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Isoniazid (INH) (general info)
- 1st line treatment of TB
- most active against sensitive strains
- small molecule water soluble
- similar in structure to pyridoxine
- in vitro bactericidal for most
- Active against extra as well as intracellular
- MDR-MTB is resistant to it
-
INH mech of action
- interferes with mycolic acid synthesis
- stops complex with AcpM and KasA from making mycolic acid
Prodrug -->activated form --> complex--> mycolioc acid
KatG changes prodrug to active
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INH resistance
- over-expression of inhA gene
- KatG (peroxidase): no converstion of pro drug to active
- (no cross resistance to ethionamide)
- KasA
- 1 in 10^6 in single drug
- 1 in 10^12 in 2 drugs
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INH pharmacokinetics
- fast absorption
- 1-2h peak plasma 3-5 mcg/ml
- metabolized by acetylation : liver N-acetyl transferase
- excretion through urine
- t1/2: 3 hr in slow acetylators and 1 hr in rapid
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INH clinical uses
- usuall dose 300mg once orally
- 5 mg/kg/day
- 15 mg/kg twice weekly if with another drug
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INH toxicity
- fever and rash, SLE (systemic lupus erythematosus)
- Isoniazid induced hepatitis
- peripheral neuropathy: common in AIDS avoid stavudine (NRTI)
- CNS toxicity (rare)
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Rifampin general info
- 1st line drug
- bactericidal against M. TB and M. Leprae
- no cross resistance with other classes
- cross resistance with rifamycin derivatives (rifabutin for AIDS)
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Rifampin mechanism
binds with beta subunit of RNA polymerase, stops transcritption of DNA to RNA
-
Rifampin resistance
mutation in rpoB and reduces binding to beta subunit.
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Rifampin pharmacokinetics
- diffuses into most tissue and macrophages
- metabolized in liver, secreted in bile
- 5-7 mcg/ml in plasma
- binds with protein and CSF conc in proportional to meningeal inflammatinon
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Rifampin clinical uses
- 10mg/kg (600mg) in conj with other drugs (INH, Ethambutol, pyrazinamide)
- Combo effective against atypical mycobateria and M. Leprae
- 4 month treatment for latent infection
- prophylactic against H. Flu type B
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Rifampin toxicity
- orange excretions
- rashes
- thrombocytopenia, nephritis
- flu like symptoms
- liver toxicity
- INDUCTION of CYP450 pathway: increases secretion of drugs like methadone, PI, and NNRTI etc.
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Ethambutol general info
- 1st line drug
- synthetic water soluble and stable
- inhibits mycobacteria
- over expression of emb leads to resistance
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ethambutol mech of action
- inhibits polymerization of arabinoglycan (cell wall component)
- inhibits arbinosyl transferase encoded by emb
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Ethambutol pharmacokinetics
- good oral absorption
- wide distribution (important cuz myco will be in macrophages)
- T1/2: 2-4 hr
- Excretion 75% unchanged, prolonged in renal disease
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Ethambutol clinical uses
15-25 mg/kg d in combo with inh or rifampin
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Ethambutol side effects
- rash
- fever
- retrobulbar neuritis (visual activity)
- contraindicati in children
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Pyrazinamide (general info, mech of action, resistance)
- 1st line drug
- poorly soluble in water
- related to nicotinamide
- inactive at neutral pH but works at 5.5 (functional in lysosome)
- mech of action unknown
- resistance: mutation in pncA (encodes pyrazinamidase)
- inhibits mycob at 20 mcg/ml
- pyrazinamide --> pyrazinoic acid
- (enzyme myco pyrazinamidase)
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Pyrazinamide pharmacokinectics
- 25 mg/kg d
- 1-2 hr peak plasma 30-50 mcg
- T1/2: 8-11 hr
- metabolized in liver, cleared through urine
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Pyrazinamide side effects
- Hepatoxociity
- N/V fever, jaundice
- hyperuricemia (acute gouty arthiritis)
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Streptomycin general info
- 1st line drug
- aminoglycoside
- 1st for treat of TB
- injectable drug
- used in combo to avoid resistance
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streptomycin mech of action
- binds to 16s rRNA ribosome
- blocks protein synthesis
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Streptomycin clinical use
- adult: 1g gives 40mcg/ml in 30-60 min
- Child: 20-40 mg/kg not exceeding 1-1.5g
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Streptomycin side effects
- N/v
- rash fever
- eosinophilia
- ototoxic: vertigo and hearing loss
- nephrotoxic: impaired renal function especially in elderly with high doses.
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Ethionamide (general info)
- second line drug
- INH class (inhibits mycolic acid synthesis)
- poor water solublility
- liver metabolism
- Side effects: GI irritation, hepatotoxic, neurotoxic (pyridoxine can help with neuro)
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Capreomycin
- 2nd line drug for mycob
- used for strep resis mTB
- protein syntheis inhibitor (ribosome)
- contraindicated in pregnancy
- Side effects: nephrotoxic, ototoxic, local pain and abscess
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cycloserine
- 2nd line of drug
- inhibits cell wall synthesis (peptidoglycan)
- secreted through urine
- Side effects: nephro and ototoxic, peripheral neuropathy and CNS toxicity (pyridoxine is recommended)
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Aminosalicylic acid
- 2nd line of treatment
- folate synthesis antagonist specific against mTB
- Side effects: GI irritation, peptic ulceration, hepatosplenomegaly, hepatitis joint pain in 3-8 weeks
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Rifabutin
- 2nd line therapy
- Related to rifampin
- active against mTB and mAvium
- Less potent inducer of CYP450 than rifampin, so used in HIV patients more.
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Dapsone
- Used for leprosy
- can be given in combo with rifampin
- Side effects: GI, fever, rash, somtimes erythema nodosum leprosum
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Clofazimine
- used for leprosy
- phenazine dye dapsone alternative
- T1/2: 2 months
- Side effects: skin discoloration and GI irritation
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