Tuberculosis is a chronic granulomatous disease and a major health problem in developing countries. About 1/3 of world's population is infected with mycobacterium tuberculosis.
A total of 1.5 million people died from TB in 2018 (including 251 000 people with HIV). Worldwide, TB is one of the top 10 causes of death and the leading cause from a single infectious agent (above HIV/AIDS).
An estimated 58 million lives were saved through TB diagnosis and treatment between 2000 and 2018.
Classification of anti-tubercular drugs
Rifampin, Isoniazid, Pyrazinamide, Ethambutol (RIPE) drugs are the first line drugs used for the treatment of TB.
ISONIAZID(H)
- It acts on extracellular and intracellular tb (bacilli within macrophages).
- It is active in acidic and alkaline medium
MOA
INH(prodrug)
↓
enters mycobacteria
↓
catalase-peroxidase enzyme converts it into active form(Kat-G)
↓
active INH
↙ ↘
forms adduct with NAD forms an adduct with NADP ↓ ↓
Inhibition of DHFRase Inhibits InhA, KasA genes
↓ ↓
Inhibition of
DNA synthesis Mycolic acid synthesis inhibited which are unique components of mycobacterial cellwall
Adverse Effects
- Peripheral neuritis, paresthesias, numbness, convulsions, mental disturbance.These effects are due to interference with production of active coenzyme pyridoxal phosphate from pyridoxine and its increased excretion through urine.
Therefore pyridoxine is given 10mg/day prophylactically to prevent neurotoxicity.
INH neurotoxicity is treated by pyridoxine 100mg/day.
- Another side effect is hepatotoxicity and INH must be stopped at the first sign of hepatotoxicity.
- It may cause drug-induced lupus and anion gap metabolic acidosis.
This drug penetrates the CNS freely and is a key chemotherapeutic agent in Tubercular Meningitis with proven potent bactericidal activity.
RIFAMPIN (R)
- It is a bactericidal drug.
- Active against M.Leprae and MAC(Mycobacterium Avium Complex).
- It affects extracellular and intracellular bacilli.
MOA
Rifampin
↓
binds to 𝛃-sub unit of DNA dependant RNA polymerase
↓
blockage of polymerization function
↓
inhibition of DNA synthesis
Adverse Effects
- Hepatitis:If jaundice develops then rifampin should be discontinued
- cutaneous:flushing, pruritus, rash, redness
- flu-like symptoms: chills, fever, headache, malaise, bone pain
- nausea ,vomiting ,diarrhoea
Uses
- Used in treatment of TB
- Used in treatment of leprosy
- Prophylaxis for meningococcal and H. influenzae meningitis
- 2nd /3rd choice drug for MRSA
ETHAMBUTOL (E)
- Ethambutol blocks arabinosyl transferase, inhibiting carbohydrate formation at the cell wall.
- It is bacteriostatic.
Adverse Effects
- optic neuritis (loss of visual acuity, red green color blindness).
- hepatotoxicity is seen.
PYRAZINAMIDE (Z)
- Pyrazinamide may cause hyperuricemia and needle shaped uric acid crystal formation.
- It precipitate gout attacks.
- can be hepatotoxic.
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