Tuberculosis Drugs PDF

Pharmacology of Drugs used in the Management of Tuberculosis Mr J Mahlangu [email protected] Office: 8Q16 Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of Witwatersrand, Sout...

Pharmacology of Drugs used in the Management of Tuberculosis Mr J Mahlangu [email protected] Office: 8Q16 Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of Witwatersrand, South Africa  Learning Objectives:  Differentiate between drugs used in the first line TB regimen and the second line drugs for TB/MDR  Describe the mechanism of action of each TB drug  Identify the adverse effects associated with each TB drug  Understand the pharmacokinetics and drug-interactions of the first line TB drugs  Identify the drugs with the risk of causing drug-induced liver injury  Identify the treatment period and agents used in the chemoprophylaxis of TB close contacts  Understand the use of TB vaccine  Outline the drugs used in the management of TB in HIV-positive patients and pregnant women Tuberculosis (TB) Pathogenesis  Airborne infectious disease  Mycobacterium tuberculosis  Spread via air droplets  via active respiratory disease: active TB  Primary infection – asymptomatic  bacteria proliferate in macrophages  Treatment  Prevent death, relapse and transmission of active TB  Prevent development of drug resistance  Hindered by:  mycobacterium resistant to antibiotics  mycobacterium cell wall lipid-rich  mycobacterial cells be dormant  require treatment beyond disappearance of clinical symptoms Diagnosis: Latent TB infection: TB skin test and TB blood test TB disease: medical history, physical examination, chest x-ray, and Xpert/culture  First line TB drugs  Correct drugs for an adequate duration of time  Directly observed therapy (DOT)  Achieve treatment completion and compliance  1st line drugs: effective with acceptable degree of toxicity  Isoniazid (H)  Rifampicin (R)  Pyrazinamide (Z)  Ethambutol (E)  First line TB drugs Intensive Phase : HRZE : 2 months  Multi-drug therapy Continuation Phase : HR: 4 months  Daily dosing Intensive phase:  Eradicate the tubercle bacilli  Clinical improvement of the illness Continuation phase:  Sterilizing effects eliminate the remaining bacilli  Prevent relapse  First line TB drugs Table 1: Children ≥ 8 years of age Intensive phase (2 Continuation phase (4 months) months) given daily given daily Doses in mg RH RH RHZE (150,75,400,275) (150,75) (300,150) Table 2: Children ≤ 8 years of age Intensive phase (2 Continuation phase (4 months) months) given daily given daily R: 10 - 20 R: 10 - 20 Target dose or range H: 7 - 15 H: 7 - 15 (mg/ kg/ dose) Z: 30 - 40  Severe/complicated TB TB meningitis, TB bones/joints, miliary TB  Intensive Phase: HRZE : 2 months  Continuation Phase: HR: 7 months Treatment = 9 months  Isoniazid  Synthetic pyridoxine analogue (pro-drug)  Activated by mycobacterial catalase peroxidase (KatG)  Resistance: Kat G , InhA mutations  MOA: inhibits mycolic acid synthesis  Clinical Uses:  Mycobacterium Tuberculosis  Non-tuberculosis mycobacteria  Chemoprophylaxis of TB  Isoniazid Catalase peroxidase activates isoniazid Activated isoniazid acts on enoyl-acyl FAS-II synthesise long chains mycolic acids  Isoniazid  PK: Isoniazid undergoes metabolism in the liver by N-acetylation  Acetyl-INH - metabolite Fast May require higher T1/2: 1hrs Hepatotoxicity acetylators dose Slow Potential for greater T1/2: 3hrs therapeutic Neurotoxicity acetylators response  Pyridoxine  Drug interactions:  Antacids decrease absorption  Inhibits Cytochrome P450 Increase plasma conc. of phenytoin/carbamazepine, warfarin Isoniazid  Rifampicin  Bactericidal  Rapidly develop resistance when used alone  PK:  Highly protein bound  Oral bioavailability decreased - food and first pass metabolism  Half-life: 2-5 hrs  Rapid metabolism in liver  Well distributed  Clinical Uses  Mycobacterium Tuberculosis  Mycobacterium Leprae (Leprosy infections)  Brucellosis, resistant staphylococcal infections  Rifampicin MOA : binds to the β-unit of DNA-dependant RNA polymerase RNA synthesis  Rifampicin  Resistance: mutations in rpo β (β subunit of RNA polymerase)  Drug interactions:  Potent inducer of cytP450 enzymes: protease inhibitors, NNRTIs, warfarin, COC, phenytoin, fluconazole, oral hypoglycaemic, theophylline, digoxin lopinavir/ritonavir  Adverse effects:  GIT effects: N, V, D, anorexia  Rash, hypersensitivity reactions  Hepatitis  Red-orange colour of fluids-tears, urine, sweat  Rifabutin  Related to rifampicin  Less potent inducer of cytP450 than rifampicin  PK:  Half life: 36 hours  Metabolized in liver  Clinical Uses:  Mycobacterium Tuberculosis  Prophylaxis in MAC  Rifapentine  Antimicrobial rifamycin derivative  Similar spectrum of activity to rifampicin  PK:  Half-life: 14–16 hours  Metabolized in liver  Eliminated primarily via biliary excretion  Clinical Uses:  TB Preventive Treatment 3HP: three months of isoniazid and rifapentine given once weekly  Pyrazinamide  Mycobactericidal intracellular mycobacteria - acidic medium  Prodrug: Hydrolysed to active pyrazinoic acid (inactive at neutral pH)  PK: Widely distributed; Half-life: 9-10 hours  Clinical Uses:  Highly specific for M. tuberculosis  Drug interactions:  Allopurinol, probenecid, diuretics  Adverse effects:  Hepatotoxicity (hepatitis, liver damage)  Hyperuricaemia, joint pain  Pyrazinamide MOA : Converted to pyrazinoic acid by mycobacterium pyrazinamidase Inhibits cell wall synthesis  Ethambutol  Inhibits mycobacterium cell wall synthesis  PK:  Widely distributed  Half-life: 3-4 hours  Mainly eliminated by excretion in urine  Crosses BBB in meningitis (10-50% penetrates the inflamed meninges)  Clinical Uses:  Only used in mycobacterial infections  Drug interactions:  Diuretics, neurotoxic agents  Adverse effects:  Ocular toxicity; retrobulbar neuritis  Hyperuricaemia, joint pain  Ethambutol MOA : Inhibits arabinosyltransferase (polymerisation of arabinogalactan required for cell wall synthesis)  MDR-TB  MDR-TB: Resistance to rifampicin and isoniazid, with or without resistance to other drugs  Second line drugs: expensive, less effective, increased side effects  DoT depends on regimen used and extent of drug resistance Intensive phase Continuation phase (6-8 months) (12 months) Bedaquiline Linezolid Linezolid Levofloxacin/ moxifloxacin Levofloxacin/ moxifloxacin Clofazimine Clofazimine Terizidone/ cycloserine Delamanid Pyrazinamide Terizidone/ cycloserine Ethinoamide Pyrazinamide Isoniazid (high dose) Ethinoamide Para-aminosalicylic acid Isoniazid (high dose) Pretomanid: BPaLM or BPaL ( 3x the upper limit of normal (with symptoms) OR  ALT> 5x the upper limit of normal (no symptoms)  Monitor ALT levels  Second-line agents (streptomycin, ethambutol, levofloxacin)  Re-introduce:  Rifampicin> Isoniazid> Pyrazinamide  Monitor liver function (ALT every 3 days)  TB Preventive Treatment (TPT)  TPT should be given to individuals at risk of developing TB  Current TPT options include:  3HP: three months of isoniazid and rifapentine given once weekly  3RH: three months of daily rifampicin and isoniazid  6H: six months of daily isoniazid  12H: 12 months of daily isoniazid  If diagnosed with TB initiate full course of TB  Babies born to mothers with active TB must be screened for congenital TB – initiate TPT or TB treatment  BCG vaccine  BCG, or Bacille Calmette-Guérin  Many countries – high prevalence  SA given at birth via intradermally  Live vaccine – prepared from bovine tubercle bacillus  Stimulate immune system  TB skin test- detect TB infection in BCG vaccinated  TB blood tests √  Contraindications:  Immunosuppression (HIV infected, immunocompromised)  Pregnancy  TB and HIV Infection  Short course of standard TB treatment  Co-treated patients monitored  HIV-infected patients with TB started on ART  Established on TB treatment (1-8 weeks)  CD4 count of