TUBERCULOSIS

Definition According to W.H.O,Tuberculosis, or

TB, is an infectious bacterial disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs. It is transmitted from person to person via droplets from the throat and lungs of people with the active respiratory disease.

Classification

First line drugs 1. Isoniazid (H) 2.Rifampin (R) 3.Ethambutol (E) 4.Streptomycin (S) 5.Pyrazinamide (P) Second line drugs 1.Ethionamide (Eto) 2.Prothionamide (Pto) 3.Cycloserine (Cs) 4.Terizidone (Trd) 5.Para-aminosalicylic acid (PAS) 6.Rifabutin 7.Thiacetazone (Thz)

Fluoroquinolones1.Ofloxacin (Ofx)2.Levofloxacin (Lvx/Lfx)3.Moxifloxacin (Mfx)4.Ciprofloxacin (Cfx)Injectable drugs1.Kanamycin (Km)2.Amikacin (Am)3.Capreomycin (Cm)

Group I First line oral anti-TB drugs Isoniazid(INH),Rifampin, Pyrazinamide,Ethambutol

Group II Injectable anti-TB drugs Streptomycin,Kanamycin, Amikacin,Capreomycin

Group III Fluoroquinolones Ofloxacin,Levofloxacin, Moxifloxacin,Ciprofloxacin

Group IV Second line oral anti-TB drugs

Ethionamide,Prothionamide,Cycloserine,Terizidone,Para-aminosalicylic acid

Group V Drugs with unclear efficacy Thiacetazone,Clarithromycin,Clofazimine,Linezolid,Amoxicillin/Clavulanate,Imipenem/Cilastatin

Alternative grouping of antitubercular drugs

Pathophysiology•Infection with TB requires inhalation of droplet nuclei. • Following deposition in the alveoli, M tuberculosis is engulfed by alveolar macrophages, but survives and multiplies within the macrophages•. Proliferating bacilli kill macrophages and are released; this event produces a response from the immune system. •Exposure may lead to clearance of M tuberculosis, persistent latent infection, or progression to primary disease.•Successful containment of TB is dependent on the cellular immune system, mediated primarily through T-helper cells (TH1 response). •T cells and macrophages form a granuloma with a centre that contains necrotic material (caseous centre), M tuberculosis, and peripheral granulation tissue consisting primarily of macrophages and lymphocytes; the granuloma serves to prevent further growth and spread of M tuberculosis.

• These individuals are non-infectious and have latent TB infection; the majority of these patients will have a normal CXR and be tuberculin skin test (TST)-positive.

Approximately 10% of individuals with latent infection will progress to active disease over their lifetime.

The risk is greatest within the 2 years following initial acquisition of M tuberculosis.

A number of conditions can alter this risk, particularly HIV infection, in which the annual risk of developing active TB is 8% to 10%.

Immunocompromised conditions and treatment with immunosuppressing medicines, including systemic corticosteroids and TNF-alpha antagonists, also contribute to re-activation.

Common Symptoms of TB DiseaseCough (2-3 weeks or more)Coughing up bloodChest painsFeverNight sweatsFeeling weak and tiredLosing weight without trying Decreased or no appetiteIf you have TB outside the lungs, you

may have other symptoms

Isoniazid (Isonicotinic acid hydrazide, H)Isoniazid is an excellent

antitubercular drug.It is primarily tuberculocidal.It acts on extracellular as well as

on intracellular TB(bacilli present with in macrophages)

Equally active in acidic or alkaline medium.

Cheapest anti-TB drug.

Mechanism of action of Isoniazid•The primary mechanism of action of Isoniazid is inhibition of synthesis of myocolic acids which are unique fatty acid components of mycobacterial cell wall.•This may explain the high selectiviy of INH for mycobacteria.•The lipid content of mycobacteria exposed to INH is reduced.•Two gene products labelled ‘InhA’ and ‘KasA’,which function in mycolic acid synthesis are the targets of INH action.•INH enters sensitive mycobacteria which convert it by a catalase-peroxidase enzyme into a reactive metabolite.•This then forms adduct with NADP as well whichinhibits mycobacterial DHFRase resulting in interruption of DNA synthesis.

Isoniazid Resistance

The incidence of primary INH resistance varies widely among different populations, depending on the extent of use and misuse of INH in that area.

According to WHO, the global weighted mean of any INH resistance among new TB patients is 7.4%.

In India resistance to INH alone or in combination with other anti-TB drugs is estimated to be 18%.

Combined with other drugs,INH has good resistance preventing action.

No cross resistance with other antitubercular drugs occurs.

Pharmacokinetics of Isoniazid INH is completely absorbed orally and penetrates all body

tissues, tubercular cavities,placenta and meninges. It is extensively metabolizd in liver; most important

pathway being N-acetylation by NAT2. The acetylated metabolite is excreted in urine. The rate of INH acetylation shows genetic variation. There are either; Fast acetylators(30-40% of Indians) INH half life ; 1hr. Slow acetylators(60-70% of Indians)INH half life ;3hr.• Acetylator status does not matter if INH is taken daily,but

biweekly regimen are less effective in fast acetylators .• INH induced peripheral neuritis is more common in slow

acetylators.

Interactions with Isoniazid

Aluminium hydroxide inhibits INH absorptionINH retards phenytoin, carbamazepine, diazepam, theophylline and warfarin

metabolism by inhibiting CYP2C19 and CYP3A4,and may raise their blood levels.

Since Rifampin is an enzyme inducer,its concurrent use counteracts the inhibitory effect of INH.

However,the net effect on metabolism of many drugs is unpredictable.

PAS inhibits INH metabolism and prologs its half life.

Adverse effects of IsoniazidPeripheral neuritis and a variety of

neurological manifestations are the most important dose-dependent toxic effects.

INH neurotoxicity is treated by pyridoxine 100mg/day.

Hepatitis is major adverse effect of Isoniazid.

LethargyRashes.Fever acne.Arthralgia.

RifampinIt is a semisynthetic derivative of rifamycin

B obtained from Streptomyces mediterranei.

Rifampin is bactericidal to M.tuberculosis and many other gram positive and gram negative bacteria like Staph. aureus,E.coli.,

H.influenzae etc.• The bactericidal action covers all the

subpopulations of TB bacilli,but acts best on slowly or intermittently dividing ones.

• It has good sterlising and resistance preventing actions.

Mechanism of action of RifampinRifampin interrupts RNA

synthesis by binding to beta subunit of mycobacterial DNA-dependent RNA polymerase encoded by rpoB gene and blocking its polymerizing function

The basis of selective toxicity is that mammalian RNA polymerase does not avidly bind rifampin

Rifampin resistance

Mycobacteria and other organisms develop resistance to rifampin rather rapidly.

Rifampin resistance is nearly always due to mutation in rpoB gene reducing its affinity for the drug.

No cross resistance with any other antitubercular drug,except rifampin congeners,has been noted.

Pharmacokinetics of Rifampin•It is well absorbed orally ( bioavailability is about 70%),but food decreases absorption;rifampin is to be taken empty stomach.•It is widely distributed in the body:penetrates intracellularly,enters tubercular cavities,caseous masses and placenta.•Though it crosses meninges,it is largely pumped out from CNS by P-glycoprotein.•It is metabolized in liver to an active deacetylated metabolite which is excreted mainly in bile,some in urine also.•Rifampin and its desacetyl derivative undergo entero-hepatic circulation.•The half life of rifampin is variable (2-5hours).

•Rifampin is a microsomal enzyme inducer-increases severalCYP3A4, CYP2D6,CYP1A2 and CYP2C subfamily.•It thus enhances its own metabolism as well as that of many drugs including warfarin, oral contraceptives, corticosteroids, sulfonyl ureas, steroids, HIV protease inhibitors, non nucleoside reverse transcriptase inhibitors(NNRTIs), theophylline,metaprolol,fluconazol, ketoconazole, clarithromycin, phenytoin etc.•Contraceptive failures have occurred.•It is advisable to switch over to an oral contraceptive containing higher dose (50 microgram) of•Estrogen or use alternative method of contraception.

Interactions with rifampin

Adverse effects of Rifampin

•Hepatitis ,a major adverse effect, generally occurs in patients with preexisting liver disease and is dose related; infrequent with ≤ 600mg/day dose.•Development of jaundice requires discontinuation of the drug-then it is reversible.•Minor reactions, usually not requiring drug withdrawal and more common with intermittent regimens, are:oCutaneous syndrome: flushing, pruritus + rash (especially on face and scalp),redness and watering of eyes.oFlu syndrome: with chills ,fever, headache, malaise and bone pain.oAbdominal syndrome :nausea, vomiting, abdominal cramp with or without diarrhoea.Urine and secretions may become orange-red—but this is harmless.Other serious but rare reactions are:oRespiratory syndrome: breathlessness which may be associated with shock and collapse.oPurpura, haemolysis, shock and renal failure.

Pyrazinamide

Chemically similar to INH, pyrazinamid (Z) was developed parallel to it in 1952.

It is weakly tuberculocidal and more active in acidic medium.

It is more lethal to intracellularly located bacilli and to those at sites showing an inflammatory response (pH is acidic at both these locations ).

It is highly effective during first to months of therapy when inflammatory changes are present.

By killing the residual intracellular bacilli it has good sterilizing activity.

Its inclusion has enabled duration of treatment to be shortened and risk of relapse is reduced.

Mechanism of action of Pyrazinamide

The mechanism of action of Z is not well established, but unlike INH it is also converted inside the mycobacterial cell into an active metabolite pyrazinoic acid by an enzyme (pyrazinamidase) encoded by pncA gene.

This metabolite gets accumulated in acidic medium and probably inhibits mycolic acid synthesis, but by interacting with a different fatty acid synthase.

Pyrazinoic acid also appears to disrupt mycobacterial cell membrane and its transport function

Pyrazinamide resistance

•Resistance to Pyrazinamide develops rapidly if it is used alone and is mostly due to mutation in pncA gene.

•Pyrazinamide is absorbed orally, widely distributed, has good penetration in CSF, because of which it is highly useful in meningeal TB; extensively metabolized in liver and excreted ion urine; plasma t½ is 6-10 hours.

Pharmacokinetics of Pyrazinamide

Hepatotoxicity is the most important dose-related adverse effect, but it appears to be less common in Indian population than in western countries.

Hyperuricaemia is common aid is due to inhibition of uric acid secretion in kidneys; gout can occur.

Other adverse effects are abdominal distress, arthralgia, flushing, rashes, fever and loss of diabetes control: repeated blood glucose monitoring is warranted in diabetics.

Adverse effects of Pyrazinamite

Ethambutol (E)

Ethambutol is selectively tuberculostatic and is active against MAC as well as some other mycobacteria, but not other types of bacteria.

Fast multiplying bacilli are more susceptible.

Added to the triple drug regimen of RHZ it has been found to hasten the rate of sputum conversion and to prevent development of resistance , the latter being the primary purpose of using it.

Mechanism of action of EthambutolThe mechanism of action of E is not fully

understood, but it has been found to inhibit arabinosyl tranferases (encoded by embAB genes) involved in arabinogalactan synthesis thereby interfering with mycolic acid incorporation in mycobacterial cell wall.

Resistance to E develops slowly and is most commonly associated with mutation in embB gene, reducing the affinity of the target enzyme for E.

No cross resistance with any other antitubercular drug has been noted.

Pharamacokinetics of EthambutolAbout ¾ of an oral dose of E is

absorbed.It is distributed widely, but penetrates

meninges incompletely and is temporarily stored in RBCs.

Less than½ of E is metabolized.It is excreted in urine by glomerular

filtration and tubular secretion; plasma t½ is ~4 hrs.

Caution is required in its use in patients with renal disease.

Adverse effects of Ethambutol Patient acceptability of E is very good and side

effects are few. Loss of visual acuity/colour vision, field defects due

to optic neuritis is the most important dose and duration of therapy dependent toxicity.

With early recognition and stoppage of the drug, visual toxicity is largely reversible.

It is contraindicated in patients with optic neuritis. Ethambutol produces few other symptoms: nausea,

rashes, fever, rarely peripheral neuritis. Hyperuricemia is due to interference with urate

excretion. It is safe during pregnancy. Ethambutol is used in MAC infection as well

Streptomycin

It was first clinically useful antitubercular drug.

It is tuberculocidal but less effective than INH or rifampin; acts only on extracellular bacilli.

Thus, other drugs and host defense mechanisms are needed to eradicate the disease.

It penetrates tubercular cavities,but does not cross CSF, and has poor action in acidic medium.

Streptomycin resistance

•Resistance developed rapidly when streptomycin was used alone in tuberculosis-most patients had a relapse.•Recent studies indicate worldwide increase in resistance to streptomycin.•In case if streptomycin resistance infection, it must be stopped at the earliest because of risk of streptomycin dependence in which case the infection flourishes when the drug is continued.•Most nontubercular mycobacteria are unaffected by streptomycin.

Streptomycin use

•Because of need for i.m. injections and lower margin of safety (ototoxicity and nephrotoxicity, especially in the elderly and those with impaired renal function) streptomycin is used only as an alternative to or in addition to other first line anti-TB drugs•Use is restricted to maximum of 2 months.•It is thus also labelled as a ‘supplemental’ first line drug.

Category & type of Patient

Duration of Treatment Drug Regimen

Category I New untreated smear

positive pulmonary T.B New (untreated)smear

negative pulmonary T.B but seriously ill

For all such cases intensive phase :- (2 months) followed by continuation phase (4 months)Total 6 months

INH+RMP+PZA+ETBINH+RMP

Category IISmear positive retreatment group due to Treatment failure Relapse/default

For all such intensive phase (2+1=3 months) followed byContinuation phase (5 months)Total 8 months

2months:-INH+RMP+PZA+ETB+SM1 month:-INH+RMP+PZA+ETBINH+RMP+ETB

Category III New (untreated)smear

negative pulmonary T.B but not seriously ill

Less severe cases of extra pulmonary T.B

For all such intensive phase(2 months)Followed by Continuation phase (4 months)Total 6 months

INH+RMP+PZAINH+RMP

*All drugs are given thrice weekly under DOT scheme Key:- INH-Isoniazid , RMP-Rifampin , PZA-Pyrazinamide , ETB-Ethambutol , SM-Streptomycin