Pharmacology . Pharmacokinetics Absorption Distribution Biotransformation (metabolism) Excretion Pharmacodynamics Receptor binding Signal transduction Physiologic effect. 59-291 Section 1, Lecture 3. Drug distribution.
59-291 Section 1, Lecture 3
The transport of a drug in the body by the bloodstream to its site of action
-most drugs not uniformly distributed throughout the total body water
-can be trapped in interstitial fluid or in plasma
- if sufficiently lipophilic (hydrophobic) can get into cells
-maybe concentrated by ion trapping
Consider a drug with a pKa= 2
H+ + A-
-actively transported into liver cells and biotrnasformed
-intestines drugs (anticancer) are pumped from blood to lumen and excreted by the body’s natural detoxifying mechanisms
Volume of Distribution
Vd the volume of fluid in which drug would need to be dissolved in order to have the same concentration in that volume as it does in plasma
INTERSTITIAL FLUID 10
INTERCELLULAT FLUID 28
Vd provides an indication of physiological distribution of a drug
Calculation of the Vd
If Vd = plasma volume or extracellular (interstitial) volume drug remains outside of cells (Plasma or interstitial fluid)
If Vd = total body water drug is evenly distributed (ie ethanol)
500mg/ 11.9 mg/L= 42 L
If Vd = >> total body water indicates drugs are concentrated in cells by ion trapping
(500mg /2mg/L= 250L)
Many weak bases have a large Vddue to intracellular ion trapping in the cells.
Intracellular pH is less than Plasma pH >> weak bases are more in ionized from inside the cells
EXERCISE: A patient suffering from hyperalbumineuria requires 5 times the normal dose of an analgesic. Why?
What kind of a Vd would you expect this patient to have for this analgesic?
First-pass effect Inactivates many drugs
Phases of Drug transformation
Phase I- create a chemical functional group on the drug that can be recognized by Phase-II enzymes. Product of phase I enzymes still have biological activity
Phase II- no biological activity
Phase I reactions
Microsomal cytochrome P450 monooxygenase system is a family of enzymes that biotransforms many drugs