Module 5 Flashcards
What are possible reasons why there may be a very poor correlation between blood levels of a drug and a patient’s response?
○ The drug is a prodrug and the parent drug is not active, e.g. codeine, tamoxifen, clopidogrel.
○ There is an active metabolite, and both the parent drug and metabolite are active, e.g. fluoxetine.
○ There is not a good equilibrium between the concentration of drug in the blood and at the active site, e.g. digoxin.
○ The drug is highly protein bound, and there is a change in protein binding, e.g. phenytoin.
○ The drug initiates a change in gene expression or some other molecule that persists after the drug is gone, e.g. prednisone, warfarin.
○ The drug irreversibly binds to its target, and the effect persists until the target protein is resynthesized, e.g. proton pump inhibitors.
○ The patient may have a deficiency in the receptor for the drug (either genetic or because it is part of an acquired tolerance) or may be on another drug that inhibits the action of the drug, e.g. salbutamol.
what is the dose-response relationship for idiosyncratic drug reactions?
○ These adverse reactions are often referred to as dose independent; that is not true!
○ What is true is most patients will not have an idiosyncratic reaction to a drug at any dose.
○ In addition, in general the mechanism of an idiosyncratic drug reaction is different from that of the therapeutic effect; therefore, there is no reason that the dose response relationship should be in the same concentration range as that for the therapeutic effect, and the dose response curve for the idiosyncratic reaction is often (but not always) shifted to the left relative to that of the therapeutic effect.
Therefore, there may be no obvious relationship to dose within the narrow range of doses used clinically.
In short everything is dose dependent, but for idiosyncratic drug reactions it may not be apparent within the narrow range of doses used clinically
Is there any way to rationalize the principles of homeopathy with the observed characteristics of dose-response relationships?
no
What level of evidence should be required to demonstrate the efficacy of homeopathy?
To quote Carl Sagan: “Extraordinary claims require extraordinary evidence.” There is no good evidence for the efficacy of homeopathy, and certainly no extraordinary evidence
A dose response curve can have many shapes, but what is the one characteristic of all dose response relationships?
As the concentration approaches 0, the effect approaches 0
How are limits for various types of environmental toxins and carcinogens set, and what sort of dose-response relationship is usually assumed when setting such limits? Are the assumptions that are usually made and the methods used to set such limits likely to be accurate? Are there good alternatives?
○ It is impossible to perform controlled experiments with carcinogens and other toxins in humans. Therefore, the only way to have some idea of what the effects in humans may be is with epidemiological studies and animal models. Most limits are based on animal studies (correlation does not equal causation).
○ Animal studies are usually performed with high concentrations for short periods of time and then extrapolated to low concentrations in humans over a longer period of time with a safety factor of 10 or more.
○ But such extrapolations are not very good approximations of human risk.
○ The toxic effects are usually assumed to have a linear dose/response relationship; however, for agents such as carcinogens there usually appears to be a threshold and a nonlinear dose/response relationship. Unfortunately there is no good way to accurately determine risk, and this often leads to a large amount of controversy.
What is hormesis?
○ Hormesis is the hypothesis that most agents that are toxic at high concentrations are actually beneficial at low concentrations.
○ The evidence for this hypothesis is controversial. It is certainly true that low concentrations of toxic substances can usually induce tolerance to higher concentrations of the same or related agents.
○ However, it is less clear that low concentrations of toxic agents generally have beneficial effects other than the induction of tolerance to the same or other toxic agents.
