pharma new update

Inhibitor of zymogen synthesis: WARFARIN

drug and disease interactions are major limitations to WARFARIN use, particularly in older patients
- more specifically, WARFARIN tends to be underutilized due to concerns about increased bleeding risk
patient education is a critical component of WARFARIN treatment
- changes in lifestyle (esp. diet, alcohol consumption), disease and/or medication (including OTC drugs) can alter the effectiveness of WARFARIN --- in both positive and negative ways
predicting drug and disease interactions is based on an understanding of the PHARMACOKINETIC and PHARMACODYNAMIC properties of WARFARIN
- PHARMACOKINETIC properties determine the concentration of a drug at its site of action; in the case of WARFARIN:
  - ABSORPTION: oral
  - DISTRIBUTION: plasma protein bound
  - METABOLISM and ELIMINATION: actions are terminated by CYP450 metabolism
- PHARMACODYNAMIC effects are those that influence the ability of WARFARIN to interact with clotting factor zymogens
another way of looking at it is to divide interactions into those that:
- INCREASE the effectiveness of WARFARIN
- DECREASE the effectiveness of WARFARIN
interactions that increase its actions are the most critical to understand because of WARFARIN's low therapeutic index

entation transcript:

1 The General Concepts of Pharmacokinetics and Pharmacodynamics
Hartmut Derendorf, PhD University of Florida

2 PHARMACOKINETICS PHARMACODYNAMICS what the body does to the drug
what the drug does to the body

3 Pharmacokinetics Pharmacodynamics PK/PD
conc. vs time Conc. Time 25 0.0 0.4 Pharmacodynamics conc. vs effect 1 10 -4 -3 Conc (log) Effect PK/PD effect vs time Time Effect 1 25

4 the time course of drug and metabolite concentrations in the body
Pharmacokinetics the time course of drug and metabolite concentrations in the body

5 Pharmacokinetics helps to optimize drug therapy:
dose dosage regimen dosage form

6 What happens to a drug after its administration ?
("Fate of drug") Liberation Absorption Distribution Metabolism Excretion

7 Pharmacokinetic Parameters Volume of distribution
Clearance Volume of distribution Half-life Protein Binding Bioavailability

8 Clearance quantifies ELIMINATION
is the volume of body fluid cleared per time unit (L/h, mL/min) is usually constant

9 Clearance Eliminating Organ CL = Q·E Q Blood Flow E Extraction Ratio

10 Clearance Q Ci Co Eliminating Organ Parameters: Blood Flow, intrinsic clearance, protein binding Good prediction of changes in clearance Steady state

11 High-extraction drugs
Low-extraction drugs

12 Clearance Clearance can be calculated from
Excretion rate / Concentration e.g. (mg/h) / (mg/L) = L/h Dose / Area under the curve (AUC) e.g. mg / (mg·h/L) = L/h

13 Clearance Total body clearance is the sum of the individual organ clearances CL = CLren + CLhep + CLother

14 Volume of Distribution
Vd = X / Cp - quantifies DISTRIBUTION - relates drug concentration (Cp) to amount of drug in the body (X) - gives information on the amount of drug distributed into the tissues

15 Apparent Volume of Distribution
X X V C1 V C2 C1 > C2 V < Vd C1 = X / V V = X / C1 C2 = X / Vd Vd = X / C2

16 Volume of Distribution
Dicloxacillin L/kg Gentamicin (ECF) 0.25 L/kg Antipyrine (TBW) 0.60 L/kg Ciprofloxacin L/kg Azithromycin 31 L/kg

17 Half-Life Half-life is the time it takes for the concentration to fall to half of its previous value Half-life is a secondary pharmacokinetic parameter and depends on clearance and volume of distribution

18 Half-Life k elimination rate constant CL clearance
Vd volume of distribution

19 Protein Binding reversibe vs. irreversible linear vs. nonlinear
rapid equilibrium The free (unbound) concentration of the drug at the receptor site should be used in PK/PD correlations to make prediction for pharmacological activity

21 vascular space extravascular space plasma protein binding
blood cell binding, diffusion into blood cells, binding to intracellular biological material tissue cell binding, diffusion into tissue cells, binding to extracellular biological material

22 Microdialysis Interstitium Capillary Cell Perfusate Dialysate

23 Microdialysis

24 Bioavailability - quantifies ABSORPTION
f is the fraction of the administered dose that reaches the systemic circulation

25 Bioavailability Rate and Extent of Absorption

26 Compartment Models Parameters: Rate constants, intercepts
Linear and nonlinear regression Complete concentration-time-profiles Steady-state and non-steady-state

27 Intravenous bolus D k X E One compartment model Dose Drug in the body
Drug eliminated

28 Plasma concentration (single dose)
Intravenous bolus Plasma concentration (single dose) D Dose C0 Initial Concentration Vd Volume of Distribution

29 Intravenous bolus Normal Plot Semilogarithmic Plot

30 Plasma concentration (multiple dose, steady state)
Intravenous bolus Plasma concentration (multiple dose, steady state) Peak Trough

31 Intravenous bolus Multiple Dose

32 First-order absorption
One compartment model D f k k A a X E Dose Drug at absorption site Drug in the body Drug eliminated

33 Oral administration Plasma concentration (single dose)

34 Oral administration

35 Oral administration Average concentration (multiple dose, steady state)

36 Oral administration Multiple Dose

37 Zero-order absorption
One compartment model D f R k A X E Dose Drug at absorption site Drug in the body Drug eliminated

38 Constant rate infusion
Plasma concentration (during infusion)

39 Constant rate infusion

40 Constant rate infusion
Plasma concentration (steady state)

41 Two-compartment model
k Xc 10 E k k 12 21 Xp Dose Xc Drug in the central compartment Xp Drug in the peripheral compartment Drug eliminated

42 Two-compartment model
Plasma concentration (single i.v. bolus dose) -phase: distribution phase -phase: elimination phase

43 Two-compartment model

44 Two-compartment model
Volume of distribution Xc Xc Xc Xp Xp Xp initially steady state elimination phase

45 Two-compartment model

46 Short-term infusion

47 Three-compartment model
Xp d k k 31 13 D k Xc 10 E k k 12 21 Xp s Xc Drug in the central compartment Xps Drug in the shallow peripheral compartment Xpd Drug in the deep peripheral compartment Dose Drug eliminated

49 Significance of Pharmacokinetic Parameters for Dosing
Maintenance Dose Loading Dose Fluctuation Dosing Interval

50 Drug Delivery Pharmacokinetics Pharmacodynamics
Biopharmaceutics PK-PD-Modeling ?

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