Pharmacology

Anti-Tubercular drugs

Anti-Tubercular drugs

  • Tuberculosis is a granulomatous disease and a major health problem in developing countries.
  • About 1/3rd of the world’s population is infected with tuberculosis.
  • The causative organism Mycobacterium tuberculosis.

Classification

First line drugs

  • It has high anti-tubercular efficacy as well as low toxicity.
  • Example:
    • Isoniazid (H)
    • Rifampicin (R)
    • Pyrazinamide (Z)
    • Ethambutol (E)
    • Streptomycin (S)

Second line drugs

  • These drugs have either low anti-tubercular efficacy or higher toxicity or both and are used in special circumstances only.
    • Ethionamide (Eto)
    • Prothionamide (Pto)
    • Cycloserine (Cs)
    • Para amino salicylic acid (PAS)
    • Rifabutin
    • Terizidone
    • Thiacetazone (Thz)
  • Fluoroquinolones
    • Ofloxacin (Ofx)
    • Levofloxacin (Lvx or Lfx)
    • Moxifloxacin (Mfx)
    • Ciprofloxacin (Cfx)
  • Injectable
    • Kanamycin (Km)
    • Amikacin (Am)
    • Capreomycin (Cm)
  • Mycobacterium is derived from Greek word “Mycos” that means waxy appearance due to composition of their cell wall.
  • More than 60% of the cell wall is lipid mainly mycolic acid.

Pathophysiology of tuberculosis

  • Entry of M. tuberculosis into the host.
  • Inside the lymph node alveolar macrophage develops by the M. tuberculosis.
  •  Primary infection occur.
  • Formation of Granuloma and mutation.

Isoniazid (Isonicotinic acid hydrazide. H)

  • It is a primary tuberculocidal.
  • Freely soluble in water.
  • Bactericidal for actively growing tubercle bacilli.
  • Penetrates into macrophages and is active against both extracellular and intracellular organism.

Mechanism of action

  • INH is inhibited the synthesis of mycolic acid which are unique fatty components of mycobacterial cell wall.
  • INH enters sensitive mycobacteria which converts it by a catalase-peroxidase enzyme into a reactive metabolites.
  • Adduct with NAD that inhibit InhA (Enol-acetyl-carrier-protein-reductase) and KasA (Acyl-carrier-protein-kinase).
  • Also adduct with NADPH, which inhibit Mycobacterial DHFRase resulting interrupting of DNA synthesis.

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.
    1. Fast acetylator (30-40% of Indians) t1/2 of INH 1hr.
    2. 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
    • Due to interference with production of the active coenzyme pyridoxal phosphate from pyridoxine and its increased excretion in urine.
  • Pyridoxine given prophylactically (10mg/day)
    • Prevent the Neurotoxicity even with higher doses.
  • Prophylactic pyridoxine must be given to diabetics, chronic alcoholics, malnourished, lactating and HIV infected patients.

Dose (INH)

  • Daily dose: 5(4-6) mg/kg, Maximum 300 mg
  • Three time per week dose: 10 (8-12), Maximum 900 mg

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)

Tuberculosis in pregnant women

  • 2HRE + 7HR (Total 9 months)
  • Contraindicated because it is ototoxicity to the fetus.
  • ‘Z’ is not recommended (due to lack of adequate teratogenicity)

Treatment of breast feeding women

  • All anti-TB drug are comparable, but baby should watched.
  • Baby should receive BCG vaccination and 6 month INH preventing treatment after ruling out active TB.

Chemoprophylaxis

  • Standard drugs: H – 300mg (10 mg/kg in children) daily for 6 months.
  • INH resistance: Combination drug H (5mg/kg) and R (10mg/kg, maximum 600 mg) daily for 3 months.

Tuberculosis in AIDS patients

  • Daily HRZE for 2 month: started immediately on the diagnosis of TB followed by continuous phase of HR for 4-7 months (Total 6-9 months)
  • Pyridoxine 25-50mg/ daily + INH, counteract neurological side effects.
  • Rifabutin (less potent enzyme inducer) given 9-12 months may be substituted for Rifampicin.

Hello! My name is Smrutiranjan Dash, a pharmacy professional. belonging from, Bargarh, Odisha. I have acquired Master degree in Pharmacy (Pharmacology) form B.P.U.T, Rourkela, Odisha. Presently I am working as an Assistant Professor at The pharmaceutical college, Barpali.

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