Anti-Tuberculosis Agents Flashcards
1
Q
Names of anti-TB drugs
A
First line
- Isoniazid (H)
- Rifampicin (R)
- Pyrazinamide (Z)
- Ethambutol (M)
Second line
- Streptomycin/Amikacin (aminoglycosides)
- Levofloxacin (fluoroquinolone)
Third line
1. Cycloserine
2
Q
Mechanism of action of isoniazid & mechanism of resistance
A
- INH (prodrug) activated by Kat G (catalase found in mycobacteria) - INH+
- INH+ (A) binds to & inhibits acyl carrier protein reductase (B) blocks action of keto-acyl synthase (Kas A) - involved in mycolic acid synthesis (essential component of mycobacteria cell wall)
Bactericidal (rapidly multiplying bacteria) & Bacteriostatic (dormant bacteria)
- Mutation of Kat G/Kas A
3
Q
PK of isoniazid
A
- readily orally absorbed, impaired by food, Al containing antacids
- diffuses readily into all tissue, penetrates CSF, secreted in breast milk
- genetic polymorphism in isoniazid metabolism - Indians are mainly slow acetylators, Chinese are fast
4
Q
Toxicity of isoniazid (6)
A
- Allergic skin reactions
- Peripheral neuritis (isoniazid promotes pyridoxine excretion - pyridoxine becomes deficient, but req for myelin sheath)
- CNS effects - convulsions, mental abnormalities
- Transient transaminasemia
- Pathologic hepatitis (risk factors - old, alcohol, rifampicin, 4-8 w after drug initiation, can result in fulminant hepatic failure)
- Pellagra - Diarrhea, Dermatitis, Dementia (reduced availability of pyridoxal phosphate for nicotinic acid formation from tryptophan - nicotinic acid deficiency) - administer pyridoxine w H
5
Q
Drug interactions of isoniazid (2)
A
- It is a hepatic enzyme inhibitor - decreases metab of other drugs - increase plasma conc of phenytoin, carbamazepine, warfarin etc - ataxia, nystagmus
- slow acetylators - greater inhibition - Concurrent administration w Rifampicin/pyrazinamide & alcohol intake - greater risk of hepatotoxicity
6
Q
Mechanism of action of rifampicin & mechanism of resistance
A
Binds selectively & strongly to β subunit of bacterial DNA-dependent RNA polymerase - inhibits RNA synthesis
- Mutation in rpoβ gene coding for enzyme - can no longer bind
7
Q
PK of rifampicin
A
- oral, best absorbed on an empty stomach
- well distributed, including phagocytes & meninges (meningitis), penetrates into tissues & kills mtb not readily accessible to other anti TB drugs esp abscesses, cavities
- deacetylated in liver into active metabolites
- entero-hepatic circulation - excreted in faeces/urine
8
Q
Spectrum of activity & uses of rifampicin (4)
A
Bactericidal effect (mtb), also has activity against other gram pos/neg, M leprae
- TB
- for tb meningitis w INH - both can penetrate meninges to CSF
- prophylactic - alternative for those exposed to INH R tb - Leprosy - use w sulphone
- Meningococcus carriers - 2 day course
- Meningococcus prophylaxis in children - 2 day course
9
Q
Toxicity of rifampicin (4)
A
- Harmless orange discolouration in urine, sweat, saliva, tears
- Skin eruptions, fever, GIT
- Hepatitis - hyperbilirubinemia, transaminasemia - more common in elderly/history of liver disease/alcoholism
- Immunologically-mediated reactions
- thrombocytopenia + associated complement fixing Abs against platelets - spontaneous intracerebral hemorrhage
- flu-like syndrome + accompanying ATN - usually w low intermittent doses
10
Q
Drug interactions of rifampicin
A
- It is a liver enzyme inducer - induces its own metab & also warfarin, HIV protease inhibitors, most nNRTIs, oral contraceptives, increased urinary excretion of methadone - methadone withdrawal symptoms
11
Q
Mechanism of action of pyrazinamide & mechanism of resistance
A
- Taken up by macrophages - activated by mtb pyrazinamidase within acidic lysosomes to active pyrazinoic acid
- Inhibits action of FA synthase I involved in cell wall synthesis
Bacteriostatic, but can be bactericidal against active mtb
- Mutation in pncA - gene that encodes pyrazinamidase
12
Q
Toxicity of pyrazinamide (5)
A
- Hepatotoxicity - dose related, with fatality
- GIT
- Rashes, photosensitivity
- Arthralgia
- Hyperuricemia - metabolite pyrazinoic acid interferes with tubular secretion of uric acid, can cause acute gouty arthritis
13
Q
Mechanism of action of ethambutol
A
- Inhibits MTB arabinosyl transferases - inhibits polymerization - disrupts mycobacterial cell wall - inhibits growth
- Affects MTB cell wall integrity - facilitates entry of lipophilic antibiotics eg rifampicin, levofloxacin
Bacteriostatic
Mostly active against INH/rifampicin resistant mtb
14
Q
PK of ethambutol
A
- good oral absorption
- enters RBCs, released slowly
- at high dose, appears in CSF in meningitis
- little hepatic metab, mostly excreted unchanged in urine, half life increased in renal impairment
15
Q
Toxicity of ethambutol (4)
A
- Visual abnormality due to optic (retrobulbar) neuritis - eg reduced visual acuity, red/green colour blindness, loss of peripheral vision - higher incidence with higher dose/longer duration
- GIT - diarrhea
- Allergic rash
- Hyperuricemia, occasional gouty arthritis
