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Diphenhydramine, tersedia dalam berbagai bentuk garam,[70]<ref>{{cite journal | vauthors = Wang C, Paul S, Wang K, Hu S, Sun CC | title=Relationships among Crystal Structures, Mechanical Properties, and Tableting Performance Probed Using Four Salts of Diphenhydramine | date=2017 | journal=Crystal Growth & Design | volume=17 | issue=11 | pages=6030–6040 | doi=10.1021/acs.cgd.7b01153 }}</ref> seperti sitrat,[71][72]<ref>{{cite journal | vauthors = Rao DD, Venkat Rao P, Sait SS, Mukkanti K, Chakole D | title=Simultaneous Determination of Ibuprofen and Diphenhydramine Citrate in Tablets by Validated LC | date=2009 | journal=Chromatographia | volume=69 | issue=9–10 | pages=1133–1136 | s2cid=97766056 | doi=10.1365/s10337-009-0977-3 }}</ref><ref>{{cite journal | vauthors = Rao DD, Sait SS, Mukkanti K | title=Development and Validation of an UPLC Method for Rapid Determination of Ibuprofen and Diphenhydramine Citrate in the Presence of Impurities in Combined Dosage Form | date=2011 | journal=Journal of Chromatographic Science | volume=49 | issue=4 | pages=281–286 | pmid=21439118 | doi=10.1093/chrsci/49.4.281 }}</ref> hidroklorida,[73]<ref>{{cite journal | vauthors = Chan CY, Wallander KA | title = Diphenhydramine toxicity in three children with varicella-zoster infection | journal = Dicp | volume = 25 | issue = 2 | pages = 130–132 | date = February 1991 | pmid = 2058184 | doi = 10.1177/106002809102500204 | s2cid = 45456788 }}</ref> dan salisilat,[74]<ref>{{cite journal | vauthors = Kamijo Y, Soma K, Sato C, Kurihara K | title = Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support | journal = Clinical Toxicology | volume = 46 | issue = 9 | pages = 864–868 | date = November 2008 | pmid = 18608279 | doi = 10.1080/15563650802116151 | s2cid = 43642257 }}</ref> menunjukkan berat molekul dan sifat farmakokinetik yang berbeda. Secara khusus, diphenhydramine hydrochloride dan diphenhydramine citrate memiliki berat molekul masing-masing 291,8 g/mol[75]<ref name="pubchem8980">{{cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/8980 | title=Diphenhydramine Hydrochloride | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> dan 447,5 g/mol,[76].<ref name="pubchem174697">{{cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/174697 | title=Diphenhydramine citrate | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> Variasi berat molekul ini mempengaruhi laju disolusi dan karakteristik penyerapan masing-masing bentuk garam. Akibatnya, dosis 25 mg diphenhydramine hydrochloride secara terapeutik setara dengan 38 mg diphenhydramine citrate. Oleh karena itu, penyesuaian dosis diperlukan untuk memperhitungkan perbedaan ini ketika beralih antar bentuk garam.[77]<ref name="salts-drugs-com">{{cite web | vauthors = Pope C | date = 28 August 2023 | url=https://www.drugs.com/medical-answers/difference-between-diphenhydramine-hydrochloride-3510045/ | title=Diphenhydramine Hydrochloride vs Citrate: What's the difference? | work = drugs.com }}</ref>
Diphenhydramine, meskipun secara tradisional dikenal sebagai antagonis, bertindak terutama sebagai agonis kebalikan dari reseptor histamin H1.[78]<ref name="pmid22021988">{{cite journal | vauthors = Khilnani G, Khilnani AK | title = Inverse agonism and its therapeutic significance | journal = Indian Journal of Pharmacology | volume = 43 | issue = 5 | pages = 492–501 | date = September 2011 | pmid = 22021988 | pmc = 3195115 | doi = 10.4103/0253-7613.84947 | doi-access = free }}</ref> Ini adalah anggota dari kelas agen antihistaminergik etanolamin.<ref name="Goodman">{{cite book |vauthors=Brunton L, Chabner B, Knollmann B | veditors = Brunton L | title = Goodman & Gilman's The Pharmacological Basis of Therapeutics | edition = 12e | year = 2011 | publisher = McGraw Hill | isbn = 978-0-07-162442-8 | pages = 242–245 | chapter = Chapter 32. Histamine, Bradykinin, and Their Antagonists }}</ref> Dengan membalikkan efek histamin pada kapiler, dapat mengurangi intensitas gejala alergi. Ia juga melintasi sawar darah-otak dan berbanding terbalik dengan reseptor H1 di pusatnya.[78]<ref name="pmid22021988"/> Efeknya pada reseptor H1 sentral menyebabkan kantuk.
Diphenhydramine adalah antimuskarinik yang kuat (antagonis kompetitif reseptor asetilkolin muskarinik) dan, dengan demikian, pada dosis tinggi dapat menyebabkan sindrom antikolinergik.[79]<ref name="urlAntihistamine Toxicity">{{cite web | url = http://emedicine.medscape.com/article/812828-overview | vauthors = Lopez AM | title = Antihistamine Toxicity | publisher = WebMD LLC | work = Medscape Reference | date = 10 May 2010 | url-status = live | archive-url = https://web.archive.org/web/20101013230957/http://emedicine.medscape.com/article/812828-overview | archive-date = 13 October 2010 | df = dmy-all }}</ref> Kegunaan diphenhydramine sebagai agen antiparkinson adalah hasil dari sifat penghambatannya pada reseptor asetilkolin muskarinik di otak.
Diphenhydramine juga bertindak sebagai penghambat saluran natrium intraseluler, yang bertanggung jawab atas tindakannya sebagai anestesi lokal.[68]<ref name="pmid11036158">{{cite journal | vauthors = Kim YS, Shin YK, Lee C, Song J | title = Block of sodium currents in rat dorsal root ganglion neurons by diphenhydramine | journal = Brain Research | volume = 881 | issue = 2 | pages = 190–8 | date = October 2000 | pmid = 11036158 | doi = 10.1016/S0006-8993(00)02860-2 | s2cid = 18560451 }}</ref> Diphenhydramine juga telah terbukti menghambat pengambilan kembali serotonin.[80]<ref name="Domino_1999"/> Telah terbukti menjadi potensiator analgesia yang diinduksi oleh morfin, namun tidak oleh opioid endogen, pada tikus besar.[81]<ref name="pmid2860599">{{cite journal | vauthors = Carr KD, Hiller JM, Simon EJ | title = Diphenhydramine potentiates narcotic but not endogenous opioid analgesia | journal = Neuropeptides | volume = 5 | issue = 4–6 | pages = 411–4 | date = February 1985 | pmid = 2860599 | doi = 10.1016/0143-4179(85)90041-1 | s2cid = 45054719 }}</ref> Obat ini juga ditemukan bertindak sebagai penghambat histamin N-metiltransferase (HNMT).[82][83]<ref name="pmid16168438">{{cite journal | vauthors = Horton JR, Sawada K, Nishibori M, Cheng X | title = Structural basis for inhibition of histamine N-methyltransferase by diverse drugs | journal = Journal of Molecular Biology | volume = 353 | issue = 2 | pages = 334–344 | date = October 2005 | pmid = 16168438 | pmc = 4021489 | doi = 10.1016/j.jmb.2005.08.040 }}</ref><ref name="pmid4402747">{{cite journal | vauthors = Taylor KM, Snyder SH | title = Histamine methyltransferase: inhibition and potentiation by antihistamines | journal = Molecular Pharmacology | volume = 8 | issue = 3 | pages = 300–10 | date = May 1972 | pmid = 4402747 }}</ref>
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