Anti-Tuberculosis Drugs Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture 8 March 02, 2013

Tuberculosis Infected by Mycobacterium tuberculosis Usually occurs in the lungs, but can affect other organs like lymph nodes, meninges, bone, adrenals or the urogenital tract One third of the world's population is thought to be infected with M. tuberculosis Treatment for TB (short for tubercle bacillus) uses antibiotics to kill the bacteria Lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut The meninges is the system of membranes which envelopes the central nervous system Adrenal gland: endocrine glands, located over kidney. tubercle bacillus: A rod-shaped aerobic bacterium (Mycobacterium tuberculosis) that causes tuberculosis 2

First-Line Drugs Isoniazid Rifampicin Ethambutol Pyrazinamide 3

Isoniazid: Mechanism of Action An important agents for the treatment of tuberculosis It is bactericidal only to Mycobacterium tuberculosis High doses are used in tuberculous meningitis Often given in combination with ethambutol or rifampicin Isoniazid: Mechanism of Action It is a prodrug; mycobacterial catalase-peroxidase (katG) converts isoniazid into an active metabolite A primary action of isoniazid is to inhibit the biosynthesis of mycolic acids (long, branched lipids that form part of the mycobacterial cell wall) Isoniazid: Resistance Mutation in KatG that decreases its activity, preventing conversion into active metabolite

Isoniazid: Pharmacokinetics Readily absorbed from the gut, diffuses well into the body tissues, including the CSF It undergoes polymorphic acetylation in the liver The half-life is less than 80 min in fast acetylators and greater than 140 min in slow acetylators Fifty to seventy per cent of a dose is excreted in the urine within 24 hours as metabolite or free drug Macrophages are white blood cells within tissues. Vitamin B6, also called pyridoxine Hepatitis is swelling and inflammation of the liver Isoniazid: Adverse Effects Peripheral neuropathy Common in patients who are slow acetylators, and which may be prevented by pyridoxine administration Hepatitis 5

Isoniazid: Drug Interactions Partly metabolized by hepatic cytochrome P450, and inhibits metabolism of certain drugs, for example, phenytoin and carbamazepine, thereby causing toxicity in some patients Phenytoin: antiepileptic drug 6

Rifampicin: Mechanism of Action Transcription is a cellular process during which RNA is synthesized using DNA as a template. RNA polymerase is the principal enzyme of transcription Rifampicin acts by inhibiting bacterial DNA-dependent RNA polymerase of mycobateria by forming a stable drug-enzyme complex Because of its high lipid solubility it diffuses easily through cell membranes to kill intracellular bacteria 7

Rifampicin: Pharmacokinetics Absorption from the gut is almost complete but is delayed by food 85-90% of the drug is protein bound in plasma but it penetrates well into most tissues, and cavities, although relatively little enters the brain and CSF Metabolized by deacetylation and is excreted mainly in the bile Rifampicin: Adverse Effects After a few hours influenza-like symptoms, flushing and rashes occur Hepatotoxicity Urine and tears become pink/red which may be a useful guide to compliance with therapy 8

Rifampicin: Drug Interactions Markedly induces hepatic microsomal cytochrome P450 activity thereby accelerating the metabolism of several commonly used drugs like Corticosteroids, Warfarin and Estrogens 9

Ethambutol: Mechanism of Action It is an inhibitor of mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall Ethambutol: Pharmacokinetics Well absorbed (75-80%) from the intestine The plasma t1/2 is 5-6 hours Contraindicated in renal failure 10

Ethambutol: Adverse Effects Retrobullar neuritis and loss of visual acuity occurs in 10% of patients on the higher dose. The first signs are loss of red-green perception. Prompt withdrawal of the drug may be followed by recovery Rashes, joint pains Nausea, abdominal pain Retrobulbar neuritis is a form of optic neuritis in which the optic nerve, which is at the back of the eye, becomes inflamed Scotomata: An area of diminished vision within the visual field 11

Pyrazinamide: Mechanism of Action The enzyme pyrazinamidase in mycobacteria cleaves off the amide portion of the molecule producing pyrazinoic acid which is bactericidal by unknown mechanisms Pyrazinamide: Pharmacokinetics Almost completely absorbed and t1/2 is 11-24 hours Pyrazinamide and its metabolites are excreted via the kidney, and renal failure necessitates dose reduction It crosses the blood-brain barrier to achieve therapeutic CSF concentrations and is therefore a drug of first choice in tuberculous meningitis 12

Pyrazinamide: Adverse Effects Hyperuricemia which may precipitate gout Pretreatment hepatic enzymes must be measured, as about 5-15% of patients develop hepatotoxicity. Measurements must be repeated during treatment Rashes and photosensitivity Hyperuricemia is a level of uric acid in the blood that is abnormally high It should be avoided if there is a history of alcohol abuse and treatment should not be continued for more than 2 months 13

Second-Line Drugs The commonest cause of treatment failure or relapse is non-compliance with therapy The previous drugs used should be known and current bacterial sensitivity found If the organisms are still sensitive to the original drugs, then more fully supervised and prolonged therapy with these drugs should be prescribed If bacterial resistance has arisen then alternative drugs are used, supervised by a clinician with experience in the use of such agents 14

Second-Line Drugs Streptomycin Capreomycin Ethionamide Prothionamide Aminosalicylic acid Fluroquinolones 15

Streptomycin: Mechanism of Action It is an aminoglycoside, actively transported across the bacterial cell wall and its antibacterial activity is due to it binding to the 30S subunit of the bacterial ribosome and inhibiting protein synthesis Streptomycin: Pharmacokinetics Oral absorption is minimal, given parenterally (IM) Mainly excreted via the kidney and dosage requires adjustment in renal impairment Crosses the blood-brain barrier when the meninges are inflamed Streptomycin: Adverse Effects Same as for other aminoglycosides 16

Ethionamide and Prothionamide Capreomycin An effective drug but, like other aminoglycosides, it can produce nephrotoxicity and ototoxicity Ethionamide and Prothionamide Structural analogs of isoniazid Both produce nausea after oral administration Toxic effects include liver damage, neuropathy and mental disturbance 17