L6: Drug Distribution

Question 1

What is drug distribution?

Answer 1

Drug distribution is the reversible process by which a drug leaves the systemic circulation and enters the interstitium (ECF) or the cells of tissues, determining how widely the drug spreads throughout the body

Question 2

What are the 4 main factors affecting drug distribution?

Answer 2

1. Blood flow (perfusion) to tissues
2. Capillary permeability
3. Degree of binding to plasma and tissue proteins (e.g. albumin)
4. Relative hydrophobicity/lipophilicity of the drug

Question 3

How does blood flow affect distribution?

Answer 3

Blood flow is not uniform across organs

Distribution order (highest to lowest): Brain, liver, kidneys > Skeletal muscle > Adipose tissue

Drugs reach highly perfused organs faster

Question 4

How is capillary permeability determined?

Answer 4

Capillary structure and drug structure determine how easily a drug leaves the blood and enters tissues

Question 5

Compare liver and brain capillary structures.

Answer 5

Liver: Large fenestrations + slit junctions → drugs freely exchange with interstitial fluid

Brain (BBB): Tight junctions + astrocyte foot processes → only lipid-soluble or carrier-mediated drugs pass. Polar/ionised drugs are blocked

Question 6

What influences the ability of a drug to cross membranes?

Answer 6

Hydrophobic drugs: Readily cross membranes; distribution depends on blood flow.

Hydrophilic drugs: Use slit junctions, limited to interstitial fluid and plasma

Question 7

What is Volume of Distribution (Vd)?

Answer 7

A hypothetical volume of fluid the drug appears to be distributed in.

Doesn’t reflect an actual physiological space but indicates drug distribution extent

Question 8

What are the body water compartments for a 70 kg adult?

Answer 8

Total body water ≈ 42 L (60% body weight)
→ ICF = 28 L
→ ECF = 14 L (10 L interstitial + 4 L plasma)

Question 9

How does drug property affect its distribution volume (Vd)?

Answer 9

Case 1: Large MW or plasma protein binding → Trapped in plasma only → Vd ≈ 4 L

Case 2: Low MW, hydrophilic → Plasma + interstitial fluid only → Vd ≈ 14 L

Case 3: Low MW, lipophilic → Plasma, interstitium, AND intracellular fluid → Vd ≈ 42 L

Question 10

What is apparent Vd?

Answer 10

Theoretical value when the drug distributes extensively into cells or binds to cellular components like lipids, nucleic acids, proteins

Question 11

What happens to drugs bound to plasma proteins?

Answer 11

Bound drugs are pharmacologically inactive.

Cannot be metabolised, excreted, or cross membranes

Only free (unbound) drug is active

Question 12

What determines drug binding to albumin?

Answer 12

1. Binding capacity:
   Low: 1 drug/albumin
   High: Many drugs/albumin

2.Affinity:
Strongest for weak acids and hydrophobic drugs

Hydrophilic/neutral drugs rarely bind

Question 13

What is competition for albumin binding?

Answer 13

Drugs compete for limited albumin binding sites.
Two classes:

Class I: Dose < binding capacity → excess binding sites → low free drug

Class II: Dose > binding capacity → binding sites saturated → high free drug

Question 14

What happens when Class I and Class II drugs are given together?

Answer 14

Class II drug displaces Class I drug from albumin

Free [Class I] increases rapidly → risk of toxicity

New equilibrium eventually forms after metabolism/excretion

Question 15

What does the risk of displacement-induced toxicity depend on?

Answer 15

1. Volume of distribution (Vd)

Large Vd → Drug moves to tissues → Mild change

Small Vd → Drug stays in plasma → Sharp spike in free conc. = toxicity

2. Therapeutic Index (TI):

Narrow TI: Even a small increase in free drug → toxic

Wide TI: Body tolerates fluctuation safely

Question 16

Clinical consequences of drug displacement?

Answer 16

Transient spike in free drug concentration. Toxicity risk for narrow TI drugs. Requires monitoring and dose adjustments if drugs affecting protein binding are added or removed