Dose-response relationship.pptVIP

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 genetic makeup, age, underlying pathology, status of immune system. DOSE similar to drug‘s effectiviness , drug’s toxicity e.g. 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). 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 comparison of drug toxicity cautions based on lethality alone, false sense, other toxicity ignored, e.g. 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, target organ, 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. Other types of toxicity tests Specific tests: reproductive studies, effect of a drug on the reproductive process mutagenicity test: genetic damage, carcinogencity test: neoplastic change, skin sensitization test: drug’s irritancy The test should be carried out in compliance for Good Laboratory Practice (GLP) for drug approval GENETICS Other than dose, factor that influence the body response to drugs: idiosyncratic (occurring for no known reason) affects pharmacodynamic and pharmacokinetic, e.g. normal difference within a species, between genders and str