Fundamentals Flashcards

1
Q

What is the purpose of Pharmacokinetic models?

A

Predicting a drug’s behavior, and concentration within complex processes

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2
Q

How does Compartment modeling help understand the behavior of drugs?

A

A compartment is composed of tissues
that behave similarly -> similar pharmacokinetics

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3
Q

What is the One-compartmental model?

A

All body tissues are considered part of the compartment

-It is assumed after a bolus dose, distribution is instantaneous within the compartment

ASSUMPTION NOT REALITY just used to make it mathematically work

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4
Q

What is the most commonly used Compartment model?

A

One-compartmental model is most frequently used in clinical practice

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5
Q

What types of drugs are explained with the one-compartment model?

A

Drugs that don’t distribute into extravascular tissues
-Polar molecules -> distribute more into the fluid compartment
-small Vd (<1L/kg) aminoglycosides

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6
Q

What are the factors affecting the one-compartment Model?

A

Fluid changes, renal failure, prematurity (babies contain 80% water)

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7
Q

Which drugs are more likely susceptible to fluid shifts?

A

-polar drugs
-small Vd
f.e. gentamycin Vd = 0.3L/kg

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8
Q

Where are most drugs bound to in the blood?

A

-Most drugs bind to Albumin

(some bind to alpha acid 1 Glycoprotein - basic drugs)

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9
Q

What does k stand for in Pharmacokinetics?

A

Eliminate rate constant

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10
Q

What is a Two compartment model?

A

consists of a central compartment and a peripheral compartment

  1. Distribution into the blood and highly perfused organs (central compartment - heart, liver, kidney, blood, lungs)
  2. Distribution more slowly into peripheral tissues
    (fat, muscle, bone, cerebrospinal fluids)
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11
Q

What types of drugs are described with the Two-compartment model

A

f.e. fat-soluble drugs
-nonpolar molecules, many carbons and rings f.e. steroids
They do not like to stay in the blood

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12
Q

From which compartment are drugs eliminated?

A

Central compartment, the drugs need to move back from the peripheral compartment into the central compartment (the blood) to be eliminated

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13
Q

How is the Two-compartment model displayed in a Log-linear graph compared to the one-compartment model?

A

Two lines:
Alpha Phase of Distribution
beta Phase Elimination

in one-compartment model: one straight line

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14
Q

What happens during the alpha and beta Phase?

A

Alpha Phase of Distribution from central into peripheral tissues

Beta Phase Elimination: Elimination of drug from central compartment to outside of the body

C = A e ^-alphat + B e ^-ßt

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15
Q

Which drug has the most rapid distribution from the central compartment into the peripheral compartment?
A alpha = 0.050 hr ^-1
B: alpha = 0.50 hr^-1
C: alpha = 0.5 hr^-1

A

Distribution from the central to the peripheral compartment is described by the slope Alpha (in hr inverse -> fraction (percentage) removed per hour)

Answer C = 0.5 per hour

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16
Q

What would the graph look like for a very fat-soluble drug like Propofol?

A

Alpha would be very steep, bc the fat-soluble drug will tend to leave the blood (central) much faster into fat-soluble tissues (peripheral)

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17
Q

Equation Vd

A

Vd = dose / Concentration

18
Q

Why is Vd often referred to as the apparent volume of distribution?

A

Drugs like tricyclic antidepressants or Digoxin can have a high Vd -> Vd does not represent the true Volume of the blood -> it stands for the fluid throughout the whole body, tissues, muscles, bones included

19
Q

How does concentration behave in the body compared to the mathematical model?

A

In reality concentration changes and it is NOT a closed system -> ELIMINATION constantly occurs

20
Q

What is the unit for the Rate of Elimination?

A

[mg/time] –> [mg/hr]

21
Q

What is the unit for the Elimination rate constant k?

k= slope

A

[hr^-1]

f.e. 0.15hr^-1 (fraction per hour)

-> 0.15*100 = 15% of the concentration of the drug is removed from the body per hour

22
Q

What is Clearance?

A

removal of drug from a volume of plasma in a given period of time

CL represents the ![Volume of plasma]! from which the drug is completely removed
-> [V/time] -> [L/hr]

-CL is expressed in volume per unit time
-CL represents drug loss from the body

23
Q

Different variables of Elimination

A

Rate of Elimination: f.e. 10mg/hr of drug is eliminated from the body

Clearance: f.e. 3L/hr of plasma eliminated from the body

Elimination rate constant: [hr^-1] fraction of drug eliminated per hour

24
Q

If the Clearance of a drug is 2L/hr, how much drug with a concentration of 100mg/L is eliminated per hour?

A

Concentration: 100 mg per 1 Liter

We have 2L so: 100*2 = 200mg of drug per hour

25
Q

Which variables of Elimination are fixed?

A

Clearance [L/hr] and the Elimination rate constant - the percentage of the drug stays the same[hr^-1]

Change of concentration [mg/L] can increase or decrease the Rate of Elimination [mg/hr]

but it doesn’t change Clearance - because the volume per hour is the same;
and it does not change the Elimination rate constant k because the fraction (f.e 15%) is the same regardless of a high or low concentration

26
Q

What does the total body clearance consist of?

A

The sum of all Clearances of different pathways: renal (kidney) + hepatic + biliary + pulmonary (exhaling) + skin

Renal and hepatic are the most common ways of clearance

27
Q

What type of process is exhibited for most drugs eliminated by the body?

A

First Order Elimination

28
Q

First Order Elimination

A

The amount of drug eliminated from the body is directly proportional to the amount in the body

The greater/lower the concentration the more rapid/slower the elimination per time

29
Q

Why is the First Elimination graph in the Linear-Linear plot curvy?

A

Because it represents high removal of drugs at high concentrations and low removal of drugs per hour at low concentrations of drug

30
Q

Which variable is fixed in the First Order Elimination?

A

-The Elimination rate constant k [hr^-1] fraction of drug removal per time stays equal

-The amount of drug eliminated decreases with time

31
Q

First Order Elimination Equation

A

Ct = C0 * e^-k*t

32
Q

What is the decay factor?

A

e^-kt

multiply to go forward - declining concentration
divide to extrapolate back - higher concentration

33
Q

Is the Half-Life in First Order Elimination constant?

A

In a First Order log-linear plot, the time needed to decrease by one-half stays constant -> because the drug is eliminated faster/slowlier at high/low doses, so the half-life stays the same regardless of the concentration

t/2 = 0.693 / k

34
Q

What is the Zero Order Elimination?

A

It occurs when the drug-eliminating enzymes reach its maximum capability

-> The amount of drug removed per hour stays equal even with high concentrations of drug
-> Concentration of drug accumulates bc the enzymes cant keep up

35
Q

Halflife at zero-order-elimination

A

The half-life at high concentration is high and low at low concentration

-the enzymes are saturated -> it takes longer to reduce the amount of drug by half at high concentration; it takes less time to reduce the drug by half at lower concentration

36
Q

Which variables are fixed or change with elimination in zero-order kinetics?

A

Fixed: Amount of drug eliminated per time [mg/hr]

Changes: Fraction of drug eliminated [hr^-1] increases per time bc:

the same amount of drug is removed -> as we reomve the same amount of drug, at low concentrations the fraction (percentage) of removed drug is higher

Changes: Clearance???

37
Q

What would be a clinical situation of zero-order elimination?

A

Overdose (not every drug goes to zero-order-phase in an overdose)

-Elimination is very slow at the early phase

38
Q

Examples of drugs exhibiting zero-order-elimination

A

-Ethanol
-Phenytoin: mix of first and zero-order-elimination

39
Q

What is specific about Phenytoin with reference to drug elimination?

A

-Michaelis-Mentin kinetics (saturation kinetics)
-Phenytoin (controls seizures) exhibits both First and zero-order-kinetics
-Switch from first to zero-order-elimination when hepatic enzymes become saturated

40
Q

Why does Phenytoin have to be dosed with caution?

A

Because above the inflection point, the concentration (Css - steady state) is rising exponentially with an increase in dose - Due to entering the zero-order-elimination-phase
-> potentially exceeding therapeutic range -> OVERDOSE

-Michaelis-Mentin Plot (Css over Dose)