ADME

Question 1

Why are some drugs administered in their inactive prodrug form?

Answer 1

• Active drug has very low oral bioavailability.
• Prodrug has greater oral bioavailability.
• Prodrug is metabolised to form greater [active drug] in plasma that what would have been achieved by taking active drug directly.

Question 2

Where in the body does drug metabolism occur?

Answer 2

• Mainly in the liver.
• Can occur in plasma (e.g. suxamethonium, a drug used in anaesthesia to produce relaxation of the muscles)
• Can occur in intestine (e.g. cocaine).

Question 3

What happens in Phase I metabolism?

Answer 3

Drug derivative is formed by oxidation, reduction or hydrolysis. Often introduces / exposes a reactive site on drug molecule.

Question 4

What is the benefit of drug derivatives produced in Phase I metabolism being more reactive?

Answer 4

• More chemiccally reactive derivative makes phase II reaction more energetically favourable.

Question 5

What happens in Phase II metabolism?

Answer 5

Conjugation of species formed in phase I with very polar molecules.
Makes metabolite less lipid soluble - more of it excreted in urine.
Reaction often occurs in cytosol of liver cell.

Question 6

What is a microsomal enzyme?

Answer 6

Drug metabolising enzymes found in the ER of liver hepatocytes.

Question 7

Name the five factors that affect drug metabolism.

Answer 7

1. Enzyme Induction
2. Enzyme Inhibition
3. Genetic Polymorphisms
4. Disease
5. Age

Question 8

How do genetic polymorphisms affect drug metabolism?

Answer 8

• Mutations in genes that code for microsomal enzymes (involved in drug metabolism) affect rate of drug metabolism.

Question 9

What are the consequences of enzyme induction?

Answer 9

• Failure of drugs to produce therapeutic effect.
• Increased clearence, decreasing half-life of drug.
• Steady state plasma concentration of drug (Css) will be less.

Question 10

Which of the following will have a quicker effect on drug metabolism?
- Enzyme Induction
- Enzyme Inhibition

Answer 10

Enzyme Inhibition

Question 11

What is the effect of disease on drug metabolism?

Answer 11

Hepatitis, Liver Cancer and cirrhosis will reduce liver function (slower metabolism of drugs).

Diseases that reduce renal function (drugs excreted without metabolism).

Overactive / underactive thyroid (increased thyroid activity = increased rate of metabolism).

Cardiovascular diseases will affect rate of delivery of drug delivery in blood to liver / kidneys.

Question 12

Give 3 examples are parenteral routes of administration.

Answer 12

• IV
• IM
• Subcutaneous Injection

Question 13

What is an advantage of the subcutaneous route of drug administration?

Answer 13

Easier than IV or IM so can-self-administered, ideal for drugs like insulin: cannot be taken orally as stomach will digest drug molecule.

Question 14

What does the oral bioavailability value (F) represent?

Answer 14

Fraction of oral dose that reaches the systemic circulation.

Question 15

Give 3 factors that affect the oral bioavailbility of a drug.

Answer 15

• Poor absorption from the gut.
• Breakdown of drug in gut.
• First pass effect.

Question 16

What is the most important factor affecting drug absorption at a membrane?

Answer 16

Lipid solubility of the drug.

Question 17

Why may the apparant volume of distribution for a drug be greater than the total body volume?

Answer 17

Drug may have accumulated in tissues leading to a relatively low plasma concentration, but a large amount of drug in the body.

Question 18

What are the 3 key pharmokinetic parameters?

Answer 18

1. Volume of Distribution (Vd)
2. Plasma half-life of drug (t_0.5)
3. Clearance (Cl)

Question 19

Define the term excretion.

Answer 19

The movement of drug from inside to outside of body.

Question 20

Define the term elimination in terms of drugs.

Answer 20

Overall removal of drug from body. Includes excretion and metabolism.

Question 21

What does the half-life of a drug represent?

Answer 21

Time it takes for the [Drug] in the plasma to fall to half its initial value from where it is measured.

Question 22

What does it mean for a drug to be pseudo-zero order?

Answer 22

At high [Drug] it is zero order (when elimination process is saturated), at low [Drug] it is first order.

Question 23

How many half-lives (roughly) does it take to achieve steady state (Css)?

Answer 23

5 half lives

Question 24

How would a greater rate of infusion influence the Css of a drug?

Answer 24

Css would be higher.

Question 25

What type of drugs may be excreted by the kidney?

Answer 25

Non-lipid soluble drugs.

Question 26

What are the 3 processes that determine drug excretion by kidney?

Answer 26

1. Glomerular Filtration at the Bowman’s Capsule (drug may be filtered in lumen of nephron).
2. Active Secretion (at proximal tubule - drug would be pumped into lumen of nephron).
3. Passive Reabsorption at distal tubule (all lipid-soluble drugs reabsorbed at this point).