Clinical Applications of Pharmacokinetics Flashcards
For IV infusion, rate of entry (R0, in units of mL/min) into the body is constant with
Time
This means that absorption by IV infusion is said to follow
Zero-order kinetics
The rate of exit, or loss from the body, however, is said to follow
First-order kinetics
In fact, the rate of loss is always equal to the
Total body clearance
Upon starting an IV infusion, the plasma concentration rises until the rate of loss equals the rate of
Input
Thereafter, the plasma concentration reaches a steady state in which drug in = drug out. The steady-state plasma concentration is denoted
Css
The achievable steady state plasma concentration depends solely on the
Infusion rate
Not achieved any faster if the infusion rate is doubled
Plateau
A general rule of thumb is that in order to approximate the steady state condition, we need how many half-lives to elapse?
4
Directly proportional to the infusion rate (R0) and inversely proportional to the total body clearance
Css
The rate of approach to steady state is independent of R0, but rather depends solely on
kd or t 1/2
What are 2 salient considerations for a discontinuous drug regimen?
Half-life and therapeutic index
A commonly employed intravenous regimen is to start with a loading dose that is
2X effective dose of drug
Then, follow with a maintenance dose that is equal to the effective dose every
Half-life
The maintenance dose replaces the amount of drug lost within the
Dosing interval (t*)
If the drug is to be administered orally rather than IV, the dosing rate need only be adjusted for the
Oral bioavailability of the drug
The most common pattern of drug administration
Fixed dose-Fixed time discontinuous drug regimen
In the fixed dose-fixed time regimen, the drug accumulates until
Input = output
Drugs are eliminated
Exponentially
Therefore, drug accumulates until its concentration increases to a point where the rate of loss = the
Input rate
During the dosing interval, we want to know the
Average amount of drug at steady state (Abavg)
For patients with renal disease, the sensitivity to drugs is
Unchanged (i.e. plasma concentration of drug that produces the desired effect is the same as in normal patients)
However, due to renal disease, we do see impairment of
Elimination
Smaller due to renal disease
Kd
Due to renal disease, kd is smaller and, thus, we have a larger
t 1/2
The degree of impairment is determined by
Severity of renal disease and contribution of renal clearance to total body clearance
If a drug is eliminated entirely by renal mechanisms, then impairment of renal clearance will be evident in the form of a decline proportional to that observed in
Creatinine clearance
Recall from physiology that creatinine clearance is used as an endogenous measure of
Renal function
Specifically, the renal component of drug clearance declines linearly with a decline in
Creatinine Clearance
However, the hepatic (metabolic) component of drug clearance remains
Unchanged
If t½ is doubled due to renal impairment (i.e., t½-ri = 2t½), then the normal regimen would result in a CSS at
2X the normal level
In this situation, in order to avoid toxicity, you must either
- ) Reduce dose by one-half (o.5Do)
2. ) Double dosing interval (2t*)
