Anti-tubercular drugs

Anti-tubercular drugs

Contents

Antitubercular drugs

•       Classification

•       Pharmacology of individual drugs

At the end of this lecture, the student will be able to:

•       Describe the mechanism of action and pharmacokinetics of First line and second line anti-TB drugs

•       Discuss the adverse effects and drug interactions of anti-TB drugs

•       Explain the DOTS therapy based on WHO guidelines

Anti-tubercular Agents

•       Tuberculosis is a chronic granulomatous disease

•       In developing countries it is a major health problem

•       30% of world population is infected with M. tuberculosis infection

•       In India > 2 million people develop active disease every year & half million die.

•       Anti-tubercular drugs used in chemotherapy of tuberculosis, a disease caused by Mycobacterium tuberculosis

•       Many drugs were developed to treat tuberculosis and they are often used in combinations to reduce the emergence of resistant strains of the mycobacterium

•       Combination chemotherapy is also used in the treatment of leprosy, caused by Mycobacterium leprae

Classification

                First-line (High efficacy, low toxicity)

–      Isoniazid

–      Rifampicin

–      Ethambutol

–      Pyrazinamide

–      Streptomycin

                Second-line (Low efficacy, high toxicity)

–      Clarithromycin

–      Ciprofloxacin

–      Capreomycin

–      Cycloserine

–      Kanamycin

–      Amikasin

–      Para amino salicylic Acid

Isoniazid (Isonicotinic Acid Hydrazid)

•        Isoniazid is an effective anti-tubercular drug and is essential component of all anti tubercular regimens

•       It is more potent among the anti-tubercular drugs, but it is not used alone in treatment of active tuberculosis

•       It acts on extracellular as well as on intercellular tubercule bacilli present within macrophages

Mode of Action

•       Acts only on mycobacteria

•       Interferes with mycolic acid synthesis (unique to mycobacterial cell wall)

•       Passes freely to mammalian cell wall

•       Effective for intracellular organism

•       Bacteriostatic – to resting organism

•       Bactericidal – to multiplying organism

Pharmacokinetics

•       Well absorbed from GIT

•       Fatty food & aluminium-containing antacids may reduce absorption

•       CSF penetration: 20% of plasma concentration with non-inflamed meninges 

•       Penetrate well into caseous material

•       Excretion – urine

•       Plasma half-life 3 hrs

Adverse Effects

•       Hepatotoxicity

–      Elderly, slow acetylators more prone

•       Polyneuropathy

–      Prevented by concurrent pyridoxine

•       Rashes, acne

•       Heamatological – haemolytic anaemia in G6PD deficiency

Drug Interactions

•       Absorption of Isoniazid is impaired if taken with food consisting carbohydrates or with aluminium-containing antacids

•       It inhibits the metabolism of phenytoin, carbamazepine, diazepam and warfarin and raised their blood levels

•       Para amino salicylic acid inhibits its metabolism and increases its metabolism

Rifampicin

•       Rifampicin is semisynthetic derivative of refamycin B, obtained from Streptomyces mediterannei

•       It is one of the most active anti tubercular drugs

•       It is active against many other Gram-positive and Gram-negative bacteria

Mechanism of Action

•       Rifampicin acts by inhibiting DNA- dependent RNA polymerase thus inhibiting RNA synthesis by suppressing the initiation step in prokaryotic but not in eukaryotic cells

•       It also enters phagocytic cells and kill intercellular microorganism including tubercule bacilli

•       It is the only drug which acts on the persisters

Pharmacokinetics

•       It is well absorbed orally and is widely distributed in the tissues and body fluids

•       It gives an orange tinge to saliva, sputum, tears and sweat

•       The drug is taken up by liver and undergoes enterohepatic cycling

•       The metabolite retains antibacterial activity but less absorbed from the GIT tract

•       Mainly Excreted in bile and also in urine

Adverse Effects

•       Unwanted effects are infrequent and include skin eruptions, fever and GIT disturbances

•       The drug should be used carefully in patients with hepatic failure as it may lead to jaundice

Drug Interactions

•       Rifampicin is an inducer of cytochrome P-450 enzymes and decreases the half-life of drugs such as warfarin, glucocorticoids, antidiabetic, oral-contraceptives leading to their failure

Anti-TB Therapy

•       Multiple drugs are used to reduce the emergence of resistance

•       Given as combination tablets

•       Taken 30 min before the breakfast as absorption of rifampicin is influenced by food

•       For pulmonary TB – 6 months treatment

•       For renal, bone and CNS infection – longer treatment

Summary

•       Isoniazid – bactericidal to rapidly dividing bacteria

•       Rifampicin - kill intracellular bacteria

•       Ethambutol – bacteriostatic against multiplying bacteria

•       Pyrazinamide - kill dormant mycobacteria

•       Adverse effects:

ü  INH- Hepatotoxicity and Polyneuropathy

ü  Rifampicin- inducer of cytochrome P-450 enzymes and decreases the half-life of drugs such as warfarin, glucocorticoids, antidiabetic, oral-contraceptives

ü  Pyrazinamide- GI disturbances, Hepatotoxicity,  gout

ü  Streptomycin- Ototoxicity, vestibular toxicity, nephrotoxicity