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Receptor‐mediated responses to drugs often desensitize with time. This reduced response to an agonist, which is usually reversible upon cessation of treatment, is called desensitization. A second exposure to the agonist after a lapse usually restores response. Agonists that desensitize receptors due to conditioning mechanisms can trigger tolerance and addiction. Some examples of addictive medicines are tranquilizers and sedatives (sleeping pills). Many of these belong to a group of similar substances called benzodiazepines, which allosterically potentiate GABA type A receptor (Sieghart, 1994). Desensitization is often used to suggest a reduced response by any mechanism – receptor phosphorylation, uncoupling, antagonistic metabolites, or negative physiological feedback that occurs over a relatively short period of time, while tolerance is reserved for reduced responsiveness developing over longer periods, usually because of receptor downregulation. Tachyphylaxis is a rapidly developing desensitization after just one or two administrations of the drug.

Figure 1.14. Target classes. (a) G‐protein‐coupled receptor (GPCR) (b) tyrosine kinase (c) nuclear receptor and (d) ion channel.

Most receptors can undergo agonist‐induced regulation. When an agonist occupies a receptor, it can result in a series of events that can lead to internalization of the receptor. The signals for internalization include phosphorylation of the receptor, which sets the stage for adapter molecules to bind to the receptor. The agonist is then removed, and the receptor is targeted for cycling back to the cell membrane or is trafficked into a degradation pathway. Cycling of the receptor is associated with resensitization of the receptor, while degradation results in a loss of total receptor density. When receptor density is decreased, it is usually associated with a shift to the right in the dose‐effect curve for agonists. An example of desensitization is the high affinity, desensitized, closed state of the nicotinic acetylcholine receptors (nAChRs), induced by chronic exposure to acetylcholine (ACh) or nicotinic drugs, leading to a gradual decrease in the rate of opening of K⁺, Na⁺, and sometimes Ca²⁺ cationic channels (milliseconds to minutes).

Sensitization has the opposite effect of tolerance, where an increase in drug effect is observed after repeated administration of certain drugs. When the body tries to return to homeostasis following a sudden discontinuation of a drug, the receptors which are deprived of their AGONISTs/blockers become hypersensitive to an agent that targets it, causing a further exacerbation of the symptoms/conditions that triggered the use of the drug in the first place. This rebound effect can be minimized by a gradual rather than a sudden discontinuation of the drug. Several anxiolytics and hypnotics have a rebound effect. For example, benzodiazepine withdrawal can cause severe anxiety and insomnia, worse than the original insomnia or anxiety disorder. Other examples causing rebound effects include sedatives like lunesta and ambien, the short acting hypnotic, triazolam (due to its high potency and ultra‐short half‐life), stimulants such as methylphenidate or dextroamphetamine antidepressants such as SSRIs, and alpha‐2 adrenergic agents such as clonidine and guanfacine. Rebound on drug withdrawal can be a factor in the chronic use of medications and drug dependence, with patients taking the medications only to ward off withdrawal or rebound withdrawal effects.

Time‐dependent changes in drug action arising from desensitization, sensitization, and rebound cause a loss of consistency in the concentration–effect relationship with increasing number of doses, leading to the serious consequences of reduced efficacy or increased toxicity with time which can be disastrous for drugs with narrow therapeutic window.