Waller Pharmacokinetics Lecture Flashcards
Therapeutic applications of pharmacokinetics
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?
First order kinetic processes
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
When is a first-order process complete?
clinically, in 4-5 half lives
most important factor is usually the elimination half-life
Zero order kinetic processes and an example
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%
What causes zero-order elimination?
Metabolizing enzyme is saturated
Transporter is saturated
Capacity-limited elimination
Volume of distribution equation
Vd = amount of drug in body/ C
Clearance equations
CL = Vd x ke
CL- Vd x .693/ half-life
Half life equation
t 1/2 = .693 x V / CL
Volume of Distribution description
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
what is the imporantce of Volume of distribution?
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
Clearance info
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
half life and its relationship to Vd and Clearance
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
assumptions of the one-compartment model
Distribution is rapid Distribution is equal Absorption is first-order Elimination is first-order All kinetic parameters remain constant with time
Single Dose
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
Varied Absorption
Varied absorption rate
Varied extent of absorption
Bioavailability – fractional extent to which unchanged drug reaches site of action following administration by any route
Bioavailability and various routes
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
Repeated Doses, Steady-State- conditions
Two conditions:
- Constant input, maintenance dose
- Constant dose & dosing interval
- —Drug A IV every 4 hours
- —Drug B PO every 8 hours x3 weeks - First-order elimination
Drug accumulates until steady-state is achieved
If two conditions not met, steady-state will not be reached
steady-state: why does plateau occur?
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
Drug concentration at steady-state
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
Greater dosing interval –> ?
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”
Rates of absorption and the steady state
The more rapid the absorption, the greater the fluctuations around the plateau
Slowing the rate of absorption blunts the fluctuations
Varied elimination and the steady state
Worry about slower than expected elimination
Steady-state changes in direct proportion to change in ke
Adjust the dose or dosing interval accordingly
Loading Dose- guidance
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)
loading dose calculation
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
Predicting Steady-State Concentration
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)
If maintenance dose changes by 25%
Css changes in direct proportion by 25%
If elimination is impaired by 50% (t1/2 is twice as long)
Css is twice as high
Compare the decimals: mcg, mg, mL, L
1 mcg = 1,000 ng
1 mg = 1,000 mcg
1 mg = 1,000,000 ng
1 L = 1000 mL
