Ethambutol + Isoniazid + Pyrazinamide + Rifampicin + Vitamin B6

Usage

• This drug combination is primarily prescribed for the treatment of drug-susceptible tuberculosis (TB). It is used to treat both pulmonary and extrapulmonary TB.
• Pharmacological Classification: Antitubercular agents, specifically a combination of antibiotics and a vitamin.
• Mechanism of Action: This combination targets multiple aspects of Mycobacterium tuberculosis physiology. Isoniazid inhibits mycolic acid synthesis, a crucial component of the bacterial cell wall. Rifampicin inhibits bacterial RNA polymerase, thereby suppressing RNA synthesis. Pyrazinamide disrupts bacterial membrane metabolism and energy production. Ethambutol interferes with cell wall synthesis by inhibiting arabinosyl transferases. Vitamin B6 (pyridoxine) is included to mitigate the peripheral neuropathy that can be caused by isoniazid.

Alternate Names

• This combination is often referred to as RIPE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) therapy, sometimes with the addition of Vitamin B6, making it RIPE + B6.
• There are several formulations with specific brand names.

How It Works

• Pharmacodynamics: The combined effect of these drugs results in bactericidal activity against Mycobacterium tuberculosis. They work synergistically to kill actively replicating bacteria and also have some activity against dormant bacteria.
• Pharmacokinetics:
  • Absorption: Rifampicin, isoniazid, pyrazinamide, and ethambutol are absorbed orally. Food can interfere with the absorption of rifampicin and isoniazid, so they are generally taken on an empty stomach.
  • Metabolism: These drugs are metabolized primarily in the liver via various pathways, including acetylation (isoniazid), hydrolysis (rifampicin), and deamidation (pyrazinamide). Rifampicin is a potent inducer of CYP450 enzymes.
  • Elimination: The drugs are eliminated through both renal and hepatic routes.

Dosage

Standard Dosage

Adults: Dosing is usually weight-based, especially for patients weighing less than 50 kg. For those over 50 kg, a fixed-dose combination tablet might be used. A typical dose could be Rifampicin 150 mg, Isoniazid 75 mg, Pyrazinamide 400 mg, and Ethambutol 275 mg, taken as a single daily dose.

Children: Dosing is strictly weight-based and formulations suitable for children must be used. Specific pediatric guidelines should be consulted.

Special Cases:

• Elderly Patients: Close monitoring for liver and kidney function is recommended, as is Vitamin B6 supplementation.
• Patients with Renal Impairment: Dose adjustments, especially for pyrazinamide and ethambutol, are usually necessary. Isoniazid and rifampicin doses may need adjustment as well.
• Patients with Hepatic Dysfunction: The drug combination should be used with caution due to the risk of hepatotoxicity. Dose adjustments may be needed, and liver function tests should be closely monitored.
• Patients with Comorbid Conditions: Patients with diabetes, HIV, malnutrition, or alcoholism require Vitamin B6 supplementation due to increased risk of peripheral neuropathy.

Clinical Use Cases

The use of this drug combination is specifically for tuberculosis treatment and not generally indicated for other clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

Dose modifications are required for renal and hepatic impairment. Drug interactions should be carefully considered, especially since rifampicin is a potent CYP450 inducer.

Side Effects

Common Side Effects:

• Nausea, vomiting
• Loss of appetite
• Abdominal discomfort
• Fatigue
• Fever
• Peripheral neuropathy (numbness and tingling in extremities)
• Discoloration of body fluids (reddish-orange urine, sweat, tears)

Rare but Serious Side Effects:

• Hepatotoxicity (liver damage)
• Optic neuritis (vision changes)
• Thrombocytopenia (low platelet count)
• Acute gout (joint pain and swelling)
• Hypersensitivity reactions (rash, itching, swelling)
• Severe skin reactions

Long-Term Effects:

• Peripheral neuropathy (if B6 is not supplemented)
• Liver damage (with chronic misuse)
• Visual impairment (with ethambutol toxicity)

Contraindications

• Severe liver disease
• Acute gout
• Hypersensitivity to any of the component drugs
• Concurrent use of certain antiviral medications
• History of drug-induced hepatitis

Drug Interactions

• Rifampicin is a potent inducer of CYP450 enzymes and can significantly decrease the efficacy of many drugs, including:
  • Antiretrovirals
  • Oral contraceptives
  • Anticoagulants
  • Antiepileptics
  • Immunosuppressants
  • Antifungals
• Isoniazid can interact with tyramine-containing foods (aged cheese, cured meats) and alcohol.
• Antacids can interfere with the absorption of rifampicin and isoniazid.

Pregnancy and Breastfeeding

• Pregnancy: Rifampicin, isoniazid, and ethambutol can be used during pregnancy but pyrazinamide is generally avoided. Supplementation with vitamin B6 and vitamin K is recommended.
• Breastfeeding: The drugs are excreted in breast milk, and potential effects on the infant are not fully known. Mothers taking these drugs should discuss the risks and benefits with their physicians.

Drug Profile Summary

• Mechanism of Action: Multi-target antitubercular activity, inhibiting cell wall synthesis, RNA synthesis, and energy production in Mycobacterium tuberculosis.
• Side Effects: Nausea, vomiting, hepatotoxicity, optic neuritis, peripheral neuropathy, drug interactions.
• Contraindications: Severe liver disease, acute gout, hypersensitivity.
• Drug Interactions: Numerous; rifampicin is a potent CYP450 inducer.
• Pregnancy & Breastfeeding: Use with caution; B6 and K supplementation recommended in pregnancy.
• Dosage: Weight-based, usually daily dosing.
• Monitoring Parameters: Liver function tests, complete blood count, visual acuity, uric acid levels.

Popular Combinations

The combination of ethambutol, isoniazid, pyrazinamide, rifampicin, and vitamin B6 itself is the most common and effective combination for drug-susceptible TB.

Precautions

• Monitor liver function, kidney function, and visual acuity.
• Supplement with vitamin B6, especially in high-risk patients.
• Advise patients about potential drug and food interactions.
• Caution patients against alcohol consumption.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ethambutol + Isoniazid + Pyrazinamide + Rifampicin + Vitamin B6?

A: Dosing is weight-based, particularly for patients under 50 kg. For adults over 50 kg, a common dose is rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg, and ethambutol 275 mg daily, along with 25-50 mg of vitamin B6. Pediatric dosing is strictly weight-based and should be determined by consulting specialized guidelines.

Q2: What are the most serious side effects to watch out for?

A: Hepatotoxicity, optic neuritis, and hypersensitivity reactions are the most serious adverse effects. Liver function tests and visual acuity should be monitored closely.

Q3: Can this combination be used in pregnant women?

A: Yes, but with caution. Pyrazinamide is generally avoided. Supplementation with vitamin B6 and K is crucial.

Q4: What are the key drug interactions to be aware of?

A: Rifampicin induces CYP450 enzymes and interacts with many drugs, reducing their efficacy. Isoniazid interacts with tyramine-containing foods and alcohol.

Q5: What is the role of vitamin B6 in this combination?

A: Vitamin B6 prevents and treats peripheral neuropathy, a common side effect of isoniazid.

Q6: How should the medication be taken?

A: On an empty stomach, at least one hour before or two hours after a meal, as food can interfere with absorption.

Q7: What should be done if a patient misses a dose?

A: The patient should take the missed dose as soon as possible unless it is almost time for the next dose. They should not double up on doses.

Q8: How long is the typical treatment duration?

A: The standard treatment regimen is six months, although it can be longer for certain types of TB or in cases of drug resistance.

Q9: What are the signs of hepatotoxicity that patients should be educated about?

A: Unexplained nausea, vomiting, dark urine, jaundice, fatigue, and abdominal pain, especially in the right upper quadrant.

Q10: What should be done if a patient develops signs of optic neuritis?

A: Ethambutol should be discontinued immediately, and the patient should be referred to an ophthalmologist.