The time course of drug effect

Designing a rational dosage regimen

Dose individualization
The goal of therapeutics is to achieve a desired beneficial
effect with minimal adverse effects.
A rational approach to this objective combines the principles
of pharmacokinetics with pharmacodynamics to understand
the dose-effect relationship.
Drug accumulation

Whenever drug doses are repeated, the drug will accumulate in the body. (in
theory it takes an infinite time to eliminate)
In practical terms, this means that if the dosing interval is shorter than 4
half-lives, accumulation will be detectable.
Inversely proportional to the fraction of the dose lost in each dosing interval.
For a drug given once every half-life, the accumulation factor is 1/0.5, or 2. The
accumulation factor predicts the ratio of the steady-state concentration to
that seen at the same time following the first dose
Dosage Regimens

A dosage regimen is a plan for drug administration over a period of time.

Optimal version means that the drug achieves desired therapeutic effect
without exceeding the minimum toxic concentration.
Schedule of maintenance doses is used in order to repeatedly administer
drug and counter the clearance, however initially given large (Loading)
dose may also be required to reach therapeutic window faster.
Maintenance Dosage
Steady state – maintenance rate of drug administration is equal to the
rate of elimination.
Clearance unit – mL/min
The number of doses to be given per day is usually determined by the
half-life of the drug and the therapeutic window (potency warning)

Volume of distribution is not needed to calculate maintenance dose

In order to maintain a concentration above the minimum therapeutic

level, either a larger dose is given at long intervals or smaller at shorter
Loading Dosage

If the therapeutic concentration must be achieved rapidly

If the Vd is large

Clearance is not needed to calculate loading dose

If the loading dose is large (Vd much larger than blood volume), the dose
should be given slowly to prevent toxicity due to excessively high plasma levels
during the distribution phase
Adjustment of the dose due to impaired elimination

Renal disease or cardiac insufficiency often reduces the clearance of drugs

that depend on renal elimination.
Liver disease can reduce metabolism, or increase elimination by lowered
blood protein synthesis.
The most important renal variable in drug elimination is glomerular filtration
rate (GFR). creatinine clearance (CLcr) is a convenient approximation of GFR
(100 mL/min, or 6 L/h)

If the drug is partially excreted by the kidney this equation will only apply to
the part that’s excreted renaly.
CLcr can be measured directly, but requires measurement of serum and urine
creatinine over 12 – 24h.
First pass effect

Liver first-pass effect can be avoided

by use of sublingual tablets and by use
of suppositories.
Suppositories tend to move upward in
the rectum thus, only about 50% of a
rectal dose can be assumed to bypass
the liver
The time course of drug effect

Immediate Effects: directly related to plasma

concentrations, however does not parallel it.
Delayed Effects: delayed in relation to plasma
concentration. (distribution)
A common cause of a delayed effect is a slow
turnover of a substance that is involved in the
expression of the drug effect. Example: Warfarin.
Cumulative Effects: Some drugs have more
effects after multiple administrations (not rapidly
reversible).
Individualization

1. Choose the target concentration, TC.

2. Predict volume of distribution (V) and clearance (CL)
(weight and renal function adjustment)
3. Give a loading dose or maintenance dose
4. Measure the response
5. Readjust (V) and clearance (CL) based on new data
6. Repeat steps 3 – 5
Katzung & Trevor’s Pharmacology Examination and
Board Review 2019 12th ed.
Pages 29 – 31
Basic and Clinical Pharmacology G. Katzung 2020
15th ed
Pages 13 – 21