Desensitisation (to drug effect)
Desensitisation refers to a reduction in a patient’s magnitude of response to a given dose of a drug. Desensitisation may occur rapidly, on a seconds to minutes timescale, and can even occur following a single dose of a drug. Rapid desensitisation is sometimes referred to as tachyphylaxis. In contrast, desensitisation that takes hours, days or weeks to develop is often referred to as tolerance.
Mechanisms of tachyphylaxis include a modified change in receptor structure in response to agonist binding (for example, appearance of a desensitised state of a ligand-gated ion channel) or phosphorylation of a receptor resulting in a reduction in agonist efficacy. Receptor phosphorylation may be followed by a slower process of internalisation – removal of receptors from the cell surface. Drugs which enhance release of endogenous compounds may become less effective as cellular stores of the compound in question become depleted.
A non-pharmacological example of tachyphylaxis that illustrates the rate at which changes occur is that of light-dark adaptation of the eye. If photons are considered as the agonist at retinal photoreceptors, moving from a dark environment into a brightly-lit environment is analogous to increasing the agonist concentration. Within a relatively short time period, a series of tachyphylaxis-related events that include isomerisation and phosphorylation reactions result in hyperpolarisation (reduced reactivity) of photoreceptor cells. As a result, the sensitivity of the retina to light is greatly reduced, with this process nearing completion in only a few minutes. On returning to the dark environment, the opposite reactions allow the eye to adapt within two or three minutes to the reduced availability of agonist (photons), although full adaptation may take close to an hour to occur. That adaptation does not occur instantly explains why pirates wore eye patches. On boarding a hijacked vessel and moving below deck (where lighting was poor) to attack the ship’s crew, the pirates would be at a significant disadvantage (for several minutes) due to an inability to see in the dimly-lit environment. However, on removing the eye patch, they had one eye that was already fully-adapted to dark conditions, allowing them to fight more effectively.
Enhanced metabolism of drugs may lower the steady state concentration and, thus, the magnitude or duration of response to a given dose of a drug. This results in tolerance when a drug is able to induce its own metabolism, a problem commonly observed with barbiturates.
