Fundamentals Flashcards
What is the purpose of Pharmacokinetic models?
Predicting a drug’s behavior, and concentration within complex processes
How does Compartment modeling help understand the behavior of drugs?
A compartment is composed of tissues
that behave similarly -> similar pharmacokinetics
What is the One-compartmental model?
All body tissues are considered part of the compartment
-It is assumed after a bolus dose, distribution is instantaneous within the compartment
ASSUMPTION NOT REALITY just used to make it mathematically work
What is the most commonly used Compartment model?
One-compartmental model is most frequently used in clinical practice
What types of drugs are explained with the one-compartment model?
Drugs that don’t distribute into extravascular tissues
-Polar molecules -> distribute more into the fluid compartment
-small Vd (<1L/kg) aminoglycosides
What are the factors affecting the one-compartment Model?
Fluid changes, renal failure, prematurity (babies contain 80% water)
Which drugs are more likely susceptible to fluid shifts?
-polar drugs
-small Vd
f.e. gentamycin Vd = 0.3L/kg
Where are most drugs bound to in the blood?
-Most drugs bind to Albumin
(some bind to alpha acid 1 Glycoprotein - basic drugs)
What does k stand for in Pharmacokinetics?
Eliminate rate constant
What is a Two compartment model?
consists of a central compartment and a peripheral compartment
- Distribution into the blood and highly perfused organs (central compartment - heart, liver, kidney, blood, lungs)
- Distribution more slowly into peripheral tissues
(fat, muscle, bone, cerebrospinal fluids)
What types of drugs are described with the Two-compartment model
f.e. fat-soluble drugs
-nonpolar molecules, many carbons and rings f.e. steroids
They do not like to stay in the blood
From which compartment are drugs eliminated?
Central compartment, the drugs need to move back from the peripheral compartment into the central compartment (the blood) to be eliminated
How is the Two-compartment model displayed in a Log-linear graph compared to the one-compartment model?
Two lines:
Alpha Phase of Distribution
beta Phase Elimination
in one-compartment model: one straight line
What happens during the alpha and beta Phase?
Alpha Phase of Distribution from central into peripheral tissues
Beta Phase Elimination: Elimination of drug from central compartment to outside of the body
C = A e ^-alphat + B e ^-ßt
Which drug has the most rapid distribution from the central compartment into the peripheral compartment?
A alpha = 0.050 hr ^-1
B: alpha = 0.50 hr^-1
C: alpha = 0.5 hr^-1
Distribution from the central to the peripheral compartment is described by the slope Alpha (in hr inverse -> fraction (percentage) removed per hour)
Answer C = 0.5 per hour
What would the graph look like for a very fat-soluble drug like Propofol?
Alpha would be very steep, bc the fat-soluble drug will tend to leave the blood (central) much faster into fat-soluble tissues (peripheral)
Equation Vd
Vd = dose / Concentration
Why is Vd often referred to as the apparent volume of distribution?
Drugs like tricyclic antidepressants or Digoxin can have a high Vd -> Vd does not represent the true Volume of the blood -> it stands for the fluid throughout the whole body, tissues, muscles, bones included
How does concentration behave in the body compared to the mathematical model?
In reality concentration changes and it is NOT a closed system -> ELIMINATION constantly occurs
What is the unit for the Rate of Elimination?
[mg/time] –> [mg/hr]
What is the unit for the Elimination rate constant k?
k= slope
[hr^-1]
f.e. 0.15hr^-1 (fraction per hour)
-> 0.15*100 = 15% of the concentration of the drug is removed from the body per hour
What is Clearance?
removal of drug from a volume of plasma in a given period of time
CL represents the ![Volume of plasma]! from which the drug is completely removed
-> [V/time] -> [L/hr]
-CL is expressed in volume per unit time
-CL represents drug loss from the body
Different variables of Elimination
Rate of Elimination: f.e. 10mg/hr of drug is eliminated from the body
Clearance: f.e. 3L/hr of plasma eliminated from the body
Elimination rate constant: [hr^-1] fraction of drug eliminated per hour
If the Clearance of a drug is 2L/hr, how much drug with a concentration of 100mg/L is eliminated per hour?
Concentration: 100 mg per 1 Liter
We have 2L so: 100*2 = 200mg of drug per hour
Which variables of Elimination are fixed?
Clearance [L/hr] and the Elimination rate constant - the percentage of the drug stays the same[hr^-1]
Change of concentration [mg/L] can increase or decrease the Rate of Elimination [mg/hr]
but it doesn’t change Clearance - because the volume per hour is the same;
and it does not change the Elimination rate constant k because the fraction (f.e 15%) is the same regardless of a high or low concentration
What does the total body clearance consist of?
The sum of all Clearances of different pathways: renal (kidney) + hepatic + biliary + pulmonary (exhaling) + skin
Renal and hepatic are the most common ways of clearance
What type of process is exhibited for most drugs eliminated by the body?
First Order Elimination
First Order Elimination
The amount of drug eliminated from the body is directly proportional to the amount in the body
The greater/lower the concentration the more rapid/slower the elimination per time
Why is the First Elimination graph in the Linear-Linear plot curvy?
Because it represents high removal of drugs at high concentrations and low removal of drugs per hour at low concentrations of drug
Which variable is fixed in the First Order Elimination?
-The Elimination rate constant k [hr^-1] fraction of drug removal per time stays equal
-The amount of drug eliminated decreases with time
First Order Elimination Equation
Ct = C0 * e^-k*t
What is the decay factor?
e^-kt
multiply to go forward - declining concentration
divide to extrapolate back - higher concentration
Is the Half-Life in First Order Elimination constant?
In a First Order log-linear plot, the time needed to decrease by one-half stays constant -> because the drug is eliminated faster/slowlier at high/low doses, so the half-life stays the same regardless of the concentration
t/2 = 0.693 / k
What is the Zero Order Elimination?
It occurs when the drug-eliminating enzymes reach its maximum capability
-> The amount of drug removed per hour stays equal even with high concentrations of drug
-> Concentration of drug accumulates bc the enzymes cant keep up
Halflife at zero-order-elimination
The half-life at high concentration is high and low at low concentration
-the enzymes are saturated -> it takes longer to reduce the amount of drug by half at high concentration; it takes less time to reduce the drug by half at lower concentration
Which variables are fixed or change with elimination in zero-order kinetics?
Fixed: Amount of drug eliminated per time [mg/hr]
Changes: Fraction of drug eliminated [hr^-1] increases per time bc:
the same amount of drug is removed -> as we reomve the same amount of drug, at low concentrations the fraction (percentage) of removed drug is higher
Changes: Clearance???
What would be a clinical situation of zero-order elimination?
Overdose (not every drug goes to zero-order-phase in an overdose)
-Elimination is very slow at the early phase
Examples of drugs exhibiting zero-order-elimination
-Ethanol
-Phenytoin: mix of first and zero-order-elimination
What is specific about Phenytoin with reference to drug elimination?
-Michaelis-Mentin kinetics (saturation kinetics)
-Phenytoin (controls seizures) exhibits both First and zero-order-kinetics
-Switch from first to zero-order-elimination when hepatic enzymes become saturated
Why does Phenytoin have to be dosed with caution?
Because above the inflection point, the concentration (Css - steady state) is rising exponentially with an increase in dose - Due to entering the zero-order-elimination-phase
-> potentially exceeding therapeutic range -> OVERDOSE
-Michaelis-Mentin Plot (Css over Dose)
