Tachyphylaxis

Tachyphylaxis is a medical term describing a decrease in the response to a drug due to previous exposure to that drug. Increasing the dose of the drug may be able to restore the original response. In this context tachyphylaxis is a synonym for drug tolerance. This can sometimes be caused by depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug's effect, or by the depletion of receptors available for the drug or neurotransmitter to bind to. This depletion is caused by the cell's reducing the number of receptors in response to their saturation. Examples: Amphetamine, ephedrine, MDMA (indirectly acting drugs)

Tachyphylaxis is characterized by the rate sensitivity: The response of the system depends on the rate with which a stimulus is presented. To be specific, a high-intensity prolonged stimulus or often-repeated stimulus may bring about a diminished response also known as desensitization.

In biological sciences, molecular interactions are the physical bases of the operation of the system. The control of the operation, in general, involves interaction of a stimulus molecule with a receptor/enzyme subsystem by, typically, binding to the macromolecule A and causing an activation or an inhibition of the subsystem by forming an activated form of the macromolecule B. The following schematic represents the activity: p  A > B

Where p is the activation rate coefficient. It is customary that p is called a rate constant, but, since the p stands for measure of the intensity of the stimulus causing the activation, p may be variable (non-constant).

The above scheme is only the necessary condition for the rate sensitivity phenomenon, and other pathways of deactivation of B may be considered, with the subsequent return to the inactive form of the receptor/enzyme A. Examples  offer particular use of such (mathematical) models in endocrinology, physiology and pharmacology.

Examples
Examples of tachyphylaxes are the following:


 * Calcitonin demonstrates tachyphylaxis in 2–3 days when being used to treat hypercalcemia of malignancy. This reaction is anticipated and calcitonin is given along with biphosphonates, which have their maximum effect in 2–3 days. (5)


 * Nitroglycerine demonstrates tachyphylaxis, requiring drug-free intervals when administered transdermally
 * Repeated doses of ephedrine may display tachyphylaxis, since it is an indirectly acting sympathomimetic amine, which will deplete noradrenaline from the nerve terminal. Thus, repeated doses result in less noradrenaline released than the initial dose.
 * Nicotine may also show tachyphylaxis over the course of a day, although the mechanism of this action is unclear.
 * Hydralazine displays tachyphylaxis if given as a monotherapy for antihypertensive treatment. It is administered with a beta-blocker with or without a diuretic.
 * Metoclopramide is another example.
 * Dobutamine, a direct-acting beta agonist used in congestive heart failure, also demonstrates tachyphylaxis.
 * Desmopressin used in the treatment of type 1 von Willebrand disease is, in general, given every 12–24 hours in limited numbers due to its tachyphylactic properties.
 * Hormone replacement when used in menopausal women in the form of estrogen and progesterone implants is cited as having potential to lead to tachyphylaxis, but that citation is based on a single study done in 1990 and no followup research is available to support this interpretation.
 * Psychedelics such as LSD-25 and psilocybin-containing mushrooms demonstrate very rapid tachyphylaxis. In other words, one may be unable to 'trip' two days in a row. Some people are able to 'trip' by taking up to three times the dosage, yet some users may not be able to negate tachyphylaxis at all until a period of days has gone by.
 * In a patient fully withdrawn from centrally-acting analgesics, viz. opioids, going back to an intermittent schedule or maintenance dosing protocol, a fraction of the old tolerance level will rapidly develop, usually starting two days after opioid therapy is resumed and, in general, leveling off after day 7. Whether this is caused directly by opioid receptors modified in the past or effecting a change in some metabolic set-point is unclear.  Increasing the dose will usually restore efficacy; relatively rapid opioid rotation may also be of use if the increase in tolerance continues.