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Tachyphylaxis (Greek ταχύς, tachys, "rapid", and φύλαξις, phylaxis, "protection") is a medical term describing an acute (sudden) decrease in the response to a drug after its administration.[1] It can occur after an initial dose or after a series of small doses. Increasing the dose of the drug may be able to restore the original response.[2] 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 to which the drug or neurotransmitter can bind. This depletion is caused by the cells reducing the number of receptors in response to their saturation. Some examples include ephedrine and MDMA which act indirectly through the release of neurotransmitters, or amphetamines which act both through direct and indirect release of neurotransmitters.


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.

Molecular interaction[edit]

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:

A \xrightarrow{\ \ p \ \ } 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[3][4][5] offer particular use of such (mathematical) models in endocrinology, physiology and pharmacology.


Hormone replacement[edit]

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[6] and no follow-up 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.[citation needed]

Centrally acting analgesics[edit]

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.

Beta-2 agonists[edit]

Inhalation of an agonist for the beta-2 adrenergic receptor, such as Salbutamol, is the most common treatment for asthma. Polymorphisms of the beta-2 receptor play a role in tachyphylaxis. Expression of the Gly-16 allele (glycine at position 16) results in greater receptor downregulation by endogenous catecholamines at baseline compared to Arg-16. This results in a greater single-use bronchodilator response in individuals homozygous for Arg-16 compared to Gly-16 homozygotes.[7] However, with regular beta-2 agonist use, asthmatic Arg-16 individuals experience a significant decline in bronchodilator response. This decline does not occur in Gly-16 individuals. It has been proposed that the tachyphylactic effect of regular exposure to exogenous beta-2 agonists is more apparent in Arg-16 individuals because their receptors have not been downregulated prior to agonist administration.[8]


Nicotine may also show tachyphylaxis over the course of a day, although the mechanism of this action is unclear.[9]

Other examples[edit]

  • Nitroglycerine and other nitrovasodilators of the nitrate type 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.
  • 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.
  • Caffeine has the potential to display tachyphylaxis if consumed in repeated high doses, such as the 30mg per 100ml of fluid common in many energy drinks.
  • Amphetamine
  • Ranitidine, used for acid reflux treatment, can display rapid tachyphylaxis within six weeks of treatment initiation, limiting its long-term use potential.

Intervention and reversal[edit]

Intranasal decongestants[edit]

Use of intranasal decongestants (such as oxymetazoline) for more than three days leads to tachyphylaxis of response and rebound congestion, caused by alpha-adrenoceptor mediated down-regulation and desensitization of response. Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal fluticasone.[10]

See also[edit]


  1. ^ Bunnel, Craig A. Intensive Review of Internal Medicine, Harvard Medical School 2009.[page needed]
  2. ^ Lehne, Richard A. (2013). "Tachyphylaxis". Pharmacology for Nursing Care. Philadelphia: Saunders. p. 81. ISBN 978-1-4377-3582-6. 
  3. ^ Ekblad EB, Licko V (January 1984). "A model eliciting transient responses". The American Journal of Physiology 246 (1 Pt 2): R114–21. PMID 6320668. 
  4. ^ Licko V, Raff H (February 1985). "Rate sensitivity of blood pressure to hypoxia". Journal of Theoretical Biology 112 (4): 839–45. doi:10.1016/S0022-5193(85)80065-5. PMID 3999765. 
  5. ^ Ličko V (1985). "Drugs, Receptors and Tolerance". Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs. pp. 311–322. ISBN 0-931890-20-9. 
  6. ^ "nal.usda.gov". 
  7. ^ Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R (December 1997). "Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing". The Journal of Clinical Investigation 100 (12): 3184–8. doi:10.1172/JCI119874. PMC 508532. PMID 9399966. 
  8. ^ Israel E, Drazen JM, Liggett SB, et al. (July 2000). "The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma". American Journal of Respiratory and Critical Care Medicine 162 (1): 75–80. doi:10.1164/ajrccm.162.1.9907092. PMID 10903223. 
  9. ^ Zuo Y, Lu H, Vaupel DB, et al. (November 2011). "Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system". Neuropsychopharmacology 36 (12): 2498–512. doi:10.1038/npp.2011.139. PMC 3194077. PMID 21796109. 
  10. ^ Vaidyanathan S, Williamson P, Clearie K, Khan F, Lipworth B (July 2010). "Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion". American Journal of Respiratory and Critical Care Medicine 182 (1): 19–24. doi:10.1164/rccm.200911-1701OC. PMID 20203244. 

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