ANTI-ANTI-TUBERCULOSIS TUBERCULOSIS

DRUGSDRUGSDr. SIDHARTH YADAV

PHYSIOLOGY & STRUCTUREGram +ve , aerobic acid fast bacilli.

Resistant to disinfectant ,detergent & common antibiotics.

Capable of intracellular growth.

Person to person spread is by aerosol.

Human are the only natural reservoir.

Disease is most common in south east asia, sub saharan region, eastern europe.

Lipid-Rich Cell Wall of MycobacteriumMycolic

acids

(Purified Protein Derivative)

GROSS & MICROSCOPIC APPEARANCE

Mycobacterium Tuberculosis (scanning EM) Mycobacterium Tuberculosis on Lowenstein-Jensen medium

THESE ARE OBLIGATE AEROBES & GROW VERY SLOWLY. IT REQUIRES APPROX. 15-30 HRS FOR DOUBLING & 6-8 WKS FOR GROWTH ON PLATES.

STAININGTHESE ARE ACID FAST BASCILLI i.e THEY ARE RESISTANT TO DECOLURATION BY ACID.ZIEHL-NEELSEN STAIN.

Mycobacterium tuberculosis (stained red) in tissue (blue).

Mycobacterium tuberculosis (stained red) in sputum

TUBERCULOSIS DIAGNOSIS

0Clinical (presenting symptoms, duration of symptoms, previous TB)

0Diagnostic Imaging(X-Rays, CT Scans, MRI’s)

0Bacteriology (smears, cultures)

0Pathology of biopsy specimens

0Epidemiological Factors

CLASSIFICATION OF DRUGS USED IN ANTI-TUBERCULOSIS TREATMENT

0 ISONIAZIDE0 RIFAMPIN0 PYRAZINAMIDE0 ETHAMBUTOL0 STREPTOMYCIN

0 AMIKACIN0 AMINOSALICYCLIC ACID0 CAPREOMYCIN0 CIPROFLOXACIN0 CLOFAZIMINE0 CYCLOSERINE0 ETHIONAMIDE0 LEVOFLOXACIN0 RIFABUTIN0 RIFAPENTINE

FIRST LINE DRUGS SECOND LINE DRUGS

0 First line drugs:- kill active bacteria, important in the early stages of infection.

0 Second line drugs:- hinder bacterial growth.

- Strengthen treatment in the case of resistant bacteria.

- Less efficient and generally more toxic than first line drugs.

ISONIAZIDE (H)0 Is the most active drug.

0 Its structurally similar to pyrodoxine.

0 Bactericidal for fast growing bacteria.

0 Is able to penetrate into phagocytic cells & thus active against both extracellular & intracellular.

0 Less effective against atypical mycobacteria.

MECHANISM OF ACTION

0 Inhibits synthesis of Mycolic acid.

0 It’s a pro drug activated by KatG.

0 Resistance to INH is associated with overexpression of inhA.

0 Overproducers of inhA express low level INH resistance & cross resistance to ethionamide.

0 KatG mutants express high level of INH resistance & usually no cross resistance to ethionamide.

PHARMACOKINETICS0 INH is readily absorbed from GIT.

0 INH readily diffuses in all body fluids.

0 Peak plasma concentration of 3-5µg/ml with in 1-2 hrs.

0 Half life is about 1-3 hrs.

0 DOSAGE :- 5mg/kg/day once daily.

Up to 10 mg/kg/day can be used if malabsorption is not an issue.

High dose upto 15mg/kg/day twice a week.

RIFAMPIN(R)0 It’s a semi-synthetic derivative of rifamycin, antibiotic

produced by STREPTOMYCES MEDITERRANEI.

0 Active against gram + & -ve , some enteric ,mycobacteria & chlamydia.

0 There is no cross resistance to other class of anti microbials but there is a cross resistance to other rifamycin derivatives.

MOA & PHARMACOKINETICS0 Inhibits RNA synthesis.

0 Resistance is from mutation in rpoB gene.

0 Human RNA polymerase does not binds with Rifampin.

0 Rifampin is bactericidal for mycobacteria.

0 Its excreted mainly through liver so dosage adjustment in renal failure is not required.

0 Rifampin is highly protein bound.CSF concentration are achieved only in presence of meningeal inflammation.

CLINICAL USAGE

0 DOSAGE :- 10 mg/kg/day

0Other indications :-

Oral dosage of 600mg twice daily fro 2 days to eliminate meningococcal carriage.

ETHAMBUTOL(E)0 Synthetic water soluble ,heat stable compound.

0 Inhibits mycobacterial arabinosyl transferase.

0 Ethambutol accumulates in renal failure.

0 Crosses the blood brain barrier only if the meninges are inflamed.

0 Mutation to ethambutanol is due to mutation in overexpression of emb Gene products or with embB structral gene.

0 Resistance to ethambutol emerges rapidly if the drug is used alone.

CLINICAL USAGE

0 DOSAGE :-15-25mg/kg as a single dose.

0 Higher doses are recommended for tuberculos meningitis.

0 Dosage is 50 mg/kg when twice weekly schedule is followed.

0 Bacteriostatic.

PYRAZINAMIDE(Z)0 At neutral p H it is inactive invitro whereas at p H 5.5 it

inhibits tuberculi bacilli.

0 Drug acts against intracellular organism.

0 Drug is converted into PYRAZINOIC ACID ,active form of drug by pyrazinamidase.

0 Encoded by pncA.

0 Resistance is due to mutation in pncA Which impairs conversion of pyrazinamide in active form & impair its uptake.

0 Sterilizing agent.

CLINICAL USAGE

0 Half life is 8-11 hrs.

0 DOSAGE :- 50-70 mg/kg/d for twice / thrice weekly treatment regmens.

0 Bacteriocidal & bacteriostatic.

STREPTOMYCIN(S)0 Active mainly against extracellular.

0 Source: Streptomyces griseus.

0 First line Anti TB drug, given by injection

Pharmacokinetics:

0 Penetrates into cells poorly & ineffective for intracellular tubercle bacilli.

0 Crosses BBB & achieves therapeutic conc. if meninges are inflamed

MECHANISM OF ACTION0 Streptomycin binds to 12 S ribosomal sub unit.

Irreversible Inhibition of protein synthesis by:0 Interference with initiation complex of peptide formation.0 Misreading of code on mRNA --- incorporation of incorrect

Amino acid into the peptide chain , resulting in non-functional or toxic protein.

0 Inhibition of translocation.0 Break up of polysomes into non functional monosomes.0 These activities occur simultaneously & overall effect is

lethal for the cell

THIACETAZONE (Tzn)0 Bacteriostatic drug.

0 Does not add the therapeutic effect to the H,S& Z but delays resistance to these drugs.

0 Half life is 12 hrs.

0 Major adverse effect is hepatitis, exfoliative dermatitis, Stevens-Jonson syndrome.

0 Tzn is not used in HIV patients due to incidence of serious toxicity.

0 Dosage :- 150 mg/d in adults & 2.5mg/kg in children.

ETHIONAMIDE (Etm)0 Bacteriostatic drug.

0 Acts on both extra & intracellular organism.

0 Resistance to Etm develops rapidly.

0 Cross resistance with Tzm ia also seen.

0 Half life is 2-3 hrs.

0 Recommended dosage is 1g/d.

0 Anorexia , nausea & abdominal complaints are common.

CYCLOSERINE (Cys)0 Obtained from S.ORCHIDACEUS.

0 Inhibits bacterial wall synthesis.

0 Bacteriostatic drug.

0 Rarely used .

0 Dosage :- 250 mg /B.D if tolerated can be increased to 500 mg B.D

ANTITUBERCULAR DRUG REGIMEN

1. Standard regimens:

0 Anti-TB drugs are given as 2/3/4 drug combination regimens for different durations.

0 Combination regimen should include at least two drugs to which mycobacteria are sensitive.

0 The response to chemotherapy is slow so given for months to years.

Standard regimens: May be given in two phases. 1. Initial Intensive Phase for 2 months 2. Continuation Phase for 4 months

Initial Intensive Phase for 2 months: Therapy is initiated with 4 drug regimen .Isoniazid , Rifampin , Pyrazinamide & Ethambutol or

Streptomycin.–

Neither Ethambutol nor Streptomycin decreases the duration of the regimen, but they provide additional coverage for mycobacteria if isolate proves to be resistant to Isoniazid / Rifampin or to both

Continuation Phase for 4 months:

A few bacilli are left, only 2/ 3 drugs are enough.0Isoniazid and Rifampin 0Isoniazid , Rifampin , Pyrazinamide / Ethambutol 0Pyridoxine: 25 to 50mg/day, to minimize adverse reactions to isoniazid.Standard regimen may be given as DOTS

DOTS: Directly Observed Treatment Short Course. Recommended by WHO in 1995. For noncompliant patient

2. Alternative regimens:0 Alternative regimens for fully susceptible organisms include:

INH + Rifampin for 9 months0 INH + Ethambutol for 18 months. 0 Intermittent (2 or 3 x weekly) high dose 4 drug regimens are

also effective.

Drug Bactericidal/Bacteriostatic

Side Effects

Isoniazid Bactericidal to rapidly dividing bacteria and bacteriostatic to slowly dividing bacteria

Rash, abnormal liver function, anemia, peripheral neuropathy, mild CNS effects

Rifampicin Bactericidal Fever, immune reactions, GI irritation, liver damage, can cause tears and urine to turn red/orange

Streptomycin

Bactericidal Damage to the ears, nausea, rash, vomiting, vertigo

Ethambutol Bacteriostatic Decrease in visual acuity, colourblindness and other visual defects, joint pain, nausea, vomiting, fever, malaise, headache, dizziness

Fluoroquinolones

Bactericidal Tendon damage, heart problems, swelling of face and throat, shortness of breath, rash, loss of consciouness

Pyrazinamide

Bacteriostatic, Bactericidal

Joint pain, nauseau, vomiting, rash, malaise, fever, photosentivity

Drug-Resistant TB: Definitions

0Mono-resistant: Resistance to a single drug 0Poly-resistant: Resistance to more than one drug,

but not the combination of isoniazid and rifampicin0Multidrug-resistant (MDR): Resistance to at least

isoniazid and rifampicin 0Extensively drug-resistant (XDR): MDR plus

resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)

GROUPS OF DRUGS FOR MDRGroup 1:first-line oral agents

• pyrazinamide (Z)

• ethambutol (e)

• rifabutin (rfb)

Group 2:injectable agents

• kanamycin (Km)

• amikacin (Am)

• capreomycin (cm)

• streptomycin (S)

Group 3:fluoroquinolones• levofloxacin (lfx) • moxifloxacin (mfx) • ofloxacin (ofx)

Group 4:oral bacteriostatic second-line agents• para-aminosalicylic acid (pAS)• cycloserine (cs)• terizidone (Trd)• ethionamide (eto) • protionamide (pto)

GROUPS OF DRUGS FOR MDR

Group 5: Agents with unclear role in treatment of drug resistant-TB

• clofazimine (cfz)

• linezolid (lzd)

• amoxicillin/clavulanate (Amx/clv)

• thioacetazone (Thz)

• imipenem/cilastatin (ipm/cln)

• high-dose isoniazid (high-dose H)b

• clarithromycin (clr)

THANK YOU…THANK YOU…