Introduction to TB and Anti-Tubercular Drugs

This section provides an introduction to tuberculosis (TB) and the two classes of anti-tubercular drugs.

TB Overview

• TB is a chronic infectious disease caused by Mycobacterium tuberculosis.

• The lesion of TB is fibrotic, making drug penetration difficult.

• Treatment for TB can last for months or even years if the patient is still positive for TB culture.

Anti-Tubercular Drugs

First-Line Drugs

• First-line anti-tubercular drugs are used first because they are cheap, effective, and have decreased dose toxicity.

• The first-line drugs include:

• Isoniazid

• Rifampicin

• Ethambutol

• Pyrazinamide

• Streptomycin

• These drugs can be remembered by the mnemonic "RIPES".

Second-Line Drugs

• Second-line anti-tubercular drugs are used after the first line doesn't work.

• They are inexpensive but not as effective and have increased toxicity compared to first-line drugs.

• The second-line drugs include:

• Fluoroquinolones

• Amikacin

• Cycloserine

• Ethionamide

• Para-Aminosalicylic Acid (PAS)

• These drugs can be remembered by the mnemonic "FACEBACK".

Isoniazid

This section focuses on the drug isoniazid, including its mechanism of action, pharmacokinetic properties, and side effects.

• Isoniazid inhibits mycolic acid synthesis in the cell wall of Mycobacterium tuberculosis.

• It is a prodrug that depends on bacterial catalysts for activation.

• Isoniazid can kill both intracellular and extracellular bacilli and is used in treatment and prophylaxis.

• It can cross the blood-CSF barrier, placenta, and tubercular cavities.

• Side effects include hepatotoxicity due to chronic use, leading to raised LFTs (AST/ALT).

• Peripheral neuritis can occur due to depletion of vitamin B6 caused by AST/ALT activity requiring pyridoxine.

• Other side effects include sideroblastic anemia, SLE (mostly associated with slow acetylators), and hemolytic anemia in G6PD-deficient patients.

• Glutathione is required to reduce oxidative stress. NADPH from g6pd converts oxidized glutathione into reduced form. In G6PD-deficient patients, oxidative stress leads to hemolytic anemia because glutathione cannot be converted into its reduced form. RBC's are more susceptible because they lack mitochondria.

Rifampin

This section focuses on rifampin or rifampicin, including its mechanism of action and bactericidal properties.

• Rifampin acts on both intracellular and extracellular bacteria and also on the ones present in caseous necrosis.

• It inhibits DNA-dependent RNA polymerase, leading to inhibition of RNA synthesis.

• Rifampin is bactericidal for Mycobacterium tuberculosis, focus agent, fluoroquinolones, Staphylococcus aureus, and E. coli.

Antitubercular Drugs

This section discusses the different antitubercular drugs and their mechanisms of action, side effects, and usage.

Rifampin

• Used for meningococcal carrier state and brucellosis treatment.

• Causes hepatotoxicity, flu-like syndrome, GI disturbances, skin rash, itching, flushing.

• Characteristic red-orange color in urine, tears, and saliva.

• Enzyme inducer that induces its own metabolism.

Pyrazinamide

• Inhibits mycolic acid synthesis but not with the same mechanism as isoniazid.

• Causes dose-dependent hepatic toxicity (hepatitis) and hyperuricemia.

Ethambutol

• Inhibits arabinosyltransferase enzyme and thus cell wall synthesis inhibition.

• Bacteriostatic drug with no cross-resistance with any other entity.

• Can cause optic neuritis with especially color vision (red-green).

Fluoroquinolones

• Ciprofloxacin, ofloxacin, moxifloxacin, levofloxacin are all bactericidal in nature.

Amikacin

• Strong enough to combat Mycobacterium tuberculosis.

• Given IV as a Seidel drug.

Cycloserine

• Cell wall synthesis inhibitor that can cross blood CSF barrier.

• Has CNS side effects such as tremor psychosis convulsions and headache.

Para-salicylic Acid

• Resembles sulfonamides in structure and inhibits folic acid synthesis.

• Cannot cross the blood-brain barrier.

• Has GI side effects, hepatic damage, and thrombocytopenia.

Regimens for Treating TB

• Multi-drug therapy is used to get rid of bacteria rapidly, prevent resistance and relapse, and shorten duration of therapy.

• Normal short course therapy is for 6 to 8 months with an intensive phase (2-3 months) and a continuation phase (4-6 months).

• Intensive phase uses four drugs while the continuation phase uses two drugs.

Anti-Tubercular Drugs

This section discusses the use of anti-tubercular drugs for treating tuberculosis.

Intensive and Continuation Phase

• The treatment consists of an intensive phase with six drugs for six to nine months, followed by a continuation phase with four drugs for 18 months.

• XDR-TB is resistant to ionize it rifampin pura quinolones and one of any case in Capri myosin etc and this is usually fatal.

• In HIV-associated TB, we prefer refer butan that is a vamp in analog but it has less enzyme-inducing activity so it will not enhance the metabolism of the H anti-HIV drugs.

First-Line Drugs in Pregnancy

• All first-line drugs are used except streptomycin which is contraindicated in pregnancy.

MAC Complex Eradication

• To eradicate MAC complex, we can use macrolides such as clarithromycin and azithromycin along with Florrick will nodes for about 18 to 24 months.

Chemoprophylaxis of Tuberculosis

• Indications for chemoprophylaxis include a newborn of a mother with active TB, young children less than six years old with positive tuberculin test, household contacts of TB patients, and additional risk factors such as diabetes mellitus malignancy and AIDS etc.

• For chemoprophylaxis, we use ionize it for about six months.