Distribution

Question 1

what does the distribution of drugs in pharmokinetics refer to?

Answer 1

The movement of drug from the systemic
circulation into other tissues
-Distribution begins shortly after the first drug molecules enter the bloodstream

Question 2

what is a broad overview of the drug distribution process? Where does most of each drug dose go?

Answer 2

-First, drug distributes to plasma
-Then extracellular tissue fluids
-Then cells

Most of each drug dose goes where it is not needed
• E.g., a lipid-soluble drug accumulating in fat
• Drug molecules reaching an organ of excretion before
reaching target receptors

Only a small fraction of each dose reaches the
target receptor sites

Question 3

intensity of a drug effect is directly proportional to what?

Answer 3

the concentration of
drug in the vicinity of target cells

Question 4

what factors effect distribution of a drug?

Answer 4

1) Physicochemical properties of drug
2) Anatomy & physiology of animal
3) Plasma protein binding
4) Tissue drug binding

Question 5

what physiochemical properties of a drug affect distribution?

Answer 5

• Solubility
• Degree of ionization
• Size, molecular weight

Question 6

what important aspects of anatomy and physiology of the animal affect drug distribution?

Answer 6

-Tissue perfusion
-Blood-Brain Barrier (BBB)

Question 7

how does tissue perfusion affect the distribution of a drug?

Answer 7

-Once drug enters blood, it distributes
to entire blood volume in 1-2 min
- In the short term, organs with higher
blood flow receive more drug
(E.g., brain, kidney, heart, liver can receive 20% of CO)
- Over the longer term, larger but less well-perfused tissues (e.g., muscle, fat,
viscera) absorb the majority of the drug as equilibration between tissues occurs
- Disease/trauma can reduce blood flow to an organ > changes clinical results

Question 8

how does the blood brain barrier affect the distribution of a drug?

Answer 8

Capillaries in the brain are much less permeable to
some water-soluble substances, due to glial cells
• Totally impermeable to plasma proteins
• Water-soluble substances will enter CNS very slowly
-Systemic administration of these is ~useless if intended
site of action is the CNS
• Drugs with high lipid solubility & low protein binding cross BBB well

Question 9

what protein is a major carrier of weak acids?

Answer 9

albumin

Question 10

if a drug binds to a protein, will it ever unbind? How much of a drug will bind vs not bind?

Answer 10

yes, binding is reversible > a given molecule will bind and unbind repeatedly
-Protein-bound drug is in equilibrium with unbound (free) drug
-Drugs differ in the proportion of molecules that are protein-bound at any given instant

Question 11

if a drug is bound to plasma protein what can it not do? What happens to it? What is the consequence of this?

Answer 11

Protein-bound fraction of drug cannot enter tissues to produce desired effect, and
cannot be excreted
> simply circulate through blood until they dissociate from the carrier
protein
> this increases the half-life of the drug but decreases the intensity of effect

Question 12

examples of some drugs that are highly bound to plasma proteins

Answer 12

 Non-steroidal anti-inflammatory drugs, e.g., aspirin
 Anticoagulants, e.g., warfarin

Question 13

when does tissue drug binding influence distribution of the drug?

Answer 13

Some drugs distribute preferentially to tissues other than blood
• May bind to tissue proteins, nucleic acids, phospholipids, etc.
• Fat-soluble drugs may accumulate in adipose tissue & other
fatty tissues (e.g., Schwann cell sheaths in CNS)
• Some drugs bind to bone (e.g., tetracycline antibiotics)

Question 14

The local anesthetic lidocaine is a weak base.
It must diffuse into neurons to reach its target receptors.
If infected tissue is more acidic than healthy tissue, would you expect lidocaine to be more or less effective in infected tissue?

Answer 14

-Bases are uncharged when they are not protonated (B)
-Acidic infected tissue leads to an environment where a base is more likely to be protonated
-therefore, lidocaine will be less effective in infected tissue

Question 15

why is mepivacaine, a local anaesthetic, better than lidocaine in infected tissue

Answer 15

-Appears to diffuse better in tissues than other local
anesthetics because it has a lower pKa
-therefore, more of it will exist in the uncharged form B, which is able to diffuse

Question 16

from a pharmacokinetic point of view the body consists of what two major
compartments? Why?

Answer 16

1) The vascular compartment
2) Everything else

-If a drug diffuses easily out of the bloodstream it is likely to distribute to most other tissues

-Some drugs remain almost entirely within the bloodstream,
but most diffuse from the blood into other tissues to some extent

Question 17

what measure is used to calculate how much drug has remained in the blood stream? What else does this tell us?

Answer 17

plasma drug concentration is used to calculate how much drug has remained in the bloodstream, which tells us how much has
diffused elsewhere

Question 18

what is the volume of distribution? How will this metric change as a drug diffuses out of the blood?

Answer 18

the volume into
which a dose of drug appears to have been diluted in the
body, found by dividing the dose/concentration

If the drug does not diffuse out of the blood compartment, the volume of distribution will be equal to the
animal’s blood volume (~70mL/kg BW)

-If some of the drug has distributed into other tissues, Vd will be greater than blood volume
-The larger the Vd, the greater the proportion of the dose that has left the blood and entered other tissues
-Vd is usually larger than blood volume, because most drugs diffuse into other tissues to some extent

Example
-If half the drug diffuses out of the bloodstream, the concentration will fall to half of what it would be if no drug diffused out, and the Vd will double
-If two-thirds of the drug diffuses out (and 1/3 remains), the concentration will fall to 1/3 of what it would be if no drug left the bloodstream, and Vd will triple

Question 19

what units do we generally express the volume of distribution in and why?

Answer 19

Because blood volume varies with body size, it is customary to express Vd in terms of L/kg BW or mL/kg BW

Question 20

A larger volume of distribution indicates what?

Answer 20

that more drug diffuses out of the bloodstream into other tissues

Question 21

Who determines the Vd of a drug?

Answer 21

manufacturer

Question 22

drugs with a small Vd generally have what property?

Answer 22

Drugs with a small Vd may require larger doses to be effective, since only a small proportion of molecules leave the bloodstream and reach the target tissue, compared to drugs with a large Vd
(This is determined by the drug company and incorporated into the label dosages)

Question 23

drugs with a large Vd generally have what property?

Answer 23

Drugs with a large Vd tend to take longer to excrete, since they must be in the vasculature in order to be delivered to an organ of elimination
Volume of Distribution (Vd)

Question 24

where do water soluble drugs tend to stay? How does this relate to their Vd values?

Answer 24

Water-soluble drugs tend to remain in ECF
• Have small-to-intermediate Vd values
• Includes plasma space (~7% of body weight) and interstitial fluid (~20% body weight)
• Does not include intracellular fluids (~30-40% body weight)

Question 25

what type of drugs tend to have high Vd values?

Answer 25

• Lipid-soluble drugs*
• Drugs that bind extensively to tissue sites outside the plasma space

Question 26

Vd is useful for calculating what?

Answer 26

Vd is useful for calculating a loading dose of a drug needed to achieve a specific plasma drug concentration

Question 27

what does the graph of plasma concentration over time look like if we assume the single compartment model of drug distribution, with IV administration and no distribution or elimination?

Answer 27

concentration immediately goes up and then remains constant

Question 28

In the single compartment model of drug distribution: This is what we would see with a drug administered IV if
elimination occurred, but no distribution to other tissues on the graph of conc vs time

Answer 28

fast spike following by slow, steady decay

Question 29

In the two compartment
model of drug
distribution: This is what we would see with a drug administered IV if
distribution to other tissues occurred, but no elimination (on conc vs time graph)

Answer 29

spike upon administration, fast decay represents distribution, but then tissue is saturated and the concentration remains constant from there on

Question 30

In the two compartment
model of drug
distribution: This resembles what we actually see with a drug administered IV, taking distribution and elimination into account (on conc vs time graph)

Answer 30

-initial spike with administration
-initial steep drop due to distribution
-slower decline after this do to excretion

Question 31

Which would be more readily excreted in the urine, a drug with a pKa of 7.4 that is a weak acid or a weak base? Assume blood pH = 7.4 and urine pH = 5.4

Answer 31

-half of drug will be in ionized form in blood as pH = pKa
-some drug will be pushed out of blood into kidney nephron
-urine pH is low, so an acid would be uncharged in this environment (AH)
-the acid will be able to diffuse back into the cells
=>the base (BH+) will be more easily excreted