DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Therapeutic
Index:
LD 50 400
= = 4
ED 50 100
49
Percentage of Individuals Responding
100
80
60
40
20
0
A
Cumulative
frequency
distribution
ED 50
5 7 10
Concentration (mg/L)
Frequency
distribution
efficacy is high and the probability of adverse effects is low (Figure
3–6). It does not guarantee either efficacy or safety. Therefore, use
of the population therapeutic window to adjust dosage of a drug
should be complemented by monitoring appropriate clinical and surrogate
markers for drug effect(s).
Percentage of Individuals Responding
100
80
60
40
20
B
Hypnosis
ED 50 ED 99
LD 1 LD 50
0
20 50 100 200 400 800
Dose (μg/kg)
Figure 3–5. Frequency distribution curves and quantal concentration-effect and dose-effect curves. A. Frequency distribution curves.
An experiment was performed on 100 subjects, and the effective plasma concentration that produced a quantal response was determined
for each individual. The number of subjects who required each dose is plotted, giving a log-normal frequency distribution
(purple bars). The red bars demonstrate that the normal frequency distribution, when summated, yields the cumulative frequency distribution—a
sigmoidal curve that is a quantal concentration-effect curve. B. Quantal dose-effect curves. Animals were injected with
varying doses of a drug and the responses were determined and plotted. The calculation of the therapeutic index, the ratio of the LD 50
to the ED 50
, is an indication of how selective a drug is in producing its desired effects relative to its toxicity. See text for additional
explanation.
Percentage of Patients Responding
100
50
Therapeutic
response
Therapeutic
window
Adverse
effects
1 2 3 4 6
Concentration of drug in plasma (ng/ml)
Figure 3–6. The relation of the therapeutic window of drug concentrations
to the therapeutic and adverse effects in the population.
The ordinate is linear; the abcissa is logarithmic.
Death
Factors Modifying Drug Action. Many factors can influence
the therapeutic efficacy and safety of a drug in an
individual patient. These same factors give rise to interindividual
variability in the dose required to obtain optimal
therapeutic effect with minimal adverse effects.
Some of the factors that contribute to the wide patientto-patient
variability in the dose required for optimal
therapy observed with many drugs are shown in
Figure 3–7. Therapeutic success and safety result from
integrating evidence of efficacy and safety with knowledge
of the individual factors that determine response in
a given patient. Determinants of inter-individual variation
in response to drugs that are due to pharmacokinetics
include disease-related alterations such as
impaired renal and liver clearance due to renal and
hepatic disease, circulatory failure, altered drug binding
to plasma proteins, impaired GI absorption, and pharmacokinetic
drug interactions. The effects of these factors
on variability of drug pharmacokinetics are
described more thoroughly in Chapters 2 and 5-7.
Pharmacogenetics. Pharmacogenetics refers to the genetic and
genomic variations that give rise to variability in both pharmacokinetic
and pharmacodynamic aspects of drug therapy. These factors
CHAPTER 3
PHARMACODYNAMICS: MOLECULAR MECHANISMS OF DRUG ACTION