Pharmacokinetics. Drug Effectiveness. Dose-response (DR) curve : Depicts the relation between drug dose and magnitude of drug effect Drugs can have more than one effect Drugs vary in effectiveness Different sites of action Different affinities for receptors
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This is a figure of two different dose response curves. You can obtain a different dose response curve for any system that the drug effects. When you vary the drug, this is the Independent variable, what you are measuring is the % of individuals responding to the drug. Here we see the drugs effects on hypnosis and death. Notice that the effective dose for 50 % of the people is 100 mg and if you double the dose to 200 mg then 1 % of your subjects die. Thus, if you want to use this drug to hypnotize 99 % of your subjects, in the process you will kill 2-3 % of your subjects.
The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
Volume 100 L
Volume 100 L (Vi)
Volume of Distribution =
Volume of blood cleared of drug per unit time
Clearance = 10 L/hr
Volume of Distribution = 100 L
What is the Elimination Rate Constant (k) ?
k = 10 Lhr -1 = 0.1 hr -1
10 % of the “Volume” is cleared (of drug) per hour
k = Fraction of drug in the body removed per hour
If V increases then k must decrease as CL is constant
Apparent volume of distribution is the theoretical volume that would have to be available for drug to disperse in if the concentration everywhere in the body were the same as that in the plasma or serum, the place where drug concentration sampling generally occurs.
Dose = Cp(Target) x Vd
Combining the two,
CLT C = kel C Vd and simplifying gives:
CLT = kel Vd
smaller t ½ and larger kel
Time to eliminate ~ 4 t1/2
t1/2 = 0.693/k
lnC2= lnC1 - kt
logC2 = logC1 - kt/2.303
t1/2 = ln2/k
100 mg given every half-life
1) glomerular filtration
glomerular structure, size constraints, protein binding
2) tubular reabsorption/secretion
- active transport, competitive/saturable, organic acids/bases - protein binding
1) Phase I and II reactions
2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney
3) Possibility of active metabolites with same or different properties as parent molecule
% bound: __[bound drug]__________ x 100
[bound drug] + [free drug]
Vd is the apparent volume of distribution
C= [drug] in plasma at some time
D= total [drug] in system
Vd gives one as estimate of how well the drug is distributed. Vd < 0.071 L/kg indicate the drug is mainly in the circulatory system.
Vd > 0.071 L/kg indicate the drug has entered specific tissues.
C = Co - ktln C = ln Co - kt
Rate = k
C = Co - kt
Constant rate of elimination regardless of [D]plasma
C vs. t graph is LINEAR
First Order Kinetics
Rate = k C
C = Co e-kt
Rate of elimination proportional to plasma concentration. Constant fraction of drug eliminated per unit time.
C vs. t graph is NOT linear, decaying exponential. Log C vs. t graph is linear.Types of Kinetics Commonly Seen
Answer: 42 g or 56 ml of pure ethanol (VdxC)
Or 120 ml of a strong alcoholic drink like whiskey
at 10 ml/h of pure ethanol, or 20 ml/h of drink.
[drug] decreases exponentially w/ time
Rate of elimination is proportional to [drug]
Plot of log [drug] or ln[drug] vs. time are linear
t 1/2 is constant regardless of [drug]
Zero Order Elimination
[drug] decreases linearly with time
Rate of elimination is constant
Rate of elimination is independent of [drug]
No true t 1/2To reiterate: Comparison
or k = FD/AUC
FDpo/AUCpo = Div/AUCiv
F= amt. of drug that enters systemic circul.
F = AUC/Dose
F = 1-E = 1-Clhep
This very useful equation calculates the magnitude of the effect of the liver’s 1st pass of an oral dose and, more precisely, to predict it from and i.v. test.
Thus, if E < 0.10, then, clearly, bioavailability F > 0.90.