Pharm: Pharmacokinetics I Flashcards
What is drug clearance (abbrev. CL)?
the theoretical volume of fluid from which a drug is removed per unit time
What are the fundamental differences between therapeutic implications of zero-order and first-order elimination kinetics?
Zero-order kinetics drugs are metabolized by enzymes, which are saturable RLS, and are metabolized at a constant amount per unit time, thus no plateau observed.
First-order kinetics drugs are metabolized at a constant fraction per unit time (half-life) and will show a plateau.
What is the concept of apparent volume distribution?
the apparent space the drug resides in
What is the concept of elimination half-life? What is its relationship to clearance and volume of distribution?
the rate of drug removal
How is elimination half-life calculated mathematically?
Ke = CL / Vd
- Ke is the elimination constant
- units is 1/min
- *The change in drug concentration with respect to time is equal to the slope of concentration vs. time plot, or -Ke, or natural log of C/Co = -Ke x t
T1/2= 0.7/Ke
What is the plateau principle, and how is it applied to drug sampling intervals and expected time course of drug in the body?
the plateau principle says that the time to steady state is dependent on the half-life; fluctuations will be proportional to the dose interval over the half-life: increasing dose interval will lead to greater fluctuations; decreasing it will lead to increased steady-state concentrations and smaller fluctuations
What are the main reasons to study pharmacokinetics?
- there is a relationship between concentration of drug (bioavailable) and its effects
- to develop a rational framework for dosing
- improve therapeutic efficacy by selecting dosing regimens to match patients’ parameters
If a clinician typically wants to maintain steady-state concentrations of a drug within the therapeutic window, how should the drug be administered?
At the same rate it’s eliminated
What is the formula for mathematically calculating dosing rate?
dosing rate = CL x Css
- CL = clearance rate
- Css = [desired] steady-state concentration
What is the formula for mathematically calculating clearance?
rate of elimination / concentration
What is the formula for mathematically calculating systemic clearance?
CL =CLrenal + CLhepatic + CLother
What is the formula for mathematically calculating rate of drug elimination of an organ?
= Q x Ca - Q x Cv =Q(Ca-Cv) *Q = blood flow to the organ *Ca = arterial drug concentration *Cv = venous drug concentration
What is the formula for mathematically calculating clearance for an organ?
CLorgan = Q[(Ca-Cv) / Ca] = Q x E *E = extraction ratio
For drugs handled by the kidney, ____ clearance is most important to watch.
renal
What is the limiting variable in drug clearance?
blood flow (presentation of drug) to the organ
What is the extraction ratio (E)?
the fraction of drug that has been presented on the arterial side that is removed by the organ
On a linear graph of drug concentration over time, how will first- and zero-order kinetic reactions appear?
first order = exponential decay
zero order = linear
On a graph of log drug concentration over linear time, how will first-order kinetic reactions appear? What does this mean?
first order = linear; this means that a constant fraction of the drug will be eliminated per unit time (ex: half-life)
Remind me: what is the volume of distribution?
the volume of fluid that would be required to contain all of the drug dose at the same concentration as exists in the blood or plasma; Vd = amount of drug in body / blood concentration
What is significant about the time at which C0/C = 2?
This is the time of the half-life– this formula indicates that the original drug concentration (C0) divided by the current concentration (C) equals 2
In the body, a drug’s half life is the time it takes for the concentration of drug in ____ to be reduced by 50%.
plasma
What is clinical significant about half-life determination?
- to determine the dosing interval
- to help determine dose
- may determine route of administration
- indicates time required to reach steady-state
True or false: a drug is usually given at half-life intervals to maintain steady state dosing.
True
What route of administration might be the best for drugs with short half-lives?
intravenous
What is a pharmacokinetic model?
model used for designing and rationalizing pharmaco-therapy regimens; single-IV dose models are a simple, one-compartment open-system model
Two compartment open model for pharmacokinetics assumes that much of a drug is in one particular compartment (often blood) and that an equilibrium exists between what? What happens during and after equilibration?
that first particular compartment (often blood) and other areas; as it equilibrates the concentration drops rapidly, following equilibration the concentration follows a first-order model for elimination
What model is most realistic for the body?
multicompartment models (requires computer assistance); clearance equals the dose divided by the area under the curve (curve of concentration in blood over time)
What is the bioavailability term, F, used for?
modifying the dosing rate equation to account for variable bioavailability which will affect the dosing rate needed to maintain steady state concentrations; added to formula as follows:
Dosing rate x F = CL x Css
About how many half-lives does it take to achieve steady-state?
about 4-5
Time to steady state is independent of ____ or ____ ____, but strictly dependent on ____.
independent of dose or dose interval; dependent on half-life
What clinical features will be seen or not seen below the therapeutic range?
no clinical benefit will be seen
What clinical features will be seen or not seen above the therapeutic range?
toxicity may be seen
Clinicians can control what aspects of drug administration that will affect the peak/trough and magnitude of the Css?
the dosing interval and the dose
What formula is used to determine the infusion rate for IV administered drugs?
CSS = infusion rate / total body clearance
What is the definition of a loading dose?
the desired steady state concentration of a drug times the volume of distribution adjusted for bioavailability;
Why might loading doses be dangerous?
due to the high concentrations that are achieved
What is the practice of loading dosing for therapeutic use?
administering enough drug to achieve desired Css when one cannot wait for 5 half-lives to achieve a therapeutic range; e.g. in heart attacks, serious heart failure, overwhelming bacterial infections, etc.
What is the practice of maintenance dosing for therapeutic use?
following the loading dose, drug is given in maintenance doses to keep the drug within the therapeutic window such that:
Dosing rate = (target Css x CL) / F
For zero order kinetics drug elimination, Km is used to modify LD, CSS, and DR equations. What is Km?
Km is the dose that produces 50% of the maximal elimination rate
For zero order kinetics drug elimination, Vm is used to modify LD, CSS, and DR equations. What is Vm?
Vm is the maximum rate of the elimination process
True or false: Loading doses are calculated in the same way whether the drug obeys zero or first order kinetics.
True. The others (DR, CSS) are calculated differently.
