Lecture 17: Pharmacodynamic principles and the time course of delayed drug effects

Question 1

In reality all drugs effects are delayed in relation to the plasma concentration, what are three mechanisms that explain this?

Answer 1

Distribution to effect side (minutes)
- Pharmacokinetic

Binding to receptor
- Binding-kinetics

Physiological intermediate (hours)
- Physiokinetics

Question 2

Describe the distribution to effect site delay:

Answer 2

Effect site not in blood (central compartment)

i.e It takes time for the drug molecule to get from the blood to the target tissues because of perfusion and diffusion through vascular wall and ECF.

I.e Brain (BBB) Thiopentone (anaesthetic)

Question 3

Describe how thiopental time course demonstrates the delay cause by distribution to effect site:

Answer 3

Thiopental is an anaesthetic and measuring plasma conc. and EEG (effect) they were able to distinguish a two minute gap between the peak dose conc. and peak effect

Question 4

Describe what the effect compartment is and plasma compartment:

Answer 4

The time course of distribution can be described empirically by having an effect compartment and a plasma compartment.

This means: The time taken to reach steady state in a pharmacokinetic system receiving constant input is determine by the elimination half life from the plasma compartment. If the drug concentrations in the plasma compartment are constant then the rate of input into the effect compartment will be constant and then time to steady state of the effect compartment will be determined by the equilibration half life.

Question 5

Describe the effect compartment equilibration with the blood suing thiopental:

Answer 5

Thiopental will distribute into the brain and at steady state it will reach equilibrium with the blood conc.

i. e the time course of accumulation of thiopental in the brain is determined by a constant rate input from the blood and by half life of loss of thiopentane from the brain. this half life is the equilibration half life.
i. e The accumulation process is the same as constant IV into the blood - with time course determined by the half loss of drug from the blood (the elimination half life)

Question 6

What is the equilibration half life determined by?

Answer 6

Volume of ‘effect compartment’

• Organ size
• Tissue binding

Clearance of ‘effect compartment’

• Blood flow
• Diffusion

Equilibration half life = Time for drug to equal between plasma and effect compartment

Question 7

Write some notes on thiopental equilibration factors:

Answer 7

Thiopental

Volume
- Limited binding to GABA
Clearance
- Rapid perfusion of brain

Equilibration half life: 1min

Question 8

Write some notes on drugs binding to receptors:

Answer 8

Drug reaches the effect compartment then binds to receptors

• Can dissociate slowly from receptors (long effect or stops other effects)

Question 9

Whats an example of a drug that binds strongly to its receptor?

Answer 9

Digoxin

- Slows AV conduction and increased cardiac contractility

Question 10

What can Cp (plasma compartment) concentration be used to predict?

Answer 10

Predict the average concentration in all other tissues of the body (note this is not specific to a particular organ or tissue, so usually not closely reflect)

Question 11

Describe the time course of digoxin:

Answer 11

For digoxin effects on cardiac contractility the effect compartment reaches a peak before the average tissue concentration in part because of the more rapid perfusion of the heart compared with other tissues such as fat.

BUT: Half life is quite slow because it takes a long time to reach binding equilibrium as a consequence of its long dissociation half life. (long dissociation half life = potent drug)

Question 12

What are some factors the equilibration half life of digoxin?

Answer 12

Volume
- Extensive binding in heart to Na/K ATPase

Clearance
- Rapid perfusion of heart

Slow unbinding from Na/K ATPase is the most likely cause of the delayed onset of digoxin effects

Question 13

What are some physiological intermediates that can delay drug effects? using warfarin as an example

Answer 13

Drug action
- Inhibition of vit K cycling

Rapid effect
- Decreased synthesis of clotting factors

Delayed response
- Prolonged coagulation time (INR)

INR = International Normalised Ratio

Question 14

Describe more specifically the action of warfarin:

Answer 14

Vit K is an essential co-factor for synthesis of clotting factors

• Warfarin is absorbed in the gut rapidly and enters the liver where it inhibits Vit K reductase and VKORC1.
• This stops the recycling of Vit K epoxide (inactive) to active vit K.
  = Stops prothrombin complex synthesis.

Question 15

Describe the time course of warfarin with different metabolisers?

Answer 15

• The time course of change in prothrombin complex is determined by the half life or proteins. (involved in blood coagulation)
• The slow elimination of prothombin complex clotting factors eventually leads to a new steady state with an associated change in INR.
• Measuring INR (effect) using three different metabolisers (change C50) and INR ratios, the time to reach new steady state INR is not affected by the C50 because it is only determined by the half life of the clotting factors.

Question 16

Describe the warfarin delayed response:

Answer 16

C50 for synthesis is 1.5mg/L

• > Synthesis is reduced 50% at the C50
• > [Prothrombin complex] is reduced 50%

Critical parameters:

• > Half-life of prothrombin complex
• > about 14h

Takes 4-half lives to reach SS
- 2-3 days

i.e takes 2-3 days to reach a new steady state INR value.

Question 17

Write some more notes on drugs with delayed effects:

Answer 17

Many drugs have delayed effects due to physiological turnover. ACE inhibitors i.e enalalpril have a slow effect on BP related to slow loss of Na and subsequent decrease in plasma volume. Na turnover takes about a week to reach a new steady state. So 2-3 weeks for BP to change.

Question 18

What is the cumulative drug response:

Answer 18

Many clinical outcome benefits and adverse effects are consequence of cumulative drug action. The time course of drug action can be used to predict cumulative responses and explain phenomena such as schedule dependence.

Question 19

What are the use of diuretics in HF?

Answer 19

Congestive HF is associated with excess fluid in the body. Removal of the excess fluid can help relieve symptoms of breathlessness and ankle swelling.

Diuretics: Used to reduce Na retention and encourage loss of fluid. (relief of symptoms)

Digoxin, ACE inhibitors, beta blockers
- used to improve survival

Question 20

What is schedule dependence:

Answer 20

When you can use repeated dosing to produce a larger response than one large dose.

Question 21

Write some notes on frusemide diuretic effect:

Answer 21

Frusemide has a rapidly reversible action on the sodium transporter in the proximal tubule.

The relationship b/w plasma concentration and the excretion rate of Na can be described by the sigmoid Emax model (Hill coefficient = 3). The Emax = loss of 180nmol/h Na. But maximum loss of Na from plasma is 140mmol of Na per litre of plasma.

Thus: Max frusemide effect is losing litre of plasma per hour. i.e dramatic change in BP.

Question 22

Describe the time course effect of frusemide:

Answer 22

The time course of frusemide effect is illustrated with a large oral dose.

The effect starts quickly and reaches a plateau for nearly 2hrs then drops away quite rapidly. The loss of effect is quicker then the plasma concentration of frusemide disappears. This is a consequence of the steep concentration effect relationship with a hill exponent of 3.

Question 23

Contrast using a 40mg and 120mg frusemide dose:

Answer 23

• The time course concentrations of the 40mg dose are always 1/3 of the concentration-time profile of the 120mg dose.
• 40mg frusemide dose can achieve nearly the same max effect as the 120mg dose.

Question 24

Describe schedule dependence with regards to frusemide:

Answer 24

The cumulative area under the curve for three 40mg doses is greater than the AUCe for the 120mg dose.

i.e 120mg dose is wasted

Question 25

Write some notes on irreversible anti-cancer agent:

Answer 25

Action:
- Irreversible binding to cell structure

Delayed effect:
- Block of cell division/cell death

Cumulative response
- Slowing or reversal of tumour growth

DRUGS THAT BIND IRREVERSIBLY DO NOT SHOW SCHEDULE DEPENDENCE

I.E CISLATIN, CYCLOPHOSPHOAMIDE

Question 26

What is dose individualisation?

Answer 26

Busulfan is used to ablate bone marrow before bone marrow transplant

• Response is due to cumulative exposure
• Plasma concentrations used to guide individual treatment (measured to adjust subsequent dose)