Pharmacokinetics Flashcards
pharmacokinetics (3)
absorption
distribution
elimination
IV meds vs PO meds
IV onset of action is immediate. Tmax is immediate. PO is not because it had to travel through multiple different organ systems before systemic circulation.
Bioavailability
the fraction of an administered dose of drug that reaches the systemic circulation unchanged
bioavailability % of PO meds vs IV meds
PO meds <1 or <100% (typically 15-95%), IV meds 1 or 100%
factors that affect PO bioavailability (4)
- solubility/ability of drug to resist breakdown in stomach
- ability of drug to permeate and resist metabolism in the GI epithelium
- ability of drug to resist metabolism in portal circulation
- ability of drug to resist metabolism within the liver, hepatic vein, lungs, etc.
first pass effect
when the concentration of a med is greatly reduced before entering systemic circulation. typically PO meds.
process of first pass effect
PO meds are absorbed in GI tract and circulated to liver via hepatic portal vein. liver metabolizes part of the med before it reaches systemic circulation. this combination results in first pass effect.
factors affecting distribution from plasma: endothelial cell fenestration
a high degree of fenestration, like in the liver and kidney, facilitates more distribution. low degree of fenestration, like in the brain, prevents distribution.
factors affecting distribution from plasma: blood flow
high blood flow like in major organ systems facilitates distribution. low blood flow, like in joints or fat or bones, leads to less distribution.
factors affecting distribution from plasma: lipophilicity and molecular weight
lipophilic drugs will pass through the membrane much easier, as will drugs with a lower molecular weight.
factors affecting distribution from plasma: protein bound
protein bound meds will have a harder time crossing the cell membrane.
factors affecting distribution from plasma: ionization
uncharged passes easier.
blood brain barrier purpose and components
the barrier that protects the CNS from outside medications. this is achieved through low fenestration, encapsulated cells, efflux transporters on the barrier (pgp transporter).
ion trapping
distribution of meds based on pH
if a drug is a weak acid…
it will want to go toward a more basic environment (plasma).
if a med is a weak base…
it will want to go towards a more acidic environment (neurons)
volume of distribution. what is it and what is the equation?
it is a proportionality constant.
equation is
amount of drug in the body divided by the concentration of drug in plasma.
Vd < 5 L
most of med is confined to plasma
Vd is between 5 - 10 L
medication is distributed throughout the blood
Vd > 42 L
med is distributed to all tissues in the body
protein bound drugs remain in
the bloodstream
drug elimination
irreversible removal of medication from the body
two categories of elimination
metabolism and excretion
drug metabolism
the enzymatic conversion of a medication to its metabolites
drug excretion
the removal of unchanged medication from the body
phase I reactions
anything that goes through cytochrome p450 or a cyp enzyme
oxidation
reduction
hydrolysis
phase II reactions (5)
glucuronidation sulfation acetylation peptide conjugation glutathione conjugation
phase 1 and phase 2
meds may go through none, one, or both.
cytochrome p450 and CYP enzymes are largely found in
the liver
active parent compound
active from ingestion to metabolism from liver, then metabolized into inactive metabolites.
prodrug
the med is inactive UNTIL it is metabolized by the liver. when metabolized, the med is transformed into an active metabolite which exhibits the therapeutic effect.
metabolism of acetaminophen
goes through both phase I and phase II
CYP mediated reaction (phase I) and then sulfation
and glutathione conjugations (phase II).
After CYP mediated reaction, you have NAPQI. This is a toxic metabolite and needs to be converted and eliminated. This is where you need a glutathione conjugation (phase II) to convert NAPQI into a less toxic metabolite.
acetaminophen toxicity
if you can’t go through the steps of metabolizing acetaminophen. after acetaminophen is metabolized through phase I and II, phase I converts acetaminophen into NAPQI. Glutathione has to then conjugate the NAPQI because it’s toxic. if not, you’ll have serious AEs like hepatocyte death.
purpose of acetylcystine
in acetaminophen overdose….provides your body with glutathione to break down NAPQI.
Half life
parameter defined by the time it takes for the concentration of a med to reach half of its present concentration
what can half life be used to determine?
how long a med will last in the body.
how many half lives to steady state?
~ 4 - 5
How many half lives to ~99% drug removal?
5 half lives.
First order kinetics
constant elimination of med per unit of time, proportional to amount of med in the body. same proportion is eliminated per unit of time, meaning the amount is variable based on plasma conc. as the conc drops, the elimination rate drops as well.
zero order kinetics
constant elimination of med in mg/hr, regardless of amount of med in body. the same amount is eliminated per unit of time regardless of plasma concentration.
elimination mechanism is saturated in ____ order kinetics
zero
phenytoin elimination and considerations.
follows zero order kinetics.
as you dose pts, you will reach a point where all receptor sites are saturated. elimination continues at same fixed rate but an increase in therapeutic effect will be seen bc of buildup of the med waiting to bind as receptors desaturate. As you get to higher concentrationss, even small changes can have big impact on therapeutic effects.
clearance (CL) equation
the rate of elimination of a drug divided by the plasma concentration of a drug
clearance equation
clearance in L/hr = elimination in mg/hr OVER concentration in mg/L
rate of elimination
clearance x concentration
steady state definition
rate of absorption is equal to the rate of elimination of given med
dosing rate equation
clearance x steady state conc
creatinine clearance
measurement used to determine level of kidney function by looking at how well your kidneys are clearing creatinine from the blood.
creatinine clearance Cockcroft-gault equation
creat clearance ml/min = (140-age) x weight in kg OVER serum creatinine mg/dl x 72 ALL MULTIPLIED BY 0.85 if female
at what creatinine clearance do you need to make renal adjustments?
below 30 or 40.
drug-drug interactions at pharmacokinetic level can happen during what 4 stages?
absorption, distribution, metabolism, excretion
what happens when there is a drug-drug interaction between two drugs metabolized by the same enzyme
competition between the two drugs for the enzyme to metabolize them. the one that loses out on being metabolized will have high concentrations of free drug.
drug-drug interactions: GI absorption (3 points)
- absorption of other drugs can be delayed by drugs that inhibit gastric emptying, like opiates
- absorption of other drugs can be increased by drugs that speed up gastric emptying, like erythromycin.
- absorption can be slowed or completely inhibited by formation of physical complexes (iron and tetracyclines)
drug-drug interactions at the level of distribution is typically related to
protein binding drugs and albumin
hypoalbuminemia and protein bound drugs
increased concentrations of free drug in circulation bc less protein is available to bind to. increased clinical effect/potential side effects. not guaranteed to be a problem.
changes in hepatic metabolism are a common cause of
drug-drug interactions
2 factors that affect hepatic metabolism in the context of drug-drug interactions
enzyme inhibition
enzyme induction
when analyzing enzyme inhibition/induction interactions, it is important to know what about a drug?
if it is an APC or a prodrug
enzyme inhibition
occurs when a medication reduces the activity of a metabolic enzyme, decreasing its metabolic capacity.
enzyme induction
occurs when a med enhances a metabolic enzyme, increasing its activity.
if a med is an inducer of a CYP3A4 enzyme and another med, normally metabolized by CYP3a4 is given, what will happen?
it will be metabolized faster
if an APC med metabolized by CYP3A4 is given with a med which induces CYP3a4, what will you expect?
the APC will be converted into an inactive metabolite at a faster rate. less of a clinical effect will be seen.
if a prodrug, normally metabolized by CYP3A4, is given with a med that induces CYP3a4, what will you expect?
the prodrug will be converted to an active metabolite quicker and a greater clinical effect will be seen.
if you have a med that inhibits CYP3A4 and then an APC given that is metabolized by cyp3a4, you should expect
a greater clinical effect/concentration because the APC will not be metabolized into an inactive metabolite as quickly. the active form of the drug will remain active for longer.
if you have a med that inhibits CYP3A4 and a prodrug metabolized by CYP3A4, what will you expect?
diminished effect. the inactive drug will not be metabolized into its active metabolite at the rate it normally would.
atorvastatin is a prodrug and CYP3A4 substrate. ketoconazole is a moderate inhibitor of CYP3A4. give them together - what is the expected outcome?
moderately diminished effect. inactive parent form would not be metabolized into its active metabolite as it normally would be.
diltiazem is an APC and known substrate of CYP3A4. St John’s Wort is a CYP3A4 inducer. Give them together - what do you expect?
diltiazem would have a diminished effect because its active parent compound would be metabolized quickly
absorption of medications is based on
route of administration
volume of distribution is a
proportionality constant
which meds cross membranes easier? protein bound or free/unbound form?
free/unbound
CYP enzymes are
hepatic enzymes responsible for drug metabolism of many meds
measuring the clearance of a med gives insight on
how well an organ is functioning
equation for volume of distribution
Vd = amount in body at equlib OVER conc in plasma
Cmax
dose concentration that dose achieves
Tmax
time is takes to reach Cmax
