Drug metabolism and general anaesthetic Flashcards
First pass effect
Drugs absorbed across GI epithelium enter the portal circulation that goes to the liver so may be metabolised there before reaching systemic circulation
Oral bioavailibity
Fraction of dose that reaches systemic circulation
Blood brain barrier features
Tight junctions
Astrocyte layer as extra membrane barriers
Drug efflux pumps like P glycoprotein (MDR1)
Volumes of fluid compartments
Plasma 3L
Interstitial fluid 11L
Intracellular fluid 28L
Effect of binding tissue but not plasma on Vd
Apparent Vd increases as conc in plasma falls due to equilibrium
Effect of binding plasma proteins
Apparent Vd decreases as the blood sample will measure both free and bound drug
Xenobiotics
Chemicals foreign to own metabolism but that can exert an effect on us
Mainly ingested so defence system focussed around GI tract
Phase 1 metabolism
Addition of a reactive chemical group
Phase 2 metabolism
Conjugation of drug via addition of small molecule to the reactive group
Generally increases water solubility, increased molecular weight and inactivates electrophile metabolites
Example of competition between substrates
Fluoxetine fitting into CYP2D6 active site
Example of competitive inhibition by non-substrates
Quinidine fitting into CYP2D6 active site
Example of non-competitive inhibition
Ketoconazole binding allosteric site on CYP3A4
Example of mechanism based inhibition
Grapefruit guide on CYP3A4
Metabolism of phenytoin
Cytochromes to hydroxyphenytoin
UGT transferase to soluble phenytoin-glucuronic acid
Metabolism of codeine
To active metabolite morphine by CYP2D6
Then conjugated by UGTs to morphine 3/6 glucuronide
- the 6 glucuronide version still active
