S2 L1 part 2 Pharmacokinetic and pharmacodynamics

Question 1

What is zero order kinetics?

(For worked example lecture - See PP, it is under lecture 2)
Also, need to go back to ICPP notes as this lecture leads on from ICPP S9, 10, 11

Answer 1

Same amount of drug is eliminated per unit time
It doesn’t increase or decrease as the concentration changes

Question 2

What is first order kinetics?

Answer 2

The same proportion of the drug is eliminated per unit time
Variable amount - concentration increases larger amount eliminated etc…

Question 3

What is the rate constant?

Answer 3

Mathematically - change in concentration/ change in time
K= 0.693/ t1/2

Question 4

What is the half life?

Answer 4

Amount of time it takes for the drug to drop to half its initial concentration
More intuitive than the rate constant- 1/ time ‘per hour’
Independent of concentration up to the saturation point (fully saturated shifts towards zero order kinetics)
Individual to each drug and process

Question 5

When is most of the drug eliminated?

Answer 5

In absolute terms - biggest amount in the first half life

Question 6

What is clearance?

Answer 6

Volume of blood cleared per unit time (ml/min)
Constant proportion not an amount
Independent of [plasma] drug
Links the elimination rate with plasma concentration

Question 7

What is the equation for clearance?

Answer 7

Rate of elimination from the body (mg/min)/ Drug concentration in plasma (mg/ml)
= ml/min

Question 8

What is the relationship between the elimination rate and the volume of distribution?

Answer 8

Inversely proportional
If drug volume is spread out the elimination rate will be lower
Elimination rate= 1/ volume of distribution

Question 9

How are the elimination rate, clearance and volume distribution related?

Answer 9

Clearance high= elimination rate high
Volume of distribution greater= elimination rate lower
Elimination rate= clearance/ volume of distribution
K (constant)= clearance/ volume of distribution

Question 10

How does the t/12 life, clearance, and volume distribution link together?

Answer 10

k= clearance (Cl) / Volume distribution (Vd)
k= 0.693/t(1/2)
Therfore
Cl/Vd= 0.693/ t1/2
Rearranged
t1/2= 0.693 x Vd / Cl

Question 11

What is the clinical significance of the relationship between the t1/2 life, clearance and volume distribution?

Answer 11

Vd- theoretical volume that needs to be cleared
Clearance- determines overall rate of elimination
Dictates t1/2
Elimination determines drug to main steady state concentration (Css)
t1/2 useful for one-off dose
Chronic treatment dosing

Question 12

What is the importance of elimination kinetics and toxicity?

Answer 12

Most drugs exhibit first order kinetics at therapeutic doses (t1/2 is constant)
High dose and alcohol, salicylic acid and phenytoin show zero order kinetics
Important consideration for toxicity and dosing

Question 13

Why is zero order kinetics for drugs dangerous?

Answer 13

Dose change can produce unpredictable change in [plasma]
t1/2 not calculable because set amount eliminated each time
e.g. alcohol- fixed amount eliminated per unit time therefore add one more drink can tip you over the edge

Question 14

Why is it clinically important to monitoring drugs?

Answer 14

Zero order kinetics- the unpredictability
Long half-life- dosing and accumulation
Narrow therapeutic window- keep it in the goldilock zone
Drug-drug interaction
Measure [plasma] for some drugs
Looking out for
- Reported or expected toxic effects
- Therapeutic effects- response that is expected/desired?

Question 15

When the the steady state concentration normally reached?

Answer 15

Usually within 4-5 t1/2 - as in it takes that amount of time to get up to the steady state
Therapeutic benefit optimal at steady state

Question 16

What happens after termination of drug administration?

Answer 16

Conversely it take another 4-5t1/2 to be eliminated from the body
Always still going to be a very small amount in the body e.g. in hair follicles
So small cannot elicit a therapeutic effect

Question 17

How is the rate of infusion determined?

Answer 17

Want to keep [plasma] at Css (steady state concentration)
Therefore the rate of infusion= rate of elimination
Rate of elimination= Cl x [plasma]
Rate of elimination= Cl x Css (as we are trying to achieve a steady state)
Therefore rate of infusion = Cl x Css

Question 18

What is the difference between a single dose and multiple doses?

Answer 18

Single dose- get a peak between absorption and distribution and elimination
Multiple dose- get a peak and slight decline as it is distributed but then it increases again as further doses are given
After 4-5 t1/2 a peak steady state will be reached - at this point peaks and troughs of steady state will be matched

Question 19

How does the oral administration affect the rate of administration?

Answer 19

Rate of administration = Dose x bioavailability correction / time

Question 20

How is oral administration dosing calculated?

Answer 20

At steady state- rate of administration= rate of elimination
Combine equations to give
Css= Dose x bioavailability correction / time (dose interval) x clearance
Since bioavailability correction and clearance are constant for a certain drug
can think of it as Css= dose / time (dose interval)

Question 21

What is a loading dose?

Answer 21

Single dose to achieve desired concentration in apparent Vd

Question 22

Why is a loading dose needed?

Answer 22

Rapid onset require or a drug with a long half life (remember steady state achieved after 4-5t1/2)
Therapeutic response needed sooner rather than later

Question 23

How can the loading dose be calculated?

Answer 23

Vd= dose / [drug]plasma
Therefore
Loading dose = Css x Vd
Using the steady state concentration you are trying to achieve

Question 24

Give a clinical example of where loading dose is required?

Answer 24

Amiodarone
- Large volume of distribution
- Predominately hepatic metabolism and biliary excretion
- Long half life 50-60 days
If it is used to treat SVT then a loading dose is required

Question 25

How does a long half life affect elimination?

Answer 25

Results in a long period before the drug is fully (almost) eliminated from the body - months
Important consideration if terminating medication or switching medications

Question 26

What are you trying to achieve with a dosing schedule?

Answer 26

Maintain dose in therapeutic range
Safe level - don’t want to overdo it
Achieve adherence - maintain dose but achievable e.g. not every 20 mins
Initiating and terminating treatment- titrating up an down/ increasing and decreasing dose to stay within the range

Question 27

How do you know if you have prescribed successfully?

Answer 27

Physiological measurements - BP, WBC, cholesterol
Feeling- MSK, mood, energy
Appearance- rash, infection, wound scan
Primary and secondary prevention - difficult as with secondary prevention might not actually feel/ see any benefit

Question 28

Define selectivity?

Answer 28

Drugs often act at or are able to elicit a response at ore than one receptor subtype
Size of response differs between subtypes
Ratio of the [drug] that achieves a given level of response at one receptor subtype vs [drug] needed at another receptor subtype

Question 29

Define affinity?

Answer 29

Strength of interaction between a drug and its receptor, governs the receptor binding-dissociation rate
Higher affinity means lower [drug] needed to occupy given proportion of receptors and elicit a given response

Question 30

Define potency?

Answer 30

Partly determined by affinity and what drug-receptor complex is able to do through its signalling
[drug] needed to elicit a given response, influence by the receptor number and the PK (EC50 or ED50)
Amount of drug require to fill half the receptors

Question 31

Define efficacy?

Answer 31

Ability to produce the maximal response of a particular system
Clinically more important than potency in most instances
A more potent drug may never achieve the response required

Question 32

In what way can drugs act?

Answer 32

Agonist
Partial agonist
Inverse agonist
Competitive antagonist
Non-competitive antagonist
Functional antagonist

Question 33

GW:

• Patient with higher body weight = Higher Vd = so will need a bigger dose of the drug
• When Vd in an equation, what should you have done with the value?
• Therapeutic index
• If clearance remains unchanged during the course of long term treatment and 10mg of drug is eliminated per day, what daily dose is required?

Answer 33

-

• Dose = Vd x plasma
  need to get total e.g. if 70kg man and Vd is 0.25L/kg, 0.25 x 70 = 17.5 , put 17.5 into the equation
• Therapeutic index =

TD50 (median maximum plasma conc that should be achieve)
ED50 (median effective dose)

• 10mg/day - To replace what is being eliminated

Question 34

Need to learn the following formula:

• Half life
• Loading dose
• Css