Drug Absorption & Distribution

Question 1

Define pharmacokinetics.

Answer 1

relates time course to concentration and therapeutic/toxic effects

Question 2

Define ADME.

Answer 2

Absorption
Distribution
Metabolism
Excretion

Question 3

Discuss mechanisms by which drugs are absorbed to reach their sites of action.

Answer 3

Aqueous - passive, small molecules, paracellular or aqueous pores

Lipid-soluble - passive, rate of absorption dependent on degree of ionization (nonionized preferred), concentration gradient, degree of solubility

Active - transporters involved, energy expenditure, unidirectional, saturable

Question 4

List factors influencing drug absorption.

Answer 4

Factors influencing drug absorption

• chemical composition and delivery formulation (tablet, solution, etc.)
• regional differences in blood flow (high flow/highly vascularized = faster absorption because maintains the concentration gradient as drug is moved along)
• membrane permeability
• availability of transport mechanisms (active vs. passive)
• ion trapping
• available surface area (greater SA, greater rate of absorption)
• pH and concentration gradients
• nonspecific binding

Question 5

Compare enteral vs. parenteral administration.

Answer 5

Enteral = oral, sublingual, buccal, rectal
Parenteral = subQ, IM, IV, intrasynovial, intrathecal (spinal cord subarachnoid), vaginal, urethral, ocular, nasal, aural, intra-peritoneal, epidural

Question 6

Explain one- and two-compartment models of drug distribution and how it affects plasma drug concentration time course.

Answer 6

one compartment - rapid equilibrium achieved; monoexponential decline in plasma concentration vs. time

two compartment - rapid distribution to a central compartment (distribution phase), then a slow distribution to tissues/target site (elimination phase); biexponential decline in plasma concentration;

Question 7

Explain Volume of Distribution and the effect of plasma protein binding on drug distribution

Answer 7

Vd = measure of how much drug is in tissues outside the plasma

theoretical volume of fluid into which the total drug concentration was administered (increases if drug is absorbed into fat)

affected by protein binding: increase in unbound fraction => increased apparent Vd

Question 8

Define drug reservoir

Answer 8

drug reservoir = accumulation of drug in tissues can prolong therapeutic/toxic effects; large doses must be given to reach a therapeutic effect for these drugs

typically, fat and muscle => gradual release once plasma levels diminish

protein binding can be considered a drug reservoir too since bound drugs may not reach their site of action and as drugs dissociate, they become active. competitive binding may occur (drugs may kick off other drugs from protein)

Question 9

What is the clinical significance of area under the curve?

Answer 9

AUC is used to determine bioavailability by AUCpo/AUCiv

AUC is used to compare clearance between individuals given the drug via the same route

Question 10

What is the clinical significance of area under the curve?

Answer 10

• used to determine bioavailability by AUCpo/AUCiv

- used to compare clearance between individuals given the drug via the same route

Question 11

What is the relationship between AUC and Clearance?

Answer 11

AUC and CL are inversely related

Question 12

What are the processes following oral drug administration?

Answer 12

• disintegration of solids and dissolution in the GI tract

- drug must pass across or between cells to reach systemic circulation

Question 13

REVIEW: define pKa for acids and bases. Define degree of ionization.

Answer 13

the pH at which 50% of a compound is ionized
acids: pKa = pH + log (HA/A-)
bases: pKa = pH + log (HB+/B)
degree of ionization = pH - pKa (see table)

Question 14

Describe the relationship between % non-ionized and pH for weak acids? weak bases?

Answer 14

weak acids: A weak acid has a pKa around pH = 8. A weak acid doesn’t want to let go of its H+ ion so at pH lower than 8, most of it will remain as HA (non-ionized) and hence, lipid soluble. For example, stomach pH of 2 would be able to readily absorb weak acids.

weak bases: A weak base has a pka around pH = 5. A weak base doesn’t want to take on an extra H+ so at pH above 5, it will remain as B and hence be lipid soluble. At pH

Question 15

Define ion trapping. Where do weak acids remain? weak bases?

Answer 15

ionized forms of drugs will remain concentrated in compartments that favor that form, while nonionized forms will equilibrate between compartments because it can permeate across membranes.

weak acids are trapped in basic compartments
weak bases are trapped in acidic compartments

Question 16

Oral administration

Answer 16

advantages - many formulations

• site of absorption depends on SA
• bioavailability = fraction of drug that reaches systemic circulation (calculated via AUC; affected by first pass metabolism through enterohepatic circulation)

disadvantages - higher doses than parenteral admin methods due to loss of drug in first pass metabolism

• enterohepatic circulation causes delayed delivery because has to go through liver twice if secreted in bile and reabsorbed in intestine
• gastric emptying time can affect absorption rates

Question 17

Sublingual/Buccal administration

Answer 17

advantages - avoids portal circulation

disadvantages - discomfort

Question 18

Rectal administration

Answer 18

advantages - 50-60% avoids portal circulation and first pass metabolism; preferred for N/V cases
disadvantages - discomfort

Question 19

Inhalation

Answer 19

• passive diffusion across a large surface area
• formulation: volatile gases and aerosol preparations
• site of absorption depends on particle size, depth and duration of inspiration

Question 20

Topical administration

Answer 20

• non-systemic use

- highly lipid-soluble compounds will reach systemic circulation

Question 21

Transdermal administration

Answer 21

• passive diffusion across skin
• advantages: controlled release, improved patient compliance, bypasses first pass and GI irritation
• disadvantages: limited number of drugs can penetrate skin, irritation, discomfort

Question 22

Define salt factor.

Answer 22

Some oral drug formulations contain an inactive salt compound that affects dosing.
Active drug = fraction that reaches systemic circulation = salt factor

Question 23

What are advantages and disadvantages of parenteral administration?

Answer 23

advantages
- more reliable, precise dosing
- fewer absorption problems (eating, first pass)
disadvantages
- needles
- pain
- tissue damage/irritation
- formulation must be solution

Question 24

subcutaneous administration

Answer 24

advantages

• slow, steady absorption
• used as a depot
• rate of absorption can be modified by altering blood flow (eating => heat => faster flow; cold => slower flow)

disadvantages

• unable to be used if pt is in shock
• only small volumes

Question 25

IM administration

Answer 25

advantages

• more rapid than SQ
• modify rate via blood flow

disadvantages

• potential infection, nerve damage
• risk of inadvertent IV administration (overdose since gets to target too fast)

Question 26

IV administration

Answer 26

advantages
- fastest, most reliable

disadvantages
- must be given gradually, in small increments to avoid a bolus effect

Question 27

Describe differential drug distribution.

Answer 27

• lipid soluble drugs will distribute all over the body
• nonlipid soluble drugs will remain in plasma and ISF
• some drugs have narrow distributions (ex: iodine almost exclusively concentrates in the thyroid)

Question 28

List factors influencing drug distribution.

Answer 28

Factors influencing drug distribution

• regional differences in blood flow (high flow = faster distr.)
• tissue mass
• transport mechanisms
• permeability characteristics (BBB, placental barrier)
• ion-trapping
• protein binding (many drugs bind reversibly to proteins and are retained in plasma…slowly dissociate and are then delivered)