Transcript Powerpoint 3

VM 8314
Drug Elimination
Dr. Wilcke
VM 8314
Drug Elimination
Biotransformation
Hepatic, Renal, Pulmonary
Secretion of unchanged drug
Renal, biliary (hepatic), GI, mammary, salivary…
Dr. Wilcke
VM 8314
Metabolism vs excretion
 Liver can do two things to drug molecules and each of them has
subtypes
 1)
Metabolism
 a.
 b.
 2)
Liver may just change the drug’s structure (metabolism)
Liver may conjugate a drug with something else (metabolism)
Secretion (not metabolism)
 a. Liver may just put a drug molecule in bile without changing it
 b. Liver may grab a conjugate (that it made in 1b) and secrete the
conjugate in bile
 1b is metabolism, 2b is not. Dr. Ehrich will also tell you
that sometimes it’s 1a -> 1b -> 2b (if the drug molecule
has to be prepared before conjugation can occur).
Dr. Wilcke
VM 8314
Metabolism vs Excretion
Kidney
1) 99% of what the kidney does to drugs is just
secretion/excretion.
Glomerular filtration does not change the drug structure
so it is not metabolism. Same for tubular secretion.
2) TECHNICALLY, the kidney also has the ability to
metabolize small molecules.
Mostly amino acids and things that look like amino
acids. This metabolic ability is rarely important but it
exists for some drugs.
Dr. Wilcke
VM 8314
Biotransformation
Conversion of drug to metabolite
Inactivates drug or…
Reduces drug activity or…
Activates drug… (would not be elimination)
Major route of elimination for lipid soluble and
protein bound drug
Because other ways out of the body are inaccessible.
Dr. Wilcke
VM 8314
Biotransformation
Chemical mechanisms
Oxidation
Hydroxylation
Hydrolysis
Reduction
Conjugation
Acetylation
Glucuronidation
Sulfation
…
Dr. Wilcke
VM 8314
Hepatic metabolism
Dr. Wilcke
VM 8314
Biliary excretion
Active secretion
High molecular weight drugs
MOSTLY conjugates (drugs themselves rarely are big
enough for the mechanism to work)
Passive secretion
Low molecular weight drugs
Biliary concentrations = plasma water
concentrations
Dr. Wilcke
VM 8314
Renal excretion
Renal elimination
Glomerular filtration +
Tubular secretion) –
Passive reabsorption
Dr. Wilcke
VM 8314
Renal excretion
Nephron animation
Animation shows glomerular filtration and passive
reabsorption, it does NOT demonstrate tubular
secretion.
Dr. Wilcke
VM 8314
Renal excretion
Passive reabsorption can be reduced
Disease
Therapeutic intervention
Decreasing passive reabsorption increases
elimination rate
Drug overdoses
Poisonings
Passive reabsorption cannot be manipulated if it
is not occuring.
Dr. Wilcke
VM 8314
Renal excretion
For most drugs and most poisons, increasing
urine output (by giving fluids or diuretics) will
NOT increase the elimination rate of the drug.
Increasing urine output will however, decrease
the concentration of the drug or poison in the
renal tubule and may spare the kidney from
damage.
Dr. Wilcke
VM 8314
Pulmonary elimination
Metabolism
Autocoids
Exhaled gases
Volatile compounds
Dr. Wilcke
VM 8314
Pulmonary metabolism
Autocoids are often metabolized in the lung
Lung is the only organ that receives 100% of the
cardiac output
Therefore, pulmonary metabolism of drugs will
produce an EXTREMELY short duration of effect.
Dr. Wilcke