1. Reading assignments: Katzung’s Basic & Clinical Pharmacology, 13 th Edi,Ch-47,p815-824;

2. LEARNING OBJECTIVES Antimycobacterial agents Appreciate the consequences of the mycobacterial life cycle in regard to chemotherapy Know mechanisms of action for antimycobacterial drugs Know the distinction between "first-line" and "second- line" anti-TB drugs, and why this distinction is disappearing Know the pharmacogenetics of isoniazid metabolism Know the appropriate use of drug combinations in antimycobacterial chemotherapy

3. The ten leading causes of dalys at ages 15–44 years, the world, 1990 RankingCauses Total Dalys (Millions) % Of total dalys 1 unipolar major depression 43.010.3 2 tuberculosis 19.74.7 3 road traffic accidents 19.64.7 4 alcohol use 14.83.5 5 self-inflicted injuries 14.63.5 6 bipolar disorder 13.23.1 7 war 13.13.1 8 violence 13.03.1 9 schizophrenia 12.53.0 10 iron-deficiency anemia 12.53.0 all causes 419.1100 adapted from murray cjl, lopez ad, editors: global burden of disease. harvard school of public health on behalf of the world health organization, cambridge, 1996.

5. Clinical Picture: (Primary & Secondary TB) Pulmonary infection (most common site) Non-pulmonary infection (lymph nodes, skin, bones, kidneys, peritoneum, pericardium,meninges,et..) Predisposing factors: Malnutrition, overcrowding, poor hygienic condition, contact with TB patient, ingestion of raw milk, diabetes, HIV infection (immune deficiency) Immunosuppressive drugs & anti-cancer chemotherapy.

6. Characteristics of Myobacteria Slow growing Can become dormant Mostly reside inside macrophage, not all drugs reach Cell wall is impermeable to many drugs Develop resistance (more if single or two drugs used) Combination therapy needed (usually 3-4 drugs) Slow response, treatment requires months to years (Usually 6 or 9 months, or up to 2 years for TB bones). Poor compliance due to prolonged Treatment, cost & Symptomatic relief.

7. G.Antimycobacterial drugs FIRST-LINE ANTI-TB DRUGS ISONIAZID ETHAMBUTOL RIFAMPIN RIFABUTIN PYRIZINAMIDE STREPTOMYCIN SECOND-LINE ANTI-TB DRUGS CYCLOSERINE ETHIONAMIDE AMIKACIN CIPROFLOXACIN OFLOXACIN CAPREOMYCIN PARA-AMINOSALICYLIC ACID

8. Anti-TB Chemotherapy Tuberculosis long dormant periods intermittent activeChronic infections with long dormant periods separating intermittent active (symptomatic) periods Mycobacteria are intracellular pathogensAnti-Tuberculosis-- Requires prolonged constant treatment –"Uncomplicated" TB6-9 months –Chemoprophylaxis1 year –Tuberculosis meningitis, Miliary tuberculosis 2 years Resistance develops rapidly to single drugs Combination chemotherapy is the general ruleCombination chemotherapy is the general rule

9. Anti-Mycobacterial Chemotherapy: Isoniazid (INH) Mechanism Mycolic Acids for mycobacterial cell wallBlocks synthesis of Mycolic Acids for mycobacterial cell wall Bactericidal in growing cells onlyPharmacokinetics Well absorbed and distributed after oral administration CNS levels ~20% of serum level; Intracellular = extracellular acetylated in the liverMetabolism key factor in pharmacokinetics-- acetylated in the liver Genetic differences (polymorphism) in acetylation Fast acetylatorsFast acetylators may require higher doses "Fast" acetylators--50% of US Blacks and Whites, most Eskimos, Asians, Native Americans t 1/2 for “Fast acetylators 3 hrst 1/2 for “Fast acetylators 3 hrs Excretion-- Urine (INH and acetylated product) Alter dosing in hepatic, not renal diseaseAlter dosing in hepatic, not renal disease

10. Anti-Mycobacterial Chemotherapy: Isoniazid (INH) Clinical use ProphylaxisProphylaxis-- Used alone for TB exposure, tuberculin convertors Combination chemotherapyCombination chemotherapy for TB– – With ethambutol, rifampin, or pyrazinamide Adverse effects Dose- and duration-dependent HepatotoxicityHepatotoxicity-- –Increases with age of patient –more common in alcoholics –May increase during pregnancy –Increases with age after 35YO; use rifampin for prophylaxis in older patients pyridoxinePeripheral and central neuropathy-- Treat with pyridoxine (Vitamin B6),common in slow acetylators Resistance Resistance-- Can develop rapidly, or is already present 10% of isolates in US resistant Higher in Caribbean, Asia (approaching 20%) Deletion of katG gene in mycobacterium

11. How INH causes peripheral & central neuropathy?

12. Mechanism Inhibits synthesis of mycobacterial cell wall glycanPharmacokinetics Well absorbed and distributed CNS level variable, 4-60% of serum Most excreted in urine-- accumulates in renal failure Adverse effects optic neuritis, decreased acuity, loss of red- greenDose-dependent optic neuritis, decreased acuity, loss of red- green differentiation Resistance Resistance-- Rapid, use in combination Anti-Mycobacterial Chemotherapy: Ethambutol

13. decreased acuity, loss of red-greenA patient diagnosed with TB was prescribed conventional anti TB regimen comprised with 3 drugs. After 6 months of therapy patient developed periocular dull pain, decreased acuity, loss of red-green differentiation. Which drug has caused this?

14. Mechanism RNA synthesisInhibits bacterial RNA synthesis Bactericidal Pharmacokinetics Pharmacokinetics-- Well absorbed and distributed bileExcreted in bile Adverse effects- Adverse effects-- Inducer of microsomal enzymesInducer of microsomal enzymes Alters t 1/2 of anticoagulants, oral contraceptives HepatotoxicHepatotoxic "Flu-like" syndrome orangeGives orange color to body fluids Clinical Use Combination chemotherapy for active disease, single agent prophylaxis for INH-intolerant patients Meningococcal infection prophylaxis Anti-Mycobacterial Chemotherapy: Rifampin

15. Discuss 3 virtual therapeutic situations potentially invite D-D interactions Patient on both antiepileptic & conventional anti TB regimen Patient on both Oral contraceptive & conventional anti TB regimen Patient receiving multidrug cocktail prescribed a conventional anti TB drug regimen

16. Pyrazinamide-- Oral, absorbed, distributed Bacteriostatic Mechanism unknown, but activated by mycobacterium Rapid resistance Cause hyperuricemia Streptomycin Streptomycin-- Was only for severe (life-threatening) cases, now used more frequently Pharmacokinetics, adverse effects typical of aminoglycosidePharmacokinetics, adverse effects typical of aminoglycoside Anti-Mycobacterial Chemotherapy: Pyrazinamide and Streptomycin

17. During a course of ATT patient took some high purine containing diet/other foodstuffs and developed Gout Or clinic-patho- biochemical features of gout-severe pain, redness & swelling involving big joints (1 st MTP being the commonest).S.Uric acid was >>7mg/dl Which drug probably has caused this ? What is the possible mechanism?

18. Rifabutin, also a derivative of Rifamycin, inhibits DNA- dependent RNA polymerase in E. coli, and interferes with DNA synthesis in M. tuberculosis. Prevention and Treatment of disseminated atypical mycobacterial infection AIDS patients. Adverse Effects Rifabutin is both a substrate and inducer of CYP450, but a less potent inducer than Rifampin. Rifabutin

19. Clinical Scenario: A 50 years old patient was recently diagnosed with pulmonary tuberculosis. He is already on multidrug cocktail for his other concomitant conditions. What precautions would you like to take while prescribing combination therapy for TB for him ?

20. Second Line Anti-TB Drugs except for highly resistant strains Toxicity outweighs therapeutic effects except for highly resistant strains –Para-aminosalicylate (PAS), Cycloserine, Ethionamide drugs—Amikacin, Ciprofloxacin, Ofloxacin –Other drugs—Amikacin, Ciprofloxacin, Ofloxacin Currently a major resurgence in TB, highly resistant strains are common 2nd line may become 1st line

21. Key features of 2 nd generation drugs ETHIONAMIDE chemically related to Isoniazid, blocks the synthesis of mycolic acid Adverse Effects Intense gastric irritation, Neurologic symptoms (Pyridoxine given) and Hepatotoxicity. CYCLOSERINE Inhibits cell wall synthesis Adverse Effects Most serious side effects during the 1 st 2 weeks of treatment (25%) are peripheral neuropathy and CNS dysfunction, including depression and psychosis. Neurologic toxicity is minimized by giving pyridoxine 150mg/d. CIPROFLOXACIN and LEVOFLOXACIN Fluoroquinolones must be used in combination with other antitubercular drugs to which the strains are susceptible

22. Understanding biology of TB Infection There is continuous shifting of bacilli between those below subpopulation. 1.Rapidly growing - High bacillary load-+nt in areas where oxygen tension is high +PH is neutral Susceptibility to drugs-H>>>R,E,S 2.Slow growing- +nt in low PH sites(intracellularly+inflamed site) Succeptibility to ATT- Z>>>H,R,E 3.Spurter – Oxygen tension low +PH neutral ATT that is susceptible is R 4.Dormant- inactive for prolonged period No ATT is useful. H-INH,R-Rifampin,E-Ethambutolol,S-Streptomycin,Z-Pyrezinamide

23. Of the first-line agents for Mycobacterium tuberculosis, only pyrazinamide requires an acidic environment (as is present within macrophage phagolysosomes) to exert antimicrobial effects. Isoniazid, rifampin, and ethambutol are more active than PZA against extracellular mycobacteria.

24. GOAL OF ATT 1.KILL DIVIDING BACILLI - to give him symptomatic relief -to make him sputum negitive 2.KILL PERSISTING BACILLI -depends upon sterilizing effect of the drug 3.PREVENT EMERGENCE OF RESISTENCE -H,R-Cidal,effective against almost all population -Z-Cidal,effective on Intracellular bacilli + inflamed site but with sterilizing activity -S-Cidal, on rapidly dividing extracellular bacilli -E-Static,prevent resistance and hasten sputum conversion

25. ATT PROFILE Includes combination of several anti TB drugs to -check the resistance -to have enhanced efficacy -to reduce incidences of A/E Conventional regimens- H+Tzn/E+-S(for initial 2 months) x12-18 months- OBSOLETE Short course Chemotherapy- -Introduced by WHO in 1997 -All first line drugs are standardized on body weight basis both for children and adult. -All regimens have INITIAL INTENSIVE PHASE 2-3 months-(to reduce bacilli load,to prevent transmission and to give symptomatic relief ) followed by CONTINUATION PHASE of 4-6 months or even longer till patient is completely sterile,no relapses.

26. DRUGS FOR LEPROSY -Treatment for several months to a person’s lifetime. WHO now recommends multidrug therapy for most patients with leprosy. Multidrug therapy hastens the eradication of bacteria, reduces the duration of active disease, and prevent worsening of disabilities. Multidrug therapy also appears to reduce overall cost, increase patient’s compliance, and increase the motivation and availability of leprosy workers.

28. DAPSONE & OTHER SULFONES Sulfones are structurally related to Sulfonamides and have similar mechanism of action. Sulfones inhibit the synthesis of folic acid by M. leprae, and exhibit a bacteriostatic action. Dapsone is used in combination with Rifampin, with or without Clofazimine to prevent the emergence of resistance.

29. Dapsone Administered orally (100mg daily), well absorbed from the gut and widely distributed throughout body fluids and tissues. The drug tends to be retained in skin, muscle, liver and kidney. Skin heavily infected with M. leprae may contain several times as much Dapsone as normal skin. Sulfones are metabolized by acetylation and excreted in urine. Renal failure requires dosage adjustment. Sulfones are also excreted into bile and are reabsorbed. Adverse Effects: G.I.T. disturbances, Peripheral Neuropathy, Optic neuritis, Blurred vision, Proteinuria and Nephrotic syndrome, Lupus-like syndrome and Hematologic toxicity. Patients with G-6-P Dehydrogenase deficiency may exhibit hemolytic anemia due to oxidation of erythrocyte membranes by Dapsone.

30. CLOFAZIMINE Clofazimine is a phenazine dye with Antimycobacterial and Anti- inflammatory effect. Clofazimine is bactericidal against M. tuberculosis, is bacteriostatic against M. leprae, and is active against M. avium intracellulare. The drug enhances the phagocytic activity of Neutrophils and Macrophages, and reduces the motility of Neutrophils and the ability of Lymphocytes to transform. Clofazimine is approved for use in combination with Dapsone and Rifampin for the treatment of Lepromatous leprosy. Its use is chiefly limited to Sulfone-resistant patients or intolerance to sulfone. Slowly and incompletely absorbed from the gut and primarily distributed to adipose tissue and RE cells, but accumulated in the liver, lungs, lymph nodes, spleen and other tissues.

31. Anti-inflammatory and Immunologic effects may be responsible for its efficacy in the prevention and treatment of Erythema Nodosum Leprosum, a type II hypersensitivity reaction seen during or after the treatment of Lepromatous Leprosy. The drug has a long half-life (about 70 days) and some of it remains in the body for years after the therapy is discontinued. Adverse Effects G.I.T. disturbances such as anorexia, N/V, abdominal pain and diarrhea. Photosensitivity, skin discoloration (ranging from red-brown to nearly black) and discoloration of bodily secretions, such as sweat, tears, sputum, feces, and urine during therapy. Clofazimine may elevate hepatic enzyme levels and may cause hepatitis; its use is generally avoided in patients with hepatic disease.

32. Antibiotics of Choice for Various Infections Drug Organism (Disease) Amoxicillin, clarithromycin(omeprazole*)Helicobacter pylori (peptic ulcer) Amoxicillin, clarithromycin (omeprazole*)Helicobacter pylori (peptic ulcer) AmpicillinListeria (meningitis) Ceftriaxone, CefeximeNeisseria gonorrhoeae (gonorrhea) Cephalosporins (third-generation)Haemophilus influenzae (pneumonia, meningitis) Klebsiella (meningitis Klebsiella (meningitis) DoxycyclineBorrelia burgdorferi (Lyme disease) Rickettsiae (Rocky Mountain spotted fever) ErythromycinLegionella (legionnaires’ disease) Fluconazole, miconazole, nystatinCandida (candidiasis) Isoniazid, rifampin, ethambutol, Mycobacterium tuberculosis pyrazinamide(tuberculosis) *Omeprazole is not an antibiotic but is used in combination with antibiotics for treatment of H. pylori.

33. Antibiotics of Choice for Various Infections Drug Organism (Disease) MacrolidesMycoplasma pneumoniae (atypical pneumonia) Legionella (legionnaires’ disease) Corynebacterium diphtheriae; Chlamydia MetronidazoleTrichomonas (trichomoniasis) Penicillin GNeisseria meningitidis (meningitis) Treponema pallidum (syphilis) Infections caused by streptococci, pneumococci, other meningococci, Bacillus anthracis, Clostridium, Bacteroides (except B. fragilis) FluroquinolonesCampylobacter (diarrhea); Shigella TetracyclineVibrio cholerae (cholera) Other tetracyclinesChlamydia (pneumonia, lymphogranuloma venereum) Trimethoprim-sulfamethoxazoleSalmonella; Shigella (diarrhea) Metronidazole or vancomycin (oral)Clostridium difficile (diarrhea)

34. Prophylactic Use of Anti-infective Drugs DrugUse CefazolinSurgical procedures Cefoxitin, CefotetanSurgical procedures where anaerobic infections are common Ampicillin or penicillinGroup B streptococcal infections Trimethoprim-sulfamethoxazolePneumocystis carinii pneumonia (PCP) UTIs RifampinHaemophilus influenzae type B Meningococcal infection ChloroquineMalaria IsoniazidTuberculosis AzithromycinMycobacterium avium complex (MAC) in patients with AIDS Ampicillin or azithromycin or clindamycinDental procedures in patients with valve abnormalities AIDS = Acquired immunodeficiency syndrome; UTI = urinary tract infection.

35. Which of the following would be the most appropriate for tuberculosis prophylaxis, in order to minimize the risk of hepatotoxicity and drug-drug interactions, in a 51-year-old man on HIV antiretroviral medications? A.Clarithromycin B.Isoniazid C.Pyrazinamide D.Rifabutin E.Rifampin Answer: D Isoniazid should not be used in patients over 50 yo

36. A 20-year-old male college student living in the dormitory has a close contact friend who developed a meningococcal infection. Which of the following medications is recommended for meningococcal prophylaxis in this patient? A.Amoxicillin B.Cefaclor C.Ceftriaxone D.Penicillin G E.Rifampin Answer: E Rifampin is used prophylactically against possible exposure to meningococci

37. PowerPoint Slides  Several of the PowerPoint slides are Copyright © 2002-04, the American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved.  Some of slides in this session are from the above mentioned format and are free for use by members of ASPET.  Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology,MUA).  Core concepts of various USMLE High yield review series like Kaplan,BRS etc. are thoroughly explored & integrated whenever necessary