Clinical Pharmacokinetics 1 Flashcards
What are the aims of clinical pharmacokinetics?
Aims to design dosage regimens which:
- Optimize therapeutic response of a drug
- Minimize chance of adverse reactions
What is plasma concentration of a drug a function of?
- The rate of input of the drug into the plasma
- The rate of distribution of the drug to the tissues
- The rate of elimination of the drug
What are the 3 most important pharmacokinetic parameters?
- Volume of distribution
- Clearance
- Bioavailability
What is volume of distribution?
A measure of the apparent space in the body available to contain the drug
What is clearance?
A measure of the body’s ability to eliminate the drug
What is bioavailability?
The fraction of drug absorbed into the systemic circulation
How do we calculate the volume distribution?
Relates the amount of drug in the body to the concentration of drug in the plasma
Vd=(Amount of drug in the body)/ (Plasma drug concentration)
Units= volume
Does the Vd refer to a physiological volume?
The Vd doesn’t necessarily refer to an identifiable physiological volume
-Vd is the volume that would be required to contain all of the drug in the body at the same concentration as it is in the blood
Describe the Vd for a drug retained within the vascular compartment
Drugs that are completely retained within the vascular compartment have a minimum Vd equal to the vascular compartment
-Drugs that have much higher concentrations in the extra vascular tissue than in the vascular compartment have a very high Vd
If a drug is bound to peripheral tissues, or partitioned into body fat, what is its concentration in plasma?
The plasma concentration will be low in these circumstances
as a result, Vd is very high
For example, the Vd for quinacrine is 50,000L in a person whose physical body volume is 70L
The Vd is a…
Proportionality factor that relates the plasma drug concentration of drug to the amount of drug in the body.
-The volume of distribution allows us to convert concentrations to amounts
What is the main use of the volume of distribution ?
The main use of the volume of distribution is to determine the loading dose to quickly achieve a target plasma concentration
How is Vd determined?
- To calculate Vd, we need to know the amount of drug in the body and the plasma drug concentration
- The only time the amount of drug in the body is known accurately is immediately after the drug has been given IV
- If we can determine the plasma concentration at time 0 (C0), then we can calculate the Vd as follows:
Vd= Dose/ C0
How is Vd determined graphically?
A dose of drug is injected IV
The plasma drug concentration is plotted vs time
- Usually, the plot shows two phases
- The rapid fall is the distribution phase
- The slower phase is the elimination phase
We linearize the curve by plotting the logarithm of the drug plasma concentration vs time
What can we extrapolate from log plasma concentration vs time graph?
Extrapolation of the elimination curve to the y-axis, yields the concentration that would have existed at the start if the dose had been instantly distributed
The initial concentration is
C0= dose/ Vd
So,
Vd=dose/C0
How can we calculate quickly calculate a target plasma drug concentration (TC)?
Dose= Vdx TC
How can we calculate clearance ?
- Clearance is defined as the volume of blood cleared of drug per unit time
- Clearance predicts the rate of elimination of the drug in relation to the drug concentration:
CL= rate of elimination of drug (amount/time) / Plasma drug concentration (amount/volume)
Units= volume per unit time
What is total body clearance ?
The sun of all the different clearance processes occurring for a given drug
What are the two major sites in drug elimination?
Kidneys and liver
What is the “first order” elimination?
For most drugs, CL is constant over the plasma concentrations used clinically
Therefore, the rate of elimination is directly proportional to the drug concentration:
Rate of elimination= CL x C
This is called “first order” elimination
What is the mathematical correlation between clearance and rate of elimination?
Rate of elimination= CL x C
For a drug eliminated with first order kinetics, CL is a constant, ie, the ratio of the rate of elimination to the plasma concentration is the same regardless of plasma concentration
CL= Rate of elimination/ C
Why do most drugs follow first order kinetics?
This occurs because the physiological mechanisms of drug elimination (enzymes and transporters) are not saturated
The dependence of the rate of drug elimination on drug plasma concentration is described by the equation:
Rate of elimination: (Vmax x C)/(Km + C)
When the drug concentration is very low compared to the Km (C
What are the properties of first order kinetics?
The initial concentration is: C0= Dose/ Vd
The concentration at a later time will depend on the rate of elimination of the drug
The drug concentration decays exponentially
For drugs with first-order kinetics of elimination the rate of elimination is directly proportional to drug concentration
When a drug follows first-order kinetics, a constant fraction of the drug is eliminated per unit of time
Plotting the logarithm of C against t yields a straight line
What is half life?
Half-life is time required to reduce the amount of drug in the body by 50% during elimination
Half-life is a constant for drugs eliminated by first-order kinetics (the great majority of drugs)
What does half-life determine?
Determines the rate at which blood concentration rises during a constant infusion and falls after infusion is stopped
A drug will accumulate until…
Until the amount administered per unit time is equal to the amount eliminated per unit time
The plasma concentration at this point is called steady state concentration (Css)
How does constant infusion affect half-life of a drug?
During constant IV infusion, every half-life the drug concentration increases 50% of the difference between the Css and the current C
During elimination, every half-life the drug concentration is reduced 50%
During a constant IV infusion of a drug:
- 50% of Css is reached after 1 half-life
- 75% after 2 half-lives
- 87.5% after 3 half lives
- 93.75% after 4 half lives
After stopping the IV infusion the drug:
- 50% of Css is lost after 1 half-life
- 75% after 2 half-lives
- 87.5% after 3 half lives
- 93.75% after 4 half lives
When can steady state be attained in terms of half lives?
- It can be assumed that steady state is attained after about 4 half-lives
- It can be assumed that the drug has been effectively eliminated after about 4 half lives
What is the formula for half-life?
T1/2= (0.693x Vd)/ CL
Doubling the infusion rate…
Doubles the Css
But increasing the infusion rate doesn’t influence time required to reach Css
What are the effects on Vd and how they affect half-life?
Effects on Vd
Obesity- increased half-life
Pathologic fluid- increased half life
What are the effects on CL that can affect half-life?
Effects on CL
Ageing- increased half-life
CYP induction- decreased half-life
CYP inhibition- increased
Cardiac failure- increased
Liver failure - increased
Renal failure- increased
Why do some drugs exhibit saturation kinetics?
Drug metabolism and tubular secretion are saturable processes
When drug concentration exceeds Km, nonlinear kinetics is observed
Rate of elimination= (Vmax x C)/(Km + C)
When C»_space; Km the equation reduces to:
Rate of elimination = (Vmax x C)/C= Vmax
Which drugs exhibit saturation kinetics?
Zero order elimination is observed with a small number of drugs:
- Aspirin at high doses
- Ethanol
- Phenytoin
What are the properties of saturation kinetics?
- The rate of elimination is maximal and independent of drug concentration
- Elimination is zero order
- A constant amount of drug is eliminated per unit time
- Recall that in first order kinetics a constant fraction of drug is eliminated per unit time
For a drug with zero-order elimination the plot of plasma concentration vs time is linear
The drug is removed at aa constant Rate of independent of plasma concentration
Summarize clearance in saturation kinetics
- Clearence isn’t constant
- Clearence varies with the concentration of drug
Rate of elimination = (Vmax x C)/(Km + C)
CL= rate of elimination/ C= Vmax/ (Km + C)
Describe half-life for drugs that follow saturation kinetics
Half life is not constant
Therefore, the concept of “4 half-lives to steady state” is NOT applicable for drugs with non-linear elimination kinetics
T1/2= (0.693x Vd)/ CL
Contrast first order and zero order kinetics
First order:
- Constant fraction of drug eliminated per unit time
- Rate of drug elimination proportional to drug plasma concentration
Zero order:
- Constant amount of drug eliminated per unit time
- Rate of drug elimination independent of drug plasma concentration
