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Antituberculosis agents
TUBERCULOSIS (TB)
The classic symptoms of active TB infection are:
a chronic cough with blood-tinged sputum,
fever, chills,
night sweats,
loss of appetite, weight loss, fatigue.
Diagnosis of active TB relies on radiology (commonly chest X-rays), as well as microscopic examination and microbiological culture of body fluids.
Diagnosis of latent TB relies on the tuberculin skin test (TST) and/or blood tests.
Mycobacterial cell wall
Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33
Chemotherapy in tuberculosis
• Goals of anti-tubercular chemotherapy
• Kill dividing bacilli: Patient is non-contagious : transmission of TB is interrupted.
• Kill persisting bacilli: To effect cure and prevent relapse.
• Prevent emergence of resistance: so that the bacilli remain susceptible to the drugs.
Antitubercular Agents
First line drugs:
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide
Antitubercular Agents
Second line drugs:
Para aminosalicylic acid (PASA)
Ethionamide
Kanamycin and other amynoglycosides
Cycloserine
Capreomycin
Antitubercular Agents
Newer Second Line drugs:
Fluoroquinolones
Microlides
Isoniazid
◼ Isoniazid is the hydralazide of isonicotinic acid.
◼ It inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell wall.
◼ Effect tuberculocidal.
◼ It acts on extracellular as well as on the intracelular mycobacteria.
Clinical use◼ Used in combination with other antituberculosis
agents in the treatment of pulmonary and extrapulmonary tuberculosis.
◼ Used as a single monotherapy in case of prophylaxis of tuberculosis.
Side effects of Isoniazid
◼ Peripheral neuropathy (occurs frequently )
◼ Hepatitis has been reported in less than 5% of patients.Jaundice have rarely been reported.
◼ Hypersensitivity
◼ Isoniazid-induced lupus-like reactions
◼ Psychosis, depression, and aggression have been rarely reported with isoniazid therapy.
◼ Exacerbations of preexisting schizophrenia.
◼ G.I.T. side effects include nausea, vomiting, and epigastric distress. A few cases of pancreatitis have been reported.
Rifampicin.
Mechanism of action: incorporation into DNA spiral, inhibition of DNA-dependent RNA-polymerase → inhibition of replication and transcription in microorganisms.Spectrum of action: wide, Mycobacterium tuberculosis, leprosy.Bactericidal.Indications: tuberculosis, leprosy, infections caused by multidrug-resistant pathogens.
Rifampicin (side effects)◼ Hepatotoxic - hepatitis, liver failure in severe cases.
◼ Respiratory – breathlessness.
◼ Cutaneous - flushing, pruritus, rash, redness and watering of eyes.
◼ Abdominal - nausea, vomiting, abdominal cramps with or without diarrhea.
◼ Flu-like symptoms - chills, fever, headache.
◼ Arthralgia, and malaise.
◼ Rifampin has good penetration into the brain, this may directly explain some malaise and dysphoria in a minority of users.
◼ Red staining of urine and other body fluids.
Pyrazinamide
◼ Pyrazinamide is derivative of INH like isoniazid. It is more active in acidic medium.
◼ More tuberculocidal to intracellularly located mycobacteria.
◼ Pyrazinamide may be bacteriostatic or bactericidal against Mycobacterium tuberculosis depending on the concentration of the drug attained at the site of infection.
Indications: Pyrazinamide is indicated for the initial treatment of active tuberculosis in adults and children.
It should only be used in conjunction with other effective antituberculous agents.
Pyrazinamide
◼ Side effects:
◼ Hyperuricemia,
◼ acute gouty arthritis,
◼ fever,
◼ loss of appetite, nausea and vomiting,
◼ yellowish discoloration of the skin and eyes.
Ethambutol
◼ An antitubercular agent that inhibits the transfer of mycolic acids into the cell wall of the tubercle bacillus.
◼ It may also inhibit the synthesis of spermidine in mycobacteria.
◼ The action is usually bactericidal, and the drug can penetrate human cell membranes to exert its lethal
effect.
◼ The most commonly recognized toxic effect of ethambutol is optic neuropathy, which generally is considered uncommon and reversible in medical literature.
◼ Other side effects: are pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations.
Ethambutol
Ethionamide◼ Ethionamide may be bacteriostatic or bactericidal in action,
depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism.
◼ The exact MECHANISM OF ACTION of ETHIONAMIDE has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.
◼ Antimicrobial spectrum of Ethionamide comprises M.tuberculosis, M. bovis and M. Segmatis.
◼ Ethionamide is structurally similar to methimazole,,has been shown to inhibit thyroid hormone synthesis, and was reported to cause hypothyroidism in several TB patients.
Para-Aminosalicylic Acid
◼ Aminosalicylic acid is an anti-mycobacterial agent used with other anti-tuberculosis drugs (most often isoniazid) for the treatment of all forms of active tuberculosis due to susceptible strains of tubercle bacilli.
◼ There are two mechanisms responsible for aminosalicylic acid's bacteriostatic action against Mycobacterium tuberculosis.
◼ Firstly, aminosalicylic acid inhibits folic acid synthesis. The binding of para-aminobenzoic acid to pteridine synthetase acts as the first step in folic acid synthesis.
◼ As bacteria are unable to use external sources of folic acid, cellgrowth and multiplication slows.
◼ Secondly, aminosalicylic acid may inhibit the synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis.
Para-Aminosalicylic Acid
◼ The most common side effects: GIT intolerance nausea, vomiting, diarrhea, and abdominal pain.
◼ Hypersensitivity reactions: fever, skin eruptions of various types, exfoliative dermatitis, lymphoma-like syndrome, leucopenia, agranulocytosis, thrombocytopenia, Coombs' positive hemolytic anemia, jaudice, hepatitis, pericarditis, hypoglycemia, optic neuritis, encephalopathy, and vasculitis and a reduction in protrombin.
◼ Crystalluria may be prevented by the maintenance of urine at a neutral or an alkaline pH!!!
Para-Aminosalicylic Acid
CHEMOPROPHYLAXIS
Prevention of active disease from latent inf.
Standard drug is isoniazid daily for 6-12 months.
OR: isoniazid + Rifampin daily for 6 months.
If Isoniazide can not be used: Rifampin (4 months)+
Pyrazinamide (2 months).
OR: Ethambutol + Pyrazinamide +
Fluoroquinolones.