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Pharmacology > Pharmacokinetics II Drug Elimination & Multiple Dosing > Flashcards

Pharmacokinetics II Drug Elimination & Multiple Dosing Flashcards

1
Q

What is the equation for volume of distribution? (Include units)

A

Vd=Dose/C0

dose =mg/kg
C0=mg/L
Vd=L/kg

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2
Q

In administering a drug, how can you achieve a longer duration of effect without giving a higher dose (since you already are close to maximum tolerated range)?

A

give repetitive dosing

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3
Q

In repetitive dosing, how long does it take to reach steady state?

A

4-6 half lives

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4
Q

What purpose does a loading dose serve?

A

If a drug takes a long time to reach therapeutic levels, then a higher dose (the loading dose) may be given initially before dropping down to a lower maintenance dose.

A LOADING DOSE MORE RAPIDLY ACHIEVES A THERAPEUTIC DRUG LEVEL

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5
Q

How is loading dose calculated?

A

Cp x Vd/F =loading dose

Cp (peak desired concentration of drug)
Vd (volume of distribution of drug in the body
F (bioavailability)

Cp= TC (target concentration)

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6
Q

How does loading dose affect the time it takes to reach steady state?

A

TIME TO REACH STEADY STATE IS NOT REDUCED BY THE LOADING DOSE

get into therapeutic range more quickly w loading dose but we have undershot target concentration and will take another 4-6 half lives before we get to steady state

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7
Q

When is steady state attained?

How is it related to dosage?

A
  • attained after approximately four half-lives

- time to steady-state independent of dosage

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8
Q

Are fluctuations directly or inversely related to dosage interval/half-life?

How are fluctuations affected by slow absorption?

A
  • proportional to dosage interval/half-life

- blunted by slow absorption

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9
Q

How is steady state concentration related to dose/dosage interval?

How is it related to CL/F?

A

proportional to dose/dosage interval

Inversely related to CL/F

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10
Q

What is the purpose of maintenance dosing?

What is calculation of this dose based upon? (How does this differ from loading dose?)

A

dosing strategy to maintain a steady state of drug in the body

Dose is based on replacing the amount of drug cleared from the body since the previous drug administration.

Clearance is the primary determinant for calculating the maintenance dose.
(volume of distribution used for loading dose)

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11
Q

How is maintenance dose calculated?

A

Maintenance Dose = CL x TC x T/F

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12
Q

Define elimination clearance.

What are the eliminating organs?

A

Irreversible drug removal from the plasma through an eliminating organ(s).

eliminating organs (kidney, liver)

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13
Q

Define intercompartmental clearance.

A

Drug distribution between plasma and tissues, a bidirectional process.

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14
Q

What type of clearance does the two compartment model exhibit?

A

intercompartmental
eliminating

drug in central compartment (plasma), can distribute bidirectionally to tissues,
unidirectionally eliminated through clearance/eliminating organ

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15
Q

What units are selected for maintenance dosing rate?

How is this dose calculated at steady state?

A

mg/day or mg/min selected in relation to expected clearance

steady state:
dosing rate= rate of elimination (CLe x target concentration)

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16
Q

How is steady state concentration calculated?

A

Css= dosing rate x F/clearance

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17
Q

For continuous I-V infusion, when is steady state attained? How is this related to dosage?

A

attained after approximately four half-times

time to steady-state independent of dosage

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18
Q

How is infusion rate calculated?

A

infusion rate= CL x Css

19
Q

How is steady state concentration related to infusion rate and CL?

A

proportional to infusion rate

Inversely related to CL

20
Q

Given infusion rate and steady state plasma concentration, how can you estimate clearance?

A

CL= I/Css

21
Q

Define first order elimination/kinetics.

A

the elimination rate of the drug is a constant FRACTION of the drug remaining in the body (rather than a constant amount of drug per hour).

Elimination half-life (t½) is constant.

22
Q

What is the equation for first order kinetics elimination rate?

A

dC/Dt= -kC

-k is elimination rate constant

23
Q

Are most drugs used clinically first or zero order kinetics?

A

Most drugs used clinically obey 1st order

kinetics.

24
Q

Which drugs exhibit zero-order kinetics of drug elimination?

What are two examples of drugs that exhibit zero order?

A

Drugs that are eliminated primarily by metabolism may display zero-order kinetics of elimination.

PHENYTOIN, ETHANOL

25
Q

Explain and define zero-order kinetics.

A

Drugs that are eliminated primarily by metabolism may display zero-order kinetics of elimination.

A fixed amount of drug is metabolized per unit time (zero-order kinetics).

26
Q

How does drug concentration affect metabolic pathways when they are saturated?

A

(zero order)
When metabolic pathways are saturated, metabolism occurs at a fixed rate, i.e. it does not change in proportion to drug concentration.

A fixed amount of drug is metabolized per unit time (zero-order kinetics).

27
Q

How can you distinguish between zero order and first order rate of elimination?

A

By looking at t(1/2) which is NOT constant in zero order

28
Q

Will first order elimination have a log or linear y-axis? Zero order?

A

first order has log scale y axis

zero order has linear y axis scale (and thus half life is not constant)

29
Q

What is the equation for elimination rate in zero order kinetics?

A

dC/dt=-k

PHENYTOIN, ETHANOL

30
Q

Which drugs may exhibit zero-order kinetics of elimination?

A 
Aspirin
Ethanol
Heparin
Phenylbutazone
Phenytoin
Salicylates
Theophylline
Tolbutamide
Warfarin
31
Q

Describe dose dependent kinetics; under what conditions will a drug follow first order/zero order?

A

When a drug’s elimination is mediated predominantly by metabolism, its elimination will tend to follow first-order kinetics when concentrations are well below the KM of the metabolic enzymes

but will follow zero-order kinetics at doses that greatly exceed the KM of the metabolic enzymes.

32
Q

Define elimination clearance. Provide units

A

Volume of plasma cleared of drug per unit time.

Units are ml/min or L/hr (flow)

33
Q

What organs may drug elimination occur through?

A

kidneys, the liver, the lung, and other organs.

liver and kidney are primary

Total Clearance is equal to the sum of all these individual and simultaneously occurring organ clearances:

CLtotal = CLrenal + CLhepatic + CLother

34
Q

Define elimination half life and provide the equation.

A

time to eliminate 50% of the body content of the drug

t(1/2)= 0.69Vd/CL

35
Q

What are the two primary pharmacokinetic parameters?

A

Elimination clearance and volume of distribution

36
Q

What effect does impaired renal function have on clearance of drugs?

How should daily dose be adjusted?

A

Impaired renal function often results in reduced clearance of drugs that are eliminated primarily by the kidneys.

Daily drug dose must be reduced by the ratio of measured clearance in renal failure (CLRF) over expected normal, average clearance (CLN).

37
Q

How can dosing rate be reduced?

A

reducing the dose,
increasing the dosing interval,

or both.

38
Q

Of what use is creatinine clearance in calculating dosage?

A

Creatinine clearance rate (CrCL) is the volume of blood plasma that is cleared of creatinine per unit time and is the most commonly used measure for approximating the glomerular filtration rate (GFR).

CrCL is not the same as clearance of a drug—it only provides a relative measure of how well the kidney is functioning. It can be used to adjust drug dosing in a patient with renal failure.

The ratio of CrCL in renal failure to CrCL in a patient with normal renal
function can also be used to adjust the dosing rate.
39
Q

What are the three determinants of hepatic drug clearance?

A
  1. Hepatic Blood Flow
    (Rate of drug delivery to the eliminating organ)
  2. Plasma Protein Binding
    (Fraction of drug available for clearance, drugs that are protein bound cannot distribute to the liver)
  3. Intrinsic Clearance
    (Hepatocellular metabolism and/or biliary excretion)
    -ability of liver’s metabolic enzymes to clear the drug or excrete it in bile
40
Q

What drugs will exhibit restrictive hepatic clearance?

Explain this concept.

A

Drugs with low hepatic extraction (Q is much greater than F x CLint)

CLh= f x CLint

Little “first pass metabolism” when given orally. A change in binding or drug metabolism/excretion activity will have a greater effect on hepatic clearance than changes in liver blood flow.

Capacity-limited clearance.

Examples: warfarin, phenytoin

41
Q

What drugs will exhibit non-restrictive hepatic clearance?

Explain this concept.

A

Drugs with high hepatic extraction (Q is much smaller than f x CLint)
Examples: lidocaine, propranolol

CLh=Q

Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance.

Flow-dependent clearance: conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.

42
Q

What effect can beta blockers have on hepatic blood flow? What will be the effect on lidocaine clearance?

A

reduce hepatic blood flow and therefore can decrease lidocaine clearance

43
Q

What factors affect the pharmacokinetic profile?

A 
Individual variability
Patient compliance
Disease states
Pharmacogenetics
Age and gender
Medication interactions

Pharmacology (13 decks)

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