Advanced Pharmacokinetics Flashcards
Acidic drugs and lipid solubility, which ones have good passage?
uncharged, lipid soluble, low pH
Basic drugs and lipid solubility, which ones have good passage?
uncharged, lipid soluble, high pH
How to treat aspirin overdose?
manipulate tubular reabsorption by administering NaHCO3 to make urine basic and make the acidic aspirin poorly soluble
Renal clearance depends on? 2 things
Renal blood flow
rate of elimination
what is drug metabolism AKA?
biotransformation
what is biotransformation? where does it mostly happen? why does it happen?
chemical change to a drug to a metabolite, happens in liver to increase water solubility for excretion
MEtabolite can be 4 things
active
nonactive
new activity - levo-dopa
toxic -epoxide
Phase I metabolism does what
creates chemical functional group like -OH, SH, COOH on the drug
why do you get drug side effects
Phase I metabolism reactions can alter CYP450 via inhibiting/enhancing
what happens in PHase II metabolism?
conjugating water soluble molecule to functional group, like adding sugar to bilirubin or morphine
Phase II products are nearly always what? 2 things
inactive
more water soluble
Renal clearance definition?
amount of blood from which drug is removed by kidneys per time
more drug in the blood, how does what affect clearance?
more effective the clearance
pathway of a drug in the body 6 things
administration
absorption
distribution
elimination(metabolism/excretion)
what is ADME?
drugs to and from their site of action: absorption distribution metabolism excretion
in first order kinetics, drugs are eliminated at a rate proportional to what?
concentration in the plasma
when do you get classic first order kinetics?
rapid IV administration and distribution
in first order kinetics, how is the drug eliminated?
exponentially via half-life
what does log10(conc) vs. time give you instead of (conc.) vs. time?
give you a gradient, easier to work with and can verify the exponential process
in a short term infusion, why does the concentration in the blood plateau?
as concentration of drug increases, the elimination also increases
if you stop infusion, what does the drug elimination curve look like?
first order kinetics, half-life decrease
Which peak is higher? IV bolus? short term IV infusion?
IV bolus
why is it good that the peak for IV infusion is not high?
good for drugs with small therepeutic windows
what is the steady state of IV infusion?
rate infusion = rate elimination
what happens if you change infusion rate by double or half?
the concentration will change proportionally
multiple dosing every hal-life give what in concentration in plasma
a two-fold variation in concentration
how do you reach steady state faster in a long term IV infusion?
loading dose
what factors determine volume of distribution?
- if drug binds to plasma proteins (greater conc in plasma - VD is small)
- if drugs binds to tissues/taken up by cells (VD is large)
What is volume of distribution?
volume of body water in which a drug appears to be dissolved in after it has distributed throughout the body
what do you have to take into account re: dosing for oral administration of drugs
first pass metabolism by liver, end up with reduced drug in system
first order elimination curve, picture it in your head
peak not as high as IV
not all drug is absorbed
what is bioavailability?
the amount of active drug that actually enters systemic circulation
what are 2 things bioavailability is affected by?
how much drug absorbed
how much drug is metabolized via:
-first pass
-local metabolism (GI before liver)
how to calculate bioavailability from graphs?
Areas under the curves
2 complicating factors in pharmacokinetics
unusual drug behaviour interpatient variability (narrow therapeutic windows)
what’s bad if bioavailability is low?
more sensitive to variability
what’s bad if you have slow distribution
drug may be eliminated before it’s fully distributed to target areas
what is zero order kinetics
drug saturates elimination processes, and makes elimination constant
what is a drug reservoir? what can happen to drug?
sites where drug accumulates:
prolong
terminate
slow distribution
Common drug reservoirs in the body: 3 places
Plasma proteins
cells
fat
what is a bad if you rapid IV admin of slow distributing drug? how to compensate?
may exceed therapeutic window
loading doses to be broken down
single dose drug with zero oder elimination a problem?
Nope
what’s the problem with multiple dosing of zero order elimination drugs?
disproportionate increase in concentration because steady state is never reached
2 examples of zero order elimination drugs?
aspirin
alcohol
2 things that effects pharmacokinetics in the elderly and neonates
reduced
renal excretion
hepatic metabolism
renal clearance of newborn is ___% of adult
20%
How long until newborn renal clearance at adult levels?
1 week
renal function decreases starting at what age? % at 50
% at 75?
20yrs
75% at 50
50% at 75
liver metabolism in newborns are deficient how? how long until 100%?
can’t do phase II conjugation
6weeks
why can’t you give morphine to mom when she’s in labour?
baby can’t metabolize morphine, no phase II conjugation could be born addicted to morphine…
how is liver metabolism affected in elderly? consequence?
reduced CYP450
increased half life
Drug-Drug interactions:
Pharmacodynamic
Pharmacokinetic
A affects B without affecting concentration
A modifies B concentration at receptor
drug drug interactions, the affect drug needs to be what to be clinically important?
narrow therapeutic window
steep concentration-response curve
pharmacokinetic drug-drug interactions interact where?
ADME absorption distribution metabolism excretion
pharmacokinetic drug-drug interactions affects absorption how?
gastric emptying rate (opiates)
formation of pooly absorbed complex in gut (calcium and tetracyclines)
pharmacokinetic drug-drug interactions affects distribution how?
displacement from plasma protein binding sites leads to transient toxicity
altering target therapeutic range
pharmacokinetic drug-drug interactions affects metabolism via induction of CYP450 can do what? 2 things
reduced half life
increased bioactivation
pharmacokinetic drug-drug interactions affects metabolism via inhibition of CYP450 can do what?
increase half-life and plasma concentration
pharmacokinetic drug-drug interactions affects excretion how? 3 things
alter:
protein binding
tubular secretion (probenecid olympics)
urine flow/pH (NaCO3 for aspirin overdose)
