Drug Distribution - Issar

Question 1

What is drug distribution?

Answer 1

The transport of the drug from the blood into tissues

Question 2

What are the drug distribution patterns? (4)

Answer 2

1. Drug confined to the blood
   • High protein binding
   o Drug will bind to plasma proteins really well
   o Majority of drug is confined to the vascular system
2. Drug has a low m.w. and water soluble compounds
   • This makes the drug uniformly distributed in body water
3. Drug concentrates into specific organs
4. Non-uniform distribution
   • Combo of 1-3

Question 3

What is the volume of drug distribution?

Answer 3

• Concentration of drug in body after distribution
• Dependent on dose and extent of distribution
• VD = (Db)/(Cp)
o VD is proportionality factor that related amount of drug in body (Db) to corresponding plasma concentration (Cp)

Question 4

What factors affect the rate of drug distribution?

Answer 4

1. Blood flow/tissue percussion
   • Proportional to volume/time
   • Organs with high perfusion rate reach higher rates of a drug in a shorter amount of time
2. Capillary/membrane permeability
   • Lipophilic drugs will diffuse through capillaries
   • Larger drugs will have difficult permeating membrane
   • Perfusion rate-limited distribution
   • Permeability-limited distribution
   o Hydrophilic drugs have restricted movement because they cannot move easily across capillary/membrane

Question 5

What factors affect the extent of drug distribution?

Answer 5

1. Lipid solubility
2. pH-pKa
3. Plasma protein binding
4. Intracellular binding
5. Extent of elimination competing with distribution

Question 6

What is irreversible drug binding?

Answer 6

Drug → reactive chemical intermediates → → covalent linkage with macromolecules
Ex: hepatotoxicity of high doses of acetaminophen

Question 7

What is reversible drug binding?

Answer 7

Free drug + free protein ⇋ drug-protein complex

Most common type of binding

Question 8

A protein-bound drug is usually:

Answer 8

o Pharmacologically inactive
o Has restricted distribution
o Cannot be metabolized
o Cannot be excreted

Question 9

What are some common proteins that bind to drugs?

Answer 9

1. Albumin = 60%; acidic drugs
2. α1-acid glycoprotein →basic drugs
3. Lipoproteins → neutral drugs

Question 10

How does protein binding effect apparent volume of distribution?

Answer 10

High D-P binding + Low free drug → Low VD
Low D-P binding + High free drug → High VD
*Lipophilicity also influences VD

Question 11

Total body water (TBW)

Answer 11

42 L

60% body weight

Question 12

Extracellular fluid (ECF)

Answer 12

14 L

1/3 TBW

Question 13

Intracellular fluid (ICF)

Answer 13

28 L

2/3 TBW

Question 14

Interstitial fluid

Answer 14

10.5 L

3/4 ECF

Question 15

Plasma

Answer 15

3.5 L

1/4 ECF

Question 16

Blood Brain Barrier (BBB)

Answer 16

o Diffusion dependent on lipid solubility and molecular mass
o P-glycoprotein efflux transporters
• Protect brain from foreign invaders
o P-gp
• Doesn’t prevent drugs from getting in, but clears it out of brain after it’s gotten in

Question 17

Placental Barrier

Answer 17

o Lipid soluble drugs diffuse in accord with their Log P, pKa and pH partitioning
o Not a perfect barrier

Question 18

Testicular Barrier (BTB)

Answer 18

o Barrier tighter than placenta

o Consists of tight junctions between Sertoli cells

Question 19

Blood

Answer 19

5 L

Question 20

Blood cells

Answer 20

2 L