Drug absorption and distribution

Question 1

What are the factors affecting drug distribution?

Answer 1

a. regional differences in blood flow
b. tissue mass
c. transport mechanisms
d. permeability characteristics
e. ion trapping
f. binding to protein

Question 2

What is the clinical significance of the area under the curve (AUC)?

Answer 2

Bioavailability (F): Used to compare amount (fraction) of drug that reaches the systemic circulation by different routes of administration

Clearance (CL): Used to compare clearance (CL) of a drug in different individuals after administration of the same dose

Question 3

How do you calculate AUC?

Answer 3

AUC = Dose (i.v.) / CL

AUC = Dose (p.o.) / (CL/F)

Question 4

How do you calculate oral F?

Answer 4

F = AUC(po) / AUC(i.v.) x 100

Question 5

What is the relationship between AUC and CL in two different patients?

Answer 5

Inverse.

CLx/CLy) = (AUCy/AUCx

Question 6

Define drug absorption

Answer 6

The processes by which drugs move from their site of administration to the plasma

Question 7

Discuss the features of aqueous diffusion

Answer 7

small molecules (

Question 8

Discuss the features of lipid diffusion

Answer 8

passive process driven by concentration gradient

the rate of absorption increases with increasing drug concentration

the more lipid-soluble the faster the rate of transport

lipid-soluble drugs cross membranes readily, but may be poorly soluble in aqueous gut fluids, which may limit their absorption

Question 9

How is lipid solubility affected by the degree of ionization?

Answer 9

non-ionized form is more lipid soluble and thus more readily absorbed

Question 10

what compounds will be absorbed in the stomach?

Answer 10

weak acids, as they will be in their protonated form (non-ionized) and thus more lipid soluble

Question 11

What is unique about the pH of the small intestine?

Answer 11

in between the pKa of weak base/weak acid, and thus can absorb the highest percentage of non-ionized acids and bases

Question 12

What is a general rule of ion trapping?

Answer 12

weak acids tend to be concentrated in more alkaline compartments

weak bases tend to be concentrated in more acidic compartments

Question 13

Why is the small intestine (rather than the stomach) the main site of absorption of most orally administered drugs?

Answer 13

much higher surface area

Question 14

What is the first pass effect?

Answer 14

some drugs are highly metabolized when they pass through the liver—only a fraction (F) of the absorbed drug reaches the systemic circulation (F = bioavailability).

Question 15

What is the enteral route?

Answer 15

through the digestive system

Question 16

What is the most common enteral route?

Answer 16

oral

Question 17

What are some things that can affect the rate of absorption in the enteral route?

Answer 17

Stomach contents (food) and gastric emptying time can affect the rates of drug absorption

Question 18

How can the enterohepatic circulation alter the bioavailability in the enteral route?

Answer 18

drugs may be secreted into the bile and reabsorbed via the intestine. This can delay delivery to the systemic circulation and may further reduce bioavailability

Question 19

What is bioavailability?

Answer 19

The fraction (F) of the administered dose that reaches the systemic circulation in its active form.

Question 20

How do you calculate Dose(p.o.)?

Answer 20

Dose(p.o.) = Dose(i.v.) / F(oral)

Question 21

What is the salt factor (S)?

Answer 21

The fraction of total drug that will be delivered as active drug to the systemic circulation

Question 22

How do you calculate loading dose?

Answer 22

(Vd x TC) / (F x S)

Question 23

How do you calculate maintenance dose?

Answer 23

(CL x TC x T) / (F x S)

Question 24

What are some advantages of buccal/sublingual administration?

Answer 24

by-passes portal circulation and therefore avoids first pass metabolism

higher pH may be beneficial for absorption of more basic drugs

Question 25

What are the advantages of rectal administration?

Answer 25

~50-60% of absorbed drug by-passes portal circulation and therefore avoids first pass metabolism.

Question 26

What are the benefits of transdermal administration?

Answer 26

controlled release of the drug into the patient—enables a steady blood-level profile user-friendly, convenient, painless, multi-day dosing—improved patient compliance bypassing the gastrointestinal (GI) tract obviates GI irritation that occurs with some drugs and avoids partial first-pass inactivation by the liver

Question 27

What is parenteral adminstration?

Answer 27

not through the digestive system

Question 28

What are the advantages of parenteral administration?

Answer 28

greater degree of reliability and precision of administered dose fewer problems with absorption: not affected by food in the stomach and no "first-pass effect"

Question 29

What are the advantages of subdermal administration?

Answer 29

slow, even absorption may be used as a depot rate of absorption may be modified by altering blood flow (temperature)

Question 30

What are the advantages of intramuscular administration?

Answer 30

more rapid absorption than subcutaneous rate of absorption may be modified by altering blood flow

Question 31

What are the advantages of i.v. administration?

Answer 31

Fastest and most reliable means of achieving a defined blood level, but with a risk of overdose to the bolus effect

Question 32

define ion trapping

Answer 32

local pH differences can result in relative concentration of drugs in different compartments

Question 33

how does protein binding influence distribution?

Answer 33

plasma proteins can bind a significant fraction of some drugs—only unbound drug distributes to tissues

Question 34

what binds acidic drugs?

Answer 34

albumin

Question 35

what binds basic drugs?

Answer 35

alpha-1 acid glycoprotein

Question 36

What is one compartment distribution?

Answer 36

a rapid equilibrium is achieved between plasma and tissue distribution following drug administration. Plasma concentration-time profile declines mono-exponentially.

Question 37

What is two compartment distribution?

Answer 37

rapid distribution to a central compartment (plasma) is followed by slow distribution to other tissues/binding sites (second compartment). This results in a bi-exponential plasma concentration-time profile the initial distribution follows a multi-exponential phase the elimination phase is monoexponential

Question 38

Define volume of distribution (Vd)

Answer 38

A measure of how evenly distributed a drug is in the body theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma

Question 39

How do you calculate Vd?

Answer 39

Vd = Dose / C0 | C0 = initial concentration at time 0

Question 40

What are the major compartments?

Answer 40

``` —plasma (5% of body weight) —interstitial fluid (16%) —intracellular fluid (35%) —transcellular fluid (2%) —fat (20%) ```

Question 41

Where are lipid-insoluble drugs confined to?

Answer 41

plasma and interstitial fluids most do not enter the brain following acute dosing

Question 42

Where do lipid-soluble drugs distribute to?

Answer 42

reach all compartments, may accumulate in fat

Question 43

What can act as drug reservoirs, and what are the effects?

Answer 43

Fat and Muscle Gradual release of drug from these sites can prolong the therapeutic effect or result in toxicity.

Question 44

What else in the plasma can act as a drug reservoir, and what will release the drug?

Answer 44

Plasma proteins can also serve as a drug reservoir Sulfonamides may compete for protein binding and increase the unbound fraction of other drug