Pharmacokinetics Flashcards
Define pharmacokinetics
What are the 4 categories of pharmacokinetics
Pharmacokinetics is the study of the way in which the body handles administered drugs.
Absorption
Distribution
Metabolism
Excretion
Draw the graphs on one set of axes that represent the relationship between drug concentration and time for any drug administered: Oral, IV and inhaled, Assuming first order kinetics.
X-axis - time
y- axis - [Drug]
- Oral
Gut –> Vein –> Liver –> Vein –> Heart –> Lungs –> Heart –> Aorta –> target organ - IV
Vein –> heart –> lungs –> heart –> aorta –> target organ - Inhaled
Lungs –> heart –> aorta –> target organ
Cmax 3 > 2 > 1 (highest to lowest)
Tmax 1 > 2 > 3 (slowest to fastest)
Differentiate first and zero order kinetics.
Draw the graph illustrating first and zero order kinetics
Give classic examples of drugs removed by first and zero order kinetics
FIRST order: a constant PROPORTION of drug is eliminated per unit time. E.g. Gentamicin
ZERO order: a constant AMOUNT of drug is eliminated per unit time. E.g. Alcohol
First order kinetics is a concentration-dependent process (higher the conc. the faster the clearance), whereas zero order kinetics is independent of concentration.
What is Michaelis Menten kinetics
Michaelis-Menten kinetics describes enzymatic reactions where a maximum rate of reaction is reached when drug concentration achieves 100% enzyme saturation
What is non-linear elimination kinetics. Give the classic example of a drug cleared by Non-linear elimination kinetics
This is the term which describes drug clearance by Michaelis-Menten processes, where a drug at low concentration is cleared by first order kinetics and at high concentrations by zero order kinetic. E.g. Phenytoin..
At low concentrations the more substrate you give the faster the reaction rate. At high concentrations, the rate of the reaction remains the same because all the enzyme molecules are “busy”, i.e. the system is saturated.
What is the Michaelis-Menton Equation
V = Vmax x S
_________
Km + S
V: Velocity of the reaction
Vmax: Maximum velocity of the reaction
S: Drub (Substrate) concentration
Km: Substance concentration at 50% of Vmax
See graph on deranged physiology website
Use a graph to apply Michaelis-Menton elimination kinetics to the concept of therapeutic index
See deranged physiology website
X - axis: Dose
Y - axis: Drug concentration at steady state
Define volume of distribution
The apparent volume of plasma into which a drug appears to distribute. It is a theoretical volume that can substantially exceed the total body volume or potentially be infinite in size.
Vd = Dose of drug / [ Measured Plasma concentration ]
Usually expressed in L/kg
What are the clinical uses of volume of distribution
- Loading dose calculations
- ? clearance by dialysis easily
- Used retrospectively to estimate the magnitude of a drug overdose
What are the drug properties that affect volume of distribution
The drug properties that influence protein binding and tissue binding
- Molecular size
- Charge
- pKa
- Lipid/water partition coefficient
What are the patient factors that affect volume of distribution
- Age
- Gender
- Body muscle/fat proportion
- level hydration
- Water distribution (oedema/effusions/ascites/pregnancy)
- Extracorporeal sites of distribution
(Circuit / filters / oxygenator etc.)
Define context sensitive half time
CSHT (Context sensitive half time) is the time required for the plasma concentration of an INFUSED drug to fall to half the concentration when the infusion was stopped.
It is not a number but rather a function of the duration of drug delivery, which is the ‘context’
For drugs described by 1 compartment models, the CSHT is the same as the half-life (e.g. there is no ‘context’ because the duration of the infusion is not relevant). However, all anaesthetic drugs are described by multiple compartments
Why is context sensitive half time clinically useful
CSHT provides clinically useful guidance of the expected increase in the time required to eliminate the drug as a function of the duration of the drug administration
Draw the graph that represents the context sensitive half times of
Diazepam: 200 minutes at 1 hour
Fentanyl: 200 minutes at 5 hours
Thiopental: 200 minutes at 7 hours
Dexmedetomidine: 80 minutes at 7 hours
Midazolam: 70 minutes at 7 hours
Alfentanil: 60 minutes at 7 hours
Ketamine: 25 minutes at 7 hours
Sufentanil: 25 minutes at 7 hours
Propofol: 25 minutes at 7 hours
Etomidate: 10 minutes at 7 hours
Remifentanil: 5 minutes at 7 hours
Define clearance
Clearance is the efficiency of irreversible elimination of drug
The volume of blood cleared of drug per unit time
It is the proportionality constant between plasma drug concentration and elimination rate
How does drug elimination rate differ from drug clearance. How do these to entities affect first order and zero order kinetics
DRUG ELIMINATION RATE is the amount of drug cleared from the blood per unit time
CLEARANCE is the volume of blood cleared of drug per unit time
In first order kinetics
- Drug elimination rate is proportional to dose
- Clearance remains independent of dose
In zero order kinetics
- Elimination rate is constant
How is clearance related to drug elimination rate
Clearance = Elimination rate / Concentration
Is effect site concentration the same as plasma concentration
Effect site concentration is the concentration of the drug at the site of its biological activity, i.e. its receptors
Plasma concentration is the concentration of the drug in plasma.
These two entities may not be the same.
What determines the rate of onset of a drug
The rate of effect onset of a drug is determined by the distribution of a drug from other compartments (e.g. central compartment) into the effect site.
What is Keo
What is t1/2 keo
Equilibration between the central and effect site compartments follows first order kinetics, and is described by the constant Keo.
When the plasma concentration is at steady state the t1/2keo is the time taken to achieve 50% effect sit concentration
Why does the equilibration between the effect site compartment and the plasma compartment follow first order kinetics?
Because the rate of movement of the drug from the plasma compartment to the effect site is dependent on the plasma concentration. This will follow first order kinetics and is defined by the constant Keo.
What is a simple way to explain the difference between plasma concentration and effect site concentration
Propofol infusion –> plot values over time
EEG (to measure sleepiness –> plot values over time
Observe delay in ‘sleepiness’ as Propofol infusion reaches a steady plasma concentration. This is because the plasma compartment must equilibrate with the effect site compartment
Why is the relationship between the peak onset time and the t1/2 keo important
The slower the t1/2 keo, the larger the bolus dose required
What is a the mathematical equation that describes a single compartment model.
Describe how the components of this equation define the graph.
C = Co . e^-kt
C: Concentration Co: Concentration at time = 0 e: e (2.716....) k: the rate constant for elimination t: time
It is a washout curve:
k –> determines the steepness of the descent of the washout curve
Co –> determines the starting point on the y-axis of the curve.
What is the time constant for an elimination curve. What is the time constant’s relationship to the elimination rate constant (k) and the half life t1/2
The time constant (tau) is the time taken for the concentration of the drug in plasma to reduce by a factor of ‘e’ (2.716).
If the inititial elimination rate of the washout curve graph is extrapolated using a straight line into the time (x) axis, this is the time constant.
time constant = 1/k
time constant = t1/2 / ln 2 (ln2 = 0.693)
This means that time constant is 44% longer than the half life.
What is the definition of an exponential function
The rate of change of the function is proportional to the dependent variable
Define half life
What is the formula for half life
Half life is the time taken for the plasma concentration of a drug in the blood to halve.
Time constant = t1/2 / 0.693
Time constant = Vd/Clearance
t1/2 = (0.693 x Vd) / Clearance
How much of the drug is eliminated by: 1 x t 1/2 2 x t 1/2 3 x t 1/2 4 x t 1/2 5 x t 1/2
1 x t 1/2 - 50% 2 x t 1/2 - 75% 3 x t 1/2 - 87.5% 4 x t 1/2 - 93.75% 5 x t 1/2 - 96.875%
How will doubling the dose of a drug affect its duration of action
It should increase the duration by about 1 half life (because its clearance is a logarithmic function
How is the concept of half life applied to first order and zero order kinetics
In first order kinetics half life is constant regardless of drug concentration
In zero order kinetics half life becomes meaningless and one refers instead to a dose or concentration removed per unit time
