• TUBERCULOSIS is an infectious disease caused by Mycobacteria; Mycobacterium tuberculosis & Mycobacterium bovis.

MODE OF TRANSMISSION Inhalation of droplets Ingestion --self swallowing of infected sputum/ or

ingestion of unpasteurised milk of infected cow Inoculation – of organism in to skin may occur

rarely from infected postmortem tissue.Transplacental – ie tuberculosis of foetus from

mother.

Macrophage with tubercle

bacilli

• Major portion of tubercle bacilli become intracellular(i.e reside in macrophage),so it is inaccessible for majority of antibiotics as they cannot penetrate easily in to the macrophage.

• It was once considered to be an incurable disease but now it is curable by a number of chemotherapeutic agents.

1st Line Essential drugs

Classification of anti TB drugs

1st Line supplemental

drugs

2nd Line drugs

Eg-RIFAMPICINISONIAZID

PYRIZINAMIDEETHAMBUTOL

(RIPE)

Eg-Rifabutin

Rifapentinstreptomycin

Eg-Fluroquinolones

AmikacinCapreomycinEthionamide

p-Aminosalicylicacid

Cycloserine(FACEPaC)

• 1st line essential drugs– most effective & basic components of anti tubercular treatment.

• 1st linesupplemental drugs– are quite effective & posseses an acceptable limit of toxicity. These are kept as reserved drugs & used in special settings.

• 2nd line drugs—these drugs are used if there is resistance to 1st line drugs or if 1st line drugs are contraindicated for some reason. These drugs are less effective & slightly more toxic than Ist line drugs(except Fluoroquinolones)

• NEWER DRUG UNDER INVESTIGATION--LINEZOLID

CATEGORY PATIENT TYPE DURATION OF TREATMENT

DRUG REGIMEN

CATEGORY 1 NEW UNTREATED SMEAR +VE PULMONARY T.B

6 MONTHS RIPE FOR 2 MONTHS , THEN R I FOR 4 MONTHS

CATEGORY 2 SMEAR +VE RETREATMENT GROUP(RELAPSEOR TREATMENT FAILURE)

8 MONTHS RIPE +STREPTOMYCIN FOR 2MONTHS;THENRIPE FOR 1 MONTH; THEN RIE FOR 5 MONTHS

CATEGORY 3 SMEAR –VE PULMONARY T.B OR LESS SEVERE EXTRAPULMONARY TB

6 MONTHS RIP FOR 2 MONTHS THEN R I FOR 4 MONTHS

Treatment of tuberculosis• One of the main reason for threrapeutic failure

has been patients poor compliancen after having symptomatic relief.

• WHO , therefore has recommended DOTS(Directly Observed Therapy for Short course) wherein the anti-TB drugs are given under direct supervision of medical professional 3 days a week.

• This helps to ensure the right drugs are taken at the right time for the full duration of treatment

• A Standardized recording and reporting

is maintained by health worker or medical professional. This helps to keep track of each individual patient and to monitor overall programme performance.

• T.B therapy normally begins with 4 1st line drugs: rifampicin + isoniazid + pyrizinamide + ethambutol for 2months followed by a course of isoniazid + rifampicin for next 4 months.

• Combination of drugs ensures prevention of resistance by mycobacteria

Individual drugs.

• INH is a pro drug & is converted into active form by bacterial enzyme catalase peroxidase.

• SITE OF ACTION– Both intracellular & extracellular ; also in casseous lesions.

• It is bactericidal to actively growing tubercle bacilli but not to dormant organisms which are only inhibited.

• It is active against mycobacterium tuberculosis & mycobacterium kansasii

Isonicotinic acid hydrazide

MECHANISM OF ACTION INH is converted to active form by catalaseperoxidase (produced by mycobacterium) .The active form inhibits mycolic acid in outer layer of cell wall. Also inhibits DNA, RNA & various oxidative enzymes.It is equally active in acidic & alkaline medium

ARABINOGLYCAN

INH(PRODRUG)

Catalase peroxidaseINH

(ACTIVE)

MYCOLIC ACID

SYNTHESIS INHIBITED

PEPTIDOGLYCAN

CELL MEMBRANE

Mycobaterium cell wall has the following layers viz. – mycosides, mycolic acid, arabinoglycan,

peptidoglycan.INH inhibits mycolic acid synthesis while ethambutol inhibit arabinoglycan layer

MECHANISM OF RESISTANCE

• Resistance to INH is due to mutation in CATALASE – PEROXIDASE GENE which is responsible for activation of INH.

• Another mechanism responsible for resistance is mutation in PROMOTER GENE , which is involved in mycolic acid biosynthesis

Pharmacokinetics • Absorption– well absorbed orally

• Distribution– readily distributed in pleural , peritoneal & synovial fluids.

CSF concentrations are reached up to 100% if meninges are inflammed.

• Metabolism – metabolised in liver by N –acetyl transferase

The rate of above reaction varies in different people i.e the reaction may be rapid or slow.

Accordingly people are classified as RAPID ACETYLATORS( rate of reaction is rapid forming acetyl INH eg.- 30-40% Indians, Japanese) & SLOW ACETYLATORS (rate of reaction is sloweg.-60-70% Indians, egyptians, jews,swedes).

Plasma half life– a)in rapid acetylators– T ½ = 1h

b)in slow acetylators– T ½ = 3h

INH N- acetyl transferase Acetyl INH Hepatotoxic

• The acetylator status of an individual may influence nature of INH toxicity but not the anti tubercular response(if INH is given once daily) because its plasma concentration normally remains above inhibitory concentration.

Peripheral neuritis --- commonly in slow acetylators because accumulated INH inhibits pyridoxine kinase which converts pyridoxine to its active form pyridoxylphosphate.

• Also INH increases excretion of pyridoxine in urine.

• This side effect can be prevented by giving vit-b6(pyridoxine) prohylactically in 10-40 mg / day.

• Hepatotoxicity --- common in fast acetylatorsbecause INH is metabolised in to acetyl INH which is hepatotoxic.

• Hepatotoxicity is a common side effect by INH in alcoholics, liver diseases & in people aged 50-65 years.

• The drug has to be discontinued at onset of symptoms like nausea, loss of apetite, abdominal pain, & on rise of amino transferase enzymes by 3 fold.

• Other side effects are allergic reactions like fever, rashes, & xerostomia , haematological changes & convulsions in seizure – prone patients, drug induced lupus erythematous.

Drug interactionsAluminium hydroxide inhibits absorption of INH.Alcohol increases risk of hepatitis. INH inhibits metabolism of phenytoin &

carbamazepine

• DOSAGE

In adult– 300mg O.D or 5mg/kg/day

For serious infections or meningitis – 600mg O.D

Duration of treatment is related to drug combination used.

RIFAMPICIN is a semisynthetic derivative of macrocyclic antibiotic Rifamycin

Anti microbial activity- bactericidal against both intracellular & extracellular tubercle bacilli. In addition , it is active against M.leprae, Staph.aureus, N meningitidis, H. influenza, Brucella, Legionella.

Mechanism of action of Rifampicin

Rifampicin inhibits bacterial DNA DEPENDENT RNA POLYMERASE.

Mammalian RNA polymerase is not inhibited , so RNA synthesis of host cells is not affected.

MECHANISM OF RESISTANCE

Resistance develops mutation in rpo B gene which prevents binding of rifampicin to RNA polymerase.

Hence if used alone resistance develops rapidly. It is a potent enzyme inducer

Pharmacokinetics

Absorption--well absorbed after oral administration

Distribution – it penetrates in all tissues , tubercular cavities, placenta. Adequate CSF levels are reached if meninges are inflammed.

It is significantly protein bound.

• Excretion – drug is excreted via bile & undergoes entero hepatic circulation.

ADVERSE EFFECTS• HEPATITIS is major side effect. It is dose

dependent & reversible. It is common in patients with underlying liver disease. Risk of hepatitis increses when used in combination with INH.

• Occasional side effects include FLU-LIKE SYNDROME characterised by fever chills , myalgias & thrombocytopenia,

• Rifampicin imparts RED ORANGE COLOR TO URINE.

DOSAGE

For T.B- 600mg(10mg/kg/day) as a single dose before breakfast.

For brucellosis – in combination with doxycycline(first choice combination)

For leprosy – in combination with dapsone

For prophylxis of meningitis caused by meningococcus—600mg B.D for 2 days.

For prophylxis of meningitis caused by H.influenza–600mg/day for 4 days.

Rifampicin can also be used for prosthetic valve endocarditis.

DRUG INTERACTIONS

Accelerates metabolism of oral contraceptives, anticoagulants, protease inhibitors used in HIV patients, which may result in therapeutic failure.

Ethambutol is a synthetic tuberculostatic drug active against M.tuberculosis, M.kamsasii & M.avium intracellulare.

MECHNISM OF ACTION

ETHAMBUTOL inhibits polymerisation of arabinoglycans of cell wall by inhibiting arabinosyl transferase

ARABINOGLYCAN

PEPTIDOGLYCAN

MYCOLIC ACIDS

CELL MEMBRANE

MECHANISM OF RESISTANCE

Resistance develops due to point mutations in emb B gene that encodes arabinosyltransferases enzyme involved in mycobacterialcell wall synthesis.

Pharmacokinetics

Bioavailability– 80%

Distribution– widely distributed in all body fluids including CSF

DOSAGE

Should not be used alone as resistance develops rapidly.

Usual daily dose is 800-1000mg orally (15mg/kg/day).

It can also be given in a dose of 1600mg/day

In the treatment of M.avium intracellulareinfection in AIDS patients– ethambutol is used in combination with rifabutin + clarithromycin.

Higher doses are needed to treat tuberculousmeningitis.

ADVERSE EFFECTS

Ethambutol if used in a dose of 25mg/kg/day for more than 9 days can cause RETROBULBAR NEURITIS IMPAIRING VISUAL ACTIVITY & RED – GREEN COLOR DISCRIMINATION.

This effect is dose related reverses slowly after discontinuing the drug.

Periodic visual activity testing is desirable during is desirable during treatment period.

• Ethambutol should be avoided in in children below 5 years where it is difficult to asses visual activity & red – green color discrimination.

• Ethambutol decreases renal excretion of urates & may precipitate gouty arthritis.

• Mild GIT intolerance , rashes, fever & dizziness are also possible.

Pyrazinamide(PZA) • It is pyrazine derivative of nicotinamide.

• Because of its hepatotoxicity its use had declined earlier.

• But recently pyrizinamide in reduced doses & in combination re emerged as 3rd most important anti tuberculosis agent.

o It is bactericidal to M.tuberculosis & is active only at low pH only.

o It is highly effective only on intracellular mycobacteria(due to acidic environment intracellularly in macrophages)

MECHNISM OF ACTION

PZA is thought to enter enter M.tuberculosis by passive diffusion & is converted to pyrizinoicacid (its active metabolite) by bacterial enzyme pyrizinamidase enzyme.

The active metabolite then inhibits mycobacterial fatty acid synthase 1 enzyme & disrupts mycolic acid synthesis needed for cell wall synthesis.

ARABINOGLYCAN

PZA

pyrizinamidasepyrizinoic

acid

MYCOLIC ACID

SYNTHESIS INHIBITED

PEPTIDOGLYCAN

CELL MEMBRANE

• Mechanism of resistance

A mutation in the gene (pnc A) that encodes pyrizinamidase is responsible for drug resistance which can be minimised by drug combination therapy.

Pharmacokinetics

Absorption– well absorbed orally

Distribution– widely diustributed in all tissues, macrophages, tubercular cavities & in meningitis.

Plasma half life– 9-10hrs.

Streptomycin • It is the first antitubercular drug.

• It is bactericidal but because of poor penetration it acts only on extracellular tubercular bacilli.

• It is also active against M.kansasii & M.aviumintracellulare.

• It is less effective than INH or Rifampicin

Pharmacokinetics

Route of administration– I.M , cant be given orally as it is highly polar

• Distribution – poorly distributed , do not penetrate most cellular compartments.

• Metabolism -- as they do not penetrate most cellular compartments , they do not undergo significant metabolism.

• Excretion- nearly all of the drug is cleared by kidneys as they do not undergo significant metabolism.

• Plasma half life– 1.5 – 3 hrs(24-48 hrs in renal insufficiency)

Mechanism of action

The mechanism of action of streptomycin is inhibition of protein synthesis of mycobacteria in the ribosome

Mechanism of resistance

Spontaneous resistance to streptomycin is related to point mutation of the genes –rpsl or rrs that encode for ribosomal proteins & ribosomal tRNArespectively.

Dosage

1000mg/day I.M (15mg/kg/day)

Should be reduced to 500-750mg in elderly & in renal insufficiency.

• Even for thrice a week dose schedule the dose structure remains the same.

Adverse effects– nephrotoxicity & ototoxicity.

IT IS a structural analogue of rifampicin.

It shares with rifampicin a common mechanism of action , common spectrum of activity , aginst gram positive & negative organisms, common molecular basis for development of resistance.

RIFABUTIN

• Hence there is cross resistance between rifabutin & rifampicin.

• But rifampicin has better activity against M.avium complex(MAC) .it is active against rifampicin resistant strains such as M.leprae & M.fortuitum. It has longer plasma half life.(45hrs)

• It is used either alone or in combination with pyrizinamide in the treatment of latent tubercular infection.

• It can be used in place of rifampicin for the treatmen of tuberculosis in HIV infected patients.

• Most important use of rifabutin is in HIV infected population for prevention & treatment of disseminated MAC.

Dosage

300mg/day(5mg/kg/day)

Adverse effects– red orange color urine, skin rash, hepatitis, neutropenia,

Drug interactions—

• May decrease plasma conc. Of theophylline, oarl anti coagulants, protease inhibitors & non nucleoside reverse transcriptase inhibitors (but less than rifampicin).

• Fluconazole increases plasma concentration of rifabutin resulting in pseudojaundice & polymyalgia syndrome.

RIFAPENTINE• Longer acting analogue of rifampicin(T ½ =13-

15hrs ).

• Its mechanism of action , cross resistance, enzyme inducion, toxic profile & clinical use is identical to rifampicin.

• It is not used alone but in 3-4 drug combination regimen.

• Drug interactions are lower than rifampicinbut greater than rifabutin

• Dosage– 600mg once or twice weekly

Fluoroquinolones• Specially used in multidrug resistant strains.

• Very effective when used as a part of combined regimen in HIV infected patients.

• Ciprofloxacin, ofloxacin, levofloxacin & moxifloxacin inhibit 90 – 95% of strains of tubercle bacilli including MAC & M.fortuitum.

• They kill intracellular pathogens because of good penetration.

• These can be substitued in drug combinations if any Ist line drugs are contraindicated.

Dosage-

Ciprofloxacin– 750mg BD or 500mg TDS

Ofloxacin– 400mg BD

Levofloxacin500mg OD (preferred over ofloxacin because of once daily dose schedule)

Moxifloxacin—400mg OD recent studies suggest use of moxifloxacin with other drugs reduces duration of therapy for drug susceptible tuberculosis.

Amikacin• It is an aminoglycoside antibiotic.

• It is 2nd choice after streptomycin & capreomycin for multi drug resistant tuberculosis.

• Most M.tuberculosis strains are that are resistant to streptomycin are sensitive to amikacin.

• It is also used in disseminated MAC

• Dose– 15mg/kg/day IM or IV for 5 days a week for 2 months. Then 1g/day thrice weekly for another 4 months.

Capreomycin

• It is tuberculocidal polypeptiode antibiotic.

• Effective against M.tuberculosis, M. kansassi, M.avium .

• It is poorly absorbed from GIT , so should be given parenterally( 1g/day IM).

• Side effects- ototoxicity & nephrotoxicity

• Rarely used tuberculostatic drug.

• It is hepatotoxic, neurotoxic & produces intense gastric irritation.

• It blocks mycolic acid synthesis.

PARA-AMINO SALICYLIC ACID

It is a structural analogue of PABA.

Acts by inhibiting folate synthesis of bacteria.

Disadvantages – poor compliance due to GIT intolerance, hypersensitivity reactions like skin rash, lupus like reactions, drug fever , joint pain, hepatitis

Dose- 8-12g/ day in 2 or 3 divided doses

Cycloserine

• It is tuberculostatic drug.

• It is excreted unchanged in urine so it is used for renal tuberculosis.

• Also Used in multi drug resistant tuberculosis

• Dose- 500 mh BD

• Side effects- psychotic behavioural changes , dizziness, peripheral neuropathy

NEWER ANTI TUBERCULAR DRUGS

LINEZOLID it is an antibiotic with 100% oral bioavailability

VERY effective against drug susceptible & drug resistant strains.

Adverse effects on prolonged use (which becomes necessary for treatment of tuberculosis) may limit its usefulness.

Adverse effects– reversible bone marrow suppresion, peripheral neuropathy.

Dose- 600mg OD

R-207910• it is di aryl quinoline derivative developed in

year 2004 & completed phase II trials.

• It inhibits proton pump for ATP synthase of M. tuberculosis.

• It remarkably shortens duration of treatment to 2 months or less.

• It is not yet available in the market.