate is a bacteriostatic agent, while Isoniazid is bactericidal).
• Mechanism of Action: Sodium aminosalicylate inhibits folic acid synthesis in Mycobacterium tuberculosis by competing with para-aminobenzoic acid (PABA). Isoniazid inhibits mycolic acid synthesis, a crucial component of the mycobacterial cell wall. These combined actions disrupt essential metabolic processes in the bacteria, leading to their death or growth inhibition.

Alternate Names

• Sodium aminosalicylate: Para-aminosalicylate sodium (PAS), 4-aminosalicylic acid (sodium salt).
• Brand Names: Paser, other brand names may exist regionally.
• Isoniazid in Combination with PAS: Pasinah, Pycamisan 33 (historical).

How It Works

• Pharmacodynamics: Isoniazid is bactericidal against actively growing M. tuberculosis by inhibiting mycolic acid synthesis, a key component of the mycobacterial cell wall. Sodium aminosalicylate is bacteriostatic, inhibiting folic acid synthesis.
• Pharmacokinetics:
  • Sodium aminosalicylate: Well-absorbed orally. Metabolized in the liver, primarily excreted in urine. Short half-life (about 1 hour).
  • Isoniazid: Well-absorbed orally or intramuscularly. Metabolized in the liver by acetylation, with genetic variations in acetylation rate affecting individual pharmacokinetics. Primarily excreted in the urine.
• Mode of Action: The combination targets two different metabolic pathways in M. tuberculosis. Sodium aminosalicylate competes with PABA for dihydropteroate synthase, inhibiting folate synthesis, which is crucial for bacterial DNA synthesis. Isoniazid inhibits the synthesis of mycolic acids, essential components of the mycobacterial cell wall.
• Elimination Pathways:
  • Sodium aminosalicylate: Renal excretion.
  • Isoniazid: Hepatic metabolism (acetylation) and renal excretion.

Dosage

Standard Dosage

Adults:

Sodium aminosalicylate: 12-15g daily divided into 2-3 doses. Isoniazid: 5mg/kg, up to a maximum of 300mg daily.

Children:

Sodium aminosalicylate: 150 mg/kg daily divided into 3-4 doses. Pediatric dosages should be carefully determined by the physician based on weight and other clinical factors. Isoniazid: 10-20 mg/kg daily, up to a maximum of 300mg.

Special Cases:

• Elderly Patients: Dose adjustments may be necessary for both drugs, particularly in the presence of renal or hepatic impairment. Consider lower starting doses and monitor closely for adverse events.

• Patients with Renal Impairment: Reduce dosage based on creatinine clearance for both drugs. Monitor closely for toxicity.

• Patients with Hepatic Dysfunction: Use both drugs with caution. Monitor liver function tests regularly. Dosage adjustments may be required.

• Patients with Comorbid Conditions: Consider drug interactions and potential exacerbation of existing conditions.

Clinical Use Cases

Isoniazid + sodium aminosalicylate is not typically used in acute medical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its use is primarily in the treatment of active or latent tuberculosis infections.

Dosage Adjustments

Dosage adjustments are necessary based on patient-specific factors, including renal function, hepatic function, slow acetylator status (for isoniazid), and other comorbid conditions. Therapeutic drug monitoring may be helpful in optimizing dosage.

Side Effects

Common Side Effects

• Sodium aminosalicylate: Nausea, vomiting, diarrhea, abdominal pain, hypersensitivity reactions (rash, fever).
• Isoniazid: Peripheral neuropathy (numbness, tingling), hepatotoxicity (liver damage), nausea, vomiting.

Rare but Serious Side Effects

• Sodium aminosalicylate: Severe hypersensitivity reactions, including drug fever, chills, and arthritis, hepatitis, agranulocytosis. Goiter or hypothyroidism.
• Isoniazid: Severe hepatotoxicity, seizures, psychosis, optic neuritis.

Long-Term Effects

• Sodium aminosalicylate: Goiter, hypothyroidism (particularly with concurrent use of ethionamide), malabsorption of vitamin B12.
• Isoniazid: Peripheral neuropathy, hepatotoxicity.

Adverse Drug Reactions (ADR)

• Sodium aminosalicylate: Severe hypersensitivity reactions, hepatitis, agranulocytosis.
• Isoniazid: Severe hepatotoxicity, seizures, psychosis.

Contraindications

• Sodium aminosalicylate: Severe renal or hepatic impairment, hypersensitivity to salicylates, severe heart failure.
• Isoniazid: Severe hepatic impairment, acute liver disease, history of isoniazid-associated hepatic injury, history of severe adverse reactions.

Drug Interactions

• Sodium aminosalicylate: Rifampicin (decreased PAS absorption), probenecid, anticoagulants (increased anticoagulant effect), digoxin.
• Isoniazid: Rifampicin (increased risk of hepatotoxicity), aluminum salts (decreased INH absorption), disulfiram, alcohol (increased risk of hepatotoxicity and neurotoxicity), antiepileptic drugs (phenytoin, carbamazepine - decreased metabolism of both drugs), benzodiazepines, warfarin (increased risk of bleeding).

Pregnancy and Breastfeeding

• Sodium aminosalicylate: Contraindicated in pregnancy and breastfeeding.
• Isoniazid: Use with caution during pregnancy and breastfeeding. Weigh benefits against potential risks. Pyridoxine supplementation is recommended for both mother and infant if used during breastfeeding.

Drug Profile Summary

• Mechanism of Action: See above.
• Side Effects: See above.
• Contraindications: See above.
• Drug Interactions: See above.
• Pregnancy & Breastfeeding: See above.
• Dosage: See above.
• Monitoring Parameters: Liver function tests (LFTs), renal function tests, signs of peripheral neuropathy, hypersensitivity reactions, complete blood count (CBC), thyroid function tests.

Popular Combinations

Isoniazid + Sodium aminosalicylate is often used in combination with other anti-TB drugs, especially in multi-drug resistant TB (MDR-TB) cases. Common combinations include other second-line drugs such as ethionamide, pyrazinamide, streptomycin, fluoroquinolones, cycloserine or amikacin depending on resistance patterns.

Precautions

• General Precautions: Baseline and periodic monitoring of liver and renal function, assess for peripheral neuropathy, monitor for hypersensitivity reactions.
• Specific Populations: See above.
• Lifestyle Considerations: Avoid alcohol during treatment. Isoniazid can interact with tyramine-containing foods (cheese, aged meats) and histamine-containing foods (tuna, skipjack).

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Isoniazid + Sodium aminosalicylate?

A: See detailed dosage guidelines above.

Q2: What are the most common side effects?

A: The most common side effects include gastrointestinal upset (nausea, vomiting, diarrhea, abdominal pain) for both drugs, peripheral neuropathy for isoniazid, and hypersensitivity reactions for sodium aminosalicylate.

Q3: What are the serious side effects that require immediate attention?

A: Severe hepatotoxicity (isoniazid), seizures (isoniazid), psychosis (isoniazid), severe hypersensitivity reactions (sodium aminosalicylate), drug fever, hepatitis (both drugs) and agranulocytosis (sodium aminosalicylate) require immediate medical attention.

Q4: What are the contraindications for using this combination?

A: Severe liver disease (especially with isoniazid) acute liver disease or previous isoniazid related liver injury, severe kidney impairment, and hypersensitivity to either drug are absolute contraindications. Relative contraindications include pre-existing gastrointestinal, hepatic, or renal conditions.

Q5: What are the key drug interactions to consider?

A: Important drug interactions include rifampicin, probenecid, anticoagulants, antiepileptic drugs, disulfiram, and alcohol.

Q6: Can this combination be used during pregnancy and breastfeeding?

A: Sodium aminosalicylate is contraindicated in pregnancy and breastfeeding. Isoniazid should be used with caution, weighing the benefits against the potential risks. Pyridoxine supplementation is recommended for both mother and infant if isoniazid is used during breastfeeding.

Q7: What monitoring parameters are important during treatment?

A: Liver function tests (LFTs), renal function tests, assessment for peripheral neuropathy, signs of hypersensitivity, complete blood count, and thyroid function tests (especially with concurrent ethionamide) are important monitoring parameters.

Q8: How does slow acetylator status affect isoniazid dosing?

A: Patients with slow acetylator status metabolize isoniazid more slowly, increasing the risk of side effects. Dosage adjustments or more frequent monitoring may be necessary.

Q9: What is the role of this drug combination in MDR-TB?

A: This combination, along with other second-line drugs, plays a crucial role in treating MDR-TB, particularly when resistance to isoniazid and rifampicin exists.

Q10: Should Sodium aminosalicylate be taken with food?

A: Yes, it is recommended to take Sodium aminosalicylate with food to minimize gastrointestinal side effects.