Waller Pharmacokinetics Lecture

Question 1

Therapeutic applications of pharmacokinetics

Answer 1

How long will toxic effects last after overdose?
What is the best dosing schedule for a drug with a low therapeutic index?
How much should doses be adjusted in the presence of renal failure?
What happens to drug concentrations when a patient skips a dose?

Question 2

First order kinetic processes

Answer 2

Most common
Rate = [C]k

Half-life of the process is a function of “k” in Rate = [C]k
The rate of elimination changes as a function of [C], and because [C] is always declining, the rate is always getting slower

t 1/2 = .693/k

Question 3

When is a first-order process complete?

Answer 3

clinically, in 4-5 half lives

most important factor is usually the elimination half-life

Question 4

Zero order kinetic processes and an example

Answer 4

Rate = k
This means the rate is constant
Concentration of the drug is irrelevant
Encountered far less frequently than first-order
Famous example: alcohol –> constant rate of metabolism whether the person has a BAL of 0.03% or 0.3%

Question 5

What causes zero-order elimination?

Answer 5

Metabolizing enzyme is saturated
Transporter is saturated
Capacity-limited elimination

Question 6

Volume of distribution equation

Answer 6

Vd = amount of drug in body/ C

Question 7

Clearance equations

Answer 7

CL = Vd x ke

CL- Vd x .693/ half-life

Question 8

Half life equation

Answer 8

t 1/2 = .693 x V / CL

Question 9

Volume of Distribution description

Answer 9

Volume of distribution relates the amount of drug (X) to the concentration in plasma
Apparent volume of fluid in which a drug would distribute
Calculate Vd at time 0
Apparent volume the drug would occupy if the entire dose were distributed instantly

Question 10

what is the imporantce of Volume of distribution?

Answer 10

Although numbers are mythical, they have important uses:
Caution drugs with small Vd
Measure free + albumin-bound drug
Calculating plasma concentration for –
Loading doses
Multiple doses
The larger the Vd, the slower the rate of elimination

Question 11

Clearance info

Answer 11

Measure of removal of drug from the body
Not a measure of amount of drug removed but indicates the volume of plasma or blood from which drug is completely removed in a given period

Useful for:
Calculating plateau concentration of drug
Understanding what happens when ke changes (e.g., renal failure)
Clearance of drug by several organs is additive
CLsystemic = CLkidney + CLliver + CLother

Question 12

half life and its relationship to Vd and Clearance

Answer 12

Elimination rate, volume of distribution, and clearance relate to how fast a drug effect will terminate

Time course in the body depends on both volume of distribution and clearance

Clearance and volume of distribution are independent factors that determine k and t1/2

t 1/2 = .693 x V / CL

Question 13

assumptions of the one-compartment model

Answer 13

Distribution is rapid
Distribution is equal
Absorption is first-order
Elimination is first-order
All kinetic parameters remain constant with time

Question 14

Single Dose

Answer 14

Increasing or decreasing dose shifts the response curve
May modulate drug effect
May prolong drug effect
Not recommended (increased risk of adverse reactions)

Repeated doses should be given

Question 15

Varied Absorption

Answer 15

Varied absorption rate

Varied extent of absorption
Bioavailability – fractional extent to which unchanged drug reaches site of action following administration by any route

Question 16

Bioavailability and various routes

Answer 16

IV– 100% by def’n. Most rapid onset.

IM- large volumes often feasible, may be painful

Subcutaneous- smaller volumes than IM; may be painful

Oral- most convenient; first- pass effect may be important

Rectal - less first-pass effect than oral

Inhalation- often very rapid onset

transdermal- usually very slow absorption, used for lack of first-pass effect; prolonged duration of action

Question 17

Repeated Doses, Steady-State- conditions

Answer 17

Two conditions:

1. Constant input, maintenance dose
   - Constant dose & dosing interval
   - —Drug A IV every 4 hours
   - —Drug B PO every 8 hours x3 weeks
2. First-order elimination

Drug accumulates until steady-state is achieved

If two conditions not met, steady-state will not be reached

Question 18

steady-state: why does plateau occur?

Answer 18

First-order elimination is critical

Rate in > rate out –> level rises

If drug stopped or all drug has been absorbed
rate out > rate in –> level drops

If constant rate & first-order out
rate in = rate out –> no change in levels

Question 19

Drug concentration at steady-state

Answer 19

Direct function of amount of drug taken per unit of time
To increase steady-state concentrations:
Increase drug dose but maintain dosing interval
Keep the same dose but give it more frequently

Question 20

Greater dosing interval –> ?

Answer 20

produces greater peaks and valleys around the plateau
Continuous IV infusion vs. different dosing intervals
Is it realistic to say that we have reached steady-state when the concentration is only stable with a continuous infusion?
We use an average “elevation”

Question 21

Rates of absorption and the steady state

Answer 21

The more rapid the absorption, the greater the fluctuations around the plateau
Slowing the rate of absorption blunts the fluctuations

Question 22

Varied elimination and the steady state

Answer 22

Worry about slower than expected elimination
Steady-state changes in direct proportion to change in ke
Adjust the dose or dosing interval accordingly

Question 23

Loading Dose- guidance

Answer 23

When possible, start with maintenance dose
Safety: if toxic effects occur at concentrations below intended steady-state, dose can be adjusted

Life threatening problems require rapid attainment of steady-state. Use loading dose
Safety: even if loading dose must be used, avoid going directly for plateau if possible (e.g., use multiple loading doses)

Question 24

loading dose calculation

Answer 24

You know what plasma concentration needs to be attained [C]
If you know an approximate volume of distribution (Vd), a loading dose can be calculated from rearranging equation

Vd = amount of drug in body / C

(Loading) Dose = Vd[C]

Best to aim for low end of therapeutic window
When switching to maintenance dose, monitor patient carefully

Question 25

Predicting Steady-State Concentration

Answer 25

Necessary parameters:
Bioavailability (F) the fraction of each dose that reaches systemic circulation
Volume of distribution (Vd) the apparent volume in which a drug would distribute
Clearance (CL) measure of drug removal
The maintenance dose

Css = (F)(Dose Rate)(t1/2) / (0.693)(Vd)

Question 26

If maintenance dose changes by 25%

Answer 26

Css changes in direct proportion by 25%

Question 27

If elimination is impaired by 50% (t1/2 is twice as long)

Answer 27

Css is twice as high

Question 28

Compare the decimals: mcg, mg, mL, L

Answer 28

1 mcg = 1,000 ng
1 mg = 1,000 mcg
1 mg = 1,000,000 ng
1 L = 1000 mL