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If linear pharmacokinetics then what is the relation to dose?
It is independent of dose.
A plot of Cp vs. time for different doses should yield parallel slopes.
A plot of AUCs of plots of Cp vs. time for different doses should be linear.
Non-linear pharmacokinetics are in relation to dose how?
Non-linear pharmacokinetics are dose dependent.
If a plot of steady state Cp vs dose yields a straight line , then the given drug follows what kind of phamacokinetics?
Michealis-Menten is what kind of pharmacokinetics?
Michealis Menten could be in play if on increasing a dose, steady state Cp increases more than expected, why?
Steady -state Cp can increase less than expected following an increase in dose, why? (2 reasons)
Participant enzymes/proteins in elimination processes are saturated.
- Because in some cases plasma protein binding sites get saturated.
- Because in some cases drugs increase the rate of their own metabolism.
5 Drug Properties of Non-Linear Pharmacokinetics:
- 1. As dose is increased the t1/2 changes.
- 2. As dose changes the ratio of metabolites changes.
- 3. Elimination does not follow 1st order kinetics.
- 4. There are competition effects-the saturation may be affected by drugs that require the same enzyme.
- 5. AUC is not proportional to amount of bioavailable drug.
Km is equal to drug concentration or the amount of drug in the body at ?
1/2 the Vmax
The clearance of a drug that follows Michaelis-Menten pharmacokinetics is:
Not a constant
Certain drugs are metabolized by multiple parallel pathways. An enzyme involved in one or more of the parallel pathways cuold get saturated before the others.
Mixed Order Elimination
An example, aspirin forms both glucuronic acid conjugate and a hippuric acid conjugate. conjugation with hippuric acid is capacity-limited.
Consequently, elimination has both first order and non-linear components. This describes what?
Mixed Order Elimination
The Michaelis-Menten equation produces what kind of curve?
The Lineweaver-Burke equation is what?
Lineweaver-Burke is linear
what does v stand for?
The rate of product/metabolite formation.
At steady-state, how does metabolism rate (drug amount removed per day) relate to daily dose?
At steady-state drug removed is equal to daily dose.
Daily dose (R) can be plotted against R/Css and from this plot the y-int is what? the slope is what?
When Cp>>Km what order is this?
Where is the concentration in relation to Km?
Zero order; when Cp>>Km elimination occurs at a constant rate equal to Vmax-elimination is zero order so linear kinetics
To the right
Ethanol, salicylate, and phytoin have low Km relative to their usual therapeutic doses, therefore, their kinetics is what order?
Zero-order (since Cp is probably bigger than Km if Km is low)
When Cp<<Km then the order of kinetics is?
Linear or non-linear kinetics?
- First-order elimination rate;
- non-linear kinetics
- Elimination occurs at a rate proportional to Cp so elimination is first order such that the rate constant is Vmax/Km
- *Principles disscussed about first order drugs apply here
Michaelis-Menten one compartment IV bolus is first order.
t= 1/Vmax (Co-Ct +Km ln Co/Ct)
Michaelis-Menten one compartment IV infusion assumes a zero-order infusion rate R and a zero-order VD and nonlinear or first order elimination.
dCp/dt = R/VD - (Vmax*Cp/Km+Cp)
Michaelis-Menten one compartment p.o.-by mouth. First order absorption along with zero-order elimination.
equation involves CGI which is the drug concentration at the gastrointestinal absorption site, and ka which is the first order absorption rate constant.
A temporal change in the rate process such as absorption or elimination.
Cyclic changes over a constant period ~24 hours in the rate process, resulting from changes in body function can affect the pharmacokinetics of certain drugs.
Non-cyclical changes and could be due to auto-induction or auto-inhibition.
Protein-bound drugs must first do what in order to be glomerularly filtered?
There can be non-linear binding to protein so what does this mean?
It means that the percentage of drug bound to proteins is not constant.
As Cp decreases (plasma concentration decreases) then the slop of the Cp vs time plot decreases.
Non-linear binding of a drug to plasma protein can cause what kind of pharmacokinetics?
Protein+drug = protein-drug complex
Clinical significance of non-linear pharmacokinetics:
As dose increases what happens to the Cl and the t1/2?
The time to reach steady state )~3-5t1/2 gets (shorter or longer) as dose increases for such a drug.
The Cl decreases and the t1/2 increases.
Knowing the Km can help decide on dosing for a patient. Such that one patient operates below saturation levels.
At the same Vmax, patients with a lower Km show:
- Greater Cp variability during dosage adjustments
- greater t1/2 changes with changes in Cp
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