Volume of distribution & Compartment models

1. Volume of Disrtibution and Compartment
Models
Dr. Sruthi N.

2. Volume of distribution (Vd)
Apparent Vd
Factors affecting Vd
Compartment models
2

3. 3

4. 4
Drug in systemic circulation gets
distributed to other tissues
Equilibrium
between unbound
drug in plasma
and tissue fluid

5. 5
Decline due to
Elimination

6. Apparent volume of distribution(aVd)
 Apparent space in the body available to contain
the drug homogenously at the concentration found
in blood, plasma, water.
 Unit:L/kg
Vd=Amount of drug in body/C
6

7. 7
Total body water
42L
Extracellular
fluid(ECF)
28L
10L
4L
14L

8. Factors affecting distribution
• Lipid solubility
• Ionization at physiological PH
• Degree of plasma protein binding
• Affinity for different tissues
• Blood flow
8

9. Lipid solubility
• Highly lipid soluble: High Vd
• Lipid:water partition coefficient
9

10. Ionization
10
PH of Blood : 7.4

11. Plasma protein binding
11
Acidic
drugs
Albumin
Basic drugs
Alpha 1 acid
glycoprotein
Phenytoin
Lidocaine

12. 12
Non selective
More than one site
No intrinsic activity
More than one drug at
a site
Site 1 : less
specific(warfarin,sulpho
namides)
Site 2: Acidic drugs
( Naproxen, Cloxacillin)

13. Bound drug
Free drug
Action,
metabolism &
excretion
Reservoir

14. Clinical significance of PPB
PPB prolongs duration of action
High PPB low volume of distribution
Temporary Reservoir
Hemodialysis and high PPB
Chronic renal and liver disease ↓ albumin  ↓ PPB
Acute phase reactant: Alpha 1 glycoprotein
 Drugs can compete for the same binding sites
displacement interactions

15. 15
CLASS I DRUGS
CLASS II DRUGS

16. Warfarin PPB- 98%
Free form-2%
Toxicity
16
Albumin
Albumin
W
W
W
W
W
W
W
W
W
W
I
Warfarin 99% bound
free form- 1%
Indomethacin(I)
Low aVd ,narrow
therapeutic index: Toxicity

17. TISSUE BINDING
Some drugs have affinity for certain tissues
 Delays elimination, serves as a reservoir prolongs
duration of action.
 Large Volume of distribution
 Local toxicity
Tissue Binding drugs
Adipose tissue Thiopentone sodium
Bone Tetracyclines
Thyroid Iodine

18. 18

19. Compartment
1) TBW
2) ECF
3) Plasma
Drugs
Small water soluble molecules
Eg: Ethanol
Large water soluble molecules
Eg: Gentamicin
Large protein molecules
Eg: antibodies

20. 4 ) Tissue
5)Bone
Highly lipid soluble particles
Eg: Diazepam
Certain ions
Eg: Lead , Fluoride

21. Blood supply
21

22. Redistribution
22
Thiopentone sodium

23. Blood and brain barrier

24. Blood brain barrier
Endothelial cells with tight junctions + glial cells
forms the BBB
 Blood CSF barrier- choroidal plexus
Only lipid soluble unionized drugs can pass through
both barriers

25. Protects the brain from toxic substances
Inflammation of meninges & brain- ↑permeability.
BBB deficient at CTZ & some periventricular sites

26. Placental barrier
• Placental membranes are lipoidal & allow free passage
of lipid soluble drugs
• P glycoprotein  placental efflux

27. 27
Vd= 10mg/1mg/5L
50L

28. 28
Vd=10mg/10mg/5L
5L

29. 29
Vd=10mg/4mg/5L=10*5/4
=12.5L

30. Significance
• High aVd: Chloroquine : Retina: toxicity
• Difficult to remove by hemodialysis
• Low aVd: Vascular compartment;high PPB
• Loading dose
30

31. Steady state
31

32. Loading dose & Vd
32
Loading dose = Target Cp * Vd
F
F: Bioavailability

33. Pharmacokinetic models
• Allows quantitative(mathematical)
description.
• Prediction of pharmacokinetic behaviour after
administration of different dose
33

34. • Compartment model
• Non-compartment model
• Physiologic model
34

35. COMPARTMENT MODELS
• The Body is represented by series of
compartments that communicate
reversibly with each other

36. COMPARTMENT
A mathematic representation of the body or an area
of the body created to study physiologic or
pharmacologic kinetic characteristics

37. HISTORY
• 1920-Widmark used compartment models for the
study of propagation of alcohol in the body

38. Assumptions
• Each compartment is not a real physiologic or
anatomic regions
• They are considered as group of tissue that have
similar distribution characteristics

39. • The rate of drug movement between the
compartment is described by the first order kinetics
• Rate constants are used to represent the entry and
exit of a drug from the compartment

40. Compartment
models
Mamillary Caternary Open Closed

41. MAMILLARY MODEL

42. CATERNARY MODEL
This is not observed physiologically, rarely used.

43. CENTRAL COMPARTMENT
• Consists of plasma and highly perfused tissues
• Rapidly equilibrate with the drug

44. PERIPHERAL COMPARTMENT
• Those with low vascularity and poor perfusion
• Includes Skin,adipocytes,bones

45. OPEN MODEL
 Input and output are unidirectional
 The drug can be eliminated from the body
CLOSED MODEL
 The dose of the drug not gets eliminated from
the body

46. ONE COMPARTMENT MODEL
• Body is considered as a single kinetically
homogenous unit
• Applies only to those drugs that distribute rapidly
throughout the body
• Elimination by first order kinectics

48. TWO COMPARTMENT MODEL
• Assumes that the drug transport between central
and the peripheral compartment
• Follows first order kinetics

51. THREE COMPARTMENT MODEL
• Includes Central ,tissue, deep tissue
• Drug distributes most rapidly in to the central
compartment

53. Applications
 Useful in drug formulation
 Characterize behaviour of drugs in individuals
 Statistical methods are used for the estimation &
data interpretation of pharmacokinetic parameter
 Bioequivalence studies
 Determine effects of pathological states in ADME
 Explaining drug interactions

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