Test 1- Pharmcokinetics Flashcards
Pharmacokinetics
Pharmacokinetics refers to using mathematical models to quantitate the time course of drug absorption and disposition in man and animals.
Understanding pharmacokinetics allows you to make decisions about drug selection and drug dosing that will maximize efficacy and minimize toxicity (and danger of residues in animals intended for consumption).
Pharmacokinetics allows us to evaluate the rate and extent
Pharmacokinetics allows us to evaluate the rate and extent of Absorption, Distribution and Elimination (Metabolism + Excretion) of drugs.
The rate refers to how fast the mass (dose) of a drug changes per unit time (mg/min) —-
the extent refers to how much the mass (dose) of a drug changes compared to total amount given. Together this describes the flux of a drug within a system.—-Area under the curve
Compartment model:
This model views the patient as a number of compartments, each compartment is a collection of tissues that have similar pharmacokinetics (not literal segments of the body).
1 and 2 compartment models
One-compartment models
One-compartment models consider the body as consisting of a single, homogeneous compartment. The volume of this theoretical compartment would equal the volume of distribution (Vd). This model may be closed (nothing leaves it) or open takes into account clearance (CLB) – the open model is closer to a biological system.
Two-compartment models
Two-compartment models consider the body as consisting of two compartments, a ‘central’ compartment where the drug is added and from where it is cleared, and a second compartment to which the drug distributes. A graphical representation of drug movement through a two-compartment model will show a distribution phase (α) and an elimination phase (β).
Multi-compartment models
Multi-compartment models do exist – you can have as many compartments as you like, but the math gets incredibly complex (beyond what we need to know)
Non-compartmental (stochastic) models
Non-compartmental (stochastic) models: These involve using statistical analysis of large numbers of actual animal data (time-plasma concentration curves). This is the primary method by which pharmacokinetic parameters are now determined in veterinary medicine. These will describe important pharmacologic parameters in terms of statistical moments – like the Mean Residence Time (which basically represents the average amount of time any given molecule of drug stays in the body).
MOST FREQUENTLY DONE TODAY
Population pharmacokinetics
This system estimates pharmacokinetics by looking at populations. Mathematical techniques allow studies of large numbers of animals with less individual sampling. This can allow for development of parameters for a drug that would apply to all breeds, ages, gender, etc.
Allometric scaling
This uses pharmacokinetic data in multiple species to try to predict the behavior of a drug in a species for which this information is unknown.
Non-linear models:
Used when drugs follow zero-order kinetics.
Bioavailability (F):
Bioavailability (F): the fraction of the given dose which finds its way into systemic circulation. This is calculated from the area under the plasma concentration-time curve (AUC) and is expressed as a proportion of the AUCIV (because if a drug is given IV then 100% of it reaches systemic circulation). This can be expressed as a decimal or %. For example – if 100mg of a drug is given orally but only 80mg makes it into systemic circulation then the bioavailability is 80%.
Area under the Curve
Bioequivalence:
Different formulations of the same drug are bioequivalent when they are absorbed to a similar extent and similar rate, e.g. if the AUC, CMAX (maximum plasma concentration) and TMAX (the time at which CMAX is reached) similar.
CMAX
maximum plasma concentration
TMAX
the time at which CMAX is reached)- rate of absorption
Half-life (t1/2):
The time required for the drug concentration to decrease by one-half (or 50%). For drugs that follow zero-order elimination the half-life will vary with dose, but most drugs we use follow first- order elimination and will have a half-life that does not change, regardless of the dose.
1 half life= 50% is gone
Zero-order elimination
The amount of drug eliminated per unit time is fixed, regardless of plasma concentration. There are relatively few drugs used in veterinary medicine that normally follow zero- order kinetics. For these drugs the rate of elimination does not change with plasma concentration, thus the half-life is variable depending on dose.
e.g. A drug for which 10mg is eliminated every hour. That amount will not change no matter how much drug you give and so the time for the drug to get to 50% of the initial concentration will be longer the more drug is given.
First-order elimination
The proportion of drug eliminated per unit time is fixed. For these drugs the rate of elimination depends on the plasma concentration, thus the rate changes over time but does so in a predictable way such that if we plot this form of elimination on semi-logarithmic paper it forms a straight line (the slope of which is kel). The vast majority (maybe 95%) of drugs used in veterinary medicine will follow this type of kinetics at therapeutic doses, and for these drugs the compartment or stochastic models work well for predicting pharmacokinetics.
e.g. A drug for which 10% is eliminated every hour. If you give 100mg then 10mg is eliminated in the first hour, if you give 200mg then 20mg is eliminated in the first hour. This leads to a predictable time to get to 50% of the original concentration no matter what that concentration was.
Drugs that normally undergo first-order elimination may convert to zero-order if
Drugs that normally undergo first-order elimination may convert to zero-order if a massive dose is given and elimination systems are saturated. When saturation occurs the clearance (CLB) decreases and the half-life (t1/2) increases which can lead to drug accumulation and potential toxicity.
elimination rate constant
The slope of the elimination on semi-log paper gives us kel (elimination rate constant) and that can be used to compare half-life to volume of distribution (Vd) and clearance (CLB) for drugs that follow first-order elimination in the following way:
Half-life is incredibly useful in the clinical setting as it can be used to
Half-life is incredibly useful in the clinical setting as it can be used to make predictions about a drug’s pharmacokinetics.
5 half-lives
5 half-lives is a commonly used value as for most clinical purposes 97% of the drug being gone means it is essentially eliminated for all intents and purposes.
trouble with using just half life
However, be cautious when using this with drug residues and withdrawal times (withholding time). If a withdrawal time is known you may consider using half-life to adjust for changes in dose, but this is not perfect and should NOT be used to estimate a withdrawal time if an established one does not exist!
The other thing you can do with half-life is to make predictions about how long it will
take an infusion or repeated dosing of a drug to reach a steady state in the plasma.
Plasma Concentration at Steady State (CpSS)
is the concentration at which the amount of drug going in (repeated dosing or CRI) is equal to the amount going out (clearance CLB) and can be calculated
For Constant Rate Infusions (CRI)
The plasma concentration will follow the same pattern as plasma elimination, only upside-down. Thus after 1 half-life the drug will be at 50% of the final steady-state concentration, after 5 half-lives of repeated dosing or CRI the plasma concentration will be 97% of the eventual ‘steady state’ concentration (again, for clinical purposes that is usually close enough).
Remember that if the dosing is continuous (CRI) plotting the plasma concentration over time would give
Remember that if the dosing is continuous (CRI) plotting the plasma concentration over time would give a smooth curve, but intermittent dosing (SID, BID, TID) will give you a sawtooth pattern, but the AVERAGE concentration will be following that same line so you can still make predictions.
therapeutic drug monitoring (TDM)
The highest concentration of each dose is the ‘peak’ and the lowest is the ‘trough’, as steady-state is reached the ‘peak’ value will not change day to day, nor will the ‘trough’ so if you wish to measure levels for therapeutic drug monitoring (TDM) you usually will choose a particular time of day and always measure it at that same time (eg. 4 hours after the morning dose).
The time it takes to reach steady-state does not change with dose, but we can get around that by giving a
The time it takes to reach steady-state does not change with dose, but we can get around that by giving a loading dose – effectively using a single dose to get the plasma concentration to a certain level and then, before the drug has been eliminated from that dose, starting repeated dosing at the maintenance rate.
The time to reach steady state is independent of dose!
Apparent Volume of Distribution (Vd)
Apparent Volume of Distribution (Vd): Is the theoretical volume a drug would occupy if it was evenly distributed through the body at the same concentration as in plasma. This is most easily visualized thinking about the one-compartment closed model –
If we have any two of D
If we have any two of Dose/Dosage (mass – e.g mg/kg), Volume of Distribution (Vd - usually L/kg) or plasma drug concentration (CP – e.g. mg/L) and we make sure our units match up then we can calculate the third part.
(Note: Vd is usually expressed as L/kg but for practice calculations we often leave off the /kg. If that is done for both Dose and Vd then the math works and things are less cluttered.)
A very low Vd suggests that
A very low Vd suggests that the drug is not being distributed to all of the tissues;
We know that the extracellular fluid usually makes up about 20% of body
weight, so a drug with a Vd close to 0.2L/kg likely distributes only to the ECF
Plasma makes up about 4% of body weight so a drug that has a Vd of 0.04L/kg
probably is confined to the bloodstream.
A very high Vd (>1L/kg) suggests that
A very high Vd (>1L/kg) suggests that the drug is distributing preferentially to tissue and may even be sequestered somewhere (if the Vd is greater than 1L/kg then the patient has to be bigger than they are, that’s not possible so instead we conclude that there is a higher concentration of drug in a compartment somewhere outside of the bloodstream).
i.e. Morphine
Total Body Clearance (CLB)
The volume of distribution of drug in the body cleared of the drug per unit time (mL/min/kg) and this is the sum of clearance by the kidneys, liver and everywhere else, thus CLB takes into account both metabolism and excretion.
This is a VOLUME not an AMOUNT
As Vd increases t1/2 increases:
This makes sense, the wider a drug is distributed then it probably has more than
one compartment and so that means it has to distribute back to the central compartment to be eliminated and that will take some time. If the Vd is lower than that redistribution doesn’t happen and at the same clearance rate the drug will be gone sooner (shorter t1/2).
As Clearance increases t1/2 decreases:
That makes sense too – if we are clearing the drug faster it will be hanging around the body for a shorter time. Likewise if the distribution is unchanged but we slow down elimination the drug will stay in the body longer.
“Elimination”
“Elimination” = Metabolism + Excretion
Rate
how fast the mass (dose) of a drug changes per unit time (mg/min)
Extent
how much the mass (dose) of a drug changes in total
Pharmacokinetics and ADME
Rate and extent of Absorption, Distribution, Metabolism and Excretion
Dosage Regimen
Dosage and route of administration
Frequency of administration
Duration of administration
Area under the curve graph
Why do we want to calculate half life?
Allows predictions to be made about plasma drug concentration for drugs that follow first-order kinetics
Can be used to predict time to steady state
Can be used to adjust withdrawal times and washout times for different dosages
Can be used to determine best dosing interval
Elimination rate constant (kel)
After 5 half-lives
After 5 half-lives ~97% of the drug is gone and is unlikely to have any more effect
Mean Residence Time (MRT)
The most useful is the Mean Residence Time (MRT) that describes the length of drug persistence in the body
When saturation occurs CLB decreases and t1/2 increases,
When saturation occurs CLB decreases and t1/2 increases, leading to drug accumulation and potential development of side effects
Population Pharmacokinetics
Estimates PK parameters for a drug in the population at large that would apply to all breeds, ages, and gender
Techniques that allow studies in large numbers of animals with less individual sampling
Interspecies extrapolation
Allometric scaling
Measure a pharmacokinetic parameter in multiple species and plot the data against weight to derive an equation to make estimates in an unknown species.
But the TIME to achieve steady state levels is
But the TIME to achieve steady state levels is independent of dose
As Vd increases, T1/2 gets
longer.
If oral Calcium binds to oral tetracycine to form insoluble precipitates, is this an example of
A. Antagonism
B. Summation
C.Syngerism
Antagonism
If famotidine raises the gastric pH and reduces absorption of an oral NSAID is this an example of:
A. Antagonism
B. Summation
C. Syngergism
A
If histamine causes gastric acid secretion and omeprazole inhibits gastric acid secretion, this is an example of
Anatgonism- physiological
If warfarin displaces phenylbutazone from its plasma protein binding site, this is an example of…
but. will increase because it will be become active
THIS IS NOT ANTAGONISM!
Examples of drugs that follow zero order kinetics
Phenylbutazone in horses
acetaminophen in cats
Phenytoin in dogs
Does the half life change if you give a higher dose?
IT WILL NOT CHANGE
Why do you have to be careful about drug residues?
If you need to washout a drug, generally 5 half lives.
However, what about in food animal, sometimes there are withholding times, so half life doesn’t always equal no drug residues.
If you limit clearance what is that going to do to your half life?
increase half life
As Vd decreases, t1/2
gets shorter
As clearance increases, t 1/2
gets shorter
