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| describe the one-compartment model of the body: |
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- one input
- one output
- one volume in which the drug is dissolved |
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- zero order
- first order
- mixed order |
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| First order kinetic formula: |
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Definition
rate= [D]k
these are the most common |
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| With a first order reaction, if the y-axis is in linear units, the process will be ____. |
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| With first order reactions, if the y-axis is in log form, the process will be ___. |
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- duration required for half of the process to be complete
- half of the remaining drug to be absorbed
- half of the remaining drug to be eliminated |
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| With first order kinetics, the half life is a function of the constant. give this equation. |
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| the constant governing absorption |
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| constant governing elimination |
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| what does it mean if ke=0.10/hour? |
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| this means that 10% of the REMAINING drug is eliminated per hour |
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| So if the ke of a drug is 0.10, what is its half life? |
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Definition
t1/2=0.693/.10
t1/2= 6.93 hours |
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| For first order kinetics, the rate of elimination changes as a function of the ___ ___, and because the ___ ___ is always ____, the rate is always getting ____. |
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Definition
- drug concentration
- drug concentration
- declining
- slower |
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| ___ changes with drug concentration, but __ ___ and ___ do not change. |
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Definition
Rate changes
half life and K do not |
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| For purposes of medicine, we will say that a first order process is complete when ____ ____ ____ have elapsed. |
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| for zero order kinetics rate is equal to? |
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| for zero order processes the ___ of the ___ is irrelevant. |
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| concentration of the drug |
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| Recognize that a rate constant of, e.g., .025%/hr is different for ethanol than for any other drug. |
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Definition
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| zero order processes are rare for ____, but more common for ____. |
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| examples of zero order inputs: |
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- infusions
- medication schedules (take 1 pill every 8 hours) |
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| give an example of zero order elimination: |
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| With 0 order processes, if the y-axis is linear units, the process is ___. |
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| With zero order processes, if the y-axis is in log units, the process is ____. |
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| what causes zero order kinetics? |
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- metabolizing enzymes get saturated
- transporter gets saturated |
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| With zero order kinetics, what happens near the end of the process when the enzymes aren't saturated anymore? |
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Definition
- first order kinetics prevail
- with alcohol, this occurs at such low blood concentration, that no physiological effect is detectable |
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| mixed order kinetic synonyms: |
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Definition
mixed-order kinetics
dose-dependent kinetics
Michaelis-Menton kinetics |
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| whats the issue with drugs that have mixed order kinetics and why? |
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Definition
| - potential for serious drug toxicity b/c drugs that are eliminated by zero order can reach high plasma concentrations rapdily, but rate does not increase with increased drug concentration |
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| define volume of distribution: |
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Definition
Vd=dose/(plasma[D])
Vd should be between 40 and 60 Liters |
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| If you calculate Vd at time 0, you are calculating the ___ volume of distribution, which is the volume of fluid that the drug would occupy if what happened? |
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Definition
- apparent volume of distribution is calculated at time 0
- if the drug were distributed instantly throughout that volume |
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From general principles, we know that drugs do not distribute instantly throughout their volume.
it takes times for the drug to come to equilibrium with different compartments (a case where our one-compartment model suffers) |
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| look at slides 32 and 33 of pharmocokinetics lecture |
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| if you see Vd in L/kg weight, its probably for ___. |
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| Vd is used to determine ___ ___. |
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| how many liters of fluid are in the plasma, how many in extracellular space, how much total body fluid? |
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Definition
4 Liters in plasma
12 Liters in extrecellular compartment
40 Liters total body water |
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| Fat soluble drugs will have a ___ plasma concentration and a ____ volume of distribution. |
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Definition
low plasma concentration
high volume of distribution |
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| why would a volume of distribution be very small? |
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Definition
| - all the drug is trapped in the plasma bound to proteins, so the plasma level is artificially high, making the Vd very small |
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| Volume of distribution is an ___ ___ number. |
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| calculating loading doses and multiple doses |
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| The larger the Vd, the ___ the rate of elimination, why? |
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Definition
slower
- because if drug is in a large volume, very little is availabe to interact with elimination mechanism |
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Definition
- apparent volume of fluid from which drug is totally removed per unit time
Cl= (Vd)(Ke) |
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| what is clearance useful for? |
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- useful for calculating plateau concentration of drug
- useful for understanding what happens when ke changes (renal failure) |
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| To figure out single dose kinetics, x-axis is in units of ___ ___ ___, while the y-axis is in ___ of ___ ___. |
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Definition
- elimination half lives
- log of drug concentrations |
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| with a single dose curve, the time to get from the dose to the the peak is constant despite the dose. |
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| with single dose kinetics, peak concentration is a direct function of the ___. So if the dose if 4 times higher, the peak will be __ times higher. |
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| With single-dose kinetics, for every doubling of the dose, the duration of effect is only extended by __ ___ ___ ___. |
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Definition
| one elimination half life |
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For most drugs, if you want to significantly extend the duration of action, you must give more than one dose.
giving a single, bigger dose usually exposes the patient to toxicity before the duration of action is increased significantly. |
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Definition
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| With single-dose kinetics, the time to peak absorption is inversely related to ___. |
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Ka
- so as Ka becomes smaller (less drug absorbed per unit time), the time to peak shifts to the right (takes longer) |
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| Depot preparations produce low, sustained ___, nearly __ ___ of absorption. |
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Definition
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| a slower rate of absorption, or smaller ka, will change the peak how? |
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| decrease the peak and shift it right |
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| why is the slowing the rate of absorption beneficial sometimes? |
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Definition
- helps to get rid of peaks and valleys
- you can help control rate of absorption by administering via different routes |
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| change in rate of elimination is inversely related to to changes in ___. |
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Definition
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| So as Ke gets smaller, the half life of elimination gets ____. |
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Definition
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| As Ke gets smaller, elimination half life gets ___, time to peak shifts to the ___ and the peak gets ___, and the duration is ___. |
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Definition
- longer
- right
- higher
- longer |
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| In single dose drugs, if Ke is smaller it really doesn't matter b/c the increased peak is no big deal, this is just important with multiple doses. |
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| ___ ___ may be a critical factor in deciding amount for subsequent doses. |
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| Repeated doses are referred to as ___ doses when the dose and dosing intervel are constant. These types of drugs are ___ order input and ___ order elimination. |
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Definition
- maintenance
- zero order input
- first order elimination |
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| With maintenance doses, drug accumulates in the system until a ___, or stable concentration is reached. |
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| what type of elimination is essential for a plateau to be reached? |
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| With maintenance dosing, at the start of the first dose, no drug is being eliminated. |
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| With developing a maintenance dose, if the second dose is given within 4-5 elmination half lives of the first dose, peak concentration attained will be ___ than the first dose. |
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| how long does it take to reach a stable plateau? |
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| Consider why the plateau occurs. Elimination rate= [D]k. After the second dose, peak concentration is higher than after the first dose, thus rate of drug ___ is higher after the second dose. This process repeats after every dose, until the amount of drug ___ ___ equal the amount of drug ___. Then a plateau has been reached. |
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Definition
- elimination
- amount of drug coming in= amount of drug being eliminated |
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| Once the plateau has been achieved, if medication is stopped, how long does it take for the drug to be completely eliminated? |
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| 4-5 elimination half lives |
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| How long it takes to reach plateau is governed soley by the ___ ___ ___. |
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at constant dose, with constant dosing interval, and drug eliminated by first-order kinetics:
4-5 elimination half-lives to reach plateau |
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| the height of the plateau is a direct function of the ___ ___. |
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Definition
maintenance dose
so if you double the dose consistently, you double the plateau |
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| greater dosing intervals produces greater __ and ___ around the plateau. |
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| the more rapid the absorption, the greater the ____ around the plateau |
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Definition
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| as Ke, or rate of elimination, gets smaller and slower, the elimination halfe life is getting ___, and the plateau ___. |
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Definition
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| we worry about slower than expected elimination not really faster than normal elimination. |
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When possible, start with maintenance dose
safety: if toxic effects occur at concentrations below the intended plateau, the drug can be discontinued or the maintenance dose can be adjusted |
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| use maintenace dose to start with not loading dose |
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Definition
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Life threatening problems require rapid attainment of the plateau. Use a loading dose.
safety: even if you must use a loading dose, avoid going directly to plateau if possible -- e.g., multiple loading doses.
The next slide illustrates two large doses given close together as loading doses |
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| even when giving a loading dose, the ___ ___ ultimately determins plateau. |
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| If you know the desired plasma concentration of the drug, how do you calculate the dose? |
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- desired plasma concentration
- approximate volume of distribution
- ([D] in plasma)= dose/Vd |
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| tips for calculating loading dose: |
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Usually it is best to aim for the low end of the therapeutic window
When switching to a maintenance dose, monitor the patient closely. For example, if ke is smaller than anticipated, the ultimate plateau may rise higher than anticipated. |
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| necessary parameters to consider when calculating the loading dose: |
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Definition
1. Bioavailability= F, the fraction of each dose that gets into the plasma
2. Volume of Distribution= Vd, the apparent volume the drug dissolves in
3. Cl= (Vd)(Ke)
4. the maintenance dose (drug per unit time)
Think BVCM: Be Very Cool Mom. |
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| plateau concentration is also known as concentration at steady state (CSS), give equation for this: |
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Css= ((F)(maintenance dose))/Cl
THIS PREDICTS THE AVERAGE CONCENTRATION, IGNORING PEAKS AND VALLEYS. |
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| If there is not information about bioavailability, assume it is __. |
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Definition
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| units of maintenace dose is quantity/per unit time. So if told someone is taking 50mg of drug X every 12 hours, what is the maintenance dose? |
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| 50/12= 4.17 mg/hour is the maintenance dose |
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