Transcript Document

59-291 Section 1, Lecture 2
PHARMACOKINETICS
[DRUG]
[DRUG] IN
BODY
FLUIDS OR
TISSUES
OVER TIME
Depends on rates of:
-drug absorption
-drug distribution
-drug elimination= rates of biotranformation + excretion
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Figure 2-4 Drug transport in the body. (From McKenry, L. M., & Salerno, E. 1995. Mosby’s
pharmacology in nursing, 19th ed. St. Louis, MO: Mosby.)
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Drug absorption
Rate of drug absorption- passage of the drug from its site of
administration into the circulation
Exception-Topically administered drugs (examples
) are absorbed directly into target tissues.
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Two suggested models show the relationship of plasma drug
concentration to the rate of drug absorption, distribution and
elimination.
K: rate constant
C: conc.
D: amount of drug in
body at that time
V: volume of the
compartment
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Most drugs cross biomembranes by passive diffusion where the
rate of absorption is proportional to the drug concentration
gradient. In which case will the rate be larger?
A
B
Out
In
Out
In
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Passive diffusion
Aqueous diffusion
Lipid Diffusion
Drug passes through
aqueous pores in
biomembranes BUT
these pores limited to
molecular wts of <40
-drug if hydrophopic and
uncharged dissolves in lipid
(hydrophobic components)
of biomembranes
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A few drugs are imported via active transport (against a
concentration gradient)
or
by facilitated diffusion with the aid of specific membrane
transport proteins e.g. Cephaloporins that are absorbed by a
transporter for dipeptides
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Effect of pH on the absorption of weak acids and bases
-many drugs are weak acids or bases
-Only non-ionized (i.e. no charge) form of drugs is soluble in
lipid membrane and can get across
Weak acids (HA) donate a proton (H+) to form anion (A-), whereas weak base (B) accept a proton to form cations (HB+)
Drugs that are weak acids:
HA
H+ + A-
Drugs that are weak bases:
BH+
Which form can
get across the
membrane?
H+ + B
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Henderson-Hasselbalch equation can be used to determine the
ratio of nonprotonated to protonated
pH = pKa + log [nonprotonated]/[protonated]
pKa: pH at which the protonated and non-protonated forms are
equal
if pKa >7 weak base; if pKa <7 weak acid
If pH<pKa
protonated form>non-protonated form
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pH
Stomach
1-2 Weak acids are more absorbed
Small intestine
6-7 Weak bases are more absorbed
if pKa >7 weak base; if pKa <7 weak acid
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Example:
Salicylic acid pKa=3
At a pH of 2
pH = pKa + log [nonprotonated]/[protonated]
2= 3 + log [nonprotonated]/[protonated]
-1 =10-1 = 0.1 = 1/10 = log [nonprotonated]/[protonated]
For a weak acid which form is uncharged?
10
1
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Amphetamine- pKa =10 does it get absorbed in the stomach
where the pH= 2?
pH = pKa + log [nonprotonated]/[protonated]
2= 10 + log [nonprotonated]/[protonated]
-8 = log [nonprotonated]/[protonated]
10-8 = 0.00000001 = 1/100,000,000= [nonprotonated]/[protonated]
For a weak base which form is uncharged?
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100,000,000
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Amphetamine- pKa =10 does it get better absorbed in the
intestine where the pH= 7?
pH = pKa + log [nonprotonated]/[protonated]
7= 10 + log [nonprotonated]/[protonated]
-3 =log [nonprotonated]/[protonated]
1/1000= [nonprotonated]/[protonated]
The ratio of two forms at a particular site influences the rate of
drug absorption, distribution or elimination
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