Pharmacology 3 Antimycobacterial drugs Lecture 12 By Prof. Dr Pharmacology 3 Antimycobacterial drugs Lecture 12 By Prof.Dr. Mohamed fahmy

Antimycobacterial drugs Mycobacteria are very slowly growing organisms Treatment of mycobacteria with chemotherapy needs longer time (6 – 18 months) Combinations of drugs are required to prevent the development of resistance

Tuberculosis (TB) A disease caused by a bacterium called Mycobacterium tuberculosis - Highly aerobic - Infects lung - Divides every 15-20 hrs - Unable to be digested by microphages - Very resistant to many disinfectants C

Lines of treatment of TB A- First line drugs Drugs with high efficacy & acceptable side effects Examples: Isoniazid, rifampicin, ethambutol, pyrazinamide & streptomycin

B- Second line drugs Less effective & more toxic than first line drugs Used when first line drugs fail and/or contraindicated Examples: Ethionamide, capreomycin, P-aminosalicylic acid, cycloserine, fluoroquinolones & macrolides

First-line drugs for tuberculosis Isoniazid (Isocid) Isonicotinic acid hydrazide (INH) It is the most active drug for treatment of TB Pharmacokinetics Well absorbed orally Distributed all over the body including CSF Acetylated in liver & excreted in urine

Mechanism of action Isoniazid is a pro-drug that is activated by a mycobacterial catalase peroxidase The active metabolite inhibits the enzyme enoyl acyl carrier protein reductase involved in the production of mycolic acid Mycolic acid is essential for the synthesis of mycobacterial cell wall

Resistance Therapeutic uses Deletion in the KatG gene that encodes for a catalase peroxidase involved in the bioactivation of INH Deletion in the InhA gene that encodes target enzyme an acyl carrier protein reductase Therapeutic uses 1- Treatment of TB in combination with rifampicin 2- Chemoprophylaxis in persons very close to active cases

Adverse effects 1- Peripheral neuritis INH combines with pyridoxine (vitamin B6) and accelerates its excretion Corrected by administration of vitamin B6 (10 mg/day) 2- Hepatotoxicity Caused by chemically reactive metabolite acetylhydrazine

Drug interactions 3- Hemolytic anemia in patients with G6PD deficiency 4- Hypersensitivity reactions Drug interactions INH inhibits metabolism of phenytoin, carbamazepine & ethosuximide actions & toxicity

Rifampicin (Rifampin, Rifadin, Rimactan) Has a wider range of antimicrobial activity than INH Pharmacokinetics Well absorbed orally Distributed all over the body including CSF Deacetylated in liver Excreted in: Bile Enterohepatic circulation Urine Red discoloration

Mechanism of action Resistance 1- Bactericidal 2- Inhibits DNA-dependent RNA polymerase enzyme synthesis of Mycobacterium mRNA 3- Does not bind to human RNA polymerase Resistance 1- Chemical modification in the target DNA-dependent RNA polymerase enzyme 2- Decreased permeability

Therapeutic uses 1- Tuberculosis in combination with INH (Rimactazid) 2- Chemoprophylaxis of meningococcal meningitis 3- Staphylococcal endocarditis, in combination with a β-lactam antibiotic 4- Leprosy, in combination with dapsone

Adverse effects Orange-red discoloration of urine, saliva & tears Liver damage & Jaundice GIT disturbances Hypersensitivity reactions Drug interactions Enzyme inducer so metabolism of warfarin & tolbutamide

Notes: 1- Rifabutine A derivative of rifampicin It is the preferred drug for use in TB-infected with the HIV patients who are concurrently treated with protease inhibitors, why? It is a less potent inducer of cytochrome P450 enzymes

2- Rifapentine Has activity similar to rifampicin Has a longer half-life than rifampicin & rifabutin, which allows weekly dosing Should not be used alone to avoid resistance

Ethambutol (Etibi) Mechanism of action Bacteriostatic Inhibits arabinosoyl transferase enzyme synthesis of arabinogalactan (a component of Mycobacterial cell wall) Adverse effects Optic neuritis & retinal damage

Inhibits synthesis of fatty acids Pyrazinamide Mechanism of action Pyrazinamide Prazinamidase in bacteria Pyrazinoic acid Inhibits synthesis of fatty acids Adverse effects Joint pain & hepatotoxicity

Second-line drugs for tuberculosis Ethionamide Similar to INH, acts by inhibition of Mycolic acid Adverse effects include peripheral neuropathy & optic neuritis Capreomycin It acts by inhibition of protein synthesis It is nephrotoxic & ototoxic

P-aminosalicylic acid Chemically related to PABA, acts by inhibition of folate synthesis Adverse effects include epigastric pain, liver damage & crystalluria Cycloserine Inhibits cell wall synthesis Neurotoxic & hepatotoxic

Fluoroquinolones Macrolides Examples: Moxifloxacin & levofloxacin Can be used when there is resistance to first-line agents Macrolides Examples: Azithromycin & clarithromycin Azithromycin is preferred for HIV-infected patients because it is least likely to interfere with the metabolism of antiretroviral drugs

Leprosy A chronic disease of the skin Caused by Mycobacterium leprae The world health organization (WHO) recommends the triple drug regimen of dapsone, clofazimine & rifampicin for 6 to 24 months ifampici

Dapsone Pharmacokinetics Well absorbed from the gastrointestinal tract Distributed throughout the body, with high levels concentrated in the skin Acetylated in liver Excreted in urine

Mechanism of action Chemically related to sulfonamides, acts by inhibition of folate synthesis via dihydrofolate synthase inhibition Adverse effects 1- Hemolysis of RBCs, especially in patients with G6PD deficiency 2- Peripheral neuropathy

Clofazimine Binds to DNA and prevents it from serving as a template for future DNA replication Has some anti-inflammatory actions, so used in patients in whom dapsone causes inflammatory side effects