Pharmacology: Block 1: Pharmacokinetics

Front 1

What is pharmacokinetics?

Back 1

The study of the relationship between drug dose and concentration of drug at it's receptor.

Front 2

What is the equation for the volume of distribution?

Back 2

Vd = Amount of drug in body (mg)/ Concentration in plasma (mg/L)

units = mg / (mg/L) = L per kg body weight

"The volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration."

Front 3

What does a high Vd indicate?

Back 3

A high Vd indicates a greater distribution to the extravascular tissues than to the vascular compartment.

Example: The Vd for chloroquine in 13,000 L/70 kg

Front 4

What does a low Vd indicate?

Back 4

A low Vd indicates a greater distribution to the vascular compartment

Example: The Vd of warfarin is 9.8 L/70kg

Front 5

What is the approx volume of total water in a 70 kg individual?

Back 5

42L (0.6/kg)

Front 6

What is the approx volume of extracellular water in a 70 kg individual?

Back 6

14L (0.2 L/kg)

Front 7

What is the approx volume of blood in a 70 kg individual?

Back 7

5.6L (0.08 L/kg)

Front 8

Immediately following IV administration of 300mg of Drug X to a 70 kg man, plasma concentration of Drug X was measured to be 3.8 mg/L. What is the Vd of Drug X?

Back 8

Vd = Amount of drug in body / Concentration in plasma

Vd = 300/3.8 = 78.9 L

Front 9

What is the definition of clearance?

Back 9

Clearance is a measure of the ability of the body to remove a drug.

Front 10

What are the three major types of clearance?

Back 10

1. First-order: Rate of elimination depends on the concentration of the drug. Plot will be hyperbolic.

2. Capacity limited (zero order): rate of elimination does not depend on the concentration of the drug. Plot is linear.

3. Flow dependent: rate of elimination depends on the rate of drug delivery to the organ of elimination.

Front 11

What is the formula for first-order clearance?

Back 11

Rate of elimination = CL * [drug]

units = L/h * mg/L = mg/h/70kg

y axis = Rate of elimination
x axis = Plasma drug concentration

Front 12

First order clearance: CL is ____over [drug] range.

Back 12

CL is CONSTANT over drug range.

Front 13

First order clearance: A constant _______ of drug is removed per unit time.

Back 13

A constant FRACTION of drug is removed per unit time.

Front 14

First order clearance can be estimated by calculating the ____ ___ ___ ___ ___ of the time-concentration profile after a drug dose.

Back 14

First-order clearance can be estimated by calculating the AREA UNDER THE CURVE (AUC) of the time-concentration profile after a drug dose.

Front 15

What are the units of first order clearance?

Back 15

L/h/70kg

Front 16

When do we see capacity limited clearance take place?

Back 16

When the drug dose exceeds clearance capacity (saturation).

Front 17

What drugs exhibit capacity clearance?

Back 17

aspirin
alcohol
phenytoin

Front 18

Capacity limited clearance: A constant _____ of drug is removed per unit time.

Back 18

A constant AMOUNT of drug is removed per unit time (i.e. the rate of elimination is constant).

Front 19

Capacity limited clearance: Clearance is ___ ______ but varies with ___ ______.

Back 19

Clearance is NOT CONSTANT but varies with DRUG CONCENTRATION.

Front 20

What is the formula for capacity limited clearance?

Back 20

Saturatable, non-linear, dose-dependent, Michaelis-Menten elimination

Rate of elimination = Vmax(C) / (Km + C)

Vmax = maximum elimination capacity
Km = drug concentration where rate of elimination is 1/2 Vmax
C = concentration of drug

Front 21

Flow-dependent clearance largely depends on what?

Back 21

The rate of drug delivery to the organ of elimination.

Front 22

What are some examples of drugs that exhibit flow-dependence?

Back 22

Morphine, propranolol.

Front 23

Flow-dependent clearance: most of the drug is cleared how/when?

Back 23

Cleared rapidly - most of the drug is cleared on the first pass through the organ of elimination.

Front 24

Drugs are eliminated by many routes (liver, kidney, lungs) thus clearance is ____?

Back 24

Additive.

Front 25

First order CL for drug X is 1.62 L/h/70kg. If plasma concentration of drug X is 3.8 mg/L immediately following oral administration of 300mg drug X to a 70 kg man, what is the rate of elimination?

Back 25

Rate of elimination = CL * [drug]

1.62 * 3.8 = 6.16 mg/h/70kg

Front 26

What is the definition of half life?

Back 26

The half life is the time required to change the plasma concentration of a drug by one-half.

Front 27

Half-life is only relevant to drugs eliminated by ____ ____ kinetics.

Back 27

Half-life is only relevant to drugs eliminated by FIRST-ORDER kinetics.

Front 28

What does t1/2 indicate during dosing? During elimination?

Back 28

During dosing, t1/2 indicates the time required to attain 50% of steady-state.

During elimination, t1/2 indicates the time required to decay 50% from steady-state.

Front 29

What is the equation for determining the half-life from the elimination constant?

Back 29

t1/2 = 0.693/k

k = - slope of log[drug] vs. time plot

unit of k = /hr
unti of t1/2 = hr

Front 30

What is the equation that relates CL, k, and Vd?

So, by substitution, how does t1/2 relate to the above equation?

Back 30

CL = kVd

t1/2 = 0.693Vd/CL

Front 31

What percentage of a drug is lost after two half-lives?

Back 31

75%

Front 32

What percentage of a drug is lost after four half-lives?

Back 32

100 --> 50 --> 25 --> 12.5 --> 6.25

0% -1-> 50% -2-> 75% -3-> 87.5% -4-> 93.75

Front 33

How much of a drug must you give before a maximum effect is achieved?

Back 33

4 half-lives (>90% of a steady-state concentration must be achieved)

Front 34

What is the "Rule of 4?"

Back 34

A drug must be administered for four half-lives before a maximum effect is seen.

Front 35

What will happen if a drug's dosing interval is less than four half-lives?

Back 35

The drug will accumulate.

Front 36

What is the equation used to calculate the concentration of a drug at any time, t?

Back 36

Ct = C(0)(0.5)^t/(t1/2)

Front 37

How can bioavailability be measured?

Back 37

Bioavailability can be measured as the area under the curve in a plot of plasma concentration vs. time.

Front 38

What is the bioavailability of a drug given intravenously?

Back 38

1 (100%)

Front 39

What is the equation for bioavailability by any route?

Back 39

AUC of the route used / AUC of IV administration.

Front 40

What administration routes avoid the first-pass effect?

Back 40

IV, IM, SC, inhalation, sublingual, and transdermal routes (do not enter the portal circulation).

Rectum partial avoids the first-pass effect.

Front 41

What is the equation for the extraction ratio?

Back 41

ER = CL in liver / Q

Q = hepatic blood flow 90L/h/70kg

Front 42

What is the equation for systemic bioavailability?

Back 42

Systemic bioavailability (F) is defined as:

F = f * (1 - ER)

f = extent of GI absorption

Front 43

If hepative blood flow is 90L/h in a 70 kg person and hepatic clearance of morphine is 60 L/h/70kg, the first pass extraction ratio is...

Back 43

.ER = CL in liver / Q

ER = 60/90 = 0.67

Front 44

If hepatic flow is 90 L/h in a 70 kg person, hepatic clearance of midazolam is 25 L/h?70 kg, and GI absorption is 44%, the systemic bioavailability of midozolam is:

Back 44

F = f * (1 - ER)

F = 0.44 * (1 - 25/90) = 0.318 = 32%

Front 45

What is the definition of bioavailability?

Back 45

Bioavailability is the fraction of unchanged drug that reaches the circulation.

Front 46

The decline in the intensity of pharmacologic effect with time following a single large dose has _ parts. Which of these parts behaves in a linear fashion?

Back 46

3 parts.

Part number 2 behaves linearly.

Front 47

(extra credit)

Gentamicin shows more renal toxicity following _____ infusion rather than ______ dosing.

Back 47

Gentamicin shows more renal toxicity following CONSTANT infusion rather than INTERMITTENT dosing.

Front 48

At a steady state, the dosing rate must equal _______________.

Back 48

At a steady state, the dosing rate must equal THE RATE OF ELIMINATION.

Front 49

What is the equation for a steady-state maintenance dose?

Back 49

Steady-state maintenance dose = (CL * TC * Dosing interval) / F

Front 50

A TC plasma [erythromycin] of 1.5 mg/L is required to treat a bacterial infection. CL for erythromycin is 38.4 L/h/70kg. Calculate the dosing rate for erythromycin administered countinuously by IV.

Back 50

CL * TC = 38.4 * 1.5 = 57.6 mg/h/70kg

Front 51

A TC plasma [erythromycin] of 1.5 mg/L is required to treat a bacterial infection. CL for erythromycin is 38.4 L/h/70kg. Calculate the dosing rate for erythromycin administered countinuously by IV.

Calculate the maintenance dose for erythromycin given orally when dosing every 12h. F<oral> for erythromycin (enteric coated) is 0.80.

Back 51

CL * TC * Dosing interval/F = 38.4 * 1.5 * 12/0.8 = 864 mg/70kg

Front 52

What is the equation for a loading dose that is given by IV administration?

Back 52

Loading dose = Vd * TC

units = L * mg/L = mg

Front 53

What is the equation for a loading dose that is given via a route other than IV?

Back 53

Loading dose for route other than IV (bioavailability, F must be considered)

Loading dose = Vd * TC/F

Front 54

(extra credit)

The loading dose of a multicompartment drug should be given how?

Back 54

Slowly, because initial plasma concentration might be toxic.

Front 55

What kind of dose do you give if you want to acheive target concentration (TC) rapidly?

Back 55

You would give a loading dose.

Front 56

What is the most important parameter for adjusting drug dosing?

Back 56

Clearance.

Front 57

What is the equation for dose adjustment for clearance in a patient with altered renal function?

Back 57

Dose<corrected> = Dose<average> * Patient's Creatinine Clearance / 100mL/min

Note that if a problem were to say that drug X is "80% cleared" by the kidney, then the equation would be:

Dose<corrected> = [Dose<average>
* Percent cleared by that organ] * Patient's Creatinine Clearance / 100mL/min

where 100mL/min is the normal creatinine clearance.

Front 58

Pancuronium is 80% cleared bt the renal route. the normal dose of pancuronium is 2mg/mL. The corrected dose for a 70kg man with a creatinine clearance of 80mL/min is:

Back 58

Apply correction to the portion of the dose that is cleared by the kidney: 0.8 * 2 = 1.6 mg/mL

Dose<corrected> = 1.6 * 80/100 = 1.28

Add portion of dose not cleared by kidney: 1.28 + 0.4 = 1.68 mg/mL

Front 59

What is the equation for a steady state dosing rate?

Back 59

Dosing rate<steady state> = CL * TC

Front 60

What is a formula for giving a maintenance dose?

Back 60

Maintenance dose = dosing rate * dosing interval

Maintenance dose = CL * Target Concentration * (dosing interval/bioavailability)

Front 61

What is the equation for giving a loading dose?

Back 61

Loading dose = Vd * Target Concentration/Bioavailability