Download Therapeutic index

Therapeutic index: therapeutic index of a drug is the ratio of the dose
that produces toxicity to the dose that produces a clinically desired or
effective response in a population of individuals.
in humans
in animals
Where: TD50 is the dose of drug that causes a toxic response in 50% of the
population and ED50 is the dose of drug that is therapeutically effective in 50% of the
population. LD lethal dose he value of LD50 for a substance is the dose required to kill
half the members of a tested population after a specified test duration
How therapeutic index is determined
Therapeutic index and quantal dose response curves
Both ED50 and TD50 are calculated from quantal dose response
curves, which represent the frequency with which each dose of drug
elicits the desired response or toxic effect in the population.
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There are some important characteristics of quantal dose-response curves
(see image above) that are worth noting:
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Dose of drug in plasma is plotted in the horizontal axis while the
percentage of individuals (animals or humans) that responds or
shows a toxic effect is represented in the vertical axis.
These curves measure all or none (positive or negative) responses.
Some examples of positive responses include: relief of headache
for an antimigraine drug, increase in heart rate of at least 20 bpm
for a cardiac stimulant, or 10 mmHg fall in diastolic blood pressure
for an antihypertensive.
Data is obtained from a population. Unlike graded dose-response
graphs, data for quantal dose-response curves is obtained
from many individuals.
ED50
The graph below shows how ED50 is calculated.
ED50
The dose required to cause a therapeutic effect (positive response) in 50%
of a population is the ED50.
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TD50
TD50
The dose required to produce a toxic effect in 50% of the studied
population is the TD50. For animal studies, LD50 is the dose that results
in death of 50% of the population.
Narrow therapeutic index drugs
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The list below mentions some examples of narrow therapeutic index
drugs:
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Warfarin
Lithium
Digoxin
Phenytoin
Gentamycin
A high Therapeutic Index (TI) is preferable for a drug to have a
favorable safety profile. At early discovery / development stage
TI is an important indicator of the probability of the successful
development of a drug.
TI is the quantitative relationship between efficacy (pharmacology) and
safety (toxicology), without considering the nature of pharmacological or
toxicological endpoints themselves. However, to convert a calculated TI
to something that is more than just a number, the nature and limitations of
.pharmacological and/or toxicological endpoints must be considered.
In general, it is the exposure of a given tissue to drug (i.e. drug
concentration over time), rather than dose, that drives the
pharmacological and toxicological effects. For example, at the same dose
there may be marked inter-individual variability in exposure due to
polymorphisms in metabolism.
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The therapeutic index varies widely among substances:
Drug
(Remifentanyl)
opioid analgesics
TI( THEARPUTIC INDEX )
33,000:1
More
safe
(Tetrahydrocannabinol) 1000:1
a sedative and analgesic of
herbal origin (cannabis)
(Diazepam)
100:1
a benzodiazepine sedativehypnotic and skeletal
muscle relaxant has
(morphine)
a sedative, antidepressant,
and analgesic also of herbal
70:1
origin (genus Papaver)
(Cocaine)
a stimulant and local
anaesthetic
Safety
15:1
10:1
Ethanol
"alcohol" in alcoholic
beverages), a widely
available sedative
Digoxin
Less
safe
2:1
(a cardiac glycoside
Other examples of drugs with a narrow therapeutic range, which may
require drug monitoring both to achieve therapeutic levels and to
minimize toxicity, include: paracetamol (acetaminophen), dimercaprol,
theophylline, warfarin and lithium carbonate.
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Some antibiotics require monitoring to balance efficacy with minimizing
adverse effects, including: gentamicin, vancomycin, amphotericin B
(nicknamed 'amphoterrible' for this very reason), and polymyxin B
The effective therapeutic index can be affected by targeting, in which the
therapeutic agent is concentrated in its area of effect. For example, in
radiation therapy for cancerous tumors, shaping the radiation beam
precisely to the profile of a tumor in the "beam's eye view" can increase
the delivered dose without increasing toxic effects, though such shaping
might not change the therapeutic index.
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