View source for Tachyphylaxis

{{Short description|Rapid and short-term onset of drug tolerance}}
'''Tachyphylaxis''' ([[Greek language|Greek]] ταχύς, ''tachys'', "rapid", and φύλαξις, ''phylaxis'', "protection") is a medical term describing an [[Acute (medicine)|acute]], sudden decrease in response to a drug after its administration (i.e., a rapid and short-term onset of [[drug tolerance]]).<ref>Bunnel, Craig A. Intensive Review of Internal Medicine, Harvard Medical School 2009.{{page needed|date=October 2014}}</ref> 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.<ref>{{cite book |last1=Lehne |first1=Richard A. |year=2013 |chapter=Tachyphylaxis |chapter-url=https://books.google.com/books?id=_4SwO2dHcAIC&pg=PA81 |page=81 |title=Pharmacology for Nursing Care |publisher=Saunders |location=Philadelphia |isbn=978-1-4377-3582-6}}</ref>
==Characteristics==
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===
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:

<math>
A \xrightarrow{\ \ p \ \ } B
</math>

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).

More complete is an open system, namely, in its simplest form,

<math>
R \xrightarrow{   } A \xrightarrow{\ \ p(S) \ \ } B \xrightarrow{\ \ q \ \ },
</math>

where '''R''' stands for the ''rate of production'' of '''A''', '''p(S)''' is the ''activation'' rate coefficient explicitly expressing its dependence on the stimulus intensity '''S''' and '''q''' represents the rate coefficient of ''removal'' from the state '''B'''. In this elementally open system the steady state of '''B''' always equal to '''R/q'''.

<!-- Three examples of the system responses to common stimulation patterns are shown in the following graphics, results of numerically solving the associated differential equations.
In Fig. 1 are shown responses to four stimulations at various levels. but for the same duration. The responses to 'constant' levels of stimulation are characterized by 'spikey' responses with the return to the basal (steady state). However, negative responses appear by the end of stimulations with the return to the basal level.

Often repeated short simulation results in diminished response, as shown in Fig.2 by the two consecutive stimulations. But if enough time is allowed to elapse between the two stimulations, (compare the first and the second stimulation at the end of the graph), the response nearly returns to the height of the first stimulation.

Various ramp stimulations (Fig.3) show the typical feature of tachyphylaxis, namely, the faster the ramp, the higher is the temporary response. With a slow enough ramp (to the same level of final stimulation), the response may disappear altogether.

When sufficiently complete data on the stimulus and response patterns are available, ''least squares methods'' may allow to specify the type of molecular interactions, similar to the discussed elemental model.-->
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<ref>{{cite journal |vauthors=Ekblad EB, Ličko V |title=A model eliciting transient responses |journal=The American Journal of Physiology |volume=246 |issue=1 Pt 2 |pages=R114–21 |date=January 1984  |doi=10.1152/ajpregu.1984.246.1.R114 |pmid=6320668 |url=http://ajpregu.physiology.org/cgi/pmidlookup?view=reprint&pmid=6320668|url-access=subscription }}</ref><ref>{{cite journal |vauthors=Ličko V, Raff H |title=Rate sensitivity of blood pressure to hypoxia |journal=Journal of Theoretical Biology |volume=112 | issue=4 | pages=839–845 |date=February 1985 | pmid=3999765 |doi=10.1016/S0022-5193(85)80065-5|bibcode=1985JThBi.112..839L }}</ref><ref>{{cite book |author=Ličko V |year=1985 |chapter=Drugs, Receptors and Tolerance |title=Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs |pages=311–322 |isbn=0-931890-20-9}}</ref> offer particular use of such (mathematical) models in endocrinology, physiology and pharmacology.

==Examples==

===Psychedelics===
[[Psychedelic drug|Psychedelics]] such as [[LSD]],<ref>{{cite book | vauthors = Buchborn T, Grecksch G, Dieterich D, Hollt V | title = Neuropathology of Drug Addictions and Substance Misuse | doi = 10.1016/B978-0-12-800212-4.00079-0 | chapter = Chapter 79 - Tolerance to Lysergic Acid Diethylamide: Overview, Correlates, and Clinical Implications | isbn = 978-0-12-800212-4 | publisher = [[Academic Press]] | pages = 848 - 849 | volume = 2 | url = https://www.sciencedirect.com/science/article/abs/pii/B9780128002124000790 | year = 2016}}</ref> and [[psilocybin]]-containing [[Psilocybin mushrooms|mushrooms]] demonstrate very rapid tachyphylaxis.

===Opioids===
In a patient fully withdrawn from [[Opioid|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 therapy is resumed and, in general, leveling off after day 7. Whether this is caused directly by [[Opioid receptor|opioid receptors]] modified in the past or affecting 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===
Inhalation of an agonist for the [[beta-2 adrenergic receptor]], such as [[salbutamol]] (albuterol — [[United States Adopted Name|USAN]]), 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.<ref>{{cite journal |vauthors=Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R |title=Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing |journal=The Journal of Clinical Investigation |volume=100 |issue=12 |pages=3184–8 |date=December 1997  |pmid=9399966 |pmc=508532 |doi=10.1172/JCI119874}}</ref> 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.<ref>{{cite journal  |vauthors=Israel E, Drazen JM, Liggett SB, etal |title=The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma |journal=American Journal of Respiratory and Critical Care Medicine |volume=162 |issue=1 |pages=75–80 |date=July 2000  |pmid=10903223 |doi=10.1164/ajrccm.162.1.9907092|s2cid=9399149 |url=https://escholarship.org/content/qt0ph8b9jj/qt0ph8b9jj.pdf?t=or2o07 }}</ref>

===Nicotine===
[[Nicotine]] may also show tachyphylaxis over the course of a day, although the mechanism of this action is unclear.<ref name="pmid21796109">{{cite journal  |vauthors=Zuo Y, Lu H, Vaupel DB, etal |title=Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system |journal=Neuropsychopharmacology |volume=36 |issue=12 |pages=2498–512 |date=November 2011  |pmid=21796109 |pmc=3194077 |doi=10.1038/npp.2011.139}}</ref>

=== Methylphenidate ===
Acute tachyphylaxis which does not carry into the next day has been observed in children taking [[methylphenidate]], and inspired the development of [[Osmotic-controlled release oral delivery system|OROS]] methylphenidate.<ref>{{Cite journal |last=Swanson |first=James |last2=Gupta |first2=Suneel |last3=Lam |first3=Andrew |last4=Shoulson |first4=Ira |last5=Lerner |first5=Marc |last6=Modi |first6=Nishit |last7=Lindemulder |first7=Elizabeth |last8=Wigal |first8=Sharon |date=February 2003 |title=Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies |url=https://pubmed.ncbi.nlm.nih.gov/12578439/ |journal=Archives of General Psychiatry |volume=60 |issue=2 |pages=204–211 |doi=10.1001/archpsyc.60.2.204 |issn=0003-990X |pmid=12578439}}</ref>

===Other examples===
*[[Nitroglycerine (pharmacology)|Nitroglycerine]] (or glyceryl trinitrate) and other [[nitrovasodilator]]s of the nitrate type demonstrates tachyphylaxis, requiring drug-free intervals of 6 to 8 hours.<ref>{{Cite book|last1=Mutschler|first1=Ernst|last2=Schäfer-Korting|first2=Monika|title=Arzneimittelwirkungen|language=de|location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|pages=554–558|isbn=978-3-8047-1763-3}}</ref>
*[[Hydralazine]] displays tachyphylaxis if given as a monotherapy for antihypertensive treatment. It is administered with a beta-blocker with or without a diuretic.{{medcn|date=October 2015}}
*[[Metoclopramide]]{{medcn|date=October 2015}}
*[[Dobutamine]], a direct-acting [[beta agonist]] used in [[congestive heart failure]], also demonstrates tachyphylaxis.{{medcn|date=October 2015}}
*[[Desmopressin]] used in the treatment of [[von Willebrand disease|type 1 von Willebrand disease]] is, in general, given every 12–24 hours in limited numbers due to its tachyphylactic properties.<ref>{{Cite book|url=https://books.google.com/books?id=UMeNCgAAQBAJ&q=However%2C+tachyphylaxis+to+DDAVP+occurs+because+endothelial+cells+require+time+to+synthesize+new+vWF+after+repeated+DDAVP+administration.&pg=PA558|title=Andreoli and Carpenter's Cecil Essentials of Medicine|last=Benjamin|first=Ivor|date=2016-01-01|publisher=Elsevier Health Sciences|isbn=9781437718997|pages=558|language=en}}</ref>
*[[Erythromycin]], used for [[gastroparesis]] treatment<ref name="UpToDate n441">{{cite web | title=UpToDate | website=UpToDate | url=https://www.uptodate.com/contents/treatment-of-gastroparesis | access-date=7 Aug 2023}}</ref>
*[[Hormone replacement therapy (menopause)|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<ref name="url">
{{cite web |url=https://ods.od.nih.gov/Research/PubMed_Dietary_Supplement_Subset.aspx?mode2=detail&origin=ibids_references&therow=240075 |title=nal.usda.gov |url-status=live |archive-url=https://web.archive.org/web/20080807031224/http://grande.nal.usda.gov/ibids/index.php?mode2=detail |archive-date=2008-08-07 }}</ref> and no follow-up research is available to support this interpretation.

==Intervention and reversal==

===Intranasal decongestants===
Use of nasal decongestants (e.g., [[oxymetazoline]]) for more than three days leads to tachyphylaxis of response and rebound [[Nasal congestion|congestion]], caused by [[alpha-adrenergic receptor]] downregulation and desensitization. The mechanism may specifically include receptor internalisation and resistance to endogenous vasoconstrictors causing worsening in symptoms post use of medication.  Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal [[fluticasone]].<ref name="pmid20203244">{{cite journal |vauthors=Vaidyanathan S, Williamson P, Clearie K, Khan F, Lipworth B |title=Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion |journal=American Journal of Respiratory and Critical Care Medicine |volume=182 |issue=1 |pages=19–24 |date=July 2010  |pmid=20203244 |doi=10.1164/rccm.200911-1701OC}}</ref>

==See also==
{{cmn|colwidth=30em|
*[[Desensitization (medicine)]]
*[[Habituation]]
*[[Mithridatism]]
*[[Physical dependence]]
*[[Physiological tolerance]]
*[[Downregulation and upregulation]]
}}

==References==
{{reflist}}

==External links==
* [https://biomathematicsblog.wordpress.com/2015/10/28/biomathematics-of-rate-sensitivity-tachyphylaxis-and-tolerance/ Tachyphylaxis and Tolerance: Biomathematics of Rate Sensitivity]
* {{MeshName|Tachyphylaxis}}


{{Pharmacology}}

[[Category:Pharmacodynamics]]