Pharmacokinetics and Drug Metabolism

Question 1

State the 5 stages of the journey of a drug through the body.

Answer 1

Administration 
Absorption 
Distribution 
Metabolism 
Excretion

Question 2

What is the difference between enteral and parenteral administration?

Answer 2

Enteral: using the GI tract
Parenteral: everything except the GI tract

Question 3

What are the advantages of intravenous administration?

Answer 3

Rapid systemic exposure

High bioavailability

Question 4

State the 2 ways in which drug molecules move around the body.

Answer 4

Bulk Flow Transfer: in the bloodstream

Diffusion Transfer: molecule by molecule over short distances

Question 5

State 4 methods by which drugs can cross lipid membrane barriers.

Answer 5

Diffusion through the lipid membrane (if appropriately lipophilic)
Diffusion through aqueous pores
Carrier molecules
Pinocytosis

Question 6

Finish the sentence: most drugs are either …… or ……

Answer 6

Weak acids or weak bases

Question 7

Which factors affect the ratio of ionized to non-ionized drug?

Answer 7

pKa of the drug

pH of the environment

Question 8

Describe and explain the difference in absorption of aspirin in the stomach and the small intestine.

Answer 8

Aspirin has a pKa of 3.4
Stomach pH is ~1 so when aspirin enters, as the pH of the stomach is lower than the pKa of aspirin, equilibrium of the aspirin is shifted towards the unionized state and is rapidly absorbed
In small intestines pH is more basic (greater than the pKa of aspirin) Thus, aspirin is ionized and hence absorption is SLOWER in the small intestine

Question 9

What is ion trapping?

Answer 9

Some ionized aspirin will enter the systemic circulation, which is an aqueous environment
As it is ionized it will not be able to move into the tissues and hence is ‘trapped’

Question 10

State 4 factors affecting drug distribution.

Answer 10

Regional blood flow
Extracellular binding (plasma-protein binding)
Capillary permeability
Localisation in tissues

Question 11

In which state can albumin bind to drugs? Ionized or non-ionized?

Answer 11

Both ionised and unionised

Question 12

State 3 types of capillary architecture.

Answer 12

Continuous (tight junctions)
Fenestrated (small gaps)
Discontinuous (large gaps)

Question 13

Give a broad example of localization of a drug in tissue.

Answer 13

Lipophilic drugs tend to localise in fatty tissues e.g. brain and testes

Question 14

What are the 2 main routes of drug excretion?

Answer 14

Kidneys (mainly)

Liver

Question 15

What types of molecule tend to get excreted via the biliary route?

Answer 15

Large MW molecules

Liver allows concentration of large MW molecules that are very lipophilic

Question 16

Via what form of molecular movement do most drugs tend to get excreted into urine?

Answer 16

Active secretion

Question 17

What happens to drug-protein complexes at the glomerulus?

Answer 17

They are not filtered into the filtrate

Question 18

Where does active secretion of acids and bases occur in the nephron?

Answer 18

Proximal convoluted tubule

Question 19

What can happen to lipid soluble drugs in the proximal and distal convoluted tubules?

Answer 19

They could be reabsorbed

Question 20

Why might treatment with I.V. sodium bicarbonate increase aspirin excretion?

Answer 20

IV sodium bicarbonate increases pH of the blood and increases the amount of ionised aspirin.
Thus, the aspirin is more water-soluble and less lipid-soluble so the kidneys can more easily excrete it and less aspirin is reabsorbed in the proximal and distal tubules
Increases rate of aspirin excretion

Question 21

What is the main purpose of the active transport systems that secrete drugs into bile?

Answer 21

Active transport of glucuronides and bile acids into the bile but drugs can hitch a ride on this mechanism

Question 22

What is a potential problem with biliary excretion of xenobiotics?

Answer 22

Enterohepatic cycling:
Gut bacteria breakdown water soluble conjugate
Free drug released, returns to liver via the enterohepatic circulation
Leads to drug persistence

Question 23

Define bioavailability.

Answer 23

Proportion of the administered drug that is available within the body to exert its pharmacological effect

Question 24

Define apparent volume of distribution.

Answer 24

Volume in which a drug appears to be distributed – an indicator of pattern of distribution

Question 25

Define biological half-life.

Answer 25

Time taken for the concentration of a drug (in blood/plasma) to fall to half its original value

Question 26

Define clearance.

Answer 26

Volume of plasma cleared of a drug per unit time

Question 27

Define First-Order kinetics.

Answer 27

When the rate of drug excretion is proportional to the concentration of drug remaining within the body
Log of drug concentration is proportional to time

Question 28

What is a difficulty faced in deciding solubility of a drug?

Answer 28

Drugs have to traverse both aqueous (compartments e.g. blood) and lipid (barriers e.g. membranes) environments

Question 29

Non polar substances can freely dissolve in…

Answer 29

Non polar solvents

i.e. can penetrate lipid membranes freely

Question 30

When are drugs more unionised?

Answer 30

Weak acids: Acidic environment

Weak bases: Alkaline environment

Question 31

Standard rule for acids

Answer 31

If pH is below pKa = more unionised

If pH is above pKa = more ionised

Question 32

Standard rule for bases

Answer 32

If pH is below pKa = more ionised

If pH is above pKa = more unionised

Question 33

Calculating ratio of unionised/ ionised

Answer 33

pKa - pH = y

10^y

Question 34

How does regional blood flow effect drug distribution?

Answer 34

The more blood to a certain tissue the more drug to a certain tissue
Highly metabolically active tissues have denser capillary networks

Question 35

How does plasma protein binding effect drug distribution?

Answer 35

If PPB, drug won’t leave blood

Need to adjust dose so sufficient amount of drug is unbound and active