Dose-response relationship.ppt

Chapter 6 Drug Toxicity
Adverse drug reactions
Paracelsus, a Swiss physician ( 1493-1541), proposed dose-toxicity relationship“all substances are poisons; there is none which is not a poison. The right dose differentiates a poison and remedy”
Dose-related and Non-dose related
ic makeup, age, underlying pathology, status of immune system.
DOSE
similar to drug‘s effectiviness , drug’s toxicity . lethality (mortality) also shows dose-response relationship, typical S-shape curve.
LD50 (the dosage of a substance that kills 50% of the animals over a set period of time following an acute exposure).
Therapeutic index (TI)= LD50/ED50
The lower TI, the smaller the margin of safety, . digoxin,
In addition to LD50, other aspect of drug’s toxicity can be measured.
TD50 (toxic dose producing the effect in 50% of the population).
LD1/ED99 is the margin of safety or the certain safety factor
probit analysis
comparison of drug toxicity
toxicity classification
cautions
based on lethality alone, false sense,
other toxicity ignored, . thalidomide could be classified as slightly toxic
extrapolation, animal species differences, uncertain for human
Evaluating the toxicity: time factor
Acute basis over a 14-d period,
subchronic /subacute, 90-d period (daily given), additional information gained, an, major toxic effects, slower onset,
chronic , life time of animal, post-mortem examination.
Story on an antiviral drug for hepatitis- a delayed toxic reaction occurred after administration was discontinued. 5/5 died suddenly, liver failure.
Important factors in these tests:
Selections of dosages, species, strain of animal, rout of exposure
Other types of toxicity tests
Specific tests:
reproductive studies, effect of a drug on the reproductive process
mutagenicity test: ic damage,
carcinogencity test: neoplastic change,
skin sensitization test: drug’s irritancy
The test should be carried out pliance for Good Laboratory Practice (GLP) for drug approval