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Flashcards in Steady State Deck (25):
1

The rate at which steady-state is approached is governed purely by what?

The terminal T1/2 of the drug

2

The difference between the present concentration and the ultimate steady-state concentration (Css) decreases what?

by 50% every T1/2

3

The steady-state concentration is purely determined by what?

Dose rate (DR) and CL.

Css = DR/CL.

4

What is the Equation for Dose Rate?

Dose rate = Dose / inter-dosing interval ("Tau")

If administered extravascularly, then one must include bioavailability;

DR = F x D/Tau.

100 mg every 2 hours is the same DR as 200 mg every 4 hours:

DR = Dose / Tau

5

If the dose is a continuous iv infusion then?

 and only then, is there a true Css as the drug ids constantly entering the circulation

6

If the dose is regular bolus doses (eg iv, oral etc), then what will there be? 

There will be fluctuation in the concentrations between doses

7

Concentrations fluctuate about?

a Css,ave bewteen the Cmax,ss and Cmin,ss

8

What is the extent of fluctuation determined by?

  • The rate constant that determines the terminal T1/2 and the interdosing interval (Tau)
    • The shorter the terminal T1/2, then there will be greater fluctuation between doses for a given Tau

    • The longer Tau, then there will be greater fluctuation between doses for a given terminal T1/2

9

How do you calculate Fluctuation?

Fluctuation = exp(k*Tau)

 

Tau = ln(Fluctuation)/k

10

Different dose regimens with the same DR will give the same _____ and _____ 

  • Css,ave but different fluctuation
    • e.g. different Css,max and Css,min
    • 100mg every 2 h will give less fluctuation than 200mg every 4 h.

11

Hepatic CL classification

  • we can simplify our thinking by classifying drugs into HIGH and LOW EH drugs based upon the hepatic CL from the blood (CLHb)
    • CLHb = CLH /(blood to plasma ratio)

  • Blood to plasma ratio cannot be lower than 0.4, as even if the drug is completely excluded from red blood cells then the blood concentration will be due puerly to the drug in the plasma, and red blood cells account for ~40-60% of blood volume (the rest is plasma) in a relatively healthy person

12

How do you calculate Hepatic Extraction Ratio?

Hepatic extration ratio = CLHb / QH

13

For High EH drugs (EH >=0.7)

  • CLH is affected mainly by changes in QH only.
  • The component of bioavailability due to first-pass metabolism is affected by QH, fu and Clint (not so simple)

14

For Low Eh drugs (EH<=0.3)

  • CLH is affected mainly by changes in fu and CLint.

  • The component of bioavailability due to first-pass metabolism is not really affect by changes in any of the above factors. It is by definition a low first-pass effect any way (<0.3).

15

Css is affected by?

bioavailability, DR and CL (Css - FxDR/CL)

16

In 3 out of the 4 different cases of administration (orally administered      High EH and LOW EH drugs and iv administered LOW EH drugs) the only factors that affect Css are?

  • fu and CLint
    • the unbound drug Css (Css,u = Css x fu) which is really the concentration which will be most related to the effects of the drug is affected only by CLint
      • hence metabolic drug-drug interactions are important in many cases

17

The last case, iv administered HIGH EH drugs Css is affected by

  • QH
    • the unbound drug Css (Css,u = Css x fu) which is really the concentration which will be most related to the effects of the       drug is affected by both QH and fu

 

18

Drug-Drug Interactions

  • It is not common for drug-drug interactions (ie. displacement from plasma proteins --> increasing fu) to result in a major impact on clinical effects of the drug in the longer term as only 1 of the 4 cases is changes in fu important in affecting Css,u (and hence affect):
    • the drug must be
      • (i) High EH
      • (ii) administered repeatedly
      • (iii) administered iv 
      • (iv) be highly bound (ie. low fu)
      • This is not a common combination, although theoretically possible

19

To design a dose regimen one is determining the _____ and the _______.  This is done to ensure that the _____ and ______ remain within the clinically acceptable limits for that drug

To design a dose regimen one is determining the dose and the interval between doses (Tau).  This is done to ensure that the Css,max and Css,min remain within the clinically acceptable limits for that drug

20

How can you estimate Tau?

  • One can estimate the Tau that will give exactly the fluctuation which will meet the theoretical limit (Fluctuation = Cmax/Cmin).

    • Tau = ln(Fluctuation)/k

21

How can you work out what dose rate is required to obtain some desired Css,ave?

  • DR = Target Css,ave x CL

  • This is a dose rate NOT the maintenance dose!

22

One then needs to choose the maintence dose and dosing interval, what is this based on?

  • This is based upon the results for the theoretical Tau, the DR and the dose sizes available, and requires your intellectual input
    • MD = DR x Tau

23

 As the approach to ___ is determined by ____, it may take a long time to reach therapeutic concentrations after starting the ____

  • As the approach to Css is determined by T1/2, it may take a long time to reach therapeutic concentrations after starting the MD
  • A loading dose (LD) can be used to help with this

24

What is a loading dose?

  • A LD simply is a larger dose that provides enough drug = that which would accumulate at steady-state
  • One chooses a concentration to target (eg. Css,max or Css,ave):

    • LD =  Cdesired x Vd

    • Incremental LD are the same concept, but only add the required extra drug to achieve a higher Css from a lower concentration

25

Why does one need to be careful in using loading doses if a drug displays marked/slow 2 compartment kinetics?

  • This is because immediately after a rapid bolus all of the drug will be in the central compartment
  • If the total Vd was used to calculate the LD, then this could result in very high concentrations immediately after the dose before distribution in to the peripheral compartment occurs