Lecture (24) Drug Therapy of Tuberculosis PDF

‫ميحرلا نمحرلا هللا‬ ‫بسم‬ Lecture (24) Drug therapy of Tuberculosis Dr. Esraa Abd ELKhalik Ahmed (Pharmacology) ILOs: 1. Name the classification of drugs used for treatment of tuberculosis. 2. Describe the mechanism of action of different antituberculous drugs. 3. Enumerate t...

‫ميحرلا نمحرلا هللا‬ ‫بسم‬ Lecture (24) Drug therapy of Tuberculosis Dr. Esraa Abd ELKhalik Ahmed (Pharmacology) ILOs: 1. Name the classification of drugs used for treatment of tuberculosis. 2. Describe the mechanism of action of different antituberculous drugs. 3. Enumerate the adverse effects and contraindications of antituberculous drugs. 4. Describe the therapeutic regimen for treatment of TB case. 1- Which one of the following antitubercular drugs induce metabolic liver enzyme? a) Rifampin b) Isoniazid c) Streptomycin d) Ethambutol 2- Which one of the following antitubercular drugs act best in acidic Ph? a) Isoniazid b) Pyrazinamide c) Streptomycin d) Rifampin More than one-quarter of the world's population has been infected with M. tuberculosis.  Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis bacteria. Tuberculosis generally affects the lungs, but it can also affect other organs of the body. The first line drugs for treatment of TB: Isoniazid, Rifampin, Pyrazinamide, Ethambutol.  Antituberculous drugs First line drugs Second line drugs 1-Rifampin 1- Streptomycin and other 2-Isoniazid (INH) aminoglycosides like 3-Pyrazinamide amikacin and kanamycin 2- Ethionamide 4-Ethambutol 3- p-aminosalicylic acid (PAS) 4- Imipenem-cilastatin 5- Fluroquinolones. The site of action of (anti-TB drugs)  Isoniazid (Isonicotinylhydrazide) (INH)  Isoniazide inhibits mycolic acid synthesis (one of mycobacterial cell wall components) of the mycobacterial cell wall. Bacterial catalaseperoxidase (encoded by KatG) is needed to convert INH to active metabolite. This explains the activity of INH on certain bacterial cells like mycobacterial tuberculosis.  Clinical uses of Isoniazid 1-Treatment of Mycobacterium tuberculosis infections (with Rifampin and other drugs). 2- Prophylaxis against tuberculosis among contacts to patients suffering from disease (Isoniazid is the only agent that can be used alone). 3- As monotherapy Isoniazid is used for latent TB control. Resistance of mycobacterial cell to INH KatG mutation or deletion is the main source of developing resistance to INH.  Adverse effects of isoniazid 1- Hepatotoxicity. 2- Drug interactions (isoniazid inhibit cytochrome P-450) 3-Drug-induced systemic lupus erythematous (SLE). 4- Metabolic acidosis. 5-Vitamin B6 deficiency ( which may lead to peripheral neuropathy and anemia). 6-Seizures (in high doses, refractory to benzodiazepines).  Isoniazid and pyridoxine (vit. B6) pyridoxine (B6) should be given with isoniazid to prevent certain adverse effects like peripheral neuropathy especially in slow acetylates. Isoniazid is contraindicated in patients with acute liver failure, severe uncontrolled diabetes, anemia from pyruvate kinase and G6PD deficiencies and severe neuropathy.  Rifamycins (Rifampin) Rifampin (U.S), rifampicin (Europe), rifapentine and rifabutin. Rifampin binds to the β-subunit of DNA- dependent RNA polymerase (rpoB) to form a stable drug-enzyme complex. This binding inhibits RNA synthesis.  Clinical uses of Rifampin 1- Rifampin has antibacterial activity against M. tuberculosis and M. leprae (causing leprosy). 2- Staphylococcal endocarditis or osteomyelitis 3- Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H. influenzae type b.  Adverse effects of Rifampin 1- Hepatotoxicity. 2- Orange-tan discoloration of skin, urine, feces, saliva, and tears. 3- Drug interactions: it induces cytochrome P-450 with concomitantly given drugs decreasing their t ½ (e.g. propranolol, cyclosporine, corticosteroids, oral contraceptives) Resistance to Rifampin in mycobacterial infections 1- Mutation in the rpoB gene reduce drug binding to RNA polymerase. N.B. Monotherapy leads to resistance.  Remember Rifampin’s 4 R’s 1.RNA polymerase inhibitor. 2.Ramps up microsomal cytochrome P-450. 3.Red/orange body fluids 4.Rapid resistance if used alone  Pyrazinamide Pyrazinamide is a prodrug that is converted to the active compound pyrazinoic acid. Pyrazinamide inhibits mycobacterial cell membrane after being converted into pyrazinoic acid by acidic medium induced by inflammatory cells. It works best at acidic pH Clinical use: Mycobacterium tuberculosis (with other drugs). Adverse effects: Hyperuricemia, hepatotoxicity.  Ethambutol Mechanism of action: decreases carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase. arabinosyl transferase III Arabinose arabinogalactan Clinical uses: Mycobacterium tuberculosis (with other drugs). Adverse effects: 1-Optic neuropathy (red-green color blindness, may be reversible). 2-Hyperuricemia.  Streptomycin Mechanism of action: It is a member of aminoglycosides (interferes with 30s component of ribosome leading to irreversible inhibition of bacterial protein synthesis). Clinical use: mycobacterium tuberculosis (2nd line). Adverse effects: tinnitus, vertigo, ataxia, nephrotoxicity. Contraindicated in pregnancy and renal failure.  Therapeutic regimen for TB Six months of treatment with isoniazid (INH), pyridoxine (vitamin B6), and rifampin, supplemented during the first 2 months with pyrazinamide and ethambutol. (A current global challenge is the rise of multidrug-resistant (MDR) and, more recently, extensively drug-resistant (XDR) Tuberculosis).  MDR-TB is resistant to at least rifampin and isoniazid. XDRTB is additionally resistant to several second-line therapies.  The treatment of drug-resistant TB depends heavily on culture sensitivities. Latent tuberculosis infection (LTBI) treatment for individuals with a positive PPD but no active disease generally consists of 9 months of INH plus pyridoxine. Note that this is not an appropriate regimen for active TB (active TB needs combination of TWO or more anti-TB rugs). References: 1- First aid for the basic sciences organ systems: Chapter 10 page 827 - 8 29. 2- First aid USML page 196- 1 98.