What are the 4 aspects of clinical pharmacokinetics?
q. Clearance- bods efficenty at removal
2. Volumeof Distribution- apparent space the drug resides in
3. Elimination Half Life- rate of drug removal
4. Bioavailability- fraction of drug absorbed
What is clearance?
(CL) is defined as the theroretical volume of fluid (ie blood and plasma ) from which a drug is removed per unit of time
What needs to happen to maintain a steady state of drug in the therapeutic window?
You need to administer the drug at the same rate at which it is eliminated. Dosing Rate= CL x Css
Css= steady state concentration of drug
CL=clearance
How would you calculate clearance?
CL= rate of elimination / concentration
What is system clearance?
The sum total of clearance by the various organs. CL = CLrenal + CLhepatic + CLother
Which type of elimination kinetic displays enzyme saturation?
When graphing concentration vs hours which displays linear elimination?
Zero Order Kinetics are saturation kinetics
Vero Order Kinetics will display a linear regression.
How would you calculate the rate of elimination in an organ?
Elimination = Q x Ca - Q x Cv = Q (Ca - Cv)
Q= blood flow to an organ Ca= concentration arterial Cv= concentration venous
Then how would you calculate the clearance of that organ?
CL = Q[(Ca - Cv) / Ca] = Q x E
E= Extraction ratio
How do you determine which organ’s clearance is most important?
Drugs handeled by the kidney, renal clearance is most important
Drugs metabolized by the liver- hepatic clearance is most important
Drug excreted by the lung- lung clearance is most important.
What is the limiting reagent for drug clearance by a particular organ?
Blood flow to that organ
What type of kinetics is rate limiting?
Zero Order- It is rate limiting because the enzyme responsible gets saturated
Which order of drug elimination shows a linear decay?
Zero Order Kinetics
When you plot concentration against time what will the slope of the connecting you data points be?
The slope is the elimination rate constant. This means that a constant fraction if drug is eliminated per unit time.
Is the absolute amount of drug removed from per unit time concentration dependent?
Yes
What is the half life of a drug (t1/2)
Half life is the time it takes for the plasma concentration or the amount fo drug in the body to be reduced by 50%
What is the volume of distribution ?
The fluid volume that would be required to contain all of the dose at the same concentration as exists in the blood or plasma
How would you calculate the volume of distribution?
Vd = [amount of drug in the body] / C[blood concentration]
What is the significance of Vd?
For some drugs the Vd describes the primary fluid compartments in which the drug is distributed. For others Vd means nothing.
What is the elimination half life?
CL / Vd= (ml/min) / ml = 1/min = elimination constant ( Ke)
What is the definition of elimination half life?
The half life is the time it takes for the plasma concentration of a drug to be reduced by 50%
What is the clinical importance of half-life determination?
- Determines the dose interval. A drug is given at half life intervals
- A factor deterining dose
- May determine route. Short half life is often given IV or by sustained release tabs.
- Provides a good indication of thme required to reach a steady state dose.
What is the one compartment open model (pharmacokinetics)
It assumes the entire human body is one compartment. This works for durgs that are distributes fairly uniformly throughout the body. Assumes an open system and degradation is linear (zero order)
What is the two compartment open model of pharmacokinetics?
It assumes that much of a drug is in a particular compartment and that an equilibrium exists between the blood and other areas.
Describe the elimination of drug from a two compartment open model.
There is an initial distribution phase followed by an elimination phase. The elimination is zero order showing a linear degradation.
What is the multi-compartment model for drug elimination?
Measures area under the curve (AUC)
CL= dose / AUC
Due to first pass metabolism what is one obsticle of mantaining a steady state dose of drug in the body?
You must account for the bioavailability of a drug. This is compensated for by using the Bioavailability factor (F) .
What is the dosing equation that incorporates F to correct for first pass metabolism ?
F x Dosing Rate = CL x Css
Dosing rate = dose / T Where T is the dosing interval
How can you calculate Cssin regard to steady state concentrations?
Css= [ F x Dose ] / [ CL x T ]
F = Bioavailability T = Dose Interval
How can you calculate Dose in regard to steady state concentrations?
Dose = [ Css x CL x T ] / F
In multiple dosing how many administrations of a drug does it take to achieve steady state?
5 half lives.
What is the plateu principle ?
With multiple doses, after time, a steady state maximum and steady state minimum are reached. The time to steady state is endependent of dose or dose intercal
Below the therapeutic minimum what will the drug do?
Below its therapeutic range the drug will have no effect.
What happens if the drug gets above its therapeutic range?
Toxicity
How do you calculate clearance rate in the multi-compartment model ?
This requires computer assistance but….
CL= dose / AUC
*You plot the Linear clearance of the IV administration and the Clearance of oral administration and calculate the area under the curve.
What relationship is necessary to understand to determine the infusion rate? Hint: Css =
Css = Infusion Rate / Total Body Clearance
What happens if you can not wait for 5 half lives to achieve a therapeutic range of a drug?
Give a loading dose
What is the formula for calculating the loading dose?
(LD) = (Css x Vd) / F
What is dangerous about using loading doses?
You can achieve relatively high concentrations of drug in the blood system
After the loading dose what is required to mantain the therapeutic window of drug concentration?
Following the loading dose you will hace to give the patients a maintenance dose
How do you calculate the maintenance does?
Dosing rate = target Css x CL / F
Describe 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 is metabolized regardless of the level of drug. No plateau is observed.
Work the practice problems that were given in lecture .
Have you done it yet?
