Anti TB Drugs TB TB y Tuberculosis y Tubercle bacillus Caused by mycobacteria (mainly Mycobacterium tuberculosis) Mycobacterium resistance Mycobacterium y Rod shaped

bacteria (neither truly gram ve or +ve) y Slow growing y Resistant to many drugs (resistant to wall-destroying antibiotics, eg. Penicillin) y Lipid rich cell walls o Impermeable to many agents o Survive long exposure to acids, alkalis, detergents, oxidative bursts, lysis by complement & antibiotics o Naturally leads to antibiotic resistance y Susceptible to antibiotics clarithromycin (due to lipid rich cell walls) y Able to develop resistance to single drug (combination of drugs needed) Antibiotics y Most antibiotics are resistant to only rapidly growing bacteria Response of infection to patients y Slow response of infections to patients y Patients must be administered for months to years (depend on drug used) Therapeutic problems in Mycobacterium Infection Microorganisms - Grow slowly (disease need to be treated 6 months 2 years) Disease Chronic Drug toxicity Development of Resistance Patient compliance y Patients who take TB treatment in an irregular & unreliable way (treatment failure, relapse, development of drug-resistant TB strains) y Requires regular follow-up (check compliance, problems with medication) y Educate patient on importance of taking drug regularly (risk of relapse, drug-resistance developing) y Reasons patient do not comply o Symptoms of TB resolved (within a few weeks of treatment) o Bulkiness of tablets o Medications taken on empty stomach (facilitate absorption) TB Treatment Difficult, Requires long course of multiple antibiotics Contacts are screened & treated Has been treated with combination therapy for over 50 years Drugs are not used singly (except latent TB or chemoprophylaxis) Regimens that use single drug y Rapid development of resistance y Treatment failure Should cure newly diagnosed patients if y Effective regimen is prescribed for adequate period of time y Patient ingests prescribed medications regularly 6 months course of chemotherapy ( effective & reliable) Aims of TB Treatment Morbidity Mortality Transmission Prevent emergence of MDR-TB (multi drug resistance TB) st (resistance to the 2 most effective 1 -line TB drugs Rifampicin, Isoniazid) Principles of Anti-TB Treatment Kill organisms Rapidly growing Isoniazid

Slowly growing Rifampicin Pyrazinamide Use in combination to prevent drug resistance Extra-pulmonary TB requires longer duration of treatment Multi-drug resistant TB y 4 5 drugs y Duration at least 18 months (may be up to 24 months) Immunocompromised patients y Longer duration y no. of drugs needed (especially those with likelihood of infection with MDR strains) Treatment Regimens Initial (Intensive) Phase 3 4 drugs are given daily (2 months)

Continuation Phase 2 3 drugs are given intermittently (4 months) Duration may be extended for severe forms of extrapulmonary tuberculosis & immunocompromised patients

Drug used to treat TB st 1 Line Drugs Greatest level of efficacy Most effective Lowest toxicity Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin

2 Line Drugs st Less effective compared to 1 line

nd

Aminoglycosides y Amikacin y Kanamycin Polypeptides y Capreomycin y Viomycin y Enviomycin Fluoroquinolones y Ciprofloxacin y Levofloxacin y Moxifloxacin Thioamides y Ethionamide y Prothionamide Cycloserine p-aminosalicylic acid

First Line Anti-TB Drugs Isoniazid Antibacterial activity Most potent anti TB drugs Never given as a single agent (resistance) Bacteriocidal Bacteriostatic Rapidly-dividing Slow -growing mycobacteria mycobacteria Selective for mycobacteria Able to penetrate cell easily (against intracellular & extracellular bacilli) Available worldwide Inexpensive Well Tolerated Mechanism of action Inhibit biosynthesis of mycolic acids (constituent of mycobacterial cell wall)

Rifam picin Antibacterial activity Bactericidal for intracellular & extracellular organism Broad spectrum of activity y Gram +ve y Gram ve y Chlamydiae

Pyrazinamide Antibacterial activity Treat TB Only used in combination with other drugs (Eg. Isoniazid & R ifampicin treatment of TB) (Never used on its own) Not used to treat other mycobacteria (innately resistant) y Mycobacterium bovis y Mycobacterium leprae Bacteriostatic Bacteriocidal (on actively replicating TB bacteria) Mechanism of action

Etham butol Antibacterial activity Bacteriostatic Active only against mycobacteria Resistance develop rapidly when used alone (always use in combination)

Streptomycin Antibacterial activity Aminoglycoside Wide spectrum antibacterial activity (1 used to treat mycobacterial infections) Poor cell penetration (active against extracellular bacilli)

Mechanism of action Inhibits DNA-dependent RNA polymerase in bacterial cells (by binding with -subunit of RNA polymerase of M. tuberculosis) Prevent transcription to RNA Prevent translation to proteins

Mechanism of action Obstruct formation of cell wall of bacteria y Inhibit mycobacterial arabinosyl transferase y Involved in polymerization of arabinogalactan (essential component of mycobacterial wall)

M. tuberculosis has pyrazinamidase (active only in acidic conditions)

Pyrazinamidase converts pyrazinaide to active form (pyrazinoic acid, which inhibit synthetase I) (synthetase I required to synthesize fatty acids) Mutations of pyrazinamidase gene (pncA) (Pyrazinamide resistance in M. tuberculosis)

Mechanism of action Inhibit protein synthesis (kill bacteria) Binds to 16 S rRNA of bacterial ribosome (interfere with binding of formyl-methionyl-tRNA to 30S subunit) Prevent initiation of protein synthesis Death of microbial cells

Pharmacokinetics Absorption y Oral (tablet, syrup) y Parenteral (I M, IV) Distribution y All bodily fluids & tissues (intracellular, CSF, necrotic tissues) y Does not bind to plasma proteins Metabolism y Liver N-acetyltransferase 2 (N-acetylation & hydrolysis) inactivated y Polymorphic Fast, Slow acetylator Excretion y 75-95% dose excreted in urine in 24h (as metabolite) y Acetylisoniazid (excretory product) (from enzymatic acetylation) y Under genetic control (Fast & Slow A cetylators) Slow acetyl transferase activity (Slow acetylators) (Produce Toxic intermediate) Ethnicity (fast acetylators ) o Eskimos o Native American Indians o Asians

Pharmacokinetics Absorption y Orally (well) Peak levels (2 4h after oral dose) Half life 6h Distribution y Many organs y Body fluids (including CSF) y Penetrates tissues & phagocytic cells (good for intracellular organisms) (those in abscesses & lung cavities) Metabolism y Enterohepatic recirculation y Partially biotransformed in liver Excretion (drug & metabolites) y Feces Clinical Uses TB Treatment (in combination with other anti-TB) Alternative to Isoniazid (For prophylaxis) y In patients with Isoniazid resistance y Rifampicin susceptible strains Leprosy Other uses y Chemoprophylaxis Meningococcal disease & Meningitis (due to H. influenzae type) y Staph endocarditis (combine with -lactam/ vancomycin) y Staphylococcal carrier states (patient with chronic furunculosis)

Pharmacokinetics Absorbed well from GI T Widely distributed in body tissues (including CSF) Metabolized by Liver Metabolic products are excreted by Kidneys

Pharmacokinetics Absorbed well from GI T Well distributed in body tissues & fluids Excreted unchanged in urine

Pharmacokinetics Cannot be given orally (poor oral absorption) Administered I M or IV Excreted via urine (need dose adjustment in renal impairment)

First Line Anti-TB Drugs (Cont.) Isoniazid Adverse Effects Neurotoxicity (most common) y Due to pyridoxine deficiency (Isoniazid promote excretion of pyridoxine & inhibit pyridoxal kinase) y Symptoms Paraesthesia, Convulsions, Muscle twitch, Ataxia y Predisposing condition Slow acetylators, Malnutrition, Alcoholism, Diabetes, AIDS y Toxic reactions corrected by pyridoxine (Vit B6) (supplementation of 25 50 mg/ day) Induced Hepatitis y Due to build up of toxic metabolic products of acetylisoniazid acetylhydrazine y Frequent in slow acetylators y Hepatic reactions are age dependent 250X incidence of hepatitis over age in fast acetylators Mild hepatitis to serious tissue necrosis Risk in A lcoholics, Pregnancy, Postpartum Immunologic y Allergic reactions Fever, Skin eruption rashes Others y Dry mouth y Urinary retention y Haemolysis (G6PD deficiency) Precautions Renal Failure y Normal dose can be given y Secreted in inactive form Hepatic Insufficiency y Dose of drug Ethanol y Induction of drug metabolizing enzymes y Isoniazid is broken down faster y Isoniazid hepatotoxicity Glucose 6-Phosphatase deficiency y Cannot adequately process the drug Drug Interactio ns Phenytoin (anticonvulsant) y Compete for drug metabolism enzymes (CYP450) y Interferes with metabolism of Isoniazid by Excretion ( Effect of Isoniazid)

Rifam picin Adverse Effects (Generally well tolerated) (<4% have significant reactions) Common y Orange color urine sweat, tears (harmless indicate patient took drug) Occasional y Rash y Fever y Nausea, Vomiting y Thrombocytopenia y Nephritis Rare y Hepatitis y Death due to liver failure (using combination of other hepatotoxic drugs) (increased incidence in chronic liver disease, old age, alcoholism)

Pyrazinamide Adverse Effects Joint pains (arthralgia)(approx. 1%)(most common) Hepatotoxicity (most dangerous) y Dose related y Among 4-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is most common cause of drug-induced hepatitis Other side effects y Nausea y Vomiting y Anorexia y Sideroblastic anemia y Skin rash y Urticaria y Pruritus y Hyperuricemia y Dysuria y Interstitial nephritis y Malaise y Porphyria (rarely) Fever (rarely) y

Etham butol Adverse Effects Retrobulbar neuritis y Loss visual acuity & red-green color blindness y Relative contraindication for young children Other side effect (rare) y Rashes y Pruritis y Joint pain

Streptomycin Adverse Effects Ototoxicity (hearing loss) y May be permanent y R isk in elderly y To risk, limit therapy < 6 months if possible Nephrotoxicity

Drug Interactio ns (Shortens half-life of many drugs) y Prednisolone y Quinidine y Ketoconazole y Proponolol y Metoprolol y Clofibrates y Sulfonylureas y Oral contraceptives y Oral anticoagulants

Chemoprophylaxis Used only in risk groups Household & close contacts with active TB +ve skin test (tuberculin test) in <35 y/o +ve skin test (tuberculin test) reactive in immunosuppressed, leukemia, Hodgkins dz HIV +ve patients with +ve TB test

Prophylaxis Drug of choice Isoniazid (300mg daily for 6 months) With increasing resistance to Isoniazid, use Isoniazid + R ifampicin Prevention of multidrug resistant TB Fluroquinolone + Pyrazinamide

Second Line Anti-TB Drugs (SLDs) 6 Classes of SLDs (treatment of TB) Aminoglycosides amikacin, kanamycin Polypeptides capreomycin, viomycin, enviomycin Fluoroquinolones ciprofloxacin, levofloxacin, ofloxacin Thioamides ethionamide, prothionamide Cycloserine p-aminosalicylic acid Consider use in st Resistance to 1 line drugs Failure of clinical response to conventional therapy Basic principles Prescribe drugs which patient has not had previously Initial regimen should consist of 3 drugs (preferably 4 or 5)(to which organism are likely to be fully sensitive) Continue treatment for 18 months (after sputum ve) to prevent relapse 2nd Line Anti-TB Drugs Kanamycin & Amikacin Aminoglycosides MOA Inhibit protein synthesis IM Multidrug resistant are susceptible to these drugs No cross resistance Adverse ototoxicity, nephrotoxicity

Cycloserine Broad spectrum antibiotic MOA Inhibit cell wall synthesis Oral Also inhibit Enterococci E. coli Staph aereus Nocardia spp. Chlamydia Eliminated in urine (60% active compound) Adverse Peripheral neuropathy CNS dysfunction epilepsy, depression, toxic psychosis + pyridoxine 150mg/d should be given

Ciprofloxacin, Ofloxacin, Levofloxacin Fluoroquinolones MOA Inhibit DNA synthesis (Inhibit DNA gyrase) Well tolerated Mycobacterial resistance develops rapidly Reserved for patients with Multidrug resistance Intolerance to 1st line drugs