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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

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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.