1st Line Anti-tubercular Drugs

st 1

Line Anti tubercular Drugs Saurabh Biswas PGT,Dept . Of Chest Medicine CNMCH

History Mycobacterium

Tuberculosis Drugs(1st line)

H isto ry

Tuberculosis known to mankind since time

immemorial- one of the deadliest diseases in the world today. No effective treatment before the last 60 years. 1946- first clinical use of streptomycin-but monotherapy led to resistance 1952-INH introduced to make a two drug regimen. 1958-data from India showed the effectiveness of supervised treatment(now DOT)

1961-discovery of ethambutol 1962-discovery of rifampicin 1974-concept of SCC daily regimen including

RZ 1980- six-month fully intermittent effective SCC evolved. 2001-possibility of 4-month ultra short-course effective regimen containing quinolones is explored

Mycobacterium tuberculosis- the bacillus

Slow growing aerobic rod-shaped organism 2-4

microm in length and 0.2 -0.8 microm in breadth. Weakly Gram positive and Acid-fast. Infects humans,monkeys,cows,buffaloes,pigs, dogs and occ. Parrots. Under experimental conditions virulent to guinea pigs and mice.

Best method to inactivate –heat- death time at

60 degree is 15 mins. More resistant to chemical agents than other bacteria-80% ethanol kills it in 2-10 mins,so recommended for disinfection of skin & rubber gloves. Daylight has lethal effect on it.

Three populations of tubercular bacilli

-postulated to be present in a tuberculosis cavity based on their anatomic and metabolic characteeristics.

A-rapidly multiplying found in caseous debris in pul cavity,B-slowly multiplying due to acidic cond.,Cmultiplying sporadically

Elimination of population “A” and “B” results in

negative sputum cultures typically after 2 months of rx. Population “C” is a potential source of relapses along with Dormant bacilli-the persisters.

Anti-tubercular Drugs(1 line) Isoniazid(H) Rifampicin(R) Pyrazinamide(Z) Ethambutol(E) Streptomycin(S)

Isonicitinic acid hydrazide bactericidal effect and low cost - the most

Isoniazid

important drug used for the treatment of TB. acts by inhibiting mycolic acid synthesis by mycobacteria activated by a catalase-peroxidase enzyme within mycobacteria bacteriostatic against resting bacilli and bactericidal against rapidly multiplying organisms, both extracellularly and intracellularly  

minimal inhibitory concentrations (MICs) of

isoniazid for wild-type (untreated) strains of M. tuberculosis are <0.1 microg/mL The MICs of this drug for NTM are often higher.

Pharmacokinetics Completely absorbed orally Penetrates all body tissues,tubercular cavities,placenta and meninges. metabolized in the liver via acetylation and hydrolysis metabolites are excreted into the urine. The rate of acetylation is genetically controlledfast & slow acetylators. T1/2-1hr in fast and 3 hrs in slow 

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30-40% Indians fast acetylators 60-70% are

slow. The standard adult daily oral dose of 300 mg produces peak serum levels of 3–5 microg/mL  

Dosage: The usual dose is 5mg/kg daily maximum upto 300mg or 10mg/kg thrice weekly upto a maximum of 600mg. 15mg/kg if given twice weekly-less effective in fast acetylators. does not require dosage adjustment in patients with renal insufficiency or with end-stage renal disease requiring chronic hemodialysis. 

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Drug interaction: Al hydroxide inhibits its absorption INH inhibits phenytoin,carbamazepine, diazepam and warfarin metabolism-may raise their blood levels. PAS inhibits INH metabolism & prolongs its t1/2 

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Contraindications: Known hypersensitivity Active hepatic disease 

UNTOWARD EFFECTS occur in ~5% rash (2%), fever (1.2%), jaundice (0.6%), and peripheral neuritis (0.2%)-Preventable with pyridoxine Risk factors for peripheral neuropathy-slow acetylators, elderly, pregnant women, human immunodeficiency virus [HIV]-infected subjects, diabetics, alcoholics, and uremics  Isoniazid hypersensitivity may result in fever, rashes, and hepatitis Hematological reactions-agranulocytosis, eosinophilia, thrombocytopenia, and anemia Vasculitis associated with antinuclear antibodies convulsions, usually in patients with known seizure 

Optic neuritis ,muscle twitching, dizziness,

ataxia, paresthesias, stupor, and potentially fatal encephalopathy euphoria, transient memory impairment, loss of self-control, and psychosis. Hepatic injury Severe hepatic injury leading to deathpresenting 4–8 weeks after initiation Drug continuation after hepatic dysfunctionworsen the damage.    

Risk factors-Alcoholic hepatitis, Age(most

important),excessive alcohol intake, history of liver disease chronic carriers of the hepatitis B virus tolerate isoniazid Up to 12% of patients may have elevated serum transaminase levels Drug to be discontinued if ALT>5-fold of normal without any signs and symptoms or if ALT>3 times normal plus signs and symptoms of hepatitis   

Rifampicin semisynthetic derivative of Streptomyces

mediterranei most important and potent antituberculous agent also active against a wide spectrum of other organisms, including some gram-positive and gram-negative bacteria, Legionella spp., M. kansasii, and M. marinum

Susceptible strains of M. tuberculosis as well as

M. kansasii and M. marinum are inhibited by 1 microg/mL. Bactericidal-both intracellularly and extracellulararly. Inhibits DNA dependent RNA polymerase, leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis  

Pharmacokinetics: absorbed readily after either PO or IV administration Serum levels of 10–20 microg/mL follow a standard adult oral dose of 600 mg eliminated rapidly in the bile, and an enterohepatic circulation ensues. drug is progressively deacetylated by hepatic CYPS after 6 hours, nearly all drug in the bile is in the deacetylated form, which retains antibacterial activity 

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Intestinal reabsorption is reduced by

deacetylation and by food-metabolism facilitates drug elimination t1/2 is progressively shortened (~40%) during the first 14 days of treatment due to induction of hepatic CYPs. t1/2 is variable-2 to 5 hrs. Dosage adjustment is not necessary in patients with renal insufficiency Penetrates cavities,caseous masses,placenta and meninges.   

Dosage: 10 mg/kg daily,2 or 3 times daily upto a maximum of 600 mg. given either 1 hour before or 2 hours after a meal 

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Drug interaction: potent inducer of hepatic CYPs- decreases the t1/2 of many drugs HIV protease and nonnucleoside reverse transcriptase inhibitors, digoxin, quinidine, mexiletine, tocainide, ketoconazole, propranolol, metoprolol, clofibrate, verapamil, cyclosporine, glucocorticoids, oral anticoagulants, theophylline, barbiturates, oral contraceptives,fluconazole, and the sulfonylureas 

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Interaction with oral anticoagulants-impair

anticoagulation Decrease effectiveness of oral contraceptives and induce adrenal insufficiency in patients with marginal adrenal reserve   

Contraindications: Known hypersensitivity Active hepatic disease 

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Untoward effects: Significant effects in <4% of patients most commonly rash (0.8%), fever (0.5%), and nausea and vomiting (1.5%) Rarely, hepatitis and deaths due to liver failure-Chronic liver disease, alcoholism, and old age increase the risk should not be administered less than twice weekly and/or in daily doses of 1.2 g or greater-flu-like syndrome with fever, chills, and myalgias develops in 20% of patients so treated 

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Exfoliative dermatitis-more frequent in HIV

positives. Temporary oliguria,dyspnea, hemolytic anemia,thrombocytopenia- these usually subside if intermittent regimen changed to daily regimen. 

Other uses: Leprosy prophylaxis of meningococcal disease and Haemophilus influenzae meningitis Combined with a b-lactam antibiotic or vancomycin-selected cases of staphylococcal endocarditis or osteomyelitis Doxycycline + R-first line therapy for brucellosis. 

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Ethambutol derivative of ethylenediamine, ethambutol is a

water-soluble compound -active only against mycobacteria Active against M. tuberculosis, M. marinum, M. kansasii, and MAC organisms Among first-line drugs, ethambutol is the least potent against M. tuberculosis Tuberculostatic 

Used in combination with other ATDs to

prevent or delay emergence of resistant strain. Growth inhibition by ethambutol requires 24 hours-inhibition of arabinosyl transferases involved in cell wall biosynthesis   

Pharmacokinetics: About 80% of an oral dose of ethambutol is absorbed from the GI tract. Concentrations in plasma peak 2–4 hours after the drug is taken-Peak serum levels of 2–4 microg/mL t1/2 of 3–4 hours. Within 24 hours, 75% of an ingested dose of ethambutol is excreted unchanged in the urine up to 15% is excreted in the form of aldehyde and dicarboxylic acid derivatives. 

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Dosage: Adults:15mg/kg daily,30mg/kg 3 times weekly or 45mg/kg twice weekly. Children:15mg/kg daily Dose to be reduced in impaired renal function 

Contraindications: Known hypersensitivity Pre-existing optic neuritis from any cause Creatinine clearance <50ml/min Children <6 yrs 

Untoward effects: optic neuritis, resulting in decreased visual acuity and red–green color blindness-<1% in patients Intensity of the visual difficulty - related to the duration of therapy after visual impairment first becomes apparent - unilateral or bilateral. Recovery usually occurs when ethambutol is withdrawn. rash, drug fever, pruritus, joint pain GI upset, malaise, headache, dizziness, confusion, disorientation, and hallucinations. 

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Numbness and tingling of the fingers owing to

peripheral neuritis –infrequent Anaphylaxis and leukopenia are rare. increased urate concentration in the blood in ~50% of patients, owing to decreased renal excretion of uric acid.   

Pyrazinamide Synthetic pyrazine analogue of nicitinamide Weakly tuberculocidal Highly active in acidic medium(it is active only

at a pH of <6.0)-itracellularly and at sites showing inflammatory response Highly effective during 1st 2 months of therapy when inflammatory changes are present. prodrug -converted by the tubercle bacillus to the active form pyrazinoic acid 

target for this compound is thought to be a

fatty acid synthase gene (fasI) involved in mycolic acid biosynthesis Susceptible strains of M. tuberculosis are inhibited by 20 microg/mL 

Pharmacokinetics: well absorbed after oral administration, with a plasma concentration range of 20–60 microg/mL 1–2 h after oral ingestion well distributed throughout the body Levels in CSF are excellent-reaching 50–100% of levels in serum The serum half-life is 9–11 h metabolized by at least two major pathways and one minor pathway in the liver 

metabolites include pyrazinoic acid, 5-

hydroxypyrazinamide, and 5 hydroxypyrazinoic acid not available in a parenteral formulation

Dosage: For 1st 2 or 3 months-25mg/kg daily,35mg/kg 3 times weekly ,50mg/kg 2 times weekly 

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Contraindications: Known hypersensitivity Severe hepatic impairment 

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UNTOWARD EFFECTS: Hepatic injury is the most serious side effect At the currently recommended dosages, the frequency of hepatotoxicity is no higher than that for concomitant isoniazid and rifampin therapy Hyperuricemia is a common adverse effectreduced by concurrent rifampin therapy Polyarthralgias encountered fairly commonlynot related to the hyperuricemia 

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Rash,fever , loss of diabetes control

Streptomycin An aminoglycoside isolated from Streptomyces

griseus active against untreated strains of M. tuberculosis, M. kansasii, and M. marinum and against some strains of MAC organisms Also active against some Gram negative organisms Tuberculocidal 

Acts only in extracellular bacilli-poor

penetration into cells Doesn’t cross CSF and poor action in acidic media. Binds to bacterial 30s ribosome-inhibits protein synthesis. Serum levels of streptomycin peak at 25–40 microg/mL after a 1.0-g dose

Pharmacokinetics: Highly ionized Neither absorbed nor destroyed in GIT Absorption from injection site-rapid Distributed extracellularly only Low concentrations in serous fluid like synovial and pleural and also in CSF. Not metabolized-excreted unchanged in urine T1/2 is 2-4 hrs-but persists longer in tissues 

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Dosage: 15mg/kg daily,2 or 3 times weekly by deep IM injection dosage must be lowered and the frequency of administration reduced (to only two or three times per week) in most patients >50 years of age and in any patient with renal impairment 

Contraindications: Known hypersensitivity Auditory nerve impairment Myasthenia gravis Pregnancy 

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UNTOWARD EFFECTS: Adverse reactions to streptomycin therapy occur in 10–20% Ototoxicity and renal toxicity are the most common and the most serious Renal toxicity, usually manifested as nonoliguric renal failure Ototoxicity involves both hearing loss and vestibular dysfunction-latter is more common and includes loss of balance, vertigo, and tinnitus 

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perioral paresthesia, eosinophilia, rash,

and drug fever

Drug interaction: Avoid use with other ototoxic drugs like higgh ceiling diuretics,minocycline Avoid concurrent use of other nephrotoxic drugs Cautious use with muscle relaxant-it may add to the action of other muscle relaxant Do not mix with any other drug in same syringe/infusion 

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Other uses: SABE –along with penicillin Plague Tularemia-drug of choice 

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