S. Balakrishnan Department of Pharmacology, Pondicherry Institute of Medical Sciences

1. S. Balakrishnan Department of Pharmacology, Pondicherry Institute of Medical Sciences

2. Absorption How long it takes after absorption till drug is detectable? (lag time or tlag). How long it takes before peak – serum or plasma concentration are achieved (tmax). What is the peak serum concentration? (Cmax)

3. Absorption problems 1 Vomiting patient Ketoconazole needs acid Patients on proton pump inhibitors (PPI), H2 blockers Take with Coca Cola

4. Absorption problems-2 Quinolones (ciprofloxacin) Bind to antacids, sucralfate Solution: PPI or H2 blocker Didanosine (ddI) unstable in acid; so: antacid in the tablet Drugs taken with (out) food

5. Distribution

6. Changing Vd Gentamicin distributes into space resembling extracellular fluid (ECF) ECF larger in shock, drops with recovery Gentamicin levels lower in shock, rise with recovery

7. Limited distribution-1 Most antibiotics well distributed, but ... Not always intracellular Not always to: Central nervous system Eye Prostate Bone Placenta Breast milk

8. Limited distribution-2 Meningitis: Higher doses to get adequate CNS levels Prostatitis: Prefer trimethoprim-sulfamethoxazole, quinolones

9. Intracellular penetration pH- only basic drugs penetrate Beta lactams ansd AGs- NO Quinolones and macrolides-YES

10. Distribution to placenta & breast milk Hard to predict Practical matter: look up data on a drug

11. Plasma protein binding Unbound drug exerts effect. Unbound drug diffuses into extra vascular sites. Slows rate of elimination - & t½ - longer dosing interval. Significant only if > 80%

12. Extensive protein binding “Good”: Allows slow, steady release of heavily bound drug, e.g. ceftriaxone “Bad”: since less “free” drug available for bacteria, e.g. Ceftriaxone Reality: Only one factor

13. Protein binding perinatal issue Sulfonamide displaces unconjugated bilirubin from serum protein Perinatally, high unbound bilirubin causes kernicterus & brain damage Don’t use sulfonamides in 3rd trimester, neonate

14. Biotransformation Phase I Phase II

15. Biotransformation: CYP 450 Often hepatic microsomal enzymes (CYP 450) Rates vary up to 6-fold from one person to the next Enzymes genetically determined

16. Biotransformation: HIV & TB Rifampin (for TB) induces CYP450 3A4 & reduces levels of indinavir (for HIV) Indinavir inhibits CYP450 3A4 & increases levels of rifampin Solution: Low dose rifabutin, high dose indinavir

17. Biotransformation: ketoconazole, erythromycin Ketoconazole, erythomycin inhibit CYP450 3A4 Slows metabolism of cisapride, levels rise, causes torsade de pointes, death Cisapride highly restricted

18. Bioavailability IV to oral switch

19. Elimination Renal vs non renal clearance Elimination t1/2

20. General concept: Elimination t1/2 Half-life Time for serum concentration to fall 50% Constant if a person is stable Varies from person to person

21. Concentration- time curve

22. Extravascularconcentration Extracellular sites reached via diffusion from blood Intracellular fluid Extracellular sites with restrictive barriers Urine

23. General concept: Clearance Quantitative measure of body’s ability to eliminate the drug Includes various forms of excretion

24. Antimicrobial concept: MIC, MBC MIC: Minimum inhibitory concentration (to inhibit growth in vitro) MBC: Minimum bactericidal concentration (to kill in vitro) MIC90: Inhibits 90% of strains

25. Break point Is in part concentration which can be achieved at the site of infection Susceptible: MIC < breakpoint Resistant: MIC > breakpoint

26. Post-antibiotic effect Persistence of effect (inhibition of growth or killing) after drug removed (or level below MIC) “PAE” + pharmacokinetics affects dosing strategy

27. Post-antibiotic effect Post antibiotic sub – MIC effects Post antibiotic – leukocyte effects

28. Important PK/PD Parameters Important PK/PD Parameters 8 Time above MIC: 6 Drug A Drug A Drug B 4 Drug B Proportion of the dosing interval when the drug concentration exceeds the MIC Antibiotic concentration (ug/ml) 2 B B 0 Time A Time above MIC

29. Important PK/PD Parameters AUC/MIC is the ratio of the AUC to MIC Peak/MIC is the ratio of the peak concentration to MIC Area under the curve over MIC PEAK Antibiotic concentration Time

33. PK/PD and Antimicrobial Efficacy • 2 main patterns of bacterial killing • Concentration dependent • Aminoglycosides, quinolones, macrolides, azalides, clindamycin, tetracyclines, glycopeptides, oxazolidinones • Correlated with AUC/MIC , Peak/MIC • Time dependent with no persistent effect • Beta lactams • Correlated with Time above MIC(T>MIC)

34. Goal of therapy based on PK/PD

37. Magnitude of PK/PD measures predictive of efficacy for select antibiotic classes versus some pathogens

38. Aminoglycoside pharmacodynamics in vivo

39. Vancomycin Outcome vs 24h-AUC/ MIC ratio

40. Fluoroquinolone PK/PD vs S. pneumoniae

41. PK/PD of beta-lactams and macrolides in otitis media

42. Concentration dependent killing….azithromycin • 24 hour AUC/ 25-immunocompetent patients • 24 hour AUC/ 125- immnocompromised patients • 24 hour AUC mg.h/ L -3 mg.h/L • Macrolide susceptible S.pneumoniae MIC90 0.12 mg/L • H. Influenzae MIC90 1-2mg/L • Macrolide resistant S. pneumoniae MIC90 >8mg/L

43. PK/PD breakpoints of parenteral beta-lactams based on serum concentrations present for >40-50% of dosing regimens shown and MIC90 values of isolates of S. pneumoniae

44. Dosage Adjustment Needed in Renal Impairment I Acyclovir ethambutol aminoglycosides, Penicillins (except antistaph) aztreonam, Quinolones cephalosporins (except cefaperazone & ceftriaxone) clarithromycin, Carbapenems

45. Dosage Adjustment Needed in Renal Impairment II daptomycin, Vancomycin doripenem, emtricitabine, famiclovir, ertapenem, flucytosine, ganciclovir, imipenem, meropenem, lamivudine, foscarnet, fluconazole,

46. C/I in renal failure Methanamine Nalidixic acid Nitrofurantoin Sulfonamides Tetracyclines except doxy & minocycline

47. Dosage adjust in hepatic impairment Chloramphenicol Clindamycin Erythromycin Metronidazole Tigecycline