Editing Amitriptyline (section)

== Interactions ==

Since amitriptyline and its active metabolite nortriptyline are primarily metabolized by cytochromes [[CYP2D6]] and [[CYP2C19]] (see [[Amitriptyline#Pharmacology | its pharmacology]]), the inhibitors of these enzymes are expected to exhibit pharmacokinetic interactions with amitriptyline. According to the prescribing information, the interaction with [[CYP2D6]] inhibitors may increase the plasma level of amitriptyline.<ref name = EMC/> However, the results in the other literature are inconsistent:<ref name="pmid15554244">{{cite journal | vauthors = Breyer-Pfaff U | title = The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man | journal = Drug Metabolism Reviews | volume = 36 | issue = 3–4 | pages = 723–746 | date = October 2004 | pmid = 15554244 | doi = 10.1081/dmr-200033482 | s2cid = 25565048 }}</ref> the co-administration of amitriptyline with a potent CYP2D6 inhibitor [[paroxetine]] does increase the plasma levels of amitriptyline two-fold and of the main active metabolite nortriptyline 1.5-fold,<ref name="pmid10672631">{{cite journal | vauthors = Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R | title = Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients | journal = Psychopharmacology | volume = 147 | issue = 4 | pages = 378–383 | date = January 2000 | pmid = 10672631 | doi = 10.1007/s002130050006 | s2cid = 22476829 }}</ref> but combination with less potent CYP2D6 inhibitors [[thioridazine]] or [[levomepromazine]] does not affect the levels of amitriptyline and increases nortriptyline by about 1.5-fold;<ref name="pmid7909176">{{cite journal | vauthors = Jerling M, Bertilsson L, Sjöqvist F | title = The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline | journal = Therapeutic Drug Monitoring | volume = 16 | issue = 1 | pages = 1–12 | date = February 1994 | pmid = 7909176 | doi = 10.1097/00007691-199402000-00001 | s2cid = 1428027 }}</ref> A case of clinically significant interaction with potent CYP2D6 inhibitor [[terbinafine]] has been reported.<ref name="pmid16175144">{{cite journal | vauthors = Castberg I, Helle J, Aamo TO | title = Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline | journal = Therapeutic Drug Monitoring | volume = 27 | issue = 5 | pages = 680–682 | date = October 2005 | pmid = 16175144 | doi = 10.1097/01.ftd.0000175910.68539.33 }}</ref>

A potent inhibitor of [[CYP2C19]] and other cytochromes [[fluvoxamine]] increases the level of amitriptyline two-fold while slightly decreasing the level of nortriptyline.<ref name="pmid8685072">{{cite journal | vauthors = Vandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T, Sechter D, Bizouard P | title = Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients | journal = Pharmacological Research | volume = 31 | issue = 6 | pages = 347–353 | date = June 1995 | pmid = 8685072 | doi = 10.1016/1043-6618(95)80088-3 }}</ref> Similar changes occur with a moderate inhibitor of CYP2C19 and other cytochromes [[cimetidine]]: amitriptyline level increases by about 70%, while nortriptyline decreases by 50%.<ref name="pmid3912187">{{cite journal | vauthors = Curry SH, DeVane CL, Wolfe MM | title = Cimetidine interaction with amitriptyline | journal = European Journal of Clinical Pharmacology | volume = 29 | issue = 4 | pages = 429–433 | date = 1985 | pmid = 3912187 | doi = 10.1007/BF00613457 | s2cid = 25430195 }}</ref> [[CYP3A4]] inhibitor [[ketoconazole]] elevates amitriptyline level by about a quarter.<ref name="pmid11583471">{{cite journal | vauthors = Venkatakrishnan K, Schmider J, Harmatz JS, Ehrenberg BL, von Moltke LL, Graf JA, Mertzanis P, Corbett KE, Rodriguez MC, Shader RI, Greenblatt DJ | title = Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies | journal = Journal of Clinical Pharmacology | volume = 41 | issue = 10 | pages = 1043–1054 | date = October 2001 | pmid = 11583471 | doi = 10.1177/00912700122012634 | s2cid = 27146286 }}</ref> On the other hand, [[cytochrome P450]] inducers such as [[carbamazepine]] and [[St. John's Wort]] decrease the levels of both amitriptyline and nortriptyline<ref name="pmid7909176"/><ref name="pmid11799342">{{cite journal | vauthors = Johne A, Schmider J, Brockmöller J, Stadelmann AM, Störmer E, Bauer S, Scholler G, Langheinrich M, Roots I | title = Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ) | journal = Journal of Clinical Psychopharmacology | volume = 22 | issue = 1 | pages = 46–54 | date = February 2002 | pmid = 11799342 | doi = 10.1097/00004714-200202000-00008 | s2cid = 25670895 }}</ref>

Oral contraceptives may increase the blood level of amitriptyline by as high as 90%.<ref name="pmid27444984">{{cite journal | vauthors = Berry-Bibee EN, Kim MJ, Simmons KB, Tepper NK, Riley HE, Pagano HP, Curtis KM | title = Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review | journal = Contraception | volume = 94 | issue = 6 | pages = 650–667 | date = December 2016 | pmid = 27444984 | doi = 10.1016/j.contraception.2016.07.011 | pmc = 11283812 }}</ref> Valproate moderately increases the levels of amitriptyline and nortriptyline through an unclear mechanism.<ref name="pmid8689811">{{cite journal | vauthors = Wong SL, Cavanaugh J, Shi H, Awni WM, Granneman GR | title = Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics | journal = Clinical Pharmacology and Therapeutics | volume = 60 | issue = 1 | pages = 48–53 | date = July 1996 | pmid = 8689811 | doi = 10.1016/S0009-9236(96)90166-6 | s2cid = 37720622 }}</ref>

The prescribing information warns that the combination of amitriptyline with [[monoamine oxidase inhibitor]]s may cause potentially lethal [[serotonin syndrome]];<ref name = EMC/> however, this has been disputed.<ref name="pmid16460699">{{cite journal | vauthors = Gillman PK | title = A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action | journal = Biological Psychiatry | volume = 59 | issue = 11 | pages = 1046–1051 | date = June 2006 | pmid = 16460699 | doi = 10.1016/j.biopsych.2005.11.016 | s2cid = 12179122 }}</ref> The prescribing information cautions that some patients may experience a large increase in amitriptyline concentration in the presence of topiramate.<ref name=DailyMed/> However, other literature states that there is little or no interaction: in a pharmacokinetic study topiramate only increased the level of amitriptyline by 20% and nortriptyline by 33%.<ref name="pmid15355124">{{cite journal | vauthors = Bialer M, Doose DR, Murthy B, Curtin C, Wang SS, Twyman RE, Schwabe S | title = Pharmacokinetic interactions of topiramate | journal = Clinical Pharmacokinetics | volume = 43 | issue = 12 | pages = 763–780 | date = 2004 | pmid = 15355124 | doi = 10.2165/00003088-200443120-00001 | s2cid = 10427097 }}</ref>

Amitriptyline counteracts the antihypertensive action of [[guanethidine]].<ref name = TGA/><ref name="pmid5468457">{{cite journal | vauthors = Meyer JF, McAllister CK, Goldberg LI | title = Insidious and prolonged antagonism of guanethidine by amitriptyline | journal = JAMA | volume = 213 | issue = 9 | pages = 1487–1488 | date = August 1970 | pmid = 5468457 | doi = 10.1001/jama.1970.03170350053016 }}</ref> When given with amitriptyline, other [[anticholinergic]] agents may result in [[hyperpyrexia]] or [[paralytic ileus]].<ref name=DailyMed>{{cite web | title=AMITRIPTYLINE HYDROCHLORIDE tablet, coated | website=DailyMed | date=24 May 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d46ff585-7082-4a7c-a88f-2acf3be0f1d5 | access-date=30 September 2024}}</ref> Co-administration of amitriptyline and [[disulfiram]] is not recommended due to the potential for the development of toxic delirium.<ref name = TGA/><ref name="pmid7092508">{{cite journal | vauthors = Maany I, Hayashida M, Pfeffer SL, Kron RE | title = Possible toxic interaction between disulfiram and amitriptyline | journal = Archives of General Psychiatry | volume = 39 | issue = 6 | pages = 743–744 | date = June 1982 | pmid = 7092508 | doi = 10.1001/archpsyc.1982.04290060083018 }}</ref> Amitriptyline causes an unusual type of interaction with the [[anticoagulant]] [[phenprocoumon]] during which great fluctuations of the [[prothrombin time]] have been observed.<ref name="urlCHAPTER 132 ORAL ANTICOAGULATION | Free Medical Textbook">{{cite web |url=https://medtextfree.wordpress.com/2012/02/09/chapter-132-oral-anticoagulation/ |title=CHAPTER 132 ORAL ANTICOAGULATION &#124; Free Medical Textbook |date=9 February 2012 |format= |access-date=2 February 2021 |archive-date=27 September 2020 |archive-url=https://web.archive.org/web/20200927103658/https://medtextfree.wordpress.com/2012/02/09/chapter-132-oral-anticoagulation/ |url-status=live }}</ref>