Drug Elimination and Multiple Dosing Flashcards
In two-compartment drug distribution, after the distribution phase, what kind of elimination do you get?
monoexponential elimination
What kind of half life do you get with monoexponential elimination?
a constant half life!
Define volume of distribution (Vd)
the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma
What is the volume of distribution a measure of?
how evenly a drug is distributed in the body
What does Vd relate?
dose (amount, mg/kg) to plasma concentration (mg/L)
Vd = Dose/C0
Why is repetitive dosing necessary?
it takes 4-6 half lives to reach a steady state
What is a loading dose?
If a drug takes a long time to reach therapeutic levels, then a higher dose (the loading dose) may be given initially before dropping down to a lower maintenance dose.
What are the three variables used to calculate loading dose?
Cp - peak desired concentration of drug
Vd - volume of distribution
F - bioavailability
loading dose = Cp * Vd / F
What is not reduced by the loading dose?
time required to reach the steady state (still takes 4-6 half lives)
Define maintenance dosing
maintains a steady state of a drug in the body
What is a maintenance dose based on?
replacing the amount of drug cleared from the body since the previous drug administration
What is the primary determinant for calculating the maintenance dose?
CL
MD = CL* TC * T / F
In a loading dose, what is the target concentration?
Cp - the highest concentration of drug you will see in plasma (the “peak”)
In a maintenance dose, what is the target concentration?
between the peak and trough - not the peak as it was for the loading dose
What is elimination clearance?
CLe - irreversible drug removal from the plasma through an eliminating organ
What is intercompartmental clearance?
CLi - drug distribution between plasma and tissues, a bidirectional process
at steady state, what is the maintenance dosing rate equal to?
rate of elimination = CLe * TC
What is steady-state concentration a function of?
dosing rate and elimination clearance
Css = (dosing rate * F) / CL
How long before steady state is achieved?
4-6 half lives
What is time to steady state independent of?
dosage
What are plasma drug fluctuations proportional to?
dosage interval/half life
What is steady state concentration proportional to in continuous IV infusion?
proportional to infusion rate
infusion rate = CL * Css
What can clearance be estimated by in continuous IV administration?
infusion rate and steady state plasma conc.
CL = I/Css
What is 1st-order elimination (kinetics)?
the elimination rate of the drug is a constant fraction of the drug remaining in the body per unit time (rather than a constant amount of drug per unit time)
most drugs used clinically
What is zero-order kinetics?
a fixed amount of drug is metabolized per unit time
What kind of drugs may display zero-order kinetics, and when would it happen?
drugs eliminated primarily by metabolism
When metabolic pathways are saturated, metabolism occurs at a fixed rate (it does not change in proportion to drug concentration)
What two drugs are examples of zero-order elimination?
phenytoin, ethanol
What is not constant in zero order, that is is 1st order?
half life
name 9 drugs that may exhibit zero-order kinetics
Aspirin Ethanol Heparin Phenylbutazone Phenytoin Salicylates Theophylline Tolbutamide Warfarin
Define dose-dependent kinetics
When a drug’s elimination is mediated predominantly by metabolism, its elimination will tend to follow first-order kinetics when concentrations are well below the KM of the metabolic enzymes, but will follow zero-order kinetics at doses that greatly exceed the KM of the metabolic enzymes.
define and name the units of elimination clearance
Volume of plasma cleared of drug per unit time.
Units are ml/min or L/hr (“flow”)
For elimination clearance, where can drug elimination occur through?
kidneys, liver, lung, and other organs
What is total clearance equal to?
CLrenal + CLhepatin + CLother
What is elimination half life?
time to eliminate 50% of the body content of the drug
t1/2 = 0.69 Vd / CL
What is time to steady state dependent on?
only dependent of the half life - not the dose!
How can you reduce the dosing rate in renal insufficiency?
reducing the dose
increasing the dosing interval
both
What is creatinine clearance rate, and what is it used for?
Creatinine clearance rate (CrCL) is the volume of blood plasma that is cleared of creatinine per unit time and is the most commonly used measure for approximating the glomerular filtration rate (GFR) - a relative measure of how well the kidney is functioning
What are the determinants of hepatic drug clearance?
hepatic blood flow
plasma protein binding
intrinsic clearance
What is restrictive hepatic clearance?
drugs with low hepatic extraction, and thus little first pass metabolism when given orally
what will have a greater influence on hepatic clearance in drugs with low hepatic clearance?
changes in binding or drug metabolism/excretion activity will have a greater effect of hepatic clearance than changes in liver blood flow. (capacity limited clearance)
What are two examples of drugs with low hepatic extraction?
warfarin, phenytoin
What is non-restrictive hepatic clearance?
drugs with high hepatic extraction
What does non-restrictive hepatic clearance exhibit
flow-dependent clearance
What is flow dependent clearance?
Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance.
conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.
What are two examples of drugs with high hepatic extraction?
lidocaine, propranolol
