Drugs for Tuberculosis: Rifampicin

Ø Isoniazid (INH) Structure: Rifamycin derivative

Ø Rifampin / Rifampicin Target:
Ø Ethambutol Ø Bactericidal -> M. tuberculosis
Ø Pyrazinamide MOA: DNA-Dependent RNA polymerase inhibitor (encoded by rpo gene)of M. tuberculosis
Ø Streptomycin and other microoganisms
• Actions dependds sa susceptability of strain and concentration -> Depende pwede Resistance:
bactericidal/bacteriostatic Ø Fast/rapid when used alone
• Treatment: Antibiotic susceptibility testing -> Treatment course of action Ø Changed sensitivity of polymerase
• Tuberculosis treatment: 3-4 different combination regimen, depende if resistant to Pharmacokinetics
INH Ø Administration:
• DOTS (Directly Observed Therapy) -> Most preferred method. o Orally
o Well absorbed and distributed to body tissues and CNS
Isoniazid Ø Meabolism:
o partially in liver
Structure: Congener of pyridoxine o Enterohepatic cycling (bile acid -> small intestine -> liver)
Parmacokinetics § Parang nasa bile ung metabolites, so drug -> liver ->
Ø Absorption: metabolite -> bile -> gallbladder -> small intestine ->
o Orally well liver ulit.
o Penetrates cells -> Intracellular actio Ø Elimination/Excretion:
Ø Metabolism: Acetylation of the Liver (Genetic influence) o Free drug and Metabolites -> Orange color
o Fast acetylators -> fast inactivation o Eliminated mainly in feces
o Slow acetylators -> slow inactivation Clinical Use
Ø Half-life Ø Combination w/ other drugs for tuberculosis treatment
o Fast acetylators: 60-90 minutes Ø Sole drug -> Latent tuberculosis
o Slow acetylators: 3-4 hours o INH resistant patients
Ø Dosage: Fast acetylators >>> than slow acetylators to achieve equivalent o In contact with INH resistant strains
therapeutic effects Ø Leprosy (Rifampicin + dapsone)
MOA: Inhibition of mycolic acid synthesis (essential component of mycobacterial cellwall) o Given together with dapsone
Resistance: Rapid if used alone § Delays resistance
Ø High Level resistance: katG mutation -> Catalase-peroxidase -> bioactivation § Monthly given
of INH (meaning ung katG iiba, kokonti enzyme, less bioactivation) Ø Resistant Staphylococci (MRSA, PRSP)
Ø Low level resistance: inhA gene deletion ->. Acyl carrier protein reductase o Vancomycin + Rifampicin
Ø Meningococcal
Target: Ø Staphylococcal
Ø Active: Growing tubercle bacilli Toxicity
Ø Less effective: Dormant organisms Ø Colors sweat, urine, tears -> orange
Clinical Use Ø Contact lenses -> stain permanently (pero harmless)
Ø Most important against tuberculosis Ø Light-chain proteinuria
Ø Main component of multiple drug regimen Ø Impair antibody responses
Ø Sole drug for Prophylaxis or Latent infections Ø Adverse effects
o Skin test converters o Skin rashes
o Close contacts of patient w/ disease o Thrombocytopenia
Toxicities o Nephritis
Ø Neurotoxicity -> 25-50 mg/d, oral, pyridoxine (competitive antagonist of o Liver dysfunction
INH) Ø Given less often thatn 2x/week
o Peripheral neuritis o Flu-like syndrome
o Restlessness o Anemia
o Muscle twitching Interactions
o Insomia Ø Induces Liver drug-metabolizing enzymes
Ø Hepatotoxicity (Rare in children) o Elimination of drugs is increased
o Abnormal liver function tests § Anticonvulsants
o Jaundice § Contraceptive
o Hepatitis § Steroids
Ø Lupus-like syndrome § Cyclosporine
Interactions § Ketoconazole
Ø Inhibit hepatic metabolism of drugs § Methadone
o Carbamazepine § Terbanafine
o Phenytoin § Warfarin
o Warfarin Other Rifampicins
Ø Hemolysis if one has G6PDH deficiency Ø Rifabutin -> Same effect, less toxicity/interactions (equally effective
anyimycobacterial agent)
o Preferred drug for AIDS patient for tuberculosis and other
mycobacterial infections
§ If taking CYP450 substrates
§ Protease inhibitors
§ Efavirenz
Ø Rifapentine
o once-weekly dosing
o INH + Rifapentine for Latent infections
Ø Rifaximin
o Not absorbed in GI tract
o Traveller’s diarrhea
 Ethambutol (ETB) ALTERNATIVE DRUGS
MOA: Arabinosyltransferases inhibitor (coded by embCAB operon) Ø Amikacin
Synthesis of arabinogalactan (cell wall component) o Tuberculosis of streptomycin-resistant or MDR mycobacterial
Resistance: Mutation of emb gene if used alone strains
Pharmaokinetics o In combi. with other drugs -> lesser resistance development
Ø Absorption: Well Orally Ø Ciprofloxacin; Ofloxacin (2nd generation fluoroquinolones)
Ø Distribution: o Straints who are resitant First-line agents (Ethambutol,
o Distributed to most tissues Isoniazid, pyrazinamide, rifampicin)
o Distributed to CNS o In combination regimens of 2 or more active agents
Ø Elimination Ø Ethiomide
o Urine o Congener of INH
o Unchanged o No cross-resistance w/ INH (similar kasi sila ng structure)
o Dose reduction is necessary in renal impirment o Therapeutic dose (effective plasma levels)
Clinical Use § Highly toxic nga lang
Ø Tuberculosis + in combination w/ other drugs • GI irritation
Toxicities • Neurologic effects
Ø Dose-dependent visual disturbances Ø p-Aminosalicylic acid (PAS)
§ Decreased visual cuity o Primary resistance is common -> not usually used
§ Red-green colorblindness o Toxicities
§ Optic neuritis § GI irritation
§ Retinal damage (Prolonged use at high doses) § Peptic ulceration
o Regressive effeect if drug is stopped § Hypersensitivity reactions
Ø Other adverse effects § Kidney function
o Headache § Liver function
o Confusion § Thyroid function
o Hyperuricemia Ø Capreomycin
o Peripheral neuritis o Ototoxicity
o Renal dysfunction
Pyrazinamide Ø Cycloserine
MOA: Unknown o Peripheral neuropathy
Ø Bacteriostatic o CNS dysfunction
Ø Metabolic conversion via pyrazinamidases (pncA gene) in M. tuberculosis Ø Bedaquiline
Resistance: o ATP synthase inhibitor in mycobacteria
Ø Mutation in genes involved in bioactivation of pyrazinamide o For TB-resistant to isoniazid and rifampicin
Ø Increased efflux system (expression nung gene nito) o Adverse eff.
Ø Rapid when used alone § Nausea
Ø Minimal cross risistance w/ other antimycobacterial drugs § Arthralgia
Pharmacokinetics § Headache
Ø Absorption: Well orally § Cardiotoxicity
Ø Penetration § Hepatotoxicity
o Body tissues
o CNS
Ø Metabolism
o Pyrazinamide -> pyrazinoic acid
Ø Excretion
o Urine
o Both parent and metabolite
Ø Plasma Half-life
o Inc. hepatic failure
o Inc. renal failure
Clinical Use
Ø Pyrazinamide + antituberculus drugs -> success of short-course treatment
Toxicity
Ø Nongouty polyarthralgia (40% patients)
Ø Hyperuricemia (commonly, asymptomatic)
Ø Adverse efects
o Myalgia
o GI irritation
o Maculopapular rash
o Hepatic dysfunction
o Porphyria
o Photosensitivity reactions
Ø Should be avoided in pregnancy

STREPTOMYCIN
Ø Aminoglycoside
Ø Used commonly due to higher prevalence of M. tuberculosis resistance
Ø In combination vs. life-threathening tuberculous disease
o Meningitis
o Military dissemination
o Severe organ tuberculosis
DRUGS FOR LEPROSY

Dapsone (Diaminodiphenylsulfone)
Ø Most active against M. leprae
Ø MOA:
o Inhibition of folic acid synthesis
Ø Resistance
o Use in combinations to delay
o Rifampicin + dapsone
o Rifampicin + clofazimine
Ø Pharmacokinetics
o Absorption: Orally
o Penetration: well in tissues
o Enterohepatic cyclincling
o Elimination:
§ Urine
§ Acetylated metabolites
Ø Adverse effects
o GI irritation
o Fever
o Skin rashes
o Methemoglobinemia
o Hemolysis (G6PDH deficiency)

Acedapsones (Sulfones)
Ø Repository form of dapsone (cheaper)
Ø Long-term effect (Inhibitory plasma conc. For several months)
Ø Uses
o Leprosy
o Pneumocystis jirovecii pneumonia (AIDS patient)

Clofazimine (others)
Ø Phenazine dye
Ø Interact with DNA
Ø Adverse Effects:
o GI irritation
o Skin discoloration
§ Red-brown to black

DRUGS FOR NONTUBERCULOUS MYCOBACTERIA (NTM)

Ø NTM = Atypical mycobacteria (M. avium complex)
Ø M. avium complex -> disseminated infections in AIDS patients
o Azithromycin/clarithromycin + ethambutol + rifabutin
Ø M. marinum, M. ulcerans
o Ethambutol
o INH
o Rifampicin
o Amikacin
o Cephalosporins
o Fluoroquinolones
o Macrolides
o Tetracyclines
Ø Treatments
o Azithromycin/clarithromycin + rifampicin
§ Prophylaxis for CD4 < 50/uL
o Azithromycin or clarithromycin only
§ Prophylaxis for CD4 < 50/uL
o