L36 - Drug Elimination - Metabolism Flashcards
What is elimination?
Irreversible loss of drug by excretion and/or metabolism
What is excretion?
Irreversible loss of chiemically unchanged drug
- mainly by kidneys (bile, sweat, saliva, air, milk
What is metabolism?
Conversion of the drug into a different chemical species, aldo called biotransformation
- mainly by liver (lungs, GI wall, blood, skin, kidney)
What does understanding elimination of a drug help to predict?
- drug conc ater uptake of med
- how liver and renal disease may affect drug conc
- interactions modifying the elimination of drugs
- variability in drug therapy
What interaction modifying the elimination of drugs do we want to predict?
- drug-drug interactions
- food-drug interactions
- natural/herbal products - drug interactions
What are the variabilities in drug therapy?
- age
- genetic differences in metabolisin enzymes
What is clearance (CI)?
The way the elimination process for each drug is described and quantified by
What are the most important pharmacokinetics parameters for a drug?
- clearance (CI)
- volume of distribution (V)
What does CI and V for a drug determine?
- the conc that will be achieved after dose
- how the conc of a drug will evolve with time
- the body exposure to the drug
= effects and toxicity
What is clearance defined as (proportionality)?
The proportionality factor that relates the elimination rate of a drug with the drug concentration in blood (plasma)
What is clearance (volume)?
Volume of fluid (blood, plasma) that is completely cleared of drug per unit time
What is the eqn for rate of elimination?
Rate = clearance x Cdrug
Mass/time = volume/time x mass/volume
The steeper the slope…
The greater the CI (vol/time)
In clearance and plasma profiles, the more curved…
The higher the CI of the drug, the faster the plasma levels decay
What is the steady state?
Rate in = rate out
Dose/time = CI x Css
What is additivity of clearance?
clearance by one organ/tissue adds to the clearacne by other organs/tissues
What is the total elimination rate?
The sum of the elimination rate by each organ
What is the eqn for rate of elimination (Sum)?
Rate of elimination - rate of renal excretion + rate of hepatic metabolism
What is the total CI?
Total CI = renal clearance + hepatic clearance
Sum of clearance(organ)
What is metabolism (biotransformation)?
A defence mechanism against undesriable foreign compounds, including drugs
What are the most common routes of metabolism?
- ox, red, hydrolysis - phase I
- conjugation - phase II
What can metabolites be?
- inactive
- toxic
- active, as the drug administered
- exploited therapeutically
What does administration of prodrugs relies on?
Metabolism to form the active compound (the metabolite) from the inactive prodrug
Where does the liver receive blood from?
- hepatic artery 25%
- hepatic portal vein from various GI segments 75%
- liver receives ~ 1.5L/min
What is the pathway of blood in the liver?
- blood arrives from both systems fuse and enter the liver capilaries called sinusoids
- blood leaves the liver via the hepatic vein -> vena cava
What does the liver do?
- secrete bile acids, empty common bile duct -> gall bladder
- excretes and metabolises drugs
What does hepatic elimination processes include?
Metabolism and biliary excretion
What does liver elimination work on?
Endo and exogenous substances
What are lipophilic chemical usually metabolised into?
More hydrophilic entities - excreted into urine or bile
What may drugs in blood be?
- bound to plasma protein
- bound to blood cells
- free (unbound)
What high biliary clearance like?
- polar
- MW >350
- actively secreted
// drugs - pravastatine, metabolies - glucuronide conjugates of drugs
what must a drug be like to be metabolised by one specific enzyme?
- right 3D structure to interact with enzyme site responsible for the reaction
- have a certain affinity for this site
What are enzyme drug reactions typically described by?
The michaelis menten equation
What do the P450 enzymes do?
ox and red of many drugs
What are some characteristics of drug metabolism?
- substrate specificity
- enzymatic reactions follow mm kinetics
- drug metabolism is saturable
- drug interactins
- variability
What is the elimination rate eqn following michaeli menten kinetics?
Elimination rate = Vmax + C/ Km + C
Vmax - max elim rate
Km - michaelis constant (conc of drug at which the rate of process equals 1/2 Vmax
When is drug metabolism saturable?
At high concs, the rate of elim becomes constant and equals Vmax
How is the MM kinetics model used for describing enzymtic reactions?
- D forms complex ED with E
- ED metabolised = M
- M leaves enzymatic site and E can accept D
What are the 2 drug interactions looked into?
- enzyme inhibition - direct or competitive
- enzyme induction - other chem increases activity of enzyme
What are enzyme inducers?
- smoking
- insecticides
- rifampin
- phenobarbita;
What are enzyme inhibitors?
- SSRIs inhibit CYP2D6 system
- grapefruit inhibits CYP3A4
What is variability?
Levels and activity of enzymes may differ in individuals = different values of clearance for a same drug
What are variability examples?
- genetic variations - fast/slow/ultra fast metaboliser
- age, physiopathology (hepatic disease)
