test 3 Flashcards
rate of elimination
mass removed per unit time (mg/hr)
which order is the clearance
first order drugs
concentration
mass per volume (mg/L)
clearance
volume per unit time (L/hr) , Q X E, flow rate times extraction ratio, clearance is a consitant and based on pt liver, kidney, and blood flow to different organs.
the resevior represents
vd
the extractor represents
organ eliminating drug
amount represents
mass of drug in the body “dose”
volume represents
vd
Q represents
blood to/from organ
C and Cout represents
drug going in / out of organ (extractor)
E represents
Extraction ratio, Rate of Elimination divided by Rate of presentation
high E vs low E
high means the liver chews it up, low means there is a slower process in the liver “how effective is the body at removing the drug”
rate of presentation
how much drug is being presented/unit time, Q X Cin - flow to the extractor and multiplying by the concentration of the drug that is entering
Rate of elimination
flow rate into and out of the extractor, Q, and multiplying by the difference between the concentration coming in and coming out OR Rate of presentation X Q X E. Concentration dependent. ROE x Cl volume cancles. ROE = Conc x CL
extraction ratio
rate of elimination divided by the rate of presentation (C in-C out)/ C in
what variables could we manipulate in order to change the rate of drug elimination
blood flow to make Q lower than normal - liver is more confined. Q and E can affect the liver to remove the drug
Cl / vd
clearance
as k becomes small
half life longer, clearance small, vd large
if Cl is big
K is big (hr -1)
fractional RoE
RoE / Ao (dose)
can you change the extraction ratio?
yes! drug inhibitor of an enzyme, enzyme inducer- cl changes and goes up, give more drug
enzyme inducer
clearance will change and go up! excreting the drug faster. half life will decrease and give more drug because of eliminating more frequent!
why does k stay the same
cl and vd are dependent on body weight. as cl increases the vd will also increae. the half life will also stay the same. if a drug is fat soluble then the k may change
other ways to say drug metabolism
xenobiotic metabolism, drug metabolism, drug biotransformation
in general drug metabolism
converts a lipophillic substance, chemical to a metabolite (product) that is more hydrophilic than the parent drug in order to facilitate elimination - filtered more easily - the drug is usually catalyzed by enzymes
in drug metabolism it is usually catalyzed by enzymes
- multiple enzymes and paths are possible for a single drug
2. multiple metabolites with varying properties are possible - metabolite can be more active than the parent drug
routes of elimination for top 200 drugs by percentage
75% metabolism
20% kidneys
15% bile (does not chemically alter the drug or else it would be metabolism - hepatocyte takes from blood and puts it in the bile!)
consequences of drug metabolism
usually inactivation, the pharmacological activity (therapeutic or toxic) may be changed, resulting metabolites can be classified as active or inactive
inactive metabolites
devoid of pharmacological activity, metabolic changes result in the termination of drug action, chemical properties of the drug are changed, affecting how a drug interacts with target or changes the distribution of the drug
EX: blocks alpha1 receptors and then blocks Beta1 receptors when metabolized
active meatabolites
have pharmacological activity, similar to the desired activity, unexpected/new activity not observed with parent drug
what effect can a quinone do
causes harm in the body - deplete glutathione which can result in no liver activity afterwards
nor/des
without a methyl group
drug bioactivation
parent drug (prodrug) has no pharmacological activity to attain pharmacological activity the prodrug must undergo metabolism - more lipophilic will cross the membrane and enhance absorption, when it overcomes activation it is now more polar
where is the highest concentration of drug metabolizing enzymes
liver
phase one reactions
oxidation, hydrolysis, reduction, add or reveal a polar functional group, inc water solubility and facilitate excretion, does not always terminate drug action, metabolite may undergo phase 2 reactions. can go through several phase one reactions, small functional group
phase two reactions
conjugation, add biomolecules to a functional group on drug or phase one metabolite. increases water solubility and facilitates elimination, increases molecular weight (sulfate or glutathione) and requires a high energy cofactor, usually terminates drug action, phase 2 conjugates may undergo phase 1 metabolism
oxidation
most common phase 1 reaction, largely catalyzed by the cytochrome 450 enzymes, responsible for metabolism of 85% of drugs, several isoforms of CYP450, broad substrate specificity, looks for lipophilic and tries to make it more hydrophilic
about CYP450
contains heme molecules bound to iron (Fe), absorbs light at or near 450 nm when Fe is bound to carbon monoxide, embedded in the endoplasmic reticulum of cells, requires a NADPH and molecular oxygen - something has to be reduced,
major CYP reactions
aromatic, aliphatic, acyclic hydroxylation alkene oxidation o and n dealkylation deamination N oxidation
hydroxylation
adding a hydroxyl group, at places with little steric hindrance, para and ortho are the most reactive by p450
alkene oxidation
converts it to an epoxide by a p450, very reactive molecule
epoxide hydrolase
converts epoxide to two alcohols with addition of H2O, no p450 added, makes the molecule much less reactive
O and N dealkylation
CYP2D6, remove methyl groups (alkyl groups)
deamination vs dealkylation
deamination removes entire amine group, dealkylation just removes the methyl and makes the amine group primary
N and S oxidation
adds an OH group. CYP. also catalyzed by flavin-containing monooxygenases (FMOs), FMOs and CYPs share a substrate
