rifampin/isoniazid

Action and Spectrum

Actions and Spectrum:  

Action:  

rifampin and isoniazid are two antibiotics often used to treat tuberculosis. rifampin works by inhibiting the RNA polymerase enzyme, which is necessary for bacterial DNA transcription. This results in inhibits bacterial RNA synthesis and, consequently, the cessation of bacterial replication. Conversely, isoniazid works by inhibiting the synthesis of mycolic acid, a vital component of the mycobacterial cell wall. This disruption of cell wall synthesis leads to the death of the bacteria. 

rifampin has a broad spectrum of activity against many Gram-positive and Gram-negative bacteria, including Mycobacterium tuberculosis, Haemophilus influenzae, and Staphylococcus aureus. It is also active against some atypical bacteria, such as Legionella pneumophila and Neisseria meningitidis. 

isoniazid has a narrower spectrum of activity and is primarily used to treat tuberculosis caused by Mycobacterium tuberculosis. It is also active against Mycobacterium avium complex (MAC) and some other mycobacteria.

Drug Interaction

Adverse Reaction

Frequency not defined 

clay-colored stools 

jaundice (yellowing of the skin or eyes) 

vision changes, confusion, hallucinations 

unusual thoughts or behavior 

easy bruising 

unusual bleeding (nose, mouth, vagina, or rectum) 

purple or red pinpoint spots under your skin. 

upper stomach pain 

Nausea  

Fever 

unusual weakness 

pale skin 

easy bruising 

feeling weak or tired 

loss of appetite 

dark urine 

fever, unusual weakness, pale skin 

Black Box Warning

Black Box Warning:  

The black box warning for rifampin/isoniazid states that these medications should be used with caution in patients with a history of liver disease or alcoholism. Both drugs can cause liver damage, and the risk of liver injury increases in patients with pre-existing liver disease or consume alcohol regularly. 

The black box warning also states that rifampin/isoniazid should be used cautiously in patients taking other medications that can cause liver damage, such as acetaminophen. The combination of these medications can increase the risk of liver injury. 

Patients taking rifampin/isoniazid should be monitored closely for signs of liver damage, including nausea, vomiting, abdominal pain, jaundice, and fatigue. If these symptoms occur, treatment with rifampin/isoniazid should be stopped immediately. 

Contraindication / Caution

Contraindication/Caution:  

Hypersensitivity to rifampin or isoniazid: Patients who have previously experienced an allergic reaction to rifampin or isoniazid should not take this medication. 

Severe liver disease: Patients with severe liver disease should not take rifampin/isoniazid as the medication can further damage the liver.  

Acute porphyria: rifampin/isoniazid is contraindicated in patients with acute porphyria, a rare genetic disorder that affects the production of heme in the body.  

Concurrent use with certain medications: rifampin/isoniazid should not be taken with certain medications, including protease inhibitors used to treat HIV and anticoagulants such as warfarin.  

Alcoholism: rifampin/isoniazid should not be taken by patients with a history of alcoholism, as both medications can cause liver damage and the combination of the two can be particularly harmful.  

Pregnancy and breastfeeding: rifampin/isoniazid should be used with caution in pregnant and breastfeeding women as the medication can pass into breast milk and may harm the baby. Patients should consult with their healthcare provider before taking this medication if they are pregnant or breastfeeding. 

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: N/A 

Lactation: Excreted into human milk is unknown 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.   

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category  

Pharmacology

Pharmacology: 

rifampin and isoniazid are two first-line agents used in the treatment of tuberculosis. rifampin is a semisynthetic derivative of rifamycin, while isoniazid is a synthetic hydrazide compound. 

Pharmacodynamics: 

The combination of rifampin and isoniazid is often used in treating tuberculosis because they target different aspects of the bacterial cell. The two drugs work synergistically to kill the bacteria and prevent the development of resistance. 

MOA:  

rifampin is a bactericidal drug that inhibits DNA-dependent RNA polymerase in susceptible bacteria, thereby preventing RNA synthesis and ultimately leading to bacterial death. rifampin’s activity is broad-spectrum, affecting both Gram-positive and Gram-negative bacteria. It has excellent penetration into tissues and body fluids, including the cerebrospinal fluid, allowing for effective treatment of extrapulmonary tuberculosis. 

isoniazid is a prodrug that requires activation by the bacterial enzyme KatG. Once activated, isoniazid targets several critical enzymes involved in mycobacterial cell wall synthesis, including the enoyl-acyl carrier protein reductase InhA and the beta-ketoacyl-ACP synthase KasA. Isoniazid also disrupts mycolic acid synthesis, a crucial component of the mycobacterial cell wall. Its activity is primarily against rapidly dividing mycobacteria and highly selective for Mycobacterium tuberculosis.  

Pharmacokinetics: 

Absorption: 

rifampin is well-absorbed after oral administration, with peak plasma concentrations occurring within 2-4 hours. isoniazid is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations occurring within 1-2 hours. 

Distribution: 

rifampin is widely distributed throughout the body, including into bone and cerebrospinal fluid. isoniazid is distributed widely throughout the body, but has poor penetration into the cerebrospinal fluid.  

Metabolism: 

rifampin is extensively metabolized in the liver by the cytochrome P450 system, with the main metabolite being desacetyl rifampin. soniazid is primarily metabolized in the liver by N-acetyltransferase 2 (NAT2) to form acetyl isoniazid, which is then further metabolized to hydrazine.  

Excretion and elimination:  

rifampin and its metabolites are primarily excreted in the bile, with some elimination in the urine. The half-life of rifampin is around 3 hours. isoniazid and its metabolites are primarily excreted in the urine, with a small amount eliminated in the feces. The half-life of isoniazid is around 1-3 hours. 

Adminstartion

Administration:  

Dosage: The typical dose for adults is 300 mg rifampin and 150 mg isoniazid once daily, or as prescribed by the doctor. 

Time of day: rifampin and isoniazid should be taken on an empty stomach, either one hour before or two hours after a meal. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: rifampin/isoniazid 

Why do we use rifampin/isoniazid?   

rifampin/Isoniazid is a combination drug therapy used for the treatment of tuberculosis (TB). rifampin is a bactericidal antibiotic that works by inhibiting RNA polymerase, an enzyme required for bacterial DNA transcription. isoniazid, on the other hand, is a bacteriostatic antibiotic that works by inhibiting the synthesis of mycolic acids, which are essential components of the bacterial cell wall. 

The combination of rifampin and isoniazid has been found to be highly effective in treating both drug-susceptible and drug-resistant strains of TB. rifampin is known to penetrate well into tissues and body fluids, including the cerebrospinal fluid, which is important for treating central nervous system TB. Additionally, the use of isoniazid in combination with rifampin has been shown to reduce the development of drug resistance and decrease the duration of treatment. 

It is important to note that the use of rifampin/isoniazid may be associated with some adverse effects, such as hepatotoxicity, gastrointestinal disturbances, and hypersensitivity reactions. Therefore, close monitoring of patients is essential during treatment to ensure early detection and management of any potential side effects.