Antitubercular Agents

Antitubercular Agents
Dr. Rajendra Nath Professor

Tuberculosis is a chronic granulomatous disease In developing countries it is a major health problem ≈ 30% of world population is infected with Myc. Tuberculosis infection In India > 2 million people develop active disease every year & half million die.

Tuberculosis It is an infection difficult to treat
Mycobacterium tuberculosis It is an infection difficult to treat ?? Typical growth characteristics Peculiar cell wall structure (waxy appearance ) due to mycolic acid. Resistance to infection emerges quickly.

Antitubercular Drugs Mycobacterium Infections
Common infection sites Lung (primary site) Intestines Brain Lymph nodes Bone Liver Kidney Aerobic bacillus Passed from infected: Humans Cows (bovine) and birds (avian) Much less common

Antitubercular Drugs Mycobacterium Infections
Tubercle bacilli are conveyed by droplets Droplets are expelled by coughing or sneezing, then gain entry into the body by inhalation Tubercle bacilli then spread to other body organs via blood and lymphatic systems Tubercle bacilli may become dormant, or walled off by calcified or fibrous tissue

Antitubercular Drugs Tuberculosis - Pathophysiology
M. tuberculosis – gram-positive, acid-fast bacillus Spread from person to person via airborne droplets Coughing, sneezing, speaking – disperse organism and can be inhaled Not highly infectious – requires close, frequent, and prolonged exposure Cannot be spread by hands, books, glasses, dishes, or other fomites

Antitubercular Drugs Tuberculosis – Clinical Manifestations
Early stages – free of symptoms Many cases are found incidentally Systemic manifestations: Fatigue, malaise, anorexia, weight loss, low-grade fevers, night sweats Weight loss – occurs late Characteristic cough – frequent & produces mucoid or mucopurulent sputum Dull or tight chest pain Some cases: acute high fever, chills, general flulike symptoms, pleuritic pain, productive cough HIV Pt with TB: Fever, cough, weight loss – Pneumocystic carinii pneumonia (PCP)

Antitubercular Drugs Tuberculosis – Diagnostic Studies
Tuberculin Skin Testing -- + reaction 2-12 weeks after the initial infection PPD – Purified protein derivative – used to detect delayed hypersensitivity response Two-step testing – health care workers 5mm > induration – Immunosuppressed patients 10 mm> “at risk” populations & health care workers 15 mm> Low risk people Chest X-ray -- used in conjunction with skin testing Multinodular lymph node involvement with cavitation in the upper lobes of the lungs Calcification – within several years after infection Bacteriologic Studies – Sputum, gastric washings –early morning specimens for acid-fast bacillus -- three consecutive cultures on different days CSF or pus from an abscess

M. tuberculosis: peculiar features
Rapid growers: In the wall of cavitary lesion, extracellular. Slow growers: intracellular, within the macrophages at inflamed sites. Spurters: intermittent growth spurts. Dormant: Do not grow for long time, become active at times of low host resistance. Bacilli continuously shift from one to other subpopulation. 9

Mycobacterial cell wall
Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33

Chemotherapy in tuberculosis
Goals of anti-tubercular chemotherapy Kill dividing bacilli: Patient is non-contagious : transmission of TB is interrupted. Kill persisting bacilli: To effect cure and prevent relapse. Prevent emergence of resistance: so that the bacilli remain susceptible to the drugs. 11

Now there is emergence of multidrug resistant ( MDR ) TB . More than 0.4 million cases globally . History First successful drug for treating TB was PAS (Para- aminosalicylic acid) developed by Lehman in 1943. Dramatic success came when Waksman

& Schutz discovered Streptomycin which has made remarkable progress. Followed by Thiacetazone by Domagk in in 1946 In 1952 Isoniazid came into being Pyrazinamide by Kushner & colleagues in 1952 & later on Rifampicin in 1957

by S. Margalith has totally changed the strategy in the chemotherapy. Ethambutol came in 1961 by Lederle -laboratories Fluoroquinolones , newer macrolides & congener of Rifampicin →Rifabutin are recent addition in antimycobacterial drugs

First line drugs: Ionized ( H) Rifampicin (R) Ethambutol (E) Pyrazinamide ( Z) Streptomycin ( S) now reserved drug in first line

Second line drugs: Thiacetazone Para aminosalicylic acid (PAS) Ethionamide ( Etm) Kanamycin Cycloserine Amikacin Capreomycin

Newer Second Line drugs: Ciprofloxacin Ofloxacin Levofloxacin Clarithromycin Azithromycin Rifabutin

Drugs used in Tuberculosis
1st line drugs high efficacy, low toxicity 2nd line drugs Low efficacy, high toxicity or both Isoniazid (INH) Rifampin Pyrazinamide Ethambutol Streptomycin Ethionamide Para aminosalicylic acid Cycloserine Amikacin/ Capreomycin Fluoroquinolones Rifabutin

Isoniazid (Isonicotinic acid hydrazide,H): Essential component of all anti TB regimen (except intolerance to H or resistance) -It is tuberculocidal , kills fast multiplying organism & inhibit slow acting organism -Acts both on intracellular ( present in macrophages ) & extracellular bacilli -It is the cheapest AT Agent

-Atypical mycobacteria are not inhibited by INH. Not active against any other micro-orgs. Mechanism of Action : Inhibit synthesis of mycolic acid ( unique fatty acid component of mycobacterial cell wall .)

-INH enters the bacilli by passive diffusion. It must be activated to become toxic to bacilli. It became toxic by Kat G (multifunctional Catalase - peroxidase , a bacterial enzyme ) which catalyzes the product from INH an Isonicotinoyl radical that subsequently inter-acts with mycobacterial NAD & NADP to produce dozen of adducts , one of these

a nicotinoyl NAD isomer which ↓ the activity of enoyl acyl carrier protein reductase (Inh A) & β- ketoacyl carrier protein synthase ( Kas A) , inhibition of these enzymes↓ the synthesis of mycolic acid an essential component of the mycobacterial cell wall & causes cell death.

MOA of 1st line drugs - - - - - - Isoniazid Mycolic Acid
Ethambutol - - Mycolic Acid Arabinogalactan Peptidoglycan Cell membrane Mitochondria (ATP) - Rifampin Pyrazinamide - - Streptomycin Protein RNA polymerase Cytoplasm - DNA R I B O S M e mRNA

(another adduct , a nicotinoyl –NADP isomer potentially mycobacterial dihydrofolate reductase → interfere with nucleic acid synthesis . These adducts also produce H2O2 , NO radical & other free radicals which are toxic to bacilli ) If INH is given alone , inherent resistant bacilli proliferate selectively & after 2-3 months an apparently resistant infection emerges .

(Mutation of the catalase –peroxidase gene in bacilli do not generate the active metabolite of INH ) - Combination therapy with INH has good resistance preventing action . There is no cross resistance .

Pharmacokinetics : -Completely absorbed orally , penetrate all body tissues, tubercular cavities , placenta & meninges . Metabolized in liver by acetylation & metabolites are excreted in urine . Rate of acetylation shows genetic variation ( fast acetylators > 30% Indians - t½ -1 hr Slow acetylators >60% Indians -t ½- 3 hrs)

(daily regimen is not affected but biweekly regimens are less effective in fast acetylators ) Dose – 4-6 mg/ kg for >50 kg – 300 mg daily - 600 mg bi-wkly

ISONIAZID (INH): Pharmacokinetics
Acetylation (Phase II) Hydrolysis (Phase I) N-acetyl transferase N-acetyl Isoniazid Isonicotinic acid Acetyl hydrazine Genetic polymorphism affects INH metabolism Slow acetylators are at higher risk of developing neuritis

ADRs - Well tolerated drug 1.Peripheral neuritis & other neurological manifestations- parasthesia , numbness, mental disorientation & rarely convulsion ( due to interference with utilization of pyridoxine & ↑ excretion in urine )

Due to this Pyridoxine given prophylactically -10 mg/day which prevents neurotoxicities (INH neurotoxicity treated with Pyridoxine-100 mg/ day ) 2. Hepatitis – more common in older patients & alcohlics ( reversible) 3. Rashes , fever , acne & arthralgia .

Rifampin ( Rifampicin , R ): -Semisynthetic derivative of Rifamycin B from Streptomyces mediterranei -Bactericidal to M. Tuberculosis & others – S. aureus Klebsiella N. meningitidis Pseudomonas H. influenzae Proteus E. coli & Legionella

Best action on slowly or intermittently dividing bacilli on extracellular as well as intracellular organisms -Also act on many atypical mycobacteria -Have good resistance preventing action

Mechanism: Inhibit DNA dependant RNA Synthesis (by ↓ bact RNA polymerase , selective because does not ↓ mammalian RNA polymerase ) TB patient usually do not get primary Rifampicin resistance – If occurs is due to mutation in the repo -B gene (β subunit of RNA polymerase ). - No cross resistance

PKT – Well absorbed orally widely distributed in the body , penetrate cavities , caseous mass, placenta & meninges . -Metabolized in liver -Excreted mainly in bile & some in urine -t½- 2-5 hrs

ADR’s Hepatitis – mainly in pts having preexisting liver disease & is dose related- Jaundice req. stoppage of drug Respiratory syndrome –breathlessness shock & collapse . 3. Purpura , hemolysis , shock , renal failure

4. Cutaneous syndrome – flushing , pruritis & rashes ( face & scalp ), redness & watering of eyes. 5. Flue syndrome – Nausea , vomiting, abdominal cramps ( Urine & secretions may become red – which are harmless & Pt should be told about this effect)

D/I Rifampicin is microsomal enzyme inducer -↑ several CYP 450 isoezymes -↑ its own metabolism as well as of others e.g.-Oral contraceptive Digoxin Warfarin Theophylline Steroids Metoprolol Sulphonyl urea Fluconazole & Ketoconazole etc.

(contraceptive failure can occur if given simultaneously in child bearing age women taking oral contraceptive)

Other uses –1. Atypical myc. Inf. (M. kansasii, marinum , avium & intracellulare ) 2. Leprosy 3. Prophylaxis of meningococcal & H. infl. meningitis 4. MRSA , Diphtheroids & legionella inf. 5. Along with Doxycycline –first line therapy in Brucellosis Dose- 10 mg ( 8-12 mg / kg), for > 50 kg = 600 mg OD

3. Pyrazinamide ( Z) Chemically≡ INH -Weak tuberculocidal more active in acidic medium -More lethal to intracellular bacilli & to those at sites showing an inflammatory response ( Therefore effective in first two months of therapy where inflammatory changes are present )

-Good sterilizing activity -It’s use enabled total duration of therapy to be shortened & risk of relapse to be reduced. Mechanism ≡ INH - ↓ fatty acid synthesis but by interacting with a different fatty acid synthesis encoding gene .

PZA is thought to enter M. tub. by passive diffusion and converted to pyrazinoic acid (its active metabolite) by bact. pyrazinamidase enz. .This metabolite inhibits mycobact. fatty acid synthase -I enz. and disrupts mycolic acid synthesis needed for cell wall synthesis -Mutation in the gene (pcn A) that encodes pyrazinamidase enzyme is responsible for drug resistance ( minimized by using drug combination therapy) .

PKT : -Absorbed orally, widely distributed ,Good penetration in CSF. -Metabolized in liver & excreted in urine. -t½ hrs

ADRs : -Hepatotoxic -dose related -Arthralgia , hyperuricaemia, flushing , rashes , fever & anaemia -Loss of diabetic control Dose – mg /kg daily , 1500 mg if > 50 kg

Ethambutol ( E) : -Tuberculostatic , clinically active as Streptomycin -Fast multiplying bact.s are more sensitive -Also act against atypical mycobacteria -If added in triple regimen (RHZ) it is found to hasten the rate of sputum conversion & to prevent development of resist.

Mech. : Not well understood . Found to ↓arabinosyl transferase III involved in arabinogalactone synthesis & also interfere with mycolic acid incorporation in mycobacterial cell wall (this is encoded by emb AB genes ) -Resistance develop slowly - No cross resistance

PKT: -3/4th of an oral dose of Ethm. is absorbed -Distributed widely but penetrates in meninges incompletely -½ metabolized , excreted in urine -caution is required in pts of renal disease -Pts acceptability is good & S/Es are low

ADRs: -Loss of visual acquity / color vision due to optic neuritis ,which is most impt. dose & duration dependent toxicity. (children can not report this complaint easily therefore not given below 6 yrs of age) -Early recognition –reversible Others- Nausea , rashes & fever

-Neurological changes -Hyper uricaemia is due to interference with urate excretion Dose – mg/kg , > 50kg -1000mg

Streptomycin (S): -It was 1st clinically useful antibiotic drug -It is protein synthesis inhibitor by combining with 30S ribosome -It is tuberculocidal , but less effective than INH / Rifampicin -Acts on extracellular bacilli only ( poor penetration in the cells )

-It penetrates tubercular cavities but does not cross BBB - Resistance when used alone (in average popul.1 in 10 to the power 8 bacilli are resistant to streptomycin –they multiply & cause relapse therefore stopped at the earliest .) - Atypical mycobact.s are ineffective Popularity ↓ due to need of IM inj. & lower margin of safety ( because of ototox. & nephrotox.). Dose- 15 ( ) mg/kg, >50 mg- 1000mg

Thiacetazone (TZN) : -First AT drug tested but weak -Discarded due to hepatotoxicity -In India revived in 1960s for oral use along with INH as a substitute to PAS

-Tuberculostatic , does not add to the therapeutic effect of H,S, R, E ADRs - Hepatotoxic Exfoliative dermatitis Stevenson Johnson’s syndrome Can cause bone marrow depression Others- Nausea , anorexia , abd. discomfort

Loose motions Mild anemia Pruritis Dose- 150 mg OD (2-5 mg/ kg ) ,used in combined tablet with INH

The Basis for Multi-Drug Therapy
1 Prevent emergence of resistance

The Basis for Multi-Drug Therapy
Mitchison, Tubercle 66: , 1985 Rapid growers Slow INH Rifampin Streptomycin INH, Rifampin Ethambutol, PZ No drug is effective Spurters 2 Antibacterial attack against all subpopulations of bacilli.

Mechanism of Resistance

Relative activity of first line Drugs
INH: potent bactericidal Rifampin: potent bactericidal Pyrazinamide: Weak bactericidal, active against intracellular bacilli. Ethamutol: bacterisostatic, prevents resistance development. Streptomycin: bactericidal, active against extracellular rapid growers. Combination is synergistic Never use a single drug for chemotherapy in tuberculosis, a combination of two or more drugs must be used. 59

PAS – Paraaminosalicylic acid: -Related to sulfonamides chemically as well as in mech. of action. -Tuberculostatic , not add to therapeutic value , only delay resistance -Interfere with absorption of Rifampicin S/E - Acceptability is poor due to frequent anorexia , nausea & epigastric pain

Other use- Goitre Liver dysfunction & Blood dyscrasias Dose gm ( 200 mg/ kg) / day Rarely used now

Ethionamide : -Tuberculostatic , having moderate efficacy -Acts both on extra as well as intracellular bacterias (Mycobacterial EthaA, an NADPH specific FAD- containing mono- oxygenases converts Ethionamide to a sulfoxide, it ↓ mycobacterial growth by ↓ the activity of the inh A gene product, the enoyl acyl reductase of fatty acid synthase II ,the same enzyme which is ↓ by INH ) -Resistance develop readily & some cross resistance to TZN -Absorbed orally ,distributed all over including CSF

S/E- Anorexia Nausea & vomiting, Rashes Hepatitis , Peripheral/ Optic neuritis Dose- 1 gm / day, but more than 0.5 gm not tolerated. - seldom used now , only used in resistance cases .

Cycloserine (Cycs): - Obtained from S. archidacces & is a chemical analogue of D- alanine -↓ Bacterial cell wall synthesis -Tuberculostatic & ↓ other G -ve organisms ( E. coli , Chlamydia) -Resistance develop slowly , no cross resist.

CNS toxicity is high , sleepiness , headache tremor , psychosis & convulsions -Rarely used (only in resistance cases) Dose – 250 mg BD Kanamycin , Amikacin & Capreomycin: Used as reserved drug in severe cases not responding to usual therapy

Newer drugs : Ciprofloxacin Ofloxacin Levofloxacin ( all are used in TB & MAC ) Clarithromycin Azithromycin ( used in MAC ) Rifabutin - > in MAC < in TB

Antitubercular Therapy
Treatment of Tuberculosis : Remarkable change, conventional 1-1½yr Tt – is replaced by more effective & less toxic 6 month-8 month therapy Rapidly growing with higher bacillary load e.g. wall of the cavity region- highly suscep. to INH & lesser extent to R,E,S b) Slow growing – intracellular & at inflamed sites – vulnerable to Z while H,R,E are lesser active

c) Spurturs - with in caseous material (where O2 tension is less ) the bacilli grow intermittently. R- is most active in this sub population d) Dormant –bacilli remain totally inactive for prolonged periods- No ATT is effective

Goals- Killing of dividing bacilli- drugs with bactericidal activity rapidly reduce the bact. load in the Pt & achieve quick sputum clearance – Pt become non con- tageous to the community - Transmission is interrupted

2. Killing of persistent bacilli for effective cure & prevention of relapse 3. Prevent emergence of resistance (Drug combination are selected to maximize the above action together with consideration of cost & convenience ) H & R are most efficacious drugs ,their combination is synergistic

Duration of therapy shortened from 12 to 9 months. Addition of Z for initial 2 months further reduces duration of treatment to 6 months DOTs –Directly observed treatment short course ,was recommended by the WHO in 1995

Short course chemotherapy- Regimen of 6-9 months treatment In 1997 WHO framed clear cut guidelines for different category of TB treatment . All regimen have initial intensive phase -2 3 months to rapidly kill the TB bacilli & bring sputum conversion & afford symptomatic relief followed by continuation phase last 4-6 months for elementary remaining bacilli t

Categories: Category I –New ( untreated ) smear +ve pulmonary TB -New smear –ve pulmonaryTB with extensive parenchymal involvement -New cases of severe forms of extra- pulmonary TB e.g.- meningitis , miliary TB , pericarditis -B/L or extensive pl. effusion , intestinal or genitourinary TB

(Revised National Tub. Control programme In India in 1997— DOTs –follow thrice wkly regimen to ↓ cost & it is more practical ) WHO : - 2HRZE(S) (initial phase)-daily - 4HR or 6HE (continuation phase,)daily total duration 6-8 months RNTCP : 2H3R3Z3E3 + 4H3R3 -total duration- 6month

Category II -Smear +ve failure ,relapse & interrupted Tt cases -Relapse- cured TB Patient again become sputum +ve -Tt after interruption –interrupted Tt x 2month →return to sputum + ve case WHO: Initial phase –daily 2 HRZES +1 HRZE Continuation phase –5HRE - total 8 month RNTCP: Initial phase -2H3R3Z3E3S3 +1H3R3Z3E3 Continuation phase -5H3R3E3 –total 8 months

Category III New cases of smear –ve pulmonary TB with limited parenchymal involvement or severe form of extra pulmonary TB . e.g.-Lymph node TB Unilateral pleural effusion Bone (excluding spine ) Peripheral joint & skin TB

WHO : Initial phase -2HRZ (daily) Continuation phase - 4HR or 6HE (daily) Total duration-6-8 months RNTCP : Initial phase -2H3R3Z3 ( daily ) Continuation phase -4H3R3 ( daily ) Total duration- 6 months

CATEGORY-WISE TREATMENT (WHO1997 & RNTCP1997)
TB Category Initial Phase (daily /3xper week) Continuation Phase (daily/3xper week) Total Duration i. 2 HRZE(S)/ 2H3R3Z3E3 4 HR/ 4H3R3 or 6HE 6 8 ii. 2 HRZES+ 1HRZE / 2H3R3Z3E3S3+1H3R3Z3E3 5 HRE or 5H3R3E3 iii. 2 HRZ/ 2H3R3Z3 4 HR/4 H3R3 or 6 HE

DOTS PLUS: Refers to DOTS programme which includes component for multidrug resistance (MDR) tuberculosis , its diagnosis , management & treatment. (It began in 2000 by WHO & implemented in India in 2010 & thus category IV is created) .

Cat IV – Chronic cases who have remained or become smear +ve after completing fully supervised Tt / close contact of most likely MDR cases MDR –TB –Resistant to both H& R & many other anti -TB drugs (Tt difficult because –one or more 2nd line drugs are to be given for months & they are less efficacious , less convenient & more toxic & expensive )

Chronic – presence of association of AIDS /Diabetes / Leukemia /Silicosis -If sensitivity of drugs known then resistant drugs are excluded -For H resistance – RZE X 12 months - For H+ R resistance- ZE+ S / Kanamycin / Capreomycin/ + Ciprofloxacin or Ofloxacin ± Ethionamide could be used

Extremely drug resistant ( XDR) TB : Term applied to bacilli that are resistant to at least 4 most effective cidal drugs i.e. H ,R Ofloxacin , one of Kanamycin / Amikacin/ Capreomycin. Global survey –reveals 20% TB isolates are MDR out of which 2% are XDR .

TB in pregnant women : WHO – H,R,Z –safe (Recommended - – 2HRZ + 6HR regimen -8 month -E can be added late -S is C/I In India Z is avoided -(2HRE +7HR total 9 month regimen )

Breast feeding mother: All ATT drugs are compatible ,baby should be watched ,the infant should receive BCG vaccination & INH prophylaxis

Indication of Glucocorticoids in TB: -In TB Pts, glucocorticoids if at all used are always used with AT drugs, they are considered in – - Miliary TB - Tuberculous Meningitis - Rapidly filling Pleural effusion & - Renal TB ( to reduce exudation & stricture formation) ( Its administration should be withdrawn gradually when the G.C. of Pts improved ).

RECENT DRUGS Three novel drugs currently under clinical
development which are active against MDR-TB- 1. Linezolid 2. OPC-67683, a nitroimidazole 3. TMC207, a diarylquinoline

Newer Antitubercular Drugs in Clinical Trials
1.LINEZOLID (Also known as 3rd line agent) Linezolid is an oxazolidinone used primarily for the treatment of drug-resistant gram-positive infections. Also active against M. tuberculosis Mechanism of action is disruption of protein synthesis by binding to the 50S bacterial ribosome. Linezolid has nearly 100% oral bioavailability, with good penetration into tissues and fluids, including CSF. Adverse effects may include optic and peripheral neuropathy, pancytopenia, and lactic acidosis .

2.TMC207 (R ) by Andries etal in 2005 : TMC207 is a new diarylquinoline with a novel mechanism of action: inhibition of the mycobacterial ATP synthetase proton pump. TMC207 is bactericidal for drug-susceptible and MDR strains of M. tuberculosis. Resistance has been reported and is due to point mutations in the gene coding for the ATP synthetase proton pump. A phase 2 randomized controlled clinical trial demonstrated substantial improvement in rates of 2-month culture conversion, with improved clearance of mycobacterial cultures, for MDR-TB patients.

This drug is metabolized by the hepatic cytochrome CYP3A4. Rifampin lowers TMC207 levels by 50%, and protease inhibitors also interact significantly with this drug. The dosage is 400 mg/d for the first 2 weeks and then 200 mg thrice weekly. Adverse effects are reported to be minimal, with nausea and slight prolongation of the QTc interval.

3. OPC AND PA 824 : The prodrugs OPC and PA 824 are novel nitro- dihydro- imidazoxazole derivatives. Antimycobacterial activity is due to inhibition of mycolic acid biosynthesis. Early clinical trials of these compounds are ongoing.

CHANGES IN RNTCP GUIDELINES IN 2010-11

Changes in RNTCP Guidelines
Discontinuation of Cat III Regimen under RNTCP The programme has now revised its categorization of patients from the earlier 3 categories (Cat I, Cat II and Cat III) to 2 categories (New and Previously treated cases)

NEW (CAT I) New Sputum smear-positive New Sputum smear-negative New Extra-pulmonary New Others PREVIOUSLY TREATED (CAT II) Smear-positive relapse Smear-positive failure Smear-positive treatment after default Others

TREATMENT Category Initial Phase Continuation Phase
New (Cat I) 2H3R3Z3E H3R3 Previously H3R3Z3E3S3/ H3R3E3 Treated H3R3Z3E3 (Cat II)

CHEMOPROPHYLAXIS Chemoprophylaxis of TB:
Prevention of active disease from latent inf. & It is indicated by +ve Mantuox test. Mantuox test / Tuberculin test – In this test purified protein derivative (PPD) is injected by intradermal route . In normal person i.e. in immunocompetent pts induration of > 5 mm & in immunocompromised Pts >10 mm induration is considered positive after giving 5 units of PPD . Subjects require prophylaxis are – - PPD +ve pts but no active disease - -ve PPD but in close contact with TB Pts -Immunocompromised Pts ( having leukemia ,HIV, taking corticosteroid) with +ve MT - HIV inf. Pts . exposed to MDR TB cases

Chemoprophylaxis Standard drug is INH daily for 6-12 months.
OR: INH + Rifampin daily for 6 months. If INH can not be used: Rifampin (4 months)/R+Z (2 months). MDR: E+Z + FQ. 98

THE DEVELOPMENT PIPELINE FOR NEW DRUGS, 2010

Rifaximin : Newer non systemic rifamycin
approved for : Traveler's diarrhea, Hepatic encephalopathy Irritable bowel syndrome, Small intestinal bacterial overgrowth & Clostridium difficile infection

The goal of the new drugs component of the Global Plan to Stop TB 2011–2015
To develop and introduce new TB drugs and drug combinations that will result in- Shorter, safer, more effective and accessible treatment regimens Cure all forms of TB Compatible with ART Suitable for children Easily managed in the field.

ACHIEVEMENTS EXPECTED BY 2015
• A new four-month TB treatment regimen • Two new drugs will be approved by regulatory authorities for drug sensitive TB • At least one new drug for the treatment of drug resistant TB will be introduced into the market • A nine-month regimen for the treatment of drug resistant TB including at least one new drug

ACHIEVEMENTS EXPECTED BY 2015
Fixed-dose combinations (FDCs) for first-line drugs (including new drugs) will be available and in use • Child-friendly first-line TB drug formulations will be under development

Anti- Leprotic agents Also known as Hansen’s disease
It is a chronic granulomatous infection caused by Mycobacterium leprae Attacks superficial tissues e.g. skin & peripheral nerves Organism grow very slowly ( org.s can not be cultured in artificial media but grows in foot pad of Armedillon.)

Anti- Leprotic agents Disease is still considered as social stigma
but it needs a change in the attitude of public to consider it just like any other disease . Important is early diagnosis & Tt. which makes it non infectious & prevents compl.s

Anti- Leprotic agents Anti- Leprotic drugs : Classification-
-Sulfone Dapsone (DDS) -Phenazine derivatives Clofazimine -Antitubercular drugs Rifampicin Ethionamide -Other Antibiotics - Ofloxacin , Minocycline & Clarithromycin

Anti- Leprotic agents Sulfones -
Derivative of 4-4’ diamino diphenyl sulfone (DDS) Dapsone: -Bacteriostatic -High risk of resistance if used alone

Anti- Leprotic agents Mechanism:
Similar to sulfonamide i.e. ↓ of dihydrofolate synthase enzyme.( Anti-inflammatory effect occurs via ↓ of tissue damage by neutrophils by ↓ neutrophil myeloperoxidase activity ,↓activity of neutrophil lysosomal enzyme , free radical scavanger ,↓ of migration of neutrophils to the inflammatory sites ) ADRs: -Nausea , vomiting , anorexia -Allergic reaction -Hemolysis in pts with G6PD deficiency -Methemoglobinaemia

Anti- Leprotic agents Neurotoxicity & Psychosis Sulphone Syndrome:
After 5/6 wks of Tt. in malnourished patients there may be exacerbation of Lepromatous Leprosy similar to Jerisch Hexheimer reaction (seen with Penicillin ) ,characterized by fever, malaise , exfoliative dermatitis , lymphadenopathy, Jaundice etc.

Anti- Leprotic agents Indication – -Leprosy
-Resistant Malaria ( with pyrimethamine) -Toxoplasma encephalitis in AIDS -Pneumocystis jirovecii in AIDS

Anti- Leprotic agents Clofazimine :
It is a dye , weak bactericidal by ↓ the function of DNA. ( membrane disruption ,↓of mycobacterial Phospholipase A2 , ↓ of mycobacterial K+ transport , generation of H2O2 , interference with the bacterial electron transport chain via ↓ of macrophages , T cells, neutrophils & complement ) - Also having anti- inflammatory activity so prevents Lepra reaction. -used for common skin ulcers & MAC S/E- Red discolouration of skin - Eosinophilic enteritis

Anti- Leprotic agents Rifampicin :
- Important antiTb drug also bactericidal to M. Leprae. Rapidly make leprosy Pts noncontagious However not satisfactory if used alone- some bacilli persist after prolonged Tt –can cause resistance . ( The congener of Rifampicin - Rifabutin is

Anti- Leprotic agents also bactericidal against M. leprae but not
superior to Rifampicin) Ethionamide - Has significant antileprotic activity but is hepatotoxic . It can be used as an alternative to Clofazimine but other substitutes are preferred.

Anti- Leprotic agents Other Antibiotics:
-Fluoroquinolones : Ofloxacin , Pefloxacin, Gatifloxacin are highly active against M. leprae ( but not Ciprofloxacin ) -Minocycline: due to high lipophilicity, it is active against M. leprae. , antibacterial activity is less than Rifampicin but more than that of Clarithromycin .

Anti- Leprotic agents Clarithromycin :
Only macrolide antibiotic having significant activity against M. leprae . It is being included in alternative MDT regimens.

Anti- Leprotic agents Diagnosis of Leprosy:
Diagnosed with any of the following- Skin lesions ( hypopigmented patches ) Impaired or loss of sensation Acid fast bacilli in skin smears Nerve thickening

Treatment of Leprosy Leprosy primarily affect skin , mucous membranes & nerves Prevalent in poors ( low socioeconomic strata ) . National Leprosy Control Programme launched in 1955 It was changed to National Leprosy Eradication Programme ( NLEP) in 1982

Treatment of Leprosy India achieved elimination of Leprosy as
a public health problem . Incidence is less than 1 case/ 10,000 population .

Treatment of Leprosy Classification: Indeterminate Tuberculoid
Borderline Lepromatous Pure neuritis ( no skin lesion ) Tuberculoid: Well defined skin lesion

Treatment of Leprosy -anesthetic patches
-Organism may or may not be found in skin lesions. -Lepromine test is positive (diagnostic for Leprosy. It evaluate the immune system of the patient & classify the type of disease.) -prolonged remission occurs

Treatment of Leprosy Lepromatous: -Ill defined skin lesions
-Skin is thickened , glossy & corrugated -Disease progresses – large nerve trunks get involved – anesthetic patches -Atrophy of skin & muscles & absorption of small bones e.g. phalanges of extremities, ulceration & spontaneous amputation occurs

Treatment of Leprosy -Lepromine test is –ve ( as cell mediated
immunity is absent ) -Smear is +ve for organism . For treatment purpose –leprosy is classified as- Multibacillary - It includes lepromatous, borderline cases with +ve skin smear test Tt- Rifampicin mg / month supervised

Treatment of Leprosy Dapsone-100 mg / day self administration
Clofazimine – 300 mg/ month supervised + 50 mg/ day self administration X 2 years- relapse – repeat Paucibacillary : ( small no. of organism)- It includes indeterminate & tuberculoid Tt- Rifampicin – mg / month supervised Dapsone – 100 mg / day self administration X minimum for 6 months-repeat if relapse

Treatment of Leprosy Single lesion paucibacillary –single dose
ROM- Rifampicin-600 mg + Ofloxacin - 400mg + Minocycline-100 mg (MDT was introduced by the WHO in 1981& was implemented under the NLEP ( National Leprosy Eradication Programme). It includes Dapsone , Rifampicin & Clofazimine . The WHO in 1994 recommended a fixed duration therapy( FDT) of 2 years for MBL & 6 months for PBL . WHO expert committee On Leprosy in 1995 recommended shortening of MDT in MBL to 12 months & this was implemented in our country since The purpose of this is to render the Pts noncontiguous & therefore cut down transmission al

Treatment of Leprosy

Treatment of Leprosy Alternative regimens :
Incorporating newer antileprotic drugs , but these are used only in case of Rifampicin resistance or when MDT is not advisable e.g.- Clofazimine + any two of Ofloxacin / Minocycline/ Clarithromycin for 6 months followed by Clofazimine + any one of Ofloxacin / Minocycline x additional 18 months . (PBL cases having few bacteria in the body & only one Skin lesion can be treated with single dose of Rifampicin -600 mg + Ofloxacin-400 mg + Minocycline -100 mg. This has been recommended by the WHO for solitary lesion of PBL.) al

Treatment of Leprosy Two types of reactional state may occur
with therapy Type I : Lepra reaction (reversal reaction) In borderline leprosy due to increased in host immunity- skin lesion & nerves become swollen & tender without systemic manifestation – Tt. – Prednisolone (Thalidomide not effective)

Treatment of Leprosy Type II :Lepra reaction ( erythema nodosum
leprosum) –observed in lepromatous leprosy – there is skin & nerve manifestation with fever & systemic involvement. Tt.- by analgesic /antipyretic for mild cases, in severe cases-Prednisolone or Thalidomide. -Chloroquine & cytotoxic drugs are also effective.

Treatment of Leprosy -Clofazimine require 3-4 wks so not suitable
for acute cases, but useful in chronic cases & prevention of this reaction . - No need to stop the antileprotic drugs .

MCQs 1. A middle aged man with chronic renal failure is diagnosed to have sputum +ve Pulmonary tuberculosis. His creatinine clearance is 25 mg/ min. All of the following Drugs need modification in doses EXCEPT : a) Isoniazid b) Streptomycin c) Rifampicin d) Ethambutol ( Ans- c ,Ref : Katzung 11/e p826) 2. A 30 year old pregnant women develops Tuberculosis. Which of the following antitubercular drug should not be given ? a) Rifampicin b) INH c) Streptomycin ( Ans- b ,Ref : KDT 6/e p748)

MCQs 3. A patient suffering from AIDS is on Zidovudine ,Lamivudine and Indinavir therapy. He develops Pulmonary tuberculosis for which treatment is started. Which of the Following should be avoided in him ? a) INH b) Ethambutol c) Pyrazinamide d) Rifampicin ( Ans- d ,Ref : KDT 6/e p741) 4. A patient of multidrug resistant Tuberculosis is on antitubercular drugs. After a few Months he develops an inability to distinguish between red & green color. Most likely drug causing these symptoms is : a) Rifampicin b) Ethambutol c) Cycloserine d) Ethionamide ( Ans -b ,Ref : KDT 6/e p742) 5. In multidrug resistant strains of M. tuberculosis which of the following drugs is likely to be effective, including those resistant to Streptomycin? a) Amikacin b) Gentamicin c) Spectinomycin d) Clarithromycin ( Ans- a ,Ref: Katzung 11/e p825)

MCQs 6. In atypical mycobacterial infection which of the following drug is active? a) Ethionamide b) Streptomycin c) INH d) Clarithromycin ( Ans- d , Ref: KDT 6/e p750) 7. Which of the following antitubercular drug DOES NOT cross blood brain barrier? a) Isoniazid b) Pyrazinamide c) Rifampicin d) Streptomycin ( Ans- d , Ref: KDT 6/e p743 ) 8. Which of the following anti-tubercular drug is implicated in the causation of transient memory loss? a) Ethambutol b) Ethionamide c) Pyrazinamide d) Isoniazid ( Ans –d , Ref : Goodman & Gilman 10/e p1277 )

MCQs 9. Most effective drug for extracellular mycobacteria is:
a) Ethambutol b) Rifampicin c) Isoniazid d) Pyrazinamide ( Ans –c , Ref : Goodman & Gilman 11/e p1205 ,1208,1211 ) 10. In severe liver disease which of the following combination of antitubercular drug can be used ? a) Isoniazid + Streptomycin b) Rifampicin + Isoniazid c) Rifampicin + Ethambutol d) Streptomycin + Ethambutol ( Ans -d , Ref: KDT 6/e p ) 11. In Leprosy , the best bactericidal agent is : a) Rifampicin b) Clofazimine c) Dapsone d) Ethionamide ( Ans-a ,Ref : KDT 6/e p753)

MCQs 12. What is the side effect of Dapsone apart from hemolytic anaemia ? a) Infective mononucleosis like syndrome b) Flu like syndrome c) Lichenoid eruptions d) G-6-PD deficiency ( Ans -a , Ref: KDT 6/e p752 ) 13. Dapsone is used in all EXCEPT : a) Dermatitis herpitiformis b) Leprosy c) Pneumocystis jiroveci pneumonia d) Tuberculosis ( Ans -d , Ref: KDT 6/e p752 ) 14. In Lepra reaction , the drug useful is : a) Penicillins b) Clofazimine c) Dapsone d) Rifampicin

MCQs 15. Treatment of Lepromatous leprosy is : a) Rifampicin + Dapsone
b) Rifampicin + Clofazimine c) Rifampicin + Dapsone + Clofazimine d) Rifampicin + Ofloxacin + Minocycline ( Ans -c , Ref: KDT 6/e p755 )

Bibliography 1.Goodman & Gilman’s ,The Pharmacological Basis of Therapeutics (12th Edition). 2. A complete Textbook of Medical Pharmacology by S. K. Srivastava ( Latest Edition ) 3.. Essentials of Medical Pharmacology by K. D. Tripathi (7th edition)

Antitubercular Agents

Similar presentations

Presentation on theme: "Antitubercular Agents"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Antitubercular Agents

Similar presentations

Presentation on theme: "Antitubercular Agents"— Presentation transcript:

Similar presentations

About project

Feedback