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S. Balakrishnan Department of Pharmacology, Pondicherry Institute of Medical Sciences. Absorption. How long it takes after absorption till drug is detectable? (lag time or t lag ). How long it takes before peak – serum or plasma concentration are achieved (t max ).

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

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S balakrishnan department of pharmacology pondicherry institute of medical sciences

S. Balakrishnan

Department of Pharmacology,

Pondicherry Institute of Medical Sciences


Absorption

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)


Absorption problems 1

Absorption problems 1

Vomiting patient

Ketoconazole needs acid

Patients on proton pump inhibitors (PPI), H2 blockers

Take with Coca Cola


Absorption problems 2

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


Distribution

Distribution


Changing v d

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


Limited distribution 1

Limited distribution-1

Most antibiotics well distributed, but ...

Not always intracellular

Not always to:

Central nervous system

EyeProstateBone

Placenta Breast milk


Limited distribution 2

Limited distribution-2

Meningitis: Higher doses to get adequate CNS levels

Prostatitis: Prefer trimethoprim-sulfamethoxazole, quinolones


Intracellular penetration

Intracellular penetration

pH- only basic drugs penetrate

Beta lactams ansd AGs- NO

Quinolones and macrolides-YES


Distribution to placenta breast milk

Distribution to placenta & breast milk

Hard to predict

Practical matter: look up data on a drug


Plasma protein binding

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%


Extensive protein binding

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


Protein binding perinatal issue

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


Biotransformation

Biotransformation

Phase I

Phase II


Biotransformation cyp 450

Biotransformation: CYP 450

Often hepatic microsomal enzymes (CYP 450)

Rates vary up to 6-fold from one person to the next

Enzymes genetically determined


Biotransformation hiv tb

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


Biotransformation ketoconazole erythromycin

Biotransformation: ketoconazole, erythromycin

Ketoconazole, erythomycin inhibit CYP450 3A4

Slows metabolism of cisapride, levels rise, causes torsade de pointes, death

Cisapride highly restricted


Bioavailability

Bioavailability

IV to oral switch


Elimination

Elimination

Renal vs non renal clearance

Elimination t1/2


General concept elimination t 1 2

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


S balakrishnan department of pharmacology pondicherry institute of medical sciences

Concentration- time curve


Extravascularconcentration

Extravascularconcentration

Extracellular sites reached via diffusion from blood

Intracellular fluid

Extracellular sites with restrictive barriers

Urine


General concept clearance

General concept: Clearance

Quantitative measure of body’s ability to eliminate the drug

Includes various forms of excretion


Antimicrobial concept mic mbc

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


Break point

Break point

Is in part concentration which can be achieved at the site of infection

Susceptible: MIC < breakpoint

Resistant: MIC > breakpoint


Post antibiotic effect

Post-antibiotic effect

Persistence of effect (inhibition of growth or killing) after drug removed (or level below MIC)

“PAE” + pharmacokinetics affects dosing strategy


Post antibiotic effect1

Post-antibiotic effect

Post antibiotic sub – MIC effects

Post antibiotic – leukocyte effects


S balakrishnan department of pharmacology pondicherry institute of medical sciences

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


S balakrishnan department of pharmacology pondicherry institute of medical sciences

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


S balakrishnan department of pharmacology pondicherry institute of medical sciences

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)


S balakrishnan department of pharmacology pondicherry institute of medical sciences

Goal of therapy based on PK/PD


S balakrishnan department of pharmacology pondicherry institute of medical sciences

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


S balakrishnan department of pharmacology pondicherry institute of medical sciences

Aminoglycoside pharmacodynamics in vivo


Vancomycin outcome vs 24h auc mic ratio

Vancomycin Outcome vs 24h-AUC/ MIC ratio


S balakrishnan department of pharmacology pondicherry institute of medical sciences

Fluoroquinolone PK/PD vs S. pneumoniae


Pk pd of beta lactams and macrolides in otitis media

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


S balakrishnan department of pharmacology pondicherry institute of medical sciences

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


S balakrishnan department of pharmacology pondicherry institute of medical sciences

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


S balakrishnan department of pharmacology pondicherry institute of medical sciences

Dosage Adjustment Needed in Renal Impairment I

Acyclovir ethambutol

aminoglycosides,Penicillins (except antistaph)

aztreonam,Quinolones

cephalosporins (except cefaperazone & ceftriaxone)

clarithromycin,Carbapenems


S balakrishnan department of pharmacology pondicherry institute of medical sciences

Dosage Adjustment Needed in Renal Impairment II

daptomycin,Vancomycin

doripenem, emtricitabine,

famiclovir, ertapenem,

flucytosine, ganciclovir,

imipenem, meropenem,

lamivudine, foscarnet,

fluconazole,


C i in renal failure

C/I in renal failure

Methanamine

Nalidixic acid

Nitrofurantoin

Sulfonamides

Tetracyclines except doxy & minocycline


Dosage adjust in hepatic impairment

Dosage adjust in hepatic impairment

Chloramphenicol

Clindamycin

Erythromycin

Metronidazole

Tigecycline


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