Pharmacokinetics I Absorption & Distribution

Question 1

Define bioavailability.

What are some factors that affect drug absorption?

Answer 1

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

a. Membrane permeability. b. Availability of transport processes.
c. Available surface area.
d. pH and concentration gradients.

Question 2

Define enteral drug administration. What are some examples?

Explain some implications of this route of administration and how it may affect bioavailability.

Answer 2

administration through the digestive tract

Ex: oral, sublingual, rectal

First-pass effect: 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).

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

Question 3

Define parenteral. What are some examples?

Answer 3

(given by routes other than the digestive
tract, usually injected))

subcutaneous
intramuscular
intravenous
intrasynovial
intrathecal
buccal
vaginal
urethral
ocular
nasal 
aural

Question 4

What does ADME stand for?

Answer 4

Absorption
Distribution
Metabolism
Excretion

Question 5

Of what significance is the measurement of drug concentration in plasma?

Answer 5

For most drugs, the concentration of drug at its site of action will be related to the concentration of drug in the systemic circulation.

Clinical pharmacokinetics relies heavily on measurements of plasma drug concentrations to predict therapeutic and/or toxic effects of drugs.

Question 6

Distinguish between one-compartment vs Two-compartment distribution.

How does plasma concentration-time profile decline?

How are steady state concentrations achieved?

Answer 6

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

Two-compartment: rapid distribution to a central compartment is followed by slow distribution to other tissues/binding sites (second compartment). This results in a biexponential
plasma concentration-time profile. (With repetitive administration, steadystate
concentrations are achieved only after 5-6 elimination half-lives (t½).

Question 7

Give three examples of drugs that display two-compartment pharmacokinetics.

Answer 7

Digoxin, lidocaine, and phenytoin are examples of drugs that display two-compartment
pharmacokinetics.

Question 8

Define volume of distribution.

Answer 8

Vd describes how large a blood volume would be required to contain the entire administered
dose at the measured concentration of drug in the blood.

Question 9

How does drug interaction in tissues like fat and muscle affect drug action?

Answer 9

Accumulation of drugs in tissues (e.g. fat & muscle) can prolong drug action.

“drug reservoirs”

Question 10

What is a “drug reservoir”?

Answer 10

Accumulation of drugs in tissues (e.g. fat & muscle) can prolong drug action.

Question 11

Define pharmacokinetics.

Answer 11

Pharmacokinetics relates the time courses of a drug’s absorption, distribution, and
elimination (metabolism & excretion) to the intensity and time course of its pharmacological
(therapeutic and/or toxic) effects.

Question 12

What is minimum effective concentration?

Duration? Intensity?

Answer 12

Minimum effective concentration: the threshold that must be reached before seeing a therapeutic effect

Duration- how long conc. remains above that minimum effective concentration threshold

Intensity- how far above that threshold it gets

Question 13

What is the clinical significance of area under the curve?

Answer 13

• Used to compare amount of drug that reaches the systemic circulation by different
  routes of administration: determine bioavailability (F).

AUC= dose/CL or F

• Used to compare clearance (CL) of a drug in different individuals after administration of
  the same dose via the same route.

Question 14

Define drug absorption.

Answer 14

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

Question 15

Describe the processes following oral drug administration.

Answer 15

• disintegration of solids and dissolution of drug in fluids of gastrointestinal tract
• passage of drug across or between cells to reach the systemic circulation.

Question 16

Name two organs that have a large surface area for absorption. Which is the main site for absorption, why?

Answer 16

Stomach, small intestine

The small intestine is the main site for absorption of most orally administered drugs because it has a much larger surface area than the stomach.

rate of absorption is directly proportional to available surface area

Question 17

Give examples of passive and active transport.

Describe the processes.

Answer 17

passive: paracellular transport, diffusion, faciliated diffusion
active: ABC transporters (use ATP-Requires expenditure of cellular energy.)

Involves specific molecular interactions:
transporters for amino acids, glucose, peptides, organic acids/bases etc. can transport structurally related drugs across membranes.
The process is saturable.
Drugs that are transported by a carrier mechanism can compete with other drugs that utilize the same mechanism—this may limit the absorption of either drug.

Question 18

What size drugs will pass across membranes via aqueous diffusion?

Describe what drives this process and describe the possible routes.

Answer 18

small molecules ( less than 100 kD mol. weight)
passive movement driven by concentration gradient
route may be paracellular or via aqueous pores

Question 19

What kind of drug diffusion is most common?

Answer 19

lipid diffusion

passive process driven by concentration gradient

(rate of absorption increases with increasing the drug concentration)

Question 20

How does lipid-solubility affect a drug’s rate of transport? Describe.

Answer 20

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.

(rate of absorption increases with increasing the drug concentration)

Question 21

What controls the degree of ionization and how does degree of ionization affect lipid solubility?

Answer 21

degree of ionization is dependent upon pH

lipid solubility is affected by the degree of ionization
(depends on pH of solutions and pKa of drug)
determine using Henderson-Hasselbalch

only NON-ionized form can diffuse across lipid bilayer; ionized form is less lipid-soluble

Question 22

Which form of Henderson-Hasselbalch equation do you use for acids/bases?

Answer 22

Slide 21

acids log AH/A-
bases log BH+/B

Question 23

How is pKa determined?

Answer 23

important to remember that the pH at which 50% of the compound is ionized is the pKa

Question 24

Is degree of ionization linear or exponential?

Answer 24

not linear

Question 25

In the stomach, at a pH of 1-3 will weak acids or bases be more readily absorbed?
Explain why.

Are weak acids more likely to concentrate in alkaline or acidic compartments?

Answer 25

at pH 1-3 a weak acid will be protonated and not ionized, therefore more readily absorbed

Because the ionized form cannot readily permeate
lipid membranes, the drug can become trapped, resulting in a greater concentration
in compartments that favor its ionized form. Weak acids become more concentrated
in more alkaline compartments; weak bases tend to concentrate in more acidic
compartments.
(ion trapping)

Question 26

What does degree of ionization depend upon?

Answer 26

the difference between pH and pKa

Question 27

How will levels of a non-ionized form of a drug compare in the blood (pH 7.4) and urine (pH 6)?

Answer 27

Non-ionized form can diffuse across lipid membranes & so it equilibrates between blood & urine

Question 28

How can you determine oral bioavailability?

Answer 28

Oral bioavailability may be estimated by comparing AUC for the orally administered drug with
AUC for the same dose of drug given to the same
patient intravenously.

Foral=AUCp.o/AUCi.v.

Question 29

Explain first-pass metabolism. What are the implications for oral dosing?

Answer 29

intestinal/hepatic

Some drugs are absorbed, transported to the liver, and secreted into the bile.
They are then deposited back into the intestine and can be reabsorbed

some drugs are highly metabolized when they pass through the liver

Thus:
Oral doses may be higher than parenteral doses because of reduced bioavailability.

Dosep.o=Dosei.v./Foral

Question 30

What is the salt factor? How must you consider this when calculating the dose?

Answer 30

A dosage adjustment is required when a drug is prepared in a formulation that provides a fraction of the total weight of drug as active drug and the remainder as an inactive salt.

The fraction of
total drug that will be delivered as active drug to the systemic circulation is called the “salt factor” (S).
The appropriate dose is determined by dividing the desired dose of active drug by the salt factor.

Question 31

What are the advantages/disadvantages of sublingual/buccal administration?

Answer 31

a. advantages:
by-passes portal circulation and therefore avoids first pass metabolism.
higher pH may be beneficial for absorption of more basic drugs.

b. disadvantages
drug taste

Question 32

What are the advantages/disadvantages of rectal administration?

Answer 32

Advantages:
approx 50-60% of absorbed drug by-passes portal circulation and therefore avoids first pass metabolism.
useful in cases of nausea and vomiting.

Disadvantages:
discomfort, inconvenience, etc.

Question 33

Describe the mechanism of inhalation of drugs. By what process are drugs absorbed? What facilitates this process?

Describe common forms.

Answer 33

Absorption is via passive diffusion and is facilitated by a large surface area.

Drug absorption varies with depth and duration of inspiration (across alveolar surface area (deep breath increases surface area, hold it in, increases duration for which drug exposed to surface area) … depth/duration of inspiration)
titrate to desired effect or use metered inhaler

Common forms include:
volatile gasses (driven by differences in partial pressures)
aerosol preparations (site of absorption dependent on particle size)

Question 34

When might a topical drug be adminstered?

Answer 34

Usually for local (non-systemic) therapy.

Highly lipid-soluble forms of drugs may reach the systemic circulation.

Common forms include:
creams
lotions
gels
ointments
shampoos

Question 35

Describe the mechanism of transdermal drug administration.

List advantages/disadvantages.

Answer 35

passive diffusion of drugs across the skin—driven by concentration gradient.

=patch
(distinct from topical administration)

Potential benefits:
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

Limitations/risks:
skin barrier limits the number of drugs that can be delivered by passive diffusion from an adhesive patch
potential discomfort, irritatio

Question 36

Describe the effect/role of blood flow in parenteral drug administration.

Answer 36

blood flow to the area maintains the concentration gradient.

drug absorption is faster in highly vascularized tissues such as skeletal muscle.

Question 37

What are some main advantages of parenteral administration?

Answer 37

greater degree of reliability and precision of administered dose
fewer problems with absorption

not affected by food in the stomach

no “first-pass effect”

Question 38

If a person is in shock, should they receive a subcutaneous injection?

Answer 38

no, not effective when peripheral circulation is impaired (e.g. in shock/cardiogenic failure)

Question 39

Will parenteral administration result in more rapid absorption intramuscularly or subcutaneously?

Answer 39

intramuscular

Question 40

What is an “bolus effect” in regards to intravenous administration? How can this be avoided?

Answer 40

to avoid a bolus effect (an excessively high plasma concentration
achieved by rapid i.v. drug administration) it may be necessary to
administer the dose over a longer period of time

(if you accidentally administer intramuscular dose)

Question 41

Many drugs bind to plasma proteins.
Which bind acidic drugs? Which bind basic drugs?

Where are protein-bound drugs found?

Answer 41

albumin binds acidic drugs

alpha1 acid glycoprotein binds basic drugs

Protein-bound drugs are retained in the plasma.

Question 42

Do Digoxin, lidocaine, and phenytoin display one or two compartment pharmacokinetics?

Answer 42

two-compartment

Question 43

With repetitive administration, steady-state concentrations are achieved only
after 5-6 elimination half-lives (t½). Does this describe one or two compartment pharmacokinetics?

Answer 43

two-compartment

Question 44

Define volume of distribution (Vd). What does it measure?

Answer 44

A measure of how evenly distributed a drug is in the body.

Volume of distribution (Vd) is a measure of how much of the administered dose
distributes outside of the plasma.

Vd is the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma.

Vd=dose/C0

(dose/initial concentration in plasma)

Question 45

How would the volume of distribution be affected in Chloroquine, a drug that readily distributes into body fat? Why?

Answer 45

Vd increases bc fat (and muscle) act as drug reservoirs;

Deposition into any reservoir limits the fraction of the drug available for diffusion from the
plasma to site of action as well as to sites of excretion (or metabolism).

Question 46

How would the Vd be affected in Heparin, a drug that has a high degree of plasma protein binding?

Answer 46

decreases; equation

Vd=Vp + [Vt x (fup/fut)]

Question 47

What % of body weight do the following compartments comprise:

plasma
interstitial fluid
intracellular fluid
transcellular fluid
fat

Answer 47

The major compartments are:
—plasma (5% of body weight)
—interstitial fluid (16%)
—intracellular fluid (35%)
—transcellular fluid (2%)
—fat (20%).

Question 48

What does it mean that a drug has a narrow distribution profile? Give an example.

Answer 48

some tissues have a particularly high affinity for the drug (iodine concentrates mainly in the thyroid gland)

Question 49

What effect can drug reservoirs have on drug administration?

Answer 49

Ultimately large amounts of a
drug can accumulate in these tissue reservoirs, especially in obese patients. In some cases more drug may be stored in these tissues than remains in the systemic circulation

Deposition into any reservoir limits the fraction of the drug available for diffusion from the
plasma to site of action as well as to sites of excretion (or metabolism).

When plasma levels of the drug decline due to metabolism or excretion, they are
replenished by diffusion from the reservoir. Gradual release of drug from these sites can
prolong the therapeutic effect or result in toxicity if drug administration is continued.

Question 50

If a drug reservoir is present, how might the loading dose be changed in some cases?

Answer 50

A reservoir may need to be saturated with the drug before a therapeutic effect is
manifest. In this case a large dose may be needed to provide an effective concentration
at the site of action of the drug.

Question 51

Give an example of drug reservoirs? What are they in the body?

Answer 51

Fat and muscle in particular can act as drug reservoirs. Ultimately large amounts of a
drug can accumulate in these tissue reservoirs, especially in obese patients. In some
cases more drug may be stored in these tissues than remains in the systemic circulation.

Plasma proteins can also serve as a drug reservoir. For a highly protein-bound drug, a large fraction of administered drug may be retained in the plasma because only the unbound drug molecules can cross cell membranes. In its protein-bound state the drug may not be distributed to its site of action. When the drug dissociates from plasma
protein (the dissociation rate will depend primarily on its affinity for the protein) it will then
be free to distribute to exert its effects.

Question 52

What is significant about sulfonamides?

Answer 52

Few therapeutic drugs affect the binding of other drugs to albumin because they occupy, at therapeutic plasma concentrations,
only a tiny fraction of the available sites.

Sulfonamides are an exception because they
occupy about 50% of the binding sites at therapeutic concentrations and so can cause
unexpected effects by displacing other drugs.