Distribution

Question 1

What are compartments?

Answer 1

diff locations in body where drug is distributed (referred to theoretically)

Question 2

describe initial absorption & distribution of drug:

Answer 2

initial absorption into “central compartment” (systemic circulation) is followed by distribution to “peripheral compartments” (ex: liver, brain, other organs & tissues);

Question 3

After absorption & entry into systemic circulation, there is…

Answer 3

… an immediate rapid distribution throughout body, esp to well perfused tissues

Question 4

What are the 4 main factors influencing distribution?

Answer 4

1. blood flow (perfusion) - depending on tissue, can range frm 3-30% of cardiac output
2. drug physiochemical properties (lipid solubility, pKa, molecular size)
3. binding of drug to plasma prots & cellular binding prots
4. barriers to distribution

Question 5

What is most abundant plasma protein?

Answer 5

Albumin; many drugs have varying affinities (weak interactions - hydrostatic interactions, van der waals, not covalent bonds)

Question 6

The Free:bound equilibrium in blood plasma is due to?

Answer 6

reversible binding

Question 7

What kind of drug can diffuse out of bloodstream and into tissues & why?

Answer 7

Free drug only; b/c plasma proteins are huge & cannot cross capillary walls

Question 8

explain the dynamic nature of free drug diffusing from blood into tissues:

Answer 8

as free drug diffuses from blood to tissue, more is released from plasma prots until tissue sites become saturated. also, as free drug is excreted, more is released from plasma prots

Question 9

What is albumin?

Answer 9

The bus; has many sites where interactions w/ chemicals/drugs can occur

Question 10

What is tissue (cellular) protein binding like in adipose tissue?

Answer 10

It’s an important storage depot for highly lipophilic drugs (& persistent organic pollutants)

Question 10

What is tissue (cellular) protein binding like in the liver & kidney?

Answer 10

they have high binding capacity for certain drugs

Question 11

What is tissue (cellular) protein binding like in bone?

Answer 11

bone binds certain drugs (ex: tetracyclines) & heavy metals (ex: lead)

Question 12

Consider tissue (cellular) protein binding in lean vs obese individuals:

Answer 12

Might need to give more drug in obese animals if it is lipophilic drug that accumulates in fat

Question 13

Consider tissue (cellular) protein binding in lactating individuals:

Answer 13

breast milk is high in fat & can accumulate lipophilic drugs where they can become route of exposure for neonate (but route of excretion for mom)

Question 14

What are some barriers to drug distribution?

Answer 14

BBB & placental “barrier”

Question 15

How does the blood brain barrier affect drug distribution?

Answer 15

• mjr barrier to many drugs b/c of tightly joined endothelial cells surrounding CNS & active (ATP-dependent) transporters for removal (MDR prots)

Question 16

when is the blood brain barrier not fully developed and what are the implications of this?

Answer 16

not fully developed in embryo & at birth; this has important toxicological implications

Question 17

How does the placental “barrier” affect drug administration?

Answer 17

• must assume that any drug entering maternal circulation is capable of crossing placenta unless proven otherwise
• drugs are tested extensively for their ability to cross placenta & cause teratogenic effects in offspring

Question 18

What is the volume of distribution? (V subscriptD)

Answer 18

• apparent fluid volume in which a drug appears to be dissolved (how widely a drug is distributed throughout body)
• “proportionality constant” used to compare distribution of drugs
• total drug dose (mg) / plasma drug conc (mg/L)

Question 19

what does high volume of distribution mean?

Answer 19

extensive distribution of drug & high affinity for tissues

Question 20

what does low volume of distribution mean?

Answer 20

drug is restricted mainly to blood plasma, mainly due to high plasma protein binding