TB.pptx

Advanced pharmacology

1. ANTI-TUBERCULOSIS MUHSINA K M PHARM (PHARMACOLOGY)

2. CONTENTS Introduction Drugs Treatment Dots therapy Reference

3. INTRODUCTION Tuberculosis (TB) is a chronic granulomatous disease & a major health problem in developing countries . 1/3 rd of worlds population is infected with Mycobacterium tuberculosis.

4. BIOLOGY OF TB

5. DRUGS FOR TB First line drugs: high efficacy- low toxicity- routinely used Second line drugs : low efficacy-higher toxicity-reserve drugs Streptomycin (1947) Ethionamide, Prothionamide , Cycloserine, Terizidone, PAS, Rifabutin, Rifapentin Isoniazid (1952) Fluoroquinolones : Ofloxacin, Moxifloxacin, Levofloxacin, Ciprofloxacin Ethambutol (1961) Injectables: Kanamycin, Amikacin, Capreomycin. Rifampicin (1962) Pyrazinamide (1970)

6. ISONIAZID(ISONICOTINIC ACID HYDRAZIDE)H MOA: inhibition of synthesis of mycolic acid- unique fatty acid in mycobacterial cell wall- lipid content of cell wall reduced. genes “ inha ” & “ kasa ” are targeted INH enters mycobacteria – converted to active metabolite by catalase peroxidase ( KatG ) Adducts with NAD & inhibits “ inhA ” & “ KasA ” Also adducts with NADPH- DHFRase inhibition- no DNA. RESISTANCE: 1 in 10^6 inherently resistant Mutation of KatG Mutation of “ InhA ” & “ KasA ” Efflux of INH & its concentrating mechanism KINETICS: Complete absorption orally-all tissues,cavities,meninges,placents . N-acetylation by NAT2(urine) Fast acetylators( t1/2:1hr) & slow acetylators( 3hr) CYP2E1Acetylhydrazine-hepatotoxic.

7. Drug interactions : Aluminium hydroxide (AIOH) Retards metabolism - Phenytoin, carbamazepine diazepam, theophylline CYP2C19 and CYP3A4 ADRs : Peripheral neuropathy - numbness, parasthesia , mental disturbance & convulsion dose dependent Why? pyridoxal INH (hydrazone) pyridoxal PO4 not formed from pyridoxine Prophylactic- pyridoxine (100 mg/day) special group Hepatitis elderly and alcoholics (CYP2E1 induced) Lethargy, rash, fever, acne and athralgia

8. RIFAMPICIN(R) MOA: Interrupts RNA synthesis Binds to B subunit of DNA- dependent RNA polymerase ( rboB ) - blocks polymerizing function Resistance : Primary resistance 1 in 1071Developes rapidly and due to mutation of rboB gene- reduces affinity for drugs,mutation in efflux pumps. Primary resistance- rare 2% No cross resistance Kinetics: well absorbed - 70% bioavailability-food Interferes Well distributed penetrates intracellularly, cavities, caseous masees and placenta Crosses meninges but pumped out p- gp Deacetylated in liver and excreted in bile and urine Enterohepatic circulation Half life 2-5 hours

9. Interactions: Hepatic microsomal enzymeInducer CYP3A4, CYP2D6, CYP1A2 and CYP2C Induces own metabolism Warfarin, OCP corticosteroids sulfonylureas, proteaseinhibitors , NNRTIs,theophylline , metoprolol, fluconazole, clarithromycin, phenytoin, NNRTIS Remember OCP-failure Uses: Leprosy, Meningococcal and H. influenzae meningitis, Brucellosis ADRS : Hepatitis-pre-existing disease + > 600 mg- jaundice discontinue Cutaneous syndrome: flushing, pruritus, rash, redness and watering of eyes Flu syndrome: chill, fever, headache, malaise and bone pain Abdominal syndrome; nausea, vomiting, abdominal cramps diarrhoea Orange-red urine Purpura, haemolysis, shock and renal failure

10. PYRAZINAMIDE(Z) Similar to INH- developed parallelly Weak bactericidal- more active in acidic medium- intracellular and inflammatory areas Highly active in first 2 months - kills residual intracellular bacilli- sterilizing Advantage: Shortening of duration of treatment and reduces risk of relapse MOA: Not clear- Inside mycobacteria – active metabolite pyrazinoic acid by pyrzinamidase ( pncA ) Accumulates in acidic medium and inhibits mycolic acid Also disrupts cell membrane and transport Resistance : when used alone mutation of pncA gene Kinetics: well absorbed orally, widedistribution , good CNS penetration (meningeal TB) excreted in urine 6-10 hourshalf life ADRs:Dose related hepatotoxicity-less among Indians (>30 mg/kg) Contraindicated in liver diseases Pregnancy Hyperuricaemia –gout Abdominal distress, athralgia , flushing, rashes, fever loss of diabetes control

11. ETHAMBUTOL Tuberculostatic- effective against MAC and some other fast multiplying bacill With HRZ regimen sputum conversion hastens and prevents resistance MOA: Not clear-Inhibits arabinosyl transferase ( embAB ) involved in arabinogalactam synthesis- mycolic acid incorporation to cell wall prevented Resistance : slowly mutation of embAB -no cross resistance to other drugs Kinetics: 3/4 of oral dose absorbed, low CNS penetration, stored in RBCS-excreted by gl filtration half life 4 hours ADRS: Good patient acceptability - low ADRs Loss of visual acuity/colour vision, field defects due to optic neuritis Stop once visual defect occurs Children? Early detected – reversible Contraindicated in optic neuritis Nausea, rash, fever, peripheral neuritis Pregnancy

12. STREPTOMYCIN First clinically useful anti-TB drug - aminoglycoside Tuberculocidal - less effective than INH or Rifampicin Only on extracellular bacilli - poor penetration Other drugs and host defence mechanism MOA: Inhibition of protein synthesis - binds to 305and 505 subunits - freeze initiation and interferes polysome formation and misreading of mRNA code Resistance: rapidly and relapse-stop in resistance Acquiring of membrane bound inactivating enzyme- phosphorylate/adenylate/acetylate the drug- conjugated drugs do not bind to target ribosomes -- -conjugation and plasmid mediated acquiring-nosocomial microbes Mutation decreasing the affinity of ribosomal proteins to drugs Decreased efficiency of transporting mechanism ADRS: Ototoxicity: Most common vestibular and cochlear damage deposition in labyrinthine fluid slowly removed greater toxicity when persistent high plasma concentration Cochlear damage- base to apex and high to low frequency sounds no regeneration of sensory cells permanent deafness Vestibular damage- Headache nausea, vomiting. dizziness, nystagmus, vertigo, ataxia Nephrotoxicity: Tubular damage urinary conc. mechanism lost, low GFR, nitrogen retention, albuminuria and casts due to deposition incortex Neuromuscular blockade: reduce Ach

13. FLOUROQUINOLONES Ofloxacin( Ofx ), Levofloxacin( Ofx ), Moxifloxacin( Mfx ), and Ciprofloxacin( Cpx ) - bactericidal Active against - MAC, M fortuitum and other atypical ones Mfx > Lfx > Ofx > Cfx (But Cfx is most in atypical) Penetrates cell and kill mycobacteria in macrophages Uses: Drug resistant TB ( Lfx is standard in MDR TB)

14. OTHER DRUGS Second line drugs: Kanamycin Km), amikacin (Am), capreomycin (Cm) Ethionamide ( Eto ) prothionamide ( Pto ). cycloserine (Cs), terizidone ( Trd ), PAS, rifabutin, rifapentine, bedaquline .

15. MANAGEMENT OF TB

16. GOALS OF ANTI-TUBERCULAR CHEMOTHERAPY Kill dividing bacilli: Drugs with early bactericidal action rapidly reduce bacillary load in the patient and achieve quick sputum negativity so that transmission of TB is interrupted. This also affords quick symptom relief. Kill persisting bacilli: To effect cure and prevent relapse. This depends on sterilizing capacity of the drug. Prevent emergence of resistance: The relative activity of the first line drugs in achieving these goals.

17. PRINCIPLES OF ANTITUBERCULOSIS CHEMOTHERAPY Mycobacterium tuberculosis is not a single species, but a complex of species with 99.9% similarity at the nucleotide level. The complex includes M. tuberculosis (typus humanus ), M. canettii , M. africanum , M. bovis , and M. microti. ANTITUBERCULOSIS THERAPY: Traditionally, first-line anti-TB agents are used for the treatment Treating TB in less than 6 months Traditionally, first-line agents were more efficacious and better tolerated- Relative to second-line agents. Second-line agents were used in case of poor tolerance or resistance to first-line agents.

18. TYPES OF ANTITUBERCULOSIS THERAPY

19. TYPES OF ANTITUBERCULOSIS THERAPY Prophylaxis : After infection with M. tuberculosis, about 10% of people will develop active disease over a lifetime. The highest risk of reactivation TB is in patients with Mantoux tuberculin skin test reaction 5 mm or greater who also fall into one of the following categories # recently exposed to TB # have HIV coinfection # have fibrotic changes on chest radiograms # post-transplantation # taking immunosuppressive medications Any person with a skin test greater than 15 mm is also at high risk of disease.

20. TYPES OF ANTITUBERCULOSIS THERAPY Prophylaxis ( Conti….): In these patients at high risk active TB, prophylaxis is recommended to prevent active disease .Prophylaxis consists of four regimens. Patient who cannot take isoniazid should be given rifampicin.

21. TYPES OF ANTITUBERCULOSIS THERAPY Definitive therapy of drug- susceptible TB : All active TB cases should be confirmed by culture or rapid diagnostic methods such as nucleic acid amplification tests The duration of therapy of drug- susceptible pulmonary TB is 6 months. #) Initial phase of therapy ( first 2 months of four drug regimen) #) Continuation phase ( last 4 months) A 9- month duration should be used for patients with cavitary disease who are still sputum culture positive at 2 months. The treatment of TB pericarditis is a special case in which the use of steroids has been advocated.

22. TYPES OF ANTITUBERCULOSIS THERAPY Definitive Therapy of Drug-Resistant TB : The XDR-TB is MDR-TB that is also resistant to fluoroquinolones and at least one of three injectable second-line drugs ( ie ., amikacin, kanamycin, or capreomycin). These diseases, virtually untreatable ( bedaquiline and delaminid in combination with optimized background regimens can be used) Therapy should be based on evidence of susceptibility and should include: at least three drugs with at least one of the injectable anti-TB agents MDR-TB, a prolonged course of 5 to 7 agents, except a shorter 9-12 month regimen if there is no resistance to fluoroquinolones and second-line injectable agents.

23. TREATMENT OF TUBERCULOSIS IN ADULTS Fixed-Dose Combinations Directly Observed Therapy (FDCs) (DOT)

24. Treatment of TB in adults Fixed-Dose Combination (FDCs): Forecox -Trac Film Coated Tab: Isoniazid, Rifampicin, Ethambutoland Pyrazinamide Rimactazid 300 Sugar Coated Tab: Isoniazid and Rifampicin Rimcure 3-FDC Film Coated Tab: Isoniazid, Rifampicin & Pyrazinamide Akurit - Z Tab: Isoniacid , Rifambin (Rifampicin), & Pyrazinamide. Akurit Tab : Isoniazid, Rifampin ( Rifmpicin ) Akurit -Z kid Tab: Isoniazid, Rifampin & Pyrazinamide. Akurit -4 : Ethambutol , Isoniazid, Rifampin , & Pyrazinamide.

25. Directly Observed Therapy (DOT) WHO introduced 6-8 month multidrug 'short course' regimens in 1995 under the Direct Observed Therapy, Short Course (DOTS)programme. Directly observed therapy (DOT) to ensure adherence and good management practice. In this patients are divided into 4 categories. #) Category I : New case of sputum smear positive or severe pulmonary TB. #) Category II: Defaulted, irregularly treated and relapse cases. #) Category III: New sputum smear negative pulmonary TB. #) Category IV: Chronic cases who remained or again became sputum smear positive after receiving fully supervised category II treatment.

26. SHORT COURSE CHEMOTHERAPY ( DOTS)

27. TB IN CHILDREN There is an increasing trend of TB cases among children in Malaysia. AntiTB drug and management of children with TB Suld be in line with the WHO Stop TB Strategy , taking into consideration the epidemiology and clinical presentation of TB in children. TB IN PREGNANT WOMEN The WHO and British Thoracic Society consider H, R, E and Z to be safe to the foetus and recommend the standard 6 month (2HRZE + 4HR) regimen for pregnant women with TB. S is contraindicated because it is ototoxic to the foetus. [Isoniazid (H), Rifampin (R), Pyrazinamide (2), Ethambutol (E)]

28. Tuberculosis in lactation Breast feeding mothers with TB should receive a full course of anti-TB drugs. First-line anti-TB drugs are safe in breast feeding. Mother and baby should stay together for continuation of breastfeeding. Once active TB in the baby is ruled out, the baby should be given six months isoniazid prophylaxis, followed by BCG vaccination. Tuberculosis in AIDS patients The association of HIV and TB infection is a serious problem. HIV positive cases have a higher incidence of extrapulmonary, more severe, more lethal and more infectious TB. Initial intensive phase therapy with daily HRZE for 2 months is started immediately on the diagnosis of TB, and is followed by a continuation phase of HR for 4-7 months (total 6-9 months). [Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E)]

29. TB CLASSIFICATION FOR DRUG REGIMEN Drug-sensitive TB : Sensitive to all 5 drugs all new cases who have never taken any drug or taken for less than 1 (one) month Multidrug resistant TB (MDR-TB): Resistant to both R and H with or without resistant to any other drug Rifampicin resistant TB (RR-TB): Resistant to R but not to H with or without resistant to other drugs-treated like MDR TB Mono-resistant TB : Resistant to 1 (one) first line drug but not to R Poly drug resistant TB : Resistant to more than one first line drug but not to R and H Extensive drug resistant TB (XDR-TB): MDR-TB with resistance to 1 fluoroquinolone and 2 Line Injectable drug.

30. DRUG SENSITIVE TB New cases: Initial 2 months: Treated with RHZ and E reduces the risk of resistance H Next 4 months After 2 months Z discontinued and continued with RHE (Old guideline E was not included and thrice weekly regime) Given daily basis Previously treated: Initial 2 months Treated with S R H Z and E 3 month: No 5 but H R Z E Next 5 months: continued with R H E In severe extrapulmonary TB: P is extended by 3-6 months in both above cases Fixed dose combinations are recommended - patient takes all the drug risk of bacilli being exposed to only 1 or 2 drugs

31. MULTI DRUG RESISTANT (MDR) TB MDR-TB is defined as resistance to both H and R, and may be any number of other (first line) drug(s). Its treatment requires complex The general principles of treatment of MDR-TB are: #) The regimen should have at least 4 drugs certain to be effective #) Efficacy may be placed on survey of similar patients who have been treated #) Avoid combining cross resistance drug. e.g. two FQs, #) Include drugs from group I to group IV (alternative classification) in a hierarchial order.Gr . I drug included (Z and E), 1 Gr.ll drug, 1 Gr.Ill drug & 2 Gr.Ivdrugs .

32. OTHER CASES RR-TB: treated like MDR-TB H is added IP & months with 7 drugs Km, Lx, Eto , 5, 7, E, and H 18 months continuation phase Lfx , Eto , 1, E and H Monodrug resistant: Resistant to 1 first line drug (DST or LPA (line probe assay): R2 of the first line drugs-1 injectable 2 line 1 FQ daily in IP of 3-6 months (Total9-12 months) Poly drug resistance: Resistance to more than 1 first line drug except R: R1 injectable 2 line 1 FQ 1 first line drug 1 oral 2nd Line ( Eto /Cs/PAS) IP of 3-6 months-injectable stopped in CP (9-12 months) Isoniazide resistant: Low level due to mutation of InhA dose Increased up to 900 mg daily but in KatG mutation- does not work.

33. XDR -TB Resistant to at least 4 effective drugs H, R, FQ and one of Km/Am/Cm Difficult to treat Standard MDR-TB drugs must be stopped Cm 1000mg, Mfx 400 mg, H 900 mg, PAS 12 gm, Linezolid 200 mg, Amoxycillin/clavulanate 875+125 (2 tablets) IP 6-12 months and P 18 months.

34. REFERENCE The pharmacological basis of therapeutics, Goodman & Gilman’s, 12 th edition, Pg no: 1550-1578 A Review on Clinical Pharmacist Care Services on Prevention and Management of Tuberculosis associated Burden in Health Care Practice by MS Umashankar , A Bharath Kumar. K D Tripathi, 8 th edition, page number: 654-673 Internet source.