Upload
kristin-douglas
View
219
Download
0
Embed Size (px)
Citation preview
8/13/2019 M9.22- Drug Metabolism
1/2
M 9.22 (C) Drug metabolism.
Explain what drug metabolism is. Recall where drug metabolism occurs.
Drug metabolism is when drugs are converted to metabolites by enzymes, in the liver.
Define phase I and phase II metabolism.
Phase I - Main function is to prepare drugs for phase II metabolism (Functional groups such
-OH, -NH2, -COOH are introduced into the drug molecule.
Phase II - Groups in a drug molecule (may or may not result from phase I) which are
conjugated with hydrophilic groups. Increasing water solubility and ease of excretion.
Name and understand reactions in phase I metabolism of lidocaine,
codeine, ethanol, chloramphenicol, procaine and aspirin.Drug
Compound
Reaction Use
Lidocaine Hydroxylation (+OH) Local anesthetic
Codeine [Oxidative] Dealkylation
(-CH2) 10% converted to morphine
Analgesic effect due to morphine,
anti-tussive due to codeine.
Ethanol Dehydrogenation (-H2) Metabolized in liver, next step is
further oxidation.
Choloraphenicol Reduction (O2 to H2) Antibacterial and antirickettsail.
Procaine Hydrolysis (Ester→Acid+Alcohol) -
Aspirin Hydrolysis (Ester→Acid+Alcohol) -
Recall main phase II conjugation pathways.In phase II metabolism a hydrophilic group is joined with a group already in the molecule
(may or may not result from phase I metabolism) giving a water soluble product
which is excreted in bile or urine.
Glucuronic Acid - Forms a glucouronide (Common in drugs with -OH, -COOH, -NH2)
-Conjugation occurs in salicyclic acid (aspirin) with glucuronic acid.
Sulfate (Sulfation) - Common for phenols, in the presence of phenols.
Glycine - Common with drugs with -COOH groups (Aspirin)
Recall structure of aspirin, its metabolism and general structures of its
metabolites (i.e. not full structures of conjugates).
Aspirin is hydrolyzed (Phase I) into salicylate ion and three
pathways may occur.
1. Glycine conjugation (Phase II) - Low doses (main pathway)
2. Glucuronic acid conjugation (Phase II) - Higher doses
3. Direct excretion - Very high doses of aspirin
Salicylate
8/13/2019 M9.22- Drug Metabolism
2/2
Understand reactions involved in the metabolism of paracetamol and
why it is toxic at high doses.
Main metabolic pathway: Sulfate (45-50%) or Glucuronic
Acid (45-50%) [Phase II]
Other pathway: N-Acetyl- p-benzoquinone imine, NAPQI,
forms at high doses (10-15g). Gluthathione pathway becomes
saturated and NAPQI attacks liver and can be fatal (Forming
protein adducts.
Explain how N-acetylcysteine is an antidote to paracetamol toxicity.
It acts by stimulating production of Glutathione. Note : Cys is a constituent of glutathione (γ-Glu-Cys-Gly)
Define prodrug.A prodrug is a pharmacologically inert precursor to an active drug
Explain reasons for use and understand what happens to the prodrug,
sulfasalazine (Note: you are not required to recall the structure of theprodrug but if you are given the structure you are expected to arrive at
the structure of the active drug and the reaction involved in its
generation).
The prodrug, sulfasalazine is administered in the
body for treatment of ulcerative colitis. The active
component is aminosalicyclic acid (5-ASA)
however cannot be administered directly due to
absoption in sites prior to the colon. Once it reachesthe colon, the azo linkage is broken by
azoreductases in the colon and the (5-ASA) is
active.