lecture 15 - pharmacodynamic principles and time course of delayed drug effects

Question 1

3 types of time courses for drug effects

Answer 1

1. immediate
2. delayed
3. cumulative

Question 2

mechanisms which explain delayed effects

Answer 2

• distribution to the receptor site
• binding to and unbinding from receptors
• turnover of a physiological mediator of the effect

Question 3

explain why a drug effect may be delayed

Answer 3

takes time for the drug to distribute to the site of action. After reaching the receptor, the process of binding to the receptor may be slow. it then takes time for the drug action to change physiological intermediate substances before the drug response is observed.

Question 4

distribution to effect site

Answer 4

effect site is not in the blood (central compartment)

it takes time for a drug molecule to get from the body to a target tissue because of the delays in perfusion of tissues and diffusion across blood vessel walls and through extracellular spaces

the rapidly mixing central blood volume is the driving force compartment for the delivery of drug to tissues

Question 5

equilibration half-life

Answer 5

also known as compartment half-life

the elimination half-life of a pharmacokinetic system is determined by the volume of distribution and clearance. these same factors affect equilibration half-life

Question 6

why does thiopentone have a short equilibration half-life

Answer 6

it reaches the brain quickly and is washed out rapidly due to high BF to the brain

Question 7

binding to receptors

Answer 7

drug reaches effect compartment then binds to receptor. Normally rapid, however, some drugs dissociate slowly from receptor causing a delay in drug effect.
e.g. digoxin

Question 8

digoxin

Answer 8

volume is not limited (due to extensive binding to Na/K ATPase in heart)

CL is great from effect compartment (due to rapid perfusion of heart)

time delay of effect associated with binding/unbinding to Na/K ATPase (mainly unbinding)

two part mechanistic model takes into account:
• distribution delay to the interstitium
• slow binding to receptor for digoxin

Question 9

physiological intermediate warfarin

Answer 9

• inhibits Vitamin K recycling
• rapid effect = decreased clotting factor synthesis
• delayed response = seen in coagulation time (INR)
• delayed response due to persistence (slow elimination) of clotting factors, eg. prothrombin complex (half-life of ~14hrs) = about 2-3 days (4 half-lives) to reach steady state effect

Question 10

diuretics and congestive heart failure

Answer 10

• digoxin, ACE inhibitors, beta-blockers used to improve survival
• diuretics do not help to improve survival, instead relieve symptoms (as major symptoms
associate with excess fluid)

Question 11

schedule dependence

Answer 11

• (50%) more effective to give separated doses rather than one big dose
• shown by larger area (greater total effect) under blue effect curves for 3x 40mg dose compared to 1x 120mg dose