Metabolism Flashcards
What is metabolism?
The enzymatic conversion of one chemical compound to another
Where does most drug metabolism occur?
Liver
Where in the body does metabolism occur?
Gut wall, lungs and blood plasma
What is drug metabolism?
Conversion of drug into a more water soluble compound by increasing its polarity
How does age affect metabolism?
Increased age results in a decline in hepatocyte number and enzyme activity
How does disease affect metabolism?
Disease state:
Reduces hepatic blood flow
Increases heart failure or shock which reduces metabolic potential of the liver
How does genetics affect metabolism?
Genetic can result in over-expression or deficiency of a particular enzyme
How do diet and lifestyle affect metabolism?
Grapefruit juice and St John’s Wort inhibit CYP450 activity
Cigarette smoke and Brussel Sprouts increase CYP450 activity
Explanation for the Rate vs Substrate Conc graph flattening out
The enzyme becomes saturated with substrate
Why is there almost no curvature in rate vs drug conc graph?
Therapeutically relevant doses only appear at the very start of the graph
What happens to drug conc with a drug that follows non-linear or zero order kinetics?
A small increase in dose may cause a disproportionately large increase in plasma concentration
What group do the main drug metabolising enzymes belong to?
CYP450s
Where are CYP450s found?
Smooth endoplasmic reticulum of cells
What is involved in Phase I of Metabolism?
Reduction, hydrolysis or oxidation
What is oxidation catalysed by in Phase I of metabolism?
CYP450s
Nomenclature of CYPs
Nomenclature is genetically based and has no functional implication
CYP2 - Family
CYP2D - Sub-family
CYP2D6 - Specific gene
What is involved in Phase II metabolism?
Conjugation with the attachment of an ionised group to the drug
Where does Phase II metabolism occur?
In hepatocyte cytoplasm
What does the attachment of an ionised group mean?
Makes the metabolite more water soluble and facilitates excretion and decreases pharmacological activity
What is the first pass effect?
Any drug taken orally will go into the stomach and pass through the liver via portal circulation before getting into systemic circulation
What does a high degree of first-pass metabolism mean?
A large proportion of dose is metabolised before it gets to systemic circulation
How can first pass be avoided?
Buccal medications
Rectal
Parenterals
What happens to CYP450 activity down the GI tract?
Decreases down the GI Tract
Duodenum - 50%
Jejunum - 30%
Ileum - 10%
Colon - 2%
What happens to pro-drugs?
Metabolised to the active form by enzymes in Phase I metabolism
What occurs in paracetamol overdose?
Not enough glutathione to conjugate
Accumulation causes toxicity and can result in hepatitis
Compounds that increase levels of gluthione are administered to allow conjugation
What happens in drug metabolism induction?
Drug A increases the rate of metabolism of Drug B
Blood concentration of drug B falls below normal therapeutic levels and drug B is ineffective
What happens in drug metabolism inhibition?
Drug A reduces the rate of metabolism of Drug B
Blood concentration of Drug B increases above safe levels and becomes toxic
What happens in CYP450 enzyme inhibition?
Quantity of CYP450 is not reduced but existing CYP405s are made less effective
What is special about Quinidine?
It inhibits a specific CYP even though it is not metabolised by it
Is alcohol an inducer or an inhibitor?
Both
Inhibitory effect is instant
Inducing effect occurs with long-term alcohol use due to time needed to synthesise new enzymes
What herbal remedies are inhibitors?
Garlic
Peppermint Oil
Milk Thistle
What herbal remedies are inducers?
St John’s Wort
Reduces effectiveness of certain drugs as they are cleared from the body more quickly
Grapefruit Juice
Antioxidants inhibit CYP3A4 in the gut wall and liver
Increases blood levels of Ca2+ channel blockers
Cranberry Juice
Antioxidants inhibit CYP450s
Warfarin levels can increase significantly
