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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]

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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?