Anti-Tubercular drugs

Resistant

·         Increase expression of InhA or by mutations that lower the enzyme’s affinity to NADH.

Pharmacokinetics

·         INH completely absorbed orally.

·         Penetrate all the body tissue, tubular cavities, placenta, and meninges.

·         Extensively metabolized in liver, most important pathway being N-acetylation.

·         The acetylated metabolic is excreted in urine.

·         The rate of INH acetylation show genetic variation.

                    i.            Fast acetylator

(30-40% of Indians) t1/2 of INH 1hr.

                  ii.            Slow acetylator

(60-70% of Indians) t1/2 of INH 3hrs.

·         Isoniazid induced peripheral neuropathy is more common in slow acetylator.

Adverse effects

·         Hepatitis

·         Rare in children, more in older people and alcoholics (chronic alcoholism induce CyP₂E₁ which generates the hepatotoxic metabolism).

·         Hepatotoxicity due to dose related damage to liver cell.

·         Peripheral Neuritis

o   Due to interference with production of the active coenzyme pyridoxal phosphate from pyridoxine and its increased excretion in urine.

·         Pyridoxine given prophylactically (10mg/day)

o   Prevent the Neurotoxicity even with higher doses.

·         Prophylactic pyridoxine must be given to diabetics, chronic alcoholics, malnourished, lactating and HIV infected patients.

Dose

 Rifamycins: Rifampin, Rifabutin and Rifapetine

·         Rifampicin is derived from the soli mold Streptomyces.

·         It shows broader antimicrobial action than Isoniazid.

·         It is never given as a single drugs in the treatment of tuberculosis.

Mechanism of action

·         Rifampin blocks transcription by interacting with β subunit (involved in the binding of RNA polymerase to DNA) of bacteria, but not human, DNA dependent RNA polymerase (specific for prokaryotic).

·         Rifampin inhibit mRNA synthesis by suppressing the initiation step.

Antimicrobial spectrum

·         Having bactericidal effect for both intra and extracellular mycobacteria, like M. tuberculosis, M. Kansasii.

·         It also used for many gram +ve and gram –ve organisms.

·         Prophylactic used for Meningitis caused by meningococci or Haemophilus influenza.

Resistance

·         Resistance to rifampin can be caused by a mutation in the affinity of the bacterial DNA-dependent RNA polymerase for the drug, or by decreased permeability.

Pharmacokinetics

·         Well absorbed orally.

·         Distribution occurs to all body fluids and organs.

·         Bioavailability is nearly 70%.

·         Food decreases absorption, so rifampin is to be take n in empty stomach.

·         Rifampin itself can induce the hepatic mixed-function oxidase, leading to a shortened half-life and numerous drug interaction.

·         Elimination via bile into the faces or via  the urine (secretion should be orange-red color)

Adverse effects

·         Nausea, Vomiting, Flushing and Rashes are most common.

·         Cholestasis jaundice (Excessive bilirubin stored in the skin and excreted throughout urine) and occasionally hepatitis.

·         Flu symptoms: chills, fever, headache, malaise (feeling discomfort and illness) and bone pain.

·         Urine color change to orange-red but is harmless.

Drug interaction

·         Rifampin induce several cytochrome p450 enzyme that can decrease the half-life of other drugs (like: Clofibrate, Digitoxin, Ketoconazole, Methadone, Oral contraceptives, prednisone propranolol, quinidine, and sulfonylureas warfarin).

·         These may leads to higher dose may require for these case.

Pyrazinamide

·         Pyrazinamide chemically similar to INH

·         Having tuberculocidal property

·         More active in acidic medium.

·         Pyrazinamide enzymatically hydrolyzed to pyrazinoic acid, which is the active form of the drug.

·         Active against tubercle bacilli in acidic medium of lysosome, as well as in macrophages.

Mechanism of action

·         Inhibit mycolic acid synthesis (Cell wall synthesis inhibition).

Adverse effect

·         Hepatotoxicity

·         Hyperuricemia (High uric acid level in the blood)

·         Abdominal distress: arthralgia (Pain in joint), flushing, rashes, fever and loss of diabetic control.

Ethambutol

·         Bacteriostatic and specific for most strains of M. tuberculosis and M. Kansasii.

Mechanism of action

·         Inhibit arabinosyl transferase, so that interfere with the synthesis of the Mycobacteria arabinogalactan cell wall.

Pharmacokinetic

·         Absorbed on oral administration.

·         Well distributed throughout the body.

·         Penetration into the CNS.

·         Both parent drugs and metabolites are excreted by glomerular filtration and tubular secretion.

Adverse effect

·         Loss of visual activity / color vision

·         Hyperuricemia

 Streptomyces

·         Tuberculocidal

·         Acts only on extracellular bacilli (because poor penetration into cells).

·         It penetrate tubular cavities, but does not cross to the CSF, and has poor action in acidic medium.

·         Streptomycin also considered as a second line drugs, because it more effective than first line agents and their toxicity often more serious.

Second line drugs

Cycloserine

·         Bacteriostatic

MOA

·         Interfere with the cell wall synthesis.

Side effect

·         Neuropsychiatric manifestation.

·         Suicidal tendencies, convulsion, psychosis.

·         Nephrotoxicity

Ethionamide

·         It the structural analogous of INH

·         Ethionamide can inhibit acetylation of INH.

·         Effective after oral administration.

·         Widely distributed in body, including CSF.

·         Neurological side effect: Psychosis

·         Hepatitis.

PAS

·         MOA: inhibition of folate synthetase.

·         Side effect: Hematological (Megaloblastic anemia)

·         Hypothyroidism

·         Hepatitis

·         Hypokalemia

·         Hypersensitivity

Management of Tuberculosis

Short course chemotherapy (DOTS – Direct Observed Therapy)

·         WHO introduced DOTS programme in 1995, under which 6-8 months multi drugs ‘short course’ regiments are framed.

·         According to severity the patients are divided into four categories.

·         Category I: New case of sputum smear positive or severe pulmonary TB, or severe forms of extra pulmonary TB (meningitis, etc.).

·         Category II: Defaulted, irregularly treated and relapse cases.

·         Category III: New sputum smear negative pulmonary TB and less severe forms of extra pulmonary TB (glandular/skin TB, etc.).

·         Category IV: Chronic cases who remained or again became sputum smear positive after receiving fully supervised category II treatment.

Tuberculosis management according to WHO (2010)