Pharmacokinetics II

Question 1

Describe distribution

Answer 1

Drugs carried in plasma water, bulk flow of water/drug taken out by hydrostatic pressure
Barriers - Blood-Brain barrier, Placenta

Question 2

Describe the factors affecting rate and extent of distribution

Answer 2

Regional blood flow
Lipid solubility
Plasma protein binding

Question 3

Describe regional blood flow

Answer 3

Rate of entry into tissues depends on rate of blood flow through capillary beds
Well-perfused tissues: Kidneys, heart, lungs, brain
Moderate: Muscle, skin
Slowly: Fat
Negligibly: Bone

Question 4

Describe the distribution of bodily fluids

Answer 4

Drug molecules in both free/bound solution forms

Weak acid/base exist in equilibrium or charged/non-charged depending on pH

Question 5

What does distribution depend on?

Answer 5

Permeability across tissue barriers
Binding within areas
pH partition
Fat (water partition)

Question 6

What is Kc dependent on?

Answer 6

Permeability of barriers
pH of areas
Binding capacity

Question 7

Describe the distribution of bodily fluids in terms of body water

Answer 7

TBW of body weight varies from 50-70%
Liquid in body: 60% of body weight
ECF: Blood plasma 5%, ISF 16%, Lymph
ICF: All cell content 35%
Transcellular fluid 2%: Cerebrospinal, intraocular, peritoneal, pleural, synovial, digestive secretions
Fat: 20%

Question 8

What is the volume of distribution (Vd)?

Answer 8

Theoretical volume that would be needed to distribute a drug it found at same conc through body as measured in serum

Question 9

Describe the link between binding of a drug and Vd

Answer 9

Binding of a drug outside plasma compartment or partitioning into body fat increases Vd beyond TBW

Question 10

Describe a high Vd

Answer 10

Non-polar
High lipid solubility
Low ionisation rate
Low plasma protein binding

Question 11

Describe a low Vd

Answer 11

Polar
Low lipid solubility
Ionised
Plasma bound

Question 12

Describe the uses of Vd

Answer 12

Planning dose regimens
Interpreting drug interaction when protein binding displacement is weird
If poisoned, whether drug can be cleared by haemodialysis (if Vd low)

Question 13

Describe Vd in obesity

Answer 13

Larger fraction of body weight in fat
TBW smaller % of BW
Plasma levels altered Adjust dose

Question 14

Describe Vd in infants and pregnancy

Answer 14

Infant: TBW larger % BW
Vd appears larger
Pregnancy: Blood volume, extracellular water and subcutaneous fat increase
Vd may increase for drugs in TBW

Question 15

Describe plasma protein binding

Answer 15

Free form - Active

Drug-protein complex - Inactive. Eg b-globulins, Albumin

Question 16

Describe albumin

Answer 16

Most vital binding protein in plasma/ISF
Binds mainly acidic drugs
Overall negative charge at blood pH

Question 17

Describe the binding to Albumin

Answer 17

Basic drugs: Bind high capacity but low affinity (many bound but readily released)
Acidic drugs: Bind low capacity but high affinity (saturation of binding site unlikely = Little bound, not readily released)

Question 18

Describe the clinical problems with plasma protein binding

Answer 18

Competition between drug/endogenous ligand
Competition between drugs for same binding sites on albumin (leads to toxicity/bleeding)
Bound drug usually inactive
Can increase/decrease elimination by kidney/liver

Question 19

Describe what happens if a drug has a large Vd

Answer 19

Amount of drug in plasma reflect small portion of that in entire body
Displacement from plasma proteins causes negligible effect on conc of free drug

Question 20

Summarise the distribution of drugs within the body

Answer 20

Most drugs absorbed by first-order process.

Steady-state - Equilibrium point where amount of drug administered exactly replaces amount of drug excreted