FRS 5. PHARMACOKINETICS WORKSHOP

Question 1

Describe phase I of drug metabolism in the liver

Answer 1

Phase I metabolism is mainly dependent on the cytochrome P450 enzyme system
o produces a more polar metabolite by the processes of oxidation, reduction and hydrolysis

Question 2

Describe phase II of drug metabolism in the liver

Answer 2

Phase II metabolism (conjugation) converts the parent drug (or metabolite) into a more polar form by
combining it with an endogenous compound such as glycine, glutamine, sulphate or glucuronic acid, or by adding an acetyl or a methyl group

Question 3

How do drugs enter the systemic circulation?

Answer 3

o directly (e.g. by intravenous injection)
o indirectly following absorption from the site of administration (typically from the small intestine following oral administration)

Question 4

Describe absorption of water soluble drugs

Answer 4

are often poorly absorbed following oral administration

o usually eliminated from the body through excretion by the kidneys into the urine

Question 5

Describe absorption of lipid soluble drugs

Answer 5

also filtered at the glomerulus, but readily cross cell membranes => reabsorption in
the proximal tubule

Question 6

What is the Therapeutic index

Answer 6

difference between concentration that achieves a therapeutic response, and the concentration that achieves a toxic response

Question 7

Why does therapeutic index vary between patients?

Answer 7

o concentration-time profile achieved with a standard dose regimen
o pharmacokinetic variability between patients
 absorption, distribution, metabolism and elimination of drugs can vary between patients
o pharmacodynamic variability
 actual response to drugs can differ between patients (e.g. target molecule may be found
in different quantities due to polymorphisms etc.)

Question 8

What is a loading dose?

Answer 8

large initial dose => can put patients straight into therapeutic range

loading dose (mg) = target concentration (mg/L) x volume of distribution (L)

Question 9

What is the apparent volume of distribution?

Answer 9

theoretical volume throughout which the drug would be evenly distributed to obtain the measured
serum concentration

(the volume of distribution is the volume of plasma that would be necessary to account for the total amount of drug in the patient’s body, if that drug were present throughout the body at the
same concentration as found in the plasma.)

Question 10

Why is the apparent volume of distribution important in calculating a loading dose?

Answer 10

decides target level

Question 11

What is the calculation for volume of distribution

Answer 11

dose (mg) / concentration (mgL-1) = volume of distribution (L)

Question 12

How does a drug being bound to plasma proteins affect volume of distribution?

Answer 12

the plasma concentration will be relatively high, and volume of distribution low

Question 13

How does a drug being bound to tissue proteins affect the volume of distribution

Answer 13

plasma concentration would be low but volume of

distribution high

Question 14

Which drugs generally have low volumes of distribution?

Answer 14

water soluble drugs that do not easily cross cell membranes generally

Question 15

Which drugs generally have high volumes of distribution?

Answer 15

lipid soluble drugs

Question 16

How is the input rate/infusion rate calculated?

Answer 16

input rate = drug dosing rate (mg/h) = steady state concentration (mg/L) x clearance (L/h)

Question 17

How is the output rate/clearance calculated?

Answer 17

output rate = steady state concentration (mg/L) x clearance (L/h) / bioavailability (F)

Question 18

What is bioavailability?

Answer 18

proportion that reaches circulation from oral dose

Question 19

How is the steady state concentration determined?

Answer 19

average steady state concentration determined by dividing infusion rate
by clearance

Question 20

What is clearance?

Answer 20

• defined as the volume of serum (or plasma, blood, etc.) cleared of drug per unit time
• therefore has the units of ml/min-1 or L/h-1
• depends on
  o rate of drug delivery (i.e. blood flow) to the liver (or kidney for some drugs)
  o efficiency, or “extraction ratio” of drug removal by the liver (or kidney)

Question 21

What can affect clearance?

Answer 21

can be altered by patient characteristics e.g. age, weight, pregnancy, renal disease, hepatic disease, cardiac disease, drug interactions etc.

Question 22

What is the significance of altered clearance rates?

Answer 22

o this means that “sick” patients often require lower doses of drugs than patients who are not so
seriously ill
o also the case for many drugs in renal and hepatic failure where the ability to clear drugs is
impaired

Question 23

What is the elimination half life?

Answer 23

time for concentration to fall to half
- half-life is directly proportional to volume of distribution and inversely proportional to
the clearance

Question 24

What is elimination half-life

Answer 24

governs the time it takes to eliminate a drug from the body and time to accumulate
to steady state on multiple dosing or during constant infusion
o takes about 4-5 half lives

Question 25

Bioavailability

Answer 25

(proportion of a drug reaching systemic circulation) depends on

• water and lipid solubility i.e. absorption from the GI tract
• first pass metabolism in the liver (passing through portal system)