Distribution

Question 1

Distribution

Answer 1

• Reversible transfer of drug between one location to another within the body.
• Depends on the rate of deliver to tissue, tissue permeability, drug bound to blood/tissue components

Question 2

Perfusion Rate Limitation

Answer 2

• Prevails when the tissue membranes essentially no barrier to distribution
• Highly lipophilic or very small molecules follow this rate

Question 3

Tissue Perfusion

Answer 3

• Varies considerably
• Well perfused tissues tend to take up drug rapidly
• Blood distribution: 14% brain, 27% liver, 22% kidneys, 15% muscle (when inactive), etc.

Question 4

Diffusion Rate Limitation

Answer 4

• Likely to occur with polar molecules diffusing across relatively impermeable membrane (BBB)
• Transfer is dependent on pKa, nature of drug, membrane
• Takes longer to achieve equilibrium

Question 5

Volumes of Distribution

Answer 5

• Relates a measured drug concentration to total amount in body
• Vd = Amount/Concentration = L
• Represents volume that must be considered when estimating the amount of drug in the body from drug concentration found in sampling compartment
• In general, drug reaches equilibrium rapidly
• Individual tissues may contain different concentrations due to differing affinities for drug
• Because of differences, Vd has NO true physiological meaning, so the term apparent volume of distribution is used which could be smaller, equal to, or larger than body mass
• Represents the result of dynamic drug distribution

Question 6

Physiological Volume

Answer 6

• Weight (kg) / Water displaced (L)
• Total body water = 64%
• Intracellular Fluid = 33%
• Extracellular Fluid = 27%
• Plasma = 4%

Question 7

Why do different drugs have different volumes? (5)

Answer 7

1. Plasma protein binding (Increases, small Vd)
2. Tissue protein binding (increases, larger Vd)
3. Lipid solubility (Increases, larger Vd)
4. Ionization (Increases, smaller Vd)
5. Membrane Permeability (Increases, larger Vd)

Question 8

Is Vd small or large if drug is contained in vascular region?

Answer 8

Small

Question 9

Is Vd small or large if drug is contained in tissues?

Answer 9

Large

Question 10

Vd Calculation

Answer 10

V = Dose/Co

• IV only
• one compartment only, simplistic approach
• May be overestimation

Question 11

Vd: Model-Independent Method

Answer 11

V = FDose / K * AUC0-INF

• AUC - trapezoidal method
• K - empirically found

Question 12

Vd: Body Weight

Answer 12

V = Weight (kg) X Percent

Question 13

Drug Protein Binding

Answer 13

• Only unbound drug diffuses across membranes
• Reversible and rapid
• Extent of binding is expressed as UNBOUND fraction
• Varies considerably between 0 & 1

Question 14

Fraction Unbound Equation

Answer 14

Fraction Unbound = Cu /Ct (Ct = Cu + Cb)

Cu - concentration unbound in plasma
Cb - concentration bound
Ct - total concentration

Question 15

Drug Protein Binding Depends on…. (4)

Answer 15

1. Affinity constant (strength of binding)
2. Molar concentration of drug
3. Protein concentration
4. Number of binding sites per protein

Question 16

Drug Binding Proteins (2)

Answer 16

1. Albumin

2. AAG

Question 17

Albumin (HSA)

Answer 17

• Most abundant (~60% of all plasma proteins)
• MW ~65,000, [plasma] = 4.5 mg/dL
• Levels increase with dehydration, high protein diet
• Levels decrease in pregnancy, neonates, geriatrics, hepatic/renal disease, bariatric surgery
• Mainly for binding weakly acidic drugs (also some basic)
• Endogenous ligands: FFA, bilirubin, hormones
• High capacity binding (3 sites), but variable affinity

Question 18

Alpha-1-acid glycoprotein (AAG)

Answer 18

• MW 44,000, [plasma] = 0.4-1 mg/dL
• Levels increase with renal disease and diabetes
• Levels decrease with oral contraception, pregnancy, neonates, and geriatrics
• Bind mainly basic drugs
• Endogenous ligands: steroids
• Low binding capacity (1 site) but HIGH affinity

Question 19

Displacement

Answer 19

• Less affinity drug is displaced in competition

- Altered free drug concentrations may alter therapeutic and toxic profiles since only free drugs interact with targets