General Principles Of Pharmacology/Responses in the patient

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The response of a patient to different doses of a drug conforms to the principles discussed for drug receptor interactions. In simple, tightly coupled systems, saturation of the receptor sites will result in the maximum possible effect; filling half of the receptor sites will produce half of the maximal effect. Frequently however, while the response is proportionally related to the drug binding, it may not be quantitatively related. First among the reasons for this are the concepts of full and partial agonism, and antagonism as mentioned earlier. With a drug that is a full agonist and a simple tightly coupled signal transduction system the response might be expected to be direct, 100% receptor occupancy resulting in 100% of the response or maximal efficacy. When full receptor occupancy results in less than the maximal effect, the drug is described as a partial agonist. The degree of this partial agonism can range all the way from an almost complete effect to barely any effect. When a drug occupies the receptors without a resultant effect, it is referred to as an antagonist. Thus an antagonist has no efficacy when studied in isolation, i.e., its occupancy of a receptor induces no response. However, it may have high therapeutic efficacy when used to antagonize the effects of a hormone, neurotransmitter, physiological ligand, or other drug.

Another explanation for the lack of a direct relationship between drug binding and a response is the presence of spare receptors. The concept of spare receptors arose from observations that, in some cases, occupancy of only a fraction of the receptors was necessary to produce a maximal response. Thus, not all the receptors were needed to maximize the response and the remainders were spare. They may not be spare for other responses induced by activation of the same receptors but which are not being detected or measured. Such a situation would occur when cascades of signals are generated by receptor activation with branch points and differential amplification steps. Depending upon the effect being measured, occupancy of all the receptors of one particular type could result in either a maximal effect or a less than maximal effect. In this case, the less than maximal effect might be fully responsive to another receptor type and affected by more than one signal pathway. Thus, any effect, which is proportionally larger than the degree of receptor occupancy, may be the result of spare receptors. This may in turn be due to bifurcating signals and multiple responses from the same set of receptors.

The response to a drug is defined in terms of several features. One such is potency, which is a function of its affinity for the receptor and factors such as absorption, excretion and degradation rates. Obviously, the higher the potency the smaller the dose required to produce an effect. However, within reasonable limits the potency of the drug is unimportant and only affects the amount of the drug that has to be administered. Two drugs may produce the same maximal effect at different dosages, thus displaying the same efficacy but different potency. More important than potency is the selectivity of the drug to produce a desired effect without side effects or toxicity. Also important is the slope of the curve, which indicates the range of dosage over which the drug acts from minimally detectable to maximally effective. The variability in the response can be related to physiological, pathological or drug-induced variation in the patient, or variation in a population of patients as discussed later. Thus variability in effectiveness of a drug given to the same patient at different times can be due to circadian changes, age, the state of the patient's health (disease can have a marked effect upon drug efficacy), or may be drug-induced as for instance by receptor down-regulation. Variability from these causes will be obvious within the individual members of a population of patients, in addition to the population variation. The latter is due to a variety of genetic and environmental causes.

Fig. 2.4 Dose Response relationships

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