Antituberculotic drugs. Anti-Leprosy drugs Flashcards
(34 cards)
Reasons for spreading of TBC
Appearance and spreading of MDR Mycobacteria
Appearance and spreading of hypersusceptibles
Insufficient or lacking th in developing countries
Tuberculin reactors with high risk
DM
Immunosuppression
Problems in treating TBC
M. Tuberculosis is resistant to bodys natural defence
system (survives in cells)
M. Tuberculosis is resistant to most general ABs
Few bacilli with genetic resistance to any single antiTBCs
is always present
Isoniazide
Mechanism of Action
Spectrum
Mechanism of Resistance
Mechanism of Action
Inhibits mycolic acid (cell wall component) synthesis
Mycolic is unique to M.Tuber; has high molecular weight
Is a prodrug: requires enzymatic activation by M.Tuber
enzyme: catalase peroxidase
Active Metabolite: Isonicotinoyl NAD(P) adduct
Main target of isonicotinyl NAD(P) adduct: enoyl ACP
reductase–> inhibition
Spectrum
Selectively active against M.Tuber
Bacteriostatic for resting, bacteriocidial for dividing
Mechanism of Resistance
Mutation of catalase peroxidase
Overexpression of enoyl APC reductase
Isoniazide
Pharmacokinetics
Side Effects
Pharmacokinetics
Rapid and complete GIT absorption
Minimal PPB, readily diffuses into all compartments
CSF conc= plasma conc
Vd=0.7l/kg–> distributed in total body water
Elimination: Biotransformation: acetylation
speed dep on whether slow or fast acetylators
Side Effects (increase with slow acetylators)
HSR
Neurotoxicity: pyridoxine depletion (increase glutamate,
decrease GABA) . Pyridoxine= cofactor!
Prev. by giving pyridoxine (B6)
Hepatotoxic: post acetylation–> hydrolysed to MAH and
hydroxylated to N hydroxy MAH–> unstable–>
spontaneous decomposition into toxic radical
formation
Other Drugs which also react with Pyridoxine
Dapsone
Penicillamine
Boric Acid
Rifampin/Rifampicin
Mechanism of Action
Spectrum
Mechanism of Resistance
Mechanism of Action
Inhibits bacterial DNA dep RNA polymerase
—> inhibition of transcription
Spectrum: Broad; bacteriostatic
M. Tuber
M. Avium/ M. Leprae
Most G+: staphylococcis aureus, clost. difficile
Several G-: Enterobacteriacae, pseudomonas, H
Influenzae, Neisseria Meningitis, Legionella
Mechanism of Resistance
Mutation in DNA dep RNA polymerase –> decreased
binding
Monotherapy
Rifampin/Rifampicin
Pharmacokinetics
SE
Pharmacokinetics
incompletely absorbed orally
Vd=0.7l/kg
elimination: biotransformation: deacetylation--> fecal
excretion
biliary excretion with EHC
SE Allergic symptoms Hepatitis GIT: nausea Discolouration of body fluids as a coloured compound
CYP INDUCER
Ethambutol
Chemistry
Mechanism of Action
Spectrum
Chemisty: 2 alcoholic OH groups, 2 secondary amino
groups–> basic compound
MoA
Inhibits synthesis of arabinogalactan (cell wall compo.)
Target enzyme: arabinosyl transferase
Spectrum
Selective for M. Tuber and other Mycobac. strains
Ethambutol
Pharmacokinetics
SE
Pharmacokinetics
70% oral absorption
Even distribution, low PPB
Elimination: mainly urinary excretion via renal tubular as
organic cations (OCT2--> MATE1)
SE
Ocular toxicity–> ocular neuritis
Hyperuricaemia: compet. inhibits secretion of uric acid
Pyrazinamide
Mechanism of Action
Spectrum
Mechanism of Action
Inhibits mycolic acid synthesis
Active form: pyrazinic acid, hydrolised upon entering M.
then exported, if environment acidic–> protonated–>
now lipophilic–> rediffuses into M
Spectrum:
M. Tuber
Ineffective against M. Avium (like INH)
Pyrazinamide
Pharmacokinetics SE
Pharmacokinetics
Well absorbed
Vd: 0.6-0.7l/kg
eliminated: tubular secretion of pyrazinic acid
xanthine oxidase partially metabolises it at =N
SE
Hepatic Injury (cholestatic)
Hyperuricemia: secreted in exchange for uric urate at
luminal OAT4–> reabsorption of urate
First Line Agents: M. Tuber
Isoniazide
Rifampicin
Ethambutol
Pyrazinamide
Typical Treatment Regimens for M. Tuber
1st 2 months: INH+rifampicin+ethambutol Months 2-6 INH+rifampicin Months 6-12 Maintenance therapy with INH
Alternatively:
INH + Rifampicin for 9 months
Second Line Agents for M Tuber
Ethionamide Cycloserine P-Aminosalicyclic Acid Aminoglycosides Fluoroquinolone Capreomycin
Ethionamide
Mechanism of Action
Spectrum
MoA
Inhibition of mycolic acid synthesis
Prodrug; activated in M. by FAD containing enzyme
that oxidises–> sulfinic acid intermediate
Target enzyme: enoyl APC reductase
Spectrum
M. Tuber
M. Leprae
Ethionamide
Pharmacokinetics
SE
Pharmacokinetics
Lipophilic –> readily absorbed and distributed
Elimination: biotransformation; metabolites–> urine
SE: Numerous therefore 2nd line GIT distrubance CNS: depression, drowsiness Endocrine disturbances--> gynecomastia, hypothyroid. Hepatitis Phototoxic
Cycloserine
Chemistry
MoA
Spectrum
Chemistry
analogue of D Alanine; contains free amino group–>
reacts with pyridoxal like INH
MoA
Inhibits incorporation of D Alanine into Cell Wall–>
decreases peptidoglycan synthesis
Spectrum
Not M. Tuber specific
G+: staph aureus, enterococci, nocardia
G-: E Coli
Cycloserine
Pharmacokinetics
SE
Pharmacokinetics
Readily absorbed and distributed
Excreted into urine 50% unchanged--> toxic in renal
insuff
Biotransformation
SE CNS (pyridoxine)
P Aminosalicylic Acid (PAS)
MoA
Spectrum
MoA
May impair folic acid synthesis; is a folic acid analogue
with an extra hydroxy group–> inhibition of DHF R
Spectrum
Specific for M. Tuber
P Aminosalicylic Acid (PAS)
Pharmacokinetics
Spectrum
Pharmacokinetics
Readily absorbed and distributed
Acetylation (NAT1–> therefore no slow or fast
acetylation as with NAT2)and Urinary excretion
unchanged
SE
GIT irritation due to large daily dose
HSR
Aminoglycosides
Amikacin
Kanamycin
Streptomycin: SE vestibular dysfunctions
Fluoroquinolones
Moxifloxacin
broad spectrum ABs
Capreomycin
Not AG but similar
Can show cross resistance; also oto and nephrotoxic
Must be given IV
