Antitubercular Drugs

ANTITUBERCULAR DRUGS

Tuberculosis is a chronic granulomatous disease and a major health problem in developing countries. About 1/3rd of the world’s population is infected with Mycobact. tuberculosis. As per WHO estimate, 9 million people globally develop active TB and 1.7 million die of it annually. In India, it is estimated that nearly 2 million people develop active disease every year and about 0.5 million die from it.

A new dimension got added in the 1980s due to spread of HIV with high prevalence of tuberculosis and Mycobact. avium complex (MAC) infection among these patients. India has a large load of HIV infected subjects, and these patients are especially vulnerable to severe forms of tubercular/MAC infection. While lately, the increase in TB case rate associated with HIV infection has been halted in the USA, no such trend is apparent in India. Emergence of ‘multidrug resistant’ (MDR) TB of which over 0.4 million cases are occurring globally every year, is threatening the whole future of current antitubercular chemotherapy.

Remarkable progress has been made in the last 60 years since the introduction of Streptomycin in 1947 for the treatment of tuberculosis. Its full therapeutic potential could be utilized only after 1952 when isoniazid was produced to accompany it. The discovery of ethambutol in 1961, rifampin in 1962, and redefinition of the role of pyrazinamide has changed the strategies in the chemotherapy of tuberculosis. Since 1970 the efficacy of short course (6–9 months) and domiciliary regimens has been demonstrated and clearcut treatment guidelines have been formulated.

Fluoroquinolones, newer macrolides and some rifampin congeners are the recent additions to the antimycobacterial drugs. According to their clinical utility the antiTB drugs can be divided into:

First line: These drugs have high antitubercular efficacy as well as low toxicity; are used routinely.

Second line: These drugs have either low antitubercular efficacy or high toxicity or both; are used in special circumstances only.

First Line Drugs

1. Isoniazid (H)

2. Rifampin (R)

3. Pyrazinamide (Z)

4. Ethambutol (E)

5. Streptomycin (S)

Second Line Drugs

1. Thiacetazone (Tzn)

2. Paraaminosalicylic acid (PAS)

3. Ethionamide (Etm)

4. Cycloserine (Cys)

5. Kanamycin (Kmc)

6. Amikacin (Am)

7. Capreomycin (Cpr)

Newer Drugs

1. Ciprofloxacin

2. Ofloxacin

3. Clarithromycin

4. Azithromycin

5. Rifabutin

Isoniazid (Isonicotinic acid hydrazide, H)

Isoniazid is the antitubercular drug parexcellence, and an essential component of all antitubercular regimens, unless the patient is not able to tolerate it or bacilli are resistant. It is primarily tuberculocidal. Fast multiplying organisms are rapidly killed, but quiescent ones are only inhibited. It acts on extracellular as well as on intracellular TB (bacilli present within macrophages); is equally active in acidic and alkaline medium. It is one of the cheapest antitubercular drugs. However, most atypical mycobacteria are not inhibited by INH.

The most plausible mechanism of action of INH is inhibition of synthesis of mycolic acids which are unique fatty acid component of mycobacterial cell wall. This may explain the high selectivity of INH for mycobacteria (it is not active against any other microorganism). The lipid content of mycobacteria exposed to INH is reduced. A gene labelled inh A which encodes for a fatty acid synthase enzyme is the target of INH action. The sensitive mycobacteria concentrate INH and convert it by a catalase-peroxidase enzyme into an active metabolite that interacts with the inh A gene.

About 1 in 106 tubercle bacilli is inherently resistant to clinically attained INH concentrations. If INH is given alone, such bacilli proliferate selectively and after 2–3 months (sometimes even earlier) an apparently resistant infection emerges. The most common mechanism of INH resistance is by mutation of the catalase-peroxidase gene so that the bacilli do not generate the active metabolite of INH. However, bacilli that lose catalase activity also appear to become less virulent; many physicians like to continue INH even when bacilli are apparently resistant to it in vitro. INH resistance may also involve mutation in the target inh A gene. Other resistant TB bacilli lose the active INH concentrating process. The incidence of primary INH resistance varies widely (1–33%) among different populations, depending on the extent of use and misuse of INH in that area. Combined with other drugs, INH has good resistance preventing action. No cross resistance with other antitubercular drugs occurs.

Pharmacokinetics

INH is completely absorbed orally and penetrates all body tissues, tubercular cavities, placenta and meninges. It is extensively metabolized in liver; most important pathway being acetylation—metabolites are excreted in urine. The rate of INH acetylation shows genetic variation. There are either:

Fast acetylators

(30–40% of Indians)       t½ of INH 1 hr.

Slow acetylators

(60–70% of Indians)       t½ of INH 3 hr.

The proportion of fast and slow acetylators differs in different parts of the world. However, acetylator status does not matter if INH is taken daily, but biweekly regimens are less effective in fast acetylators. Isoniazid induced peripheral neuritis appears to be more common in slow acetylators.

Interactions Aluminium hydroxide inhibits INH absorption.

INH inhibits phenytoin, carbamazepine, diazepam and warfarin metabolism: may raise their blood levels.

PAS inhibits INH metabolism and prolongs its t½.

Dose of all first line drugs is given in Table 55.1.

Adverse Effects INH is well tolerated by most patients. Peripheral neuritis and a variety of neurological manifestations (paresthesias, numbness, mental disturbances, rarely convulsions) are the most important dose-dependent toxic effects. These are due to interference with utilization of pyridoxine and its increased excretion in urine (see Ch. No. 67). Pyridoxine given prophylactically (10 mg/day) prevents the neurotoxicity even with higher doses, but routine use is not mandatory. INH neurotoxicity is treated by pyridoxine 100 mg/day.

Hepatitis, a major adverse effect of INH, is rare in children, but more common in older people and in alcoholics. It is due to dose-related damage to liver cells and is reversible on stopping the drug.

Other side effects are rashes, fever, acne and arthralgia.

ISONEX 100, 300 mg tabs, ISOKIN 100 mg tab, 100 mg per 5 ml liq.

Rifampin (Rifampicin, R)

It 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, N. meningitidis, H. influenzae, E.coli, Klebsiella, Pseudomonas, Proteus and Legionella. Against TB bacilli, it is as efficacious as INH and better than all other drugs. The bactericidal action covers all subpopulations of TB bacilli, but acts best on slowly or intermittently (spurters) dividing ones, as well as on many atypical mycobacteria. Both extra and intracellular organisms are affected. It has good sterilizing and resistance preventing actions.

Rifampin inhibits DNA dependent RNA synthesis. Probably, the basis of selective toxicity is that mammalian RNA polymerase does not avidly bind rifampin.

Mycobacteria and other organisms develop resistance to rifampin rather rapidly. However, the incidence of resistant TB is less than 10–7 and it is quite unusual for a patient to have primary rifampin resistant tubercular infection. Rifampin resistance is nearly always due to mutation in the repoB gene (for the β subunit of RNA polymerase—the target of rifampin action) reducing its affinity for the drug. No cross resistance with any other antitubercular drug has been noted.

Pharmacokinetics

It is well absorbed orally, widely distributed in the body: penetrates cavities, caseous masses, placenta and meninges. 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 enterohepatic circulation. The t½ of rifampin is variable (2–5 hours).

Interactions

Rifampin is a microsomal enzyme inducer—increases several CYP450 isoenzymes, including CYP3A4, CYP2D6, CYP1A2 and CYP2C subfamily. It thus enhances its own metabolism as well as that of many drugs including warfarin, oral contraceptives, corticosteroids, sulfonylureas, digitoxin, steroids, HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors (NNRTIs), theophylline, metoprolol, fluconazole, ketoconazole, etc. Contraceptive failures have occurred: switch over to an oral contraceptive containing higher dose (50 μg) of estrogen or use alternative method of contraception.

Adverse Effects

The incidence of adverse effects is similar to INH.

Hepatitis, a major adverse effect, generally occurs in patients with preexisting liver disease and is doserelated: development of jaundice requires discontinuation of the drug—then it is reversible. Other serious but rare reactions are:

·    ‘Respiratory syndrome’: breathlessness which may be associated with shock and collapse.

·          Purpura, haemolysis, shock and renal failure. Minor reactions usually not requiring drug withdrawal and more common with intermittent regimens are:

·          ‘Cutaneous syndrome’: flushing, pruritus + rash (especially on face and scalp), redness and watering of eyes.

·          ‘Flu syndrome’: with chills, fever, headache, malaise and bone pain.

·    ‘Abdominal syndrome’: nausea, vomiting, abdominal cramps with or without diarrhoea.

Urine and secretions may become orange-red— but this is harmless.

Other Uses Of Rifampin

·          Leprosy (see Ch. No. 56)

·      Prophylaxis of Meningococcal and H. influenzae meningitis and carrier state.

·  Second/third choice drug for MRSA, diphtheroids and Legionella infections.

·   Combination of doxycycline and rifampin is the first line therapy of brucellosis.

RCIN 150, 300, 450, 600 mg caps, 100 mg/5 ml susp. RIMACTANE, RIMPIN 150, 300, 450 mg caps, 100 mg/ 5 ml syr.; RIFAMYCIN 450 mg cap, ZUCOX 300, 450, 600 mg tabs; to be taken 1 hour before or 2 hour after meals.

Pyrazinamide (Z)

Chemically similar to INH, pyrazinamide (Z) was developed parallel to it in 1952. It is weakly tuberculocidal but 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 the first 2 months of therapy when inflammatory changes are present. By killing the residual intracellular bacilli it has good ‘sterilizing’ activity. Its use has enabled regimens to be shortened and risk of relapse to be reduced. Mechanism of antimycobacterial action of Z resembles INH; it inhibits mycolic acid synthesis, but by interacting with a different fatty acid synthase encoding gene. Resistance to Z develops rapidly if it is used alone, and is due to mutation in the pncA gene which encodes for the enzyme generating the active metabolite of Z.

Pyrazinamide is absorbed orally, widely distributed, has good penetration in CSF, extensively metabolized in liver and excreted in urine; plasma t½ is 6–10 hours.

Hepatotoxicity is the most important doserelated adverse effect, but it appears to be less

common in the Indian population than in western countries. Daily dose is now limited to 25–30 mg/ kg which produces only a low incidence of hepatotoxicity. It is contraindicated in patients with liver disease.

Hyperuricaemia is common and is due to inhibition of uric acid secretion in kidney: gout can occur.

Other adverse effects are arthralgia, flushing, rashes, fever and loss of diabetes control.

PYZINA 0.5, 0.75, 1.0 g tabs, 0.3 g kid tab; PZACIBA 0.5, 0.75 g tabs, 250 mg/5 ml syr; RIZAP 0.75, 1.0 g tabs.

Ethambutol (E)

Ethambutol is selectively tuberculostatic and clinically as active as S. Fast multiplying bacilli are more susceptible as are many atypical mycobacteria. 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 mechanism of action of E is not fully understood, but it has been found to inhibit arabinosyl transferases involved in arabinogalactan synthesis and to interfere with mycolic acid incorporation in mycobacterial cell wall. Resistance to E develops slowly; in many cases it is due to alteration in the drug target gene. No cross resistance with any other antitubercular drug has been noted.

About 3/4 of an oral dose of E is absorbed. It is distributed widely but penetrates meninges incompletely and is temporarily stored in RBCs. Less than ½ 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.

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. Because young children may be unable to report early visual impairment, it should not be used below 6 years of age. With early recognition and stoppage of therapy, visual

toxicity is largely reversible. Ethambutol produces few other symptoms: nausea, rashes, fever, neurological changes are infrequent. Hyperuricemia is due to interference with urate excretion. It is a commonly used antitubercular drug.

MYCOBUTOL, MYAMBUTOL, COMBUTOL 0.2, 0.4, 0.6, 0.8, 1.0 g tabs.

Streptomycin (S)

The pharmacology of streptomycin is described in Ch. No. 53. It was the first clinically useful antitubercular drug. It is tuberculocidal, but less effective than INH or rifampin; acts only on extracellular bacilli (because of poor penetration into cells). Thus, host defence mechanisms are needed to eradicate the disease. It penetrates tubercular cavities, but does not cross to the CSF, and has poor action in acidic medium.

Resistance developed rapidly when streptomycin was used alone in tuberculosis—most patients had a relapse. In an average population of TB, 1 in 108 to 1 in 106 bacillus is resistant to S; these bacilli selectively multiply and stage a comeback after initial control. In case of S-resistant infection, it must be stopped at the earliest because of chances of S-dependence—the infection flourishing when the drug is continued. Most atypical mycobacteria are unaffected by S.

Popularity of S in the treatment of tuberculosis had declined due to need for i.m. injections and lower margin of safety, because of ototoxicity and nephrotoxicity, especially in the elderly and in those with impaired renal function.

Thiacetazone  (Tzn,  Amithiozone)

Thiosemicarbazones were the first antitubercular drugs tested, but were weak. Domagk studied their action. Thiacetazone was found to be the best out of many derivatives. It was tried in the west, found to be hepatotoxic and discarded. In India, interest in Tzn was revived in the 1960s for oral use along with INH as a substitute for PAS. Though, its importance has declined, it continues to be used as a convenient low cost drug to prevent emergence of resistance to INH and more active agents.

Thiacetazone is a tuberculostatic, low efficacy drug; does not add to the therapeutic effect of H, S or E, but delays resistance to these drugs. It is orally active, and primarily excreted unchanged in urine with a t½ of 12 hr.

The major adverse effects of Tzn are hepatitis, exfoliative dermatitis, Stevens-Johnson syndrome and rarely bone marrow depression. The common side effects are anorexia, abdominal discomfort, loose motions and minor rashes. A mild anaemia persists till Tzn is given. Tzn is a reserve anti-TB drug, sometimes added to INH in alternative regimens. It should not be used in HIV positive cases, because incidence of serious toxicity is higher.

Dose: 150 mg OD in adults, 2.5 mg/kg in children. It is frequently used as combined tablet with isoniazid.

Paraamino salicylic acid (PAS)

Introduced in 1946, it is related to sulfonamides— chemically as well as in mechanism of action. It is not active against other bacteria: selectivity may be due to difference in the affinity of folate synthase of TB and other bacteria for PAS.

PAS is tuberculostatic and one of the least active drugs: does not add to the efficacy of more active drugs that are given with it; only delays development of resistance— probably, by directly inhibiting episomal resistance transfer. Resistance to PAS is slow to develop. It is used as the sodium salt (large doses that are needed may cause Na+ overload) or calcium salt (better gastric tolerance is claimed).

PAS is absorbed completely by the oral route and distributed all over except in CSF. About 50% PAS is acetylated; competes with acetylation of INH—prolongs its t½. PAS formulations interfere with absorption of rifampin. It is excreted rapidly by glomerular filtration and tubular secretion; t½ is short, ~1 hour.

Patient acceptability of PAS is poor because of frequent anorexia, nausea and epigastric pain. Other adverse effects are rashes, fever, malaise, goiter, liver dysfunction and blood dyscrasias.

Dose: 10–12 g (200 mg/kg) per day in divided doses; SODIUMPAS 0.5 g tab, 80 g/100 g granules. It is rarely used now.

Ethionamide  (Etm)

It is a tuberculostatic drug of moderate efficacy introduced in 1956. It acts on both extra and intracellular organisms. Atypical mycobacteria are sensitive. Resistance to Etm develops rapidly and some cross resistance with Tzn is seen. It is absorbed orally, distributes all over, including CSF, completely metabolized and has a short duration of action (t½ 2–3 hr).

Anorexia, nausea, vomiting and abdominal upset are common, especially in Indian patients. Though the recommended dose of Etm is 1 g/day, more than 0.5 g is generally not tolerated. Other side effects are aches and pains, rashes, hepatitis, peripheral or optic neuritis, mental disturbances and impotence. It is seldom used; only in case of resistance to better tolerated drugs.

Dose: 0.5–0.75 g (10–15 mg/kg) per day; ETHIDE, ETHIOCID, MYOBID 250 mg tab.

Cycloserine (Cys)

It is an antibiotic obtained from S. orchidaceus, and is a chemical analogue of Dalanine: inhibits bacterial cell wall synthesis by inactivating the enzymes which recemize Lalanine and link two D alanine residues. Cys is tuberculostatic and inhibits some other gram-positive bacteria, E. coli, Chlamydia also. Resistance to Cys develops slowly: no cross resistance.

Cycloserine is absorbed orally, diffuses all over, CSF concentration is equal to that in plasma. About 1/3rd of a dose is metabolized, the rest is excreted unchanged by kidney. The CNS toxicity of Cys is high—sleepiness, headache, tremor and psychosis; convulsions may be prevented by pyridoxine 100 mg/day. It is rarely used; only in resistant cases. The shelf life of Cys in warm climate is short.

Dose: 250 mg BD, increased if tolerated upto 500 mg BD.

CYCLORINE, COXERIN, MYSER 250 mg cap.

Kanamycin, Amikacin and Capreomycin are more toxic antibiotics used as reserve drugs in rare cases not responding to the usual therapy, or infection by atypical mycobacteria. Any one of these is used at a time in combination with the commonly employed drugs to which resistance has not developed. Because all exhibit similar ototoxicity and nephrotoxicity, they are not combined among themselves or with streptomycin. Capreomycin, in addition, can induce electrolyte abnormalities. All act by inhibiting protein synthesis. None is effective orally; none penetrates meninges. All are excreted unchanged by the kidney. All are given in a dose of 0.75–1.0 g i.m. per day.

Kanamycin and amikacin are aminoglycosides and have been described in Ch. No. 53. Amikacin is a very promising drug for atypical mycobacteria including M. avium. Capreomycin is available as

KAPOCIN 0.5, 0.75, 1.0 g inj.

NEWER DRUGS

Ciprofloxacin, Ofloxacin, Moxifloxacin (see Ch 50 for description) The fluoroquinolones are a useful new addition to the antitubercular drugs. Ciprofloxacin, ofloxacin, moxifloxacin, gatifloxacin and sparfloxacin are active against M. tuberculosis as well as M. avium complex (MAC) and M. fortuitum. They penetrate cells and kill mycobacteria lodged in macrophages as well. Because of their good tolerability, ciprofloxacin and ofloxacin are being increasingly included in combination regimens against MDR tuberculosis and MAC infection in HIV patients. They are also being used to supplement ethambutol + streptomycin in cases when H, R, Z have been stopped due to hepatotoxicity. However, neither ciprofloxacin nor ofloxacin have enhanced the sterilizing ability of long-term regimens containing H and R. The generally employed doses are ciprofloxacin 1500 mg/day and ofloxacin 800 mg/day in 2 divided doses. Sparfloxacin is more active against mycobacteria in vitro, but has been used clinically to a lesser extent.

Clarithromycin, Azithromycin

These newer macrolide antibiotics are most active against nontubercular mycobacteria including MAC, M. fortuitum, M. Kansasii and M. marinum. Clarithromycin has been used to a greater extent because its MIC values are lower, but azithromycin may be equally efficacious due to its higher tissue and intracellular levels. For MAC and other atypical mycobacterial infection the dose of clarithromycin is 500 mg BD and that of azithromycin 500 mg OD in combination with other drugs. In AIDS patients, lifelong therapy is required—may cause ototoxicity.

Rifabutin

It is related to rifampin in structure and mechanism of action; but less active against M. tuberculosis and more active against MAC. Only partial cross resistance occurs between the two. In a dose of 300 mg/day rifabutin is used for prophylaxis of MAC infection in AIDS patients. For the treatment of established MAC infection, it has been added to ethambutol + clarithromycin/azithromycin. Gastrointestinal intolerance, rashes, granulo-cytopenia, myalgia and uveitis have been noted as adverse effects. Reactions similar to those produced by rifampin can also occur. Like rifampin, it is an enzyme inducer, but weaker. It is substituted for rifampin for M. tuberculosis infection in HIV patients who receive a protease inhibitor and/or a NNRTI, whose metabolism is markedly induced by rifampin.

Some antitubercular combinations

RIFATER: Rifampin 120 mg, isoniazid 80 mg, pyrazinamide 250 mg tab.

RCINEX: Rifampin 600 mg, isoniazid 300 mg tab; R

CINEXZ: Rifampin 225 mg, isoniazid 150 mg, pyrazinamide 750 mg tab.

RIMACTAZID, RIFADININH, Rifampin 450 mg, isoniazid 300 mg tab.

MYCONEX 600 and 800; Isoniazid 300 mg, ethambutol 600 mg or 800 mg tab, COMBUNEX Isoniazid 300 mg, ethambutol 800 mg tab.

ARZIDE, ISORIFAM: Rifampin 450 mg, isoniazid 300 mg cap.

BITEBEN, ISOZONE, UNITHIBEN: Isoniazid 75 mg, thiacetazone 37.5 mg tab, ISOZONE FORTE—double strength.

INAPAS: sod PAS 834 mg, isoniazid 25 mg tab; sod PAS 3.34 g + isoniazid 100 mg per measure granules. INABUTOL: Isoniazid 150 mg, ethambutol 400 mg tab; INABUTOL FORTE—double strength. ISOKIN–300: Isoniazid 300 mg, vit B₆ 10 mg tab.

IPCAZIDE: Isoniazid 100 mg, vit B₆ 5 mg per 5 ml liq.

Antitubercular combipacks (packs of 1 day’s dose)

AKT4:       R 450 mg 1 cap + Z 750 mg 2 tab + E 800 mg H 300 mg 1 tab.

AKT3:R 450 mg 1 cap + E 800 mg H 300 mg 1 tab.

CX5:R 450 mg 1 cap + Z 750 mg 2 tab + E 800 mg H 300 mg pyridoxine 10 mg 1 tab.

RIFACOMZ and RIMACTAZIDEZ:R 450 mg H 300 mg 1 tab. + Z 750 mg 2 tab.

RIFACOMEZ: R 450 mg H 300 mg 1 tab. + Z 750 mg 2 tab + E 800 mg 1 tab.

Fixed dose combination of antitubercular drugs with vitamins (except INH + Vit B₆) are banned in India.