12.Distribution

What is the definition of drug distribution?

The process by which an active substance that has entered systemic circulation is spread from the circulation to other body fluids.

What is the difference between Primary and Secondary Distribution?

Primary: First phase; influenced by blood supply (perfusion) to tissues.

​Secondary (Redistribution): Second phase; influenced by the tissue affinity of the substance.

Name the 4 body fluid compartments and their approximate volumes/percentages.

Intracellular fluid: 40% (28L)

​Extracellular (tissue) fluid: 15% (11L)

​Plasma: 5% (3L)

​Transcellular fluid: ~1-2% (~1-2L).

What are the two primary plasma proteins for drug binding and what do they bind?

Albumin: Binds acidic substances with high affinity and basic substances with high capacity.

​Alpha-1 acid glycoprotein: Binds basic substances with high affinity.

How does inflammation affect Albumin and Alpha-1 acid glycoprotein levels?

Albumin: Decreases (Negative acute phase protein).

​Alpha-1 acid glycoprotein: Increases (Positive acute phase protein).

Why is highly bound drug fraction considered "inert"?

It cannot escape circulation, bind to receptors, or be removed by hemodialysis.

What is the clinical consequence of displacing Warfarin (99% bound) by only 5%?

The free (active) fraction increases from 1% to 6%—a six-fold increase in effect/toxicity.

Why do drugs accumulate in high concentrations in the Liver?

1. Drugs taken orally enter portal veins first.

2. Blood flow in liver sinusoids is slow.

3. Endothelium is fenestrated (porous).

4. High number of active transporters.

What is the danger of certain parenteral drugs (e.g., Bleomycin) in the Lungs?

They can cause pulmonary fibrosis due to intense blood flow and first-pass through the lungs.

Which drugs/substances accumulate in bone and what are the effects?

Tetracyclines: Discoloration/malformation of bones and teeth.

​Lead (Pb2+): Stored in bone; can be mobilized during pregnancy.

What is "pH trapping"?

When basic drugs enter acidic organelles (like lysosomes), become protonated/charged, and can no longer diffuse back out.

What substances are excluded from the Blood-Brain Barrier (BBB)?

Strongly hydrophilic/ionized drugs.

​Very strong protein-bound drugs (e.g., Suramin).

​P-glycoprotein (Pgp) substrates (e.g., Digoxin).

Is the placenta an effective barrier against lipophilic molecules?

No. It only delays the effect (e.g., Atropine takes 1 min for the mother but 15 min for the fetus) and provides no protection in chronic treatment.

FDA Pregnancy Categories: A

Controlled human studies show no risk; considered safe.

FDA Pregnancy Categories: B

Animal studies show no risk; no human data. Generally safe.

FDA Pregnancy Categories: C

Animal studies show risk; human data lacking. Use only if benefit > risk.

FDA Pregnancy Categories: D

Positive evidence of human fetal risk. Use only in life-threatening cases.

FDA Pregnancy Categories: X

Proven fetal abnormalities. Contraindicated in pregnancy.