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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. - PowerPoint PPT Presentation
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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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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.
Drug absorption
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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 timeV: 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?
Out In
A B
Out In
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Passive diffusion
Aqueous diffusion
Drug passes through aqueous pores in biomembranes BUT these pores limited to molecular wts of <40
Lipid Diffusion
-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+ H+ + B
Which form can get across the membrane?
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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 acidIf 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]
10 1
For a weak acid which form is uncharged?
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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]
100,000,0001
For a weak base which form is uncharged?
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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
Amphetamine- pKa =10 does it get better absorbed in the intestine where the pH= 7?