Wherever we look, evolution has created many different receptors that function to mediate responses to any individual chemical signal. In some cases, the same chemical acts on completely different structural receptor classes. For example, acetylcholine uses ligand-gated ion channels (nicotinic AChRs) to initiate a fast (in milliseconds) excitatory postsynaptic potential (EPSP) in post-ganglionic neurons. Acetylcholine also activates a separate class of G protein-coupled receptors (muscarinic AChRs), which mediate slower (seconds to minutes) modulatory effects on the same neurons. In addition, each structural class usually includes multiple subtypes of receptor, often with significantly different signaling or regulatory properties. For example, many biogenic amines (eg, norepinephrine, acetylcholine, histamine, and serotonin) activate more than one receptor, each of which may activate a different G protein, as previously described (see also Table 2–1). The existence of many receptor classes and subtypes for the same endogenous ligand has created important opportunities for drug development. For example, propranolol, a selective antagonist of β adrenoceptors, can reduce an accelerated heart rate without preventing the sympathetic nervous system from causing vasoconstriction, an effect mediated by α1 adrenoceptors.
The principle of drug selectivity may even apply to structurally identical receptors expressed in different cells, eg, receptors for steroids (Figure 2–6). Different cell types express different accessory proteins, which interact with steroid receptors and change the functional effects of drug-receptor interaction. For example, tamoxifen is a drug that binds to steroid receptors naturally activated by estrogen. Tamoxifen acts as an antagonist on estrogen receptors expressed in mammary tissue but as an agonist on estrogen receptors in bone. Consequently, tamoxifen may be useful not only in the treatment of breast cancer but also in the prevention of osteoporosis by increasing bone density (see Chapters 40 and 42). Tamoxifen may create complications in postmenopausal women, however, by exerting an agonist action in the uterus, stimulating endometrial cell proliferation.
New drug development is not confined to agents that act on receptors for extracellular chemical signals. Increasingly, pharmaceutical chemists are determining whether elements of signaling pathways distal to the receptors may also serve as targets of selective and useful drugs. We have already discussed drugs that act on phosphodiesterase and some intracellular kinases. Several new kinase inhibitors and modulators are presently in therapeutic trials, and there are preclinical efforts under way directed at developing inhibitors of specific G proteins.
In this chapter, we have dealt with receptors as molecules and shown how receptors can quantitatively account for the relation between dose or concentration of a drug and pharmacologic responses, at least in an idealized system. When faced with a patient who needs treatment, the prescriber must make a choice among a variety of possible drugs and devise a dosage regimen that is likely to produce maximal benefit and minimal toxicity. To make rational therapeutic decisions, the prescriber must understand how drug-receptor interactions underlie the relations between dose and response in patients, the nature and causes of variation in pharmacologic responsiveness, and the clinical implications of selectivity of drug action.
A. Graded Dose-Response Relations
To choose among drugs and to determine appropriate doses of a drug, the prescriber must know the relative pharmacologic potency and maximal efficacy of the drugs in relation to the desired therapeutic effect. These two important terms, often confusing to students and clinicians, can be explained by referring to Figure 2–15, which depicts graded dose-response curves that relate the dose of four different drugs to the magnitude of a particular therapeutic effect.
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