S2 L1 part 2 Pharmacokinetic and pharmacodynamics Flashcards
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
Same amount of drug is eliminated per unit time
It doesn’t increase or decrease as the concentration changes
What is first order kinetics?
The same proportion of the drug is eliminated per unit time
Variable amount - concentration increases larger amount eliminated etc…
What is the rate constant?
Mathematically - change in concentration/ change in time
K= 0.693/ t1/2
What is the half life?
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
When is most of the drug eliminated?
In absolute terms - biggest amount in the first half life
What is clearance?
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
What is the equation for clearance?
Rate of elimination from the body (mg/min)/ Drug concentration in plasma (mg/ml)
= ml/min
What is the relationship between the elimination rate and the volume of distribution?
Inversely proportional
If drug volume is spread out the elimination rate will be lower
Elimination rate= 1/ volume of distribution
How are the elimination rate, clearance and volume distribution related?
Clearance high= elimination rate high
Volume of distribution greater= elimination rate lower
Elimination rate= clearance/ volume of distribution
K (constant)= clearance/ volume of distribution
How does the t/12 life, clearance, and volume distribution link together?
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
What is the clinical significance of the relationship between the t1/2 life, clearance and volume distribution?
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
What is the importance of elimination kinetics and toxicity?
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
Why is zero order kinetics for drugs dangerous?
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
Why is it clinically important to monitoring drugs?
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?
When the the steady state concentration normally reached?
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
What happens after termination of drug administration?
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
How is the rate of infusion determined?
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
What is the difference between a single dose and multiple doses?
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
How does the oral administration affect the rate of administration?
Rate of administration = Dose x bioavailability correction / time
How is oral administration dosing calculated?
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)
What is a loading dose?
Single dose to achieve desired concentration in apparent Vd
Why is a loading dose needed?
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
How can the loading dose be calculated?
Vd= dose / [drug]plasma
Therefore
Loading dose = Css x Vd
Using the steady state concentration you are trying to achieve
Give a clinical example of where loading dose is required?
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
How does a long half life affect elimination?
Results in a long period before the drug is fully (almost) eliminated from the body - months
Important consideration if terminating medication or switching medications
What are you trying to achieve with a dosing schedule?
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
How do you know if you have prescribed successfully?
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
Define selectivity?
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
Define affinity?
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
Define potency?
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
Define efficacy?
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
In what way can drugs act?
Agonist
Partial agonist
Inverse agonist
Competitive antagonist
Non-competitive antagonist
Functional antagonist
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?
-
- 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
Need to learn the following formula:
- Half life
- Loading dose
- Css
