metabolism and excretion of drugs Flashcards
what are the mechanisms the body uses to protect itself
1* Prevent from entering blood or sensitive tissue (eg BBB)
2* Physical removal from the body (urine, bile, sweat, perspiration)
3* Biochemical transformation which aims to removed products faster than the should be removed faster than parent compound .
what is biotransformation
this is the conversion of a drug to a form that can easily be excreted
what is the aim of drug metabolism
to break down the drug in molecules that can easily be excreted.
mechanism of biotransformation
making the drug more polar and thus less lipophilic and there is no absorption
enzymes involved in phase 1 reactions
cytochrome p50
short chain dehydrogenases
examples of reactions that take place in phase 1 reactions
reactions that aim to modify an existing drug or modifying an existing one
for example
hydrolysis
reduction
oxidation
some of the functional groups that are involved in the phase 1 reactions
-OH; -NH2 ; -SH
site for phase 1 reactions
liver but can take place in the lungs , small intestine and kidney
cellular organelle that has enzymes for phase 1 reactions
enzymes are at the membrane of the smooth endoplasmic reticulum
some in the cytosol
some in the mitochondria
toxicity of the intermediates that are produced
some of the intermediates may form adducts with other molecules such as DNA since they are electrophilic.
This may lead to bioactivation.
examples of biological molecules that are bioactivated
DNA - negatively charged
Proteins - depends diff proteins with a different charge .
examples of drugs that have a tendency of bioactivation
quinone and quinone analogues
benefit of phase 1 metabolism
activation of prodrugs ( that is drugs that were taken in in their inactive form)
cytochrome p450
an enzyme that is used in phase 1 metabolism
cytochrome p450 strains
60 individual enzymes; 18
families
factors that lead to the formation of the different strains of cytochrome p450
mutations and polymorphisms
characteristics of molecules in phase 2 reactions
- , larger
- weak acids so they can possibly ionise while in the SI and they will not be absorbed.
3.more likely to be bound to a plasma molecule such as albumin.
phase 2 reaction
involves addition of a different molecule that is conjugation
conjugation of a intermediate metabolite
phase 2 reaction
1.addition of co -factors and co-substrates.
2.addition of glucuronic acid which is the most common this process is known as glucuronidation.
acetaminophen metabolism
1.cytochrome p450 that breaks down and there is a hydrolysis reaction that involves addition of a quinone.
2.there is addition of a glutathione in the formation of a conjugate that is taken in through renal clearance.
cyp450 enzymes action can be increased and reduced
yes
CYP2E1 action and St , Johns Wort
action of st john`s wort plant causes the increase of metabolism in paracetamol increasing the likelihood of toxicity.
CYP3A4 enzyme and grapefruit juice
grapefruit inhibits the action of CYP3A4 therefore there is less metabolism of drugs.
omeprazole and CYP3A4
may induce that is increase in the metabolic pathway of the drug.
polymorphic variation and cyp450
polymorphic variation because of of DNA differences leads to difference in expression of the receptors.
what is the mechanism of action for warfarin
Intrinsic and extrinsic converge on
common pathway (drug target)
excretion of drugs
rate of removal of a drug from the blood in relation to plasma concentration.
clearance of a drug formula
rate of drug elimination / the plasma concentration ( ml/min)
low clearance
means there is the most circulation most of the drug is not in the plasma
what is meant by total clearance
renal
hepatic
lung
clearance in the kidney
function of the
1. glomerular filtration
2.tubular secretion
3.reabsorption(active )
factors that influence filtration
drug must be free in the plasma and this depends on the volume of distribution and protein binding, kidney perfusion the kidney must be healthy.
clearance of the glomerular filtrate
that is a function of the amount that is being filtered to the rate of filtration.
total renal clearance
when there is no secretion and there is no reabsorption
measurement of glomerular filtrate
creatine
inulin
factors that influence the process of filtration
size - large molecules
charge - with a charge
where does active renal secretion take place
occurs in the proximal tubule
characteristics of drugs that are pass through active secretion
1.Weak acid/base; Nucleoside; Pglycoprotein transporters
2.Can clear drugs too large to filter
3.Again depends on blood flow; free
drug
4,Saturable becausee they depend on transporters
transporters during secretion
transporters for weak acid
weak bases transporters
p glycoprotein transporters
nucleoside transporters
purpose of active secretion
there is excretion of particles that were unable to be excreted in the glomerular filtrate.
factors that affect the process of drug secretion
flow of blood
free drug that is unbound that can easily cross the membrane.
what is a term for the transporters of secretion failing to transport the free material
they are saturable
example of rapidly secreted drugs
beta lactam antibiotics
frusemide
ranitidine
ribavirin
verapamil
passive tubular reabsorption
movement of the molecules back to the blood circulation
factors that favor passive tubular reabsorption
1.lipid solubility
2. concentration gradient - that is movement from a high conc grad to a low conc grad.
3.dehydration that means there is more reabsorption.
4.urine flow rate -high flow rate reduces gradient and there is limited reabsorption.
5.pH and ion trapping a weak acid is more ionisation less likely to be reabsorbed.
urinary alkalization
this is to enhance clearance
this is done by making sure there is no ionisation of the weak acids and there is reduced reabsorption
for example aspirin.
test for a healthy kidney
renal clearance is proportional to GFR
measurement of GFR
creatine clearance
hepatic clearance factors
1.free drug
2.flow of blood
hepatic clearance
the rate of clearance = extraction ratio* blood flow into the liver
