Pharmacology IV -TB Drugs PDF

ANTI-MYCOBACTERIAL DRUG I Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  3 Mycobacteria Mycobacteria - Intracellular pathogens, can survive inside the macrophage…so scary… -...

ANTI-MYCOBACTERIAL DRUG I Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  3 Mycobacteria Mycobacteria - Intracellular pathogens, can survive inside the macrophage…so scary… - Resistant to most antibiotics [lipid rich cell wall & slow cell division (18-24 hours)] Note: Most antibiotics target fast growing bacteria - Human are mainly affected by Mycobacterium tuberculosis and mycobacterium leprae (leprosy) - Nevertheless, Nontuberculosis mycobactera (NTM) infection are increasing (M. avium-intracellulare, M.  5 Tuberculosis Pulmonary (90%) - Most initial infections are asymptomatic (latent tuberculosis). - May become a chronic illness and cause extensive scarring in the lungs’ upper lobes. - Early lung lesions heal without residual changes except occasional pulmonary/ tracheobronchial lymph node calcification. Extrapulmonary (15-20%) - infection spreads outside the lungs - More common in immunocompromised and children.  13 Tuberculosis Strategies to overcome drug resistance Multidrug therapy - Reduce the bacterial population as rapidly as possible to prevent the emergence of drug-resistance bacteria. - First line: 1) Isoniazid 2) Rifampin* 3) Ethambutol short-course 4) Pyrazinamide chemotherapy Note: Rifabutin or rifapentine may replace rifampin - Second line for MDR-TB (TB resistant to at least isoniazid and rifampin): 1) Aminoglycoside (streptomycin, kanamycin, or amikacin) or capreomycin 2) Fluoroquinolone (levofloxacin or moxifloxacin) 3) Any first-line drugs that remain active 4) Any one or more (Cycloserine, ethionamide, or p- aminosalicylic acid).  6 Tuberculosis Risk groups Close contacts with TB patients immunosuppressed People from countries with high incidence of TB Factors that increase risk of developing active TB HIV+ , Injecting drug users, Organ transplantation, Haematological malignancy (leukaemia and lymphomas), Chronic renal failure or receiving haemodialysis, Silicosis (chronic lung disease caused by inhaling particles of silica/substances leading to loss of lung function) TB’s therapeutic problems: I. Patients compliance II. Intracellular location of mycobacteria III. Organism grows slowly: difficult to culture and response to chemotherapy is slow (treated for 6 months-2 years). IV. Resistant strains: particularly in patients receive prior therapy or who fail to adhere to the treatment  19 Isoniazid (INH) The most potent anti-TB drug for prophylaxis and treatment Mechanism of action: Isoniazid is activated by mycobacterial catalase– peroxidase (KatG) which in turn inhibiting enzymes acyl carrier protein reductase (InhA) and β-ketoacyl- ACP synthase (KasA). The synthesis of mycolic acid is disrupted. InhA KasA Mycolic acid X Antibacterial Spectrum: Specific for M. tuberculosis. Most non-tuberculosis mycobacteria are resistant to isoniazid. Effective against rapidly growing bacilli and intracellular organisms.  22 Isoniazid (INH) Resistance Chromosomal mutations: I. Mutation or deletion of KatG (producing non-functional mutants KatG) II. Varying mutations of the acyl carrier proteins III. Overexpression of InhA Note: Cross-resistance may occur between isoniazid and other anti- Pharmacokin TB drugs. etics Readily oral absorption (Avoid high-fat meals) Distributes into all body fluids (including CSF), cells and caseous material (necrotic tissue resembling cheese that is produced in tuberculous lesions) Undergoes N-acetylation and hydrolysis to produce inactive products Fast acetylators: T1/2 = 90 mins Slow acetylators: T1/2 = 3-4 hours Excretion: Glomerular filtration and secretion  27 Isoniazid (INH) Adverse 1)effects Peripheral neuritis (most common): Paresthesias of the hands and feet due to pyridoxine (vitamin B6) deficiency (Can be corrected by supplementation of 25-50 mg per day of pyridoxine). 2) Hepatitis (most severe side effects): Due to a toxic metabolite of monoacetyl hydrazine. Incidence increases with age, among patients who take rifampin, or among those who drink alcohol daily. 3) Convulsions in patients prone to seizures 4) Hypersensitivity reactions include rashes and fever 5)Drug potentiation (Isoniazid inhibits the metabolism of carbamazepine and phenytoin causing nystagmus and ataxia). Slow acetylators are particularly at risk.  6 Rifamycins: rifampin, rifabutin, and rifapentine Rifampin Broader spectrum > isoniazid (never give as a single agent) blocks RNA transcription by interacting with the β subunit of mycobacterial DNA-dependent RNA polymerase Bactericidal (target extra and intracellular mycobacteria) Prophylaxis for individual exposed to meningitis caused by meningococci or Haemophilus influenzae. Highly active against M. Leprae Resistance: MUTATIONS of RNA polymerase gene (↓ drug’s affinity)  6 Rifamycins: rifampin, rifabutin, and rifapentine Rifampin (PK) Well oral absorption and distribution (including CSF). CYP450 inducer. Elimination: Bile and faeces (mainly) and urine [Note: Urine, faeces and secretions have an orange-red colour. Tears may even stain soft contact lenses orange-red] Adverse effects Nausea, vomiting, and rash (most common). ↑ risk of hepatic dysfunction when rifampin + isoniazid. Intermittent dosing (≥ 1.2 g): flu-like syndrome, fever, chills, myalgia. May extend to acute renal failure, haemolytic anaemia and shock. Drug interactions Patients receive higher dosages for coadministered drugs Switch to drugs less affected by rifampin  6 Rifamycins: rifampin, rifabutin, and rifapentine Rifabutin For TB patients co-infected with HIV who are receiving protease inhibitors (PIs) or several of the non-nucleoside reverse transcriptase inhibitors (NNRTIs). 40% less potent inducer. Rifabutin has adverse effects similar to rifampin (can also cause uveitis, skin hyperpigmentation, and neutropenia). Rifapentine Activity > ripamfin long half-life In combination with isoniazid, rifapentine may be used once weekly in patients with LTBI and in select HIV-negative patients with minimal pulmonary TB.  Pyrazinamide Short course oral agent (first 2 months), Unknown MOA. Active against tuberculosis bacilli in acidic lesions and in macrophages. Bacteria pyrazinamidase Pyrazinami Pyrazinoic acid (active de drug) Well distribution including CSF Cause liver toxicity and uric acid retention (rarely precipitates a gouty attack).  Ethambutol Bacteriostatic (specific for mycobacteria). inhibits arabinosyl transferase (cell wall synthesis). Well distribution, low penetration into CNS Excreted in the urine. Adverse effects: Optic neuritis (Diminished visual acuity and loss of ability to discriminate between red and green). Risk ↑ with higher doses and in renal impairment patient. Decreased Uric acid excretion (Monitor gout patients). Summary  3 Second lines treatment for TB 1. Streptomycin: - against extracellular organisms - streptomycin-resistant organisms may be treated with kanamycin or amikacin 2. Para-aminosalicylic acid (PAS): - 18 months standard regimen from 1950s- 1960s - Treat MDR-TB. 3. Capreomycin (Avoid with streptomycin): - inhibit protein synthesis. - Reserved for MDR-TB (TDM is needed to monitor nephrotoxicity and ototoxicity). 4. Cycloserine: - disrupts d-alanine incorporation into the bacterial cell wall. - Well distribution including CSF.  3 Second lines treatment for TB 5. Ethionamide: - Analog of INH - Disrupts mycolic acid synthesis in a different pathway from INH. - Wide distribution including CSF. - Metabolised in the liver to both active and inactive metabolites. - Nausea, vomiting, and hepatotoxicity (Common). - May cause hypothyroidism, gynecomastia, alopecia, impotence, and CNS effects. 6. Fluoroquinolones: Moxifloxacin and levofloxacin for MDR-TB. 7. Macrolides: - Azithromycin is preferred to avoid drug interactions (clarithromycin is a both a substrate and inhibitor of CYP 450).  3 Second lines treatment for TB less effective and more toxic than the first- line agents! Leprosy  3 Anti-Leprosy drug Dapsone inhibits dihydropteroate synthetase in the folate synthesis pathway (bacteriostatic). Treat Pneumocystis jirovecii pneumonia in immunosuppressed patients. Well oral absorption and distribution (concentrate in the skin). Parent drug undergoes hepatic acetylation. Both parent drug and metabolites are eliminated in the urine. Adverse reactions: - Haemolysis (especially in G6PD patients) - Methemoglobinemia - Peripheral neuropathy  3 Anti-Leprosy drug Clofazimine Bind to DNA (Block DNA synthesis). May generate cytotoxic oxygen radicals to kill the bacteria. Also against M. tuberculosis and NTM. Well oral absorption and distribution (not into CNS). Accumulates in tissues (allowing intermittent therapy) T1/2= 70 days Possesses anti-inflammatory properties to control Type II lepra reaction (erythema nodosum leprosum). Side effects: - pink to brownish-black discoloration of the skin.  3 Anti-Leprosy drug WHO recommended MultiDrug Treatment regimen (Free of charge by WHO) Multibacillary (MB) leprosy Adults: Rifampicin : 600 mg once a month Dapsone : 100 mg daily Clofazimine : 300 mg once a month 50 mg daily (Duration= 12 months). Paucibacillary (PB) leprosy Adults: Rifampicin : 600 mg once a month Dapsone : 100 mg daily (Duration= 6 months) Single Skin Lesion Paucibacillary leprosy Adults: Rifampicin : 600 mg Ofloxacin : 400 mg Minocycline : 100 mg (Single dose)  18 Antimicrobials Used in the Treatment of Tuberculosis  31 T H A N  K O U ;) )