ISONIAZID; RIFAPENTINE

Indications

• Treatment of active tuberculosis
• Prevention of tuberculosis in susceptible individuals, especially close contacts of infected persons

Dosage

Adults: 10 mg/kg daily (maximum per dose 300 mg) for 3 months, to be taken by mouth or via intramuscular or intravenous

Mechanism of action

Isoniazid is activated by the bacterial catalase-peroxidase KatG, which reduces the ferric form of the enzyme and enables it to react with oxygen to form an oxyferrous enzyme complex. The active form of isoniazid then inhibits the synthesis of mycolic acids by forming a covalent adduct with NAD, inhibiting the enoyl reductase InhA. This inhibition is crucial for the integrity of the mycobacterial cell wall, leading to the bactericidal activity of isoniazid against actively growing Mycobacterium tuberculosis.

Pharmacodynamics

Isoniazid is a bactericidal agent particularly effective against the Mycobacterium genus, including M. tuberculosis, M. bovis, and M. kansasii. It exhibits bactericidal properties during periods of rapid mycobacterial growth and becomes bacteriostatic when the bacteria are in a dormant state. Given its mechanism of action, isoniazid is highly selective, targeting mycobacteria without significant effects on other types of bacteria.

Pharmacokinetics

Isoniazid is well-absorbed following oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It is widely distributed in body tissues and crosses the blood-brain barrier. The drug is metabolized in the liver primarily through acetylation, with variable metabolism rates observed in different populations due to genetic polymorphisms in acetylation. The elimination half-life ranges from 1 to 4 hours, and the drug is excreted in the urine, predominantly as metabolites.

Contra-indications

• History of hypersensitivity to isoniazid
• Acute liver disease
• Severe hepatic impairment
• Previous history of isoniazid-induced liver injury

Adverse effects

• Hepatitis
• Peripheral neuropathy
• Optic neuritis
• Gastrointestinal disturbances
• Rash
• Fever
• Agranulocytosis
• Hematological disorders
• Lupus-like syndrome

Interactions

• Carbamazepine: Increased risk of hepatotoxicity
• Cycloserine: Increased risk of CNS toxicity
• Phenytoin: Increased concentration of phenytoin
• Levodopa: Decreased effects of levodopa
• Lomitapide: Increased exposure
• Antiepileptics: Unknown interactions leading to increased concentrations

Precautions

• Monitor liver function during treatment
• Use with caution in patients with renal impairment
• Patients with diabetes or a history of peripheral neuropathy should be monitored closely
• Ocular monitoring for young children on treatment

Pregnancy

Not known to be harmful; however, prophylactic pyridoxine is recommended.

Breast-feeding

Amount too small to be harmful; monitor infant for possible toxicity.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets
• Oral suspension
• Intramuscular injection
• Intravenous injection

Indications

• Tuberculosis (TB)
• Latent tuberculosis infection
• Active pulmonary tuberculosis

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated, including the patient’s weight and renal function.

Mechanism of action

Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis. This inhibition leads to suppression of RNA synthesis, resulting in cell death. Its effectiveness is particularly noted against intracellular bacteria within human monocyte-derived macrophages.

Pharmacodynamics

Rifapentine acts as an antibiotic by inhibiting the activity of DNA-dependent RNA polymerase in bacterial cells, specifically targeting Mycobacterium tuberculosis. This mechanism disrupts RNA synthesis, contributing to its bactericidal effects. It has a broad spectrum of activity against various gram-positive and gram-negative organisms, although its primary use is restricted to mycobacterial infections due to the potential for rapid emergence of resistant strains.

Pharmacokinetics

Rifapentine is well absorbed when administered orally and achieves widespread distribution in body tissues and fluids, including the central nervous system. It is metabolized primarily in the liver and is excreted mainly in bile, with minimal excretion in urine. There is no need for dose adjustments in cases of renal insufficiency, making it a suitable option for patients with compromised renal function.

Contra-indications

• Hypersensitivity to rifapentine or any component of the formulation
• Severe hepatic impairment
• Concurrent use of certain drugs that can cause severe liver injury

Adverse effects

• Hepatotoxicity
• Rash
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Hematological effects (thrombocytopenia, leukopenia)
• Flu-like symptoms
• Discoloration of body fluids (urine, sweat, saliva)

Interactions

• May interact with anticoagulants (e.g., warfarin) leading to altered anticoagulant effect
• Reduced efficacy of hormonal contraceptives
• Potential interactions with antiretroviral drugs
• Inducer of cytochrome P450 enzymes, which can affect the metabolism of other drugs

Precautions

• Monitor liver function tests before and during therapy
• Assess for signs of allergic reaction
• Use caution in patients with a history of liver disease
• Evaluate for potential drug interactions prior to initiation

Pregnancy

Rifapentine is classified as Category C. Risk cannot be ruled out, and it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Rifapentine is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets (150 mg, 300 mg)

Mechanism of action

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular <i>Mycobacterium tuberculosis</i> organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from <i>Mycobacterium tuberculosis</i>, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA. Although the mechanism of action of isoniazid is unknown, several hypotheses have been proposed. These include effects on lipids, nucleic acid biosynthesis, and glycolysis. ... /It has been suggested that/ a primary action of isoniazid /is/ to inhibit the biosynthesis of mycolic acids, important constituents of the mycobacterial cell wall. Because mycolic acids are unique to mycobacteria, this action would explain the high degree of selectivity of the antimicrobial activity of isoniazid. Exposure to isoniazid leads to a loss of acid fastness and a decrease in the quantity of methanol-extractable lipid of the microorganisms. Isoniazid is bacteriostatic for "resting" bacilli but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 ug/ml.

Pharmacodynamics

Isoniazid is a bactericidal agent active against organisms of the genus Mycobacterium, specifically <i>M. tuberculosis</i>, <i>M. bovis</i> and <i>M. kansasii</i>. It is a highly specific agent, ineffective against other microorganisms. Isoniazid is bactericidal when mycobacteria grow rapidly and bacteriostatic when they grow slowly.

Mechanism of action

Rifapentine has shown higher bacteriostatic and bactericidal activities especially against intracellular bacteria growing in human monocyte-derived macrophages. Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of M. tuberculosis. Rifapentine acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death.

Pharmacodynamics

Rifapentine is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis. Because of rapid emergence of resistant bacteria, use is restricted to treatment of mycobacterial infections and a few other indications. Rifampin is well absorbed when taken orally and is distributed widely in body tissues and fluids, including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in urine, but dose adjustments are unnecessary with renal insufficiency.