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
Heroin
Rapidly crosses BBB due to acetyl groups
Urine being slightly acidic
tends to trap weak bases while weak acids reabsorbed
If we want to excrete weak acids give sodium bicarbonate to increase the pH of the urine
Meyer Overton correlation
Partial pressure of anaesthetic needed to produce anaesthesia is inversely proportional to oil-gas partition coefficient
More soluble in oil means more potent
Problems with lipid theories of GAs
Size cut off; once alkanes get too big, increasing lipid solubility doesn’t alter potency
Some anaesthetics not lipid soluble
Stereospecificity of some drugs; suggest receptor binding
Correlation between anaesthetics and ability to inhibit Luciferase
Positive correlation
This may be target
Requirements for anaesthetic target proteins
- Reversible anaesthetic effect at site
- Must be in plausible locations
- Stereoselectivity in vitro must match in vivo
Anaesthetic target proteins
GABAa receptor: propofol found to increase duration of hyper polarising Cl- current
TASK: action of halothane and isoflourane
NMDA receptors: action of xenon and isoflurane
Injectable anaesthetics
Thionetal: fast onset but hangover
Propofol and etomidate for induction of anaesthesia not maintenance
Effect of low blood:gas partition coefficient
Rapid induction (as alveolar PP increases rapidly)
Rapid recovery
NO
Effect of high blood:gas partition coefficient
Higher potency
More hangover effect
Ether
Hangover effect
Due to drug re-enteing venous blood from low flow tissue/fat
