Pharmacokinetics I and II Flashcards
Clinical Pharmacokinetics
Is concerned with the following quantitative (measured) parameters:
- Clearance - body’s efficiency of drug removal
- Volume of distribution - apparent space the drug resides in
- Elimination half-life - rate of drug removal
- Bioavailability- fraction of drug absorbed
Why is it necessary to understand clinical pharmacokinetics?
- There is a relationship between concentration of drug (from an accessible compartment) and its effects
- Develop a rational framework for dosing
- Improve therapeutic efficacy by selecting dosing regimens to match patients parameters
What is the most important concept to be considered when a rational regimen for long-term drug administration is to be designed?
Clearance (CL)
Define clearance
theoretical volume of fluid (i.e. blood, plasma) from which a drug is removed per unit time.
The clinician usually wants to maintain steady-state concentrations of a drug within the therapeutic window. How must it be administered?
Thus one needs to administer the drug at the same rate it is eliminated
Dosing rate = CL x CSS
What is the dosing rate equation?
Dosing rate = CL x CSS where CL is clearance from the systemic circulation and Css is the
steady-state concentration of the drug.
What is the equation for clearance?
CL = rate of elimination/ concentration
Systemic clearance is the sum total of clearance by the various organs: give the equation
CL = CLrenal + CLhepatic + CLother
What is the rate of elimation equation for an organ?
The rate of elimination of an organ = Q x CA – Q x CV = Q x (CA – CV) where Q is the blood flow to the organ.
The clearance for the organ is then defined as:
CL = Q[(CA – CV)/ CA] = Q x E where E is referred to as the extraction ratio.
What is the limiting variable no matter the organ wrt clearance?
it is important to note that blood flow (i.e. presentation of the drug) to the organ is the limiting variable.
Wrt elimination, there are 2 types of kinetics. describe them
Two distinct types of kinetics:
First order kinetics (most drugs obey first order kinetics)
Zero order kinetics (also known as saturation kinetics). Only a few, but some very important drugs obey zero order kinetics.
What does the graph look like for the kinetcs of elimination?
The slope of this straight line is what for a particular drug? and what does it mean?
the elimination rate constant (Ke) for that particular drug.
This means that a constant fraction of drug is eliminated per unit time.
The absolute amount of drug removed from per unit time will be concentration-dependent
What is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%?
Half-life: (t1/2)
What is volume of distribution?
give the equation
- Vd = Amount of drug in the body / C (Blood concentration )
- The fluid volume that would be required to contain all of the dose at the same concentration as exists in the blood or plasma.
For some drugs the Vd describes what? for other the Vd does what?
the primary fluid compartments in which a drug is distributed.
Give the quantities of the fluid compartments wrt plasma volume, extracellular fluid volume, total body water
plasma volume is 4 liters
Extracellular fluid volume is 12 liters
total body water is 40 liters
Describe the Elimination half-life (t 1/2 ) wrt the elimination constant. give equations and work a sample out when C/Co = 2
CL / Vd = (ml/min) / ml = 1/min = elimination constant (Ke)
The change is [drug]p with respect to time is therefore: dC/dt = -Ke ln (C/Co) = -Ke * t or ln (Co/C) = Ke * t
ex:When Co/C = 2: ln 2 = Ke * t 1⁄2
because ln 2 = 0.693 Ke = 0.693 / t 1⁄2 Ke 0.7/ t 1
What are the 4 Clinical importances of half-life determination?
- Determine dosing interval. A drug is usually given at half-life intervals.
- A factor in determining dose. .
- May determine route. Drugs with very short half-lives are preferably given I.V. or by sustained release tablets.
- Provides a good indication of the time required to reach steady-state after a dosage regimen is initiated.
Of the Pharmacokinetic Models, describe the “one compartment open model (single IV dose)”
For many drugs this is an adequate representation.
- Assumes entire human body is one compartment.
- This works for drugs that are distributed fairly uniformly throughout the body.
- Assumes an open system (excretion). Is not adequate for all situations.
Of the Pharmacokinetic Models, describe the Two compartment open model. Draw a graph to represent it showing the elimination and distribution phases
Assumes that much of a drug is in a particular compartment and that an equilibrium exists between the blood and other areas. (single IV dose)
Of the pharmacokinetic models, describe the Multicompartment models. Draw graph and give equation clearance wrt AUC when using the mulicompartment model
Requires computer assistance
Measures area under the curve (AUC)
More widely used that first two models.
With a multicompartment model:
CL = dose / AUC
What are the results from first pass metabolism or poor absorption parameters?
bioavailability is decreased
only a fraction of drug dose may have access to the systemic circulation. This is often the case with oral administration.
dosing rate needed to maintain steady state drug concentrations must be modified to account for this loss. The bioavailability term (F) is used to modify the equation. Give it.
WRT (F) and timing intervals, how we can predict the steady state concentrations after various dosing schedules as? (equations)
F x Dosing rate = CL x Css
Because dosing rate = dose/T ; where T is the dosing interval
Multiple dosing regimens are most common in clinical situations. How many half lives does it take to achieve a steady state?
about 5 half-lives to achieve steady state
With time, a steady state maximum (Css,max) and a steady state minimum (Css,min) are achieved. Time to steady state is independent of what? What is it strictly dependent on?
independent of dose or dose interval
strictly dependent on t 1/2 (plateau principle)
Draw a graph and equation used for multiple dosings wrt to time and concentrations when achieving the steady state
Give the relationship of multiple dosings wrt therapeutic range
Below therapeutic range, no beneficial effect.
Above therapeutic range, toxicity may be seen
In general, physician can control only two things, the dosing interval and the dose (within the limits of dosage forms available). What as a result does this control?
control the peak and trough and the magnitude of the Css
For Intravenous infusion - pharmacokinetics, what is required to achieve a steady state?
Time required to achieve steady state is 5 half-lives
To determine infusion rate, must know the relationship of Css, infusion rate, and total body clearance. Show a graph defining this wrt [] and time
Css = (infusion rate) / (total body clearance)
There are situations where one cannot wait for 5 half-lives to achieve a therapeutic range. In these instances, such as heart attack, failure, bacterial infections, etc, How is this overcome?
In these situations, the use of a loading dose of a drug is warranted.
Define loading dose
the desired steady state of a drug times
the volume of distribution adjusted for bioavailability
Give the equation for a loading dose. What is something that must be closely monitored wrt loading dose?
Loading dose (LD) = (Css x Vd) / F
Loading doses can be particulary dangerous due to the high concentrations that are achieved.
Following the loading dose, how do patients maintain Css within the desired therapeutic window? Give the equation for this
given maintenance doses in order to keep the Css within the desired therapeutic window such that
Dosing rate = target Css x CL / F
No plateau is observed during what order of kinetics? why?
Zero order kinetics
If the enzymes that metabolize a drug are rate limiting i.e. the enzyme is saturated at usual levels of drug in the body then the same amount of drug (ug/hr) is metabolized regardless of the level of drug.
What are 6 drugs exhibit zero order kinetics?
- Ethanol
- Heparin
- Phenytoin
- Aspirin
- Amobarbital
- Tetracycline
For zero order elimination kinetics the following equations are employed. (3)
- LD = (Vd x Css)/F
- Css = (Km x DR)/(Vm- DR)
- DDR = (Css x (Vm – DR))/ Km
Km is the dose that produces 50% of
the maximal elimination rate
Vm is the maximum rate of the process
A new cognitive enhancer (Tavalinagra ®) is a weak base with a pKa of 5.4. Approximately, what percent of the drug is absorbed from the stomach to the plasma when administered orally? (assume pH 1.4 stomach and 7.4 plasma) show a graph
pH = pKa + log [Unprotonated]/[Protonated]
For a weak base then: pH = pKa + log [B]/[BH+]
- In the stomach:
- 1.4 – 5.4 = log [B]/[BH+]
- 4 = log [B]/[BH+]
- 0.0001 = [B]/[BH+]
- In the plasma:
- 7.4 – 5.4 = log [B]/[BH+]
- 2 = log [B]/[BH+]
- 100 = [B]/[BH+]
Tavalinostat ® (yet another cognitive enhancer) is cleared at 2 ml/min * kg and has a volume of distribution of 100L (concentrating mostly in the brain). It has a minimum effective concentration of 0.5 mg/L. A normally healthy, but quite anxious 70 kg male medical student takes 200 mg of it before his pharmacokinetics test. Approximately how long will it be before it is no longer effective?
First we’ll get the half-life of the drug:
- t 1⁄2 = 0.7 (Vd)/CL
- t 1⁄2 = 0.7 (100 L)/ (2 ml/ min*kg) (70 kg)
- T 1⁄2 = 70 L / (140 ml/ min)
- T 1⁄2 = 500 min ≈ 8 hr
Then we’ll figure out [drug]p :
- Vd = dose/conc.
- Conc. = dose/Vd
- Conc. = 200 mg/ 100L
- Conc. = 2 mg/ L
Your patient’s blood concentration of drug X is 80 μg/ml. The drug has a half life of 12 hrs. In how many hours will the drug concentration be 5 μg/ml?
A) 8
B) 16
C) 24
D) 48
The bioavailability of Drug A is 80% while Drug B is 20%. Assuming they have similar molecular weights, effective concentrations, and elimination kinetics, how much of Drug B should you give if Drug A is given in 100 mg doses every 6 hours?
A) 100 mg every 6 hours
B) 100 mg every 24 hours
C) 200 mg every 12 hours
D) 400 mg every 6 hours
Drug A has a half-life of 24 hours. If administered every 12 hours, when will it reach steady-state?
A) 12 hours
B) 24 hours
C) 48 hours
D) 60 hours
E) 120 hours
The target plasma concentration of Drug X is 10 mg/l. If Drug X distributes to total body water and is 100% bioavailable, which of the following would be an appropriate loading dose?
A) 10 mg
B) 40 mg
C) 100 mg
D) 400 mg
Drug A is retained mainly in the blood. If after a 1000 mg oral administration of Drug A, the blood concentration of the drug is 200 mg/l, what is the bioavailability of Drug A?
A) 100%
B) 80%
C) 20%
D) 2%
E) none of the above
