Diphenhydramine mechanism of action
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Diphenhydramine Mechanism of Action: Histamine H1 Receptor Antagonism
Diphenhydramine is primarily known as a first-generation antihistamine that works by competitively blocking histamine H1 receptors. By doing so, it prevents histamine from binding to these receptors, which reduces allergic symptoms such as bronchoconstriction, vasodilation, increased capillary permeability, and gastrointestinal smooth muscle spasms . This H1 antagonism also contributes to its sedative effects, as it acts on both peripheral and central histamine receptors .
Anticholinergic Effects and Central Nervous System Impact
In addition to its antihistaminic action, diphenhydramine is a potent competitive antagonist of muscarinic acetylcholine receptors. This anticholinergic activity can lead to side effects such as dry mouth, blurred vision, urinary retention, constipation, and central nervous system effects like sedation, agitation, or even psychosis at high doses .
Sodium Channel Blockade and Local Anesthetic Properties
Diphenhydramine also exhibits local anesthetic effects by inhibiting neuronal sodium (Na+) currents. It binds selectively to the inactivated state of sodium channels, preventing the propagation of nerve impulses. This mechanism is similar to that of traditional local anesthetics and explains its use in some pain management scenarios . The drug’s structure, particularly its two phenyl groups, is key to its interaction with sodium channels .
Neuromuscular Junction and Muscle Effects
At the neuromuscular junction, diphenhydramine can augment or block muscle twitches depending on the concentration. At higher concentrations, it can cause neuromuscular blockade that is not reversed by typical cholinesterase inhibitors, indicating a direct effect on neuromuscular transmission. It also reduces the action of acetylcholine on muscle, further supporting its anticholinergic properties .
Inhibition of Voltage-Gated Proton Channels (Hv1)
Recent research has shown that diphenhydramine can inhibit voltage-gated proton channels (Hv1), leading to acidification within certain cells, such as leukemic T cells. This acidification can trigger apoptosis, suggesting a potential pro-apoptotic effect of the drug in some cancer cells .
Modulation of Inflammatory and Oxidative Pathways
Diphenhydramine has demonstrated anti-inflammatory and antioxidant effects in animal models. It can reduce the expression of inflammatory markers and oxidative stress, which may contribute to its protective effects in conditions like periodontitis .
Analgesic and Antidystonic Actions
Diphenhydramine has been used as an analgesic adjuvant, especially in cases of refractory cancer pain, although the exact mechanism for its pain-relieving effects is not fully understood. Its antihistaminic and possible sodium channel-blocking actions are thought to play a role . Additionally, its ability to reduce dystonic reactions is linked to its antihistamine properties, particularly in the central nervous system .
Conservation of Mechanism Across Species
Studies in zebrafish have shown that the molecular targets of diphenhydramine are conserved between humans and zebrafish, supporting the relevance of its known mechanisms of action across different organisms .
Conclusion
Diphenhydramine acts through multiple mechanisms: it is a competitive antagonist at histamine H1 and muscarinic acetylcholine receptors, a sodium channel blocker with local anesthetic properties, and an inhibitor of voltage-gated proton channels. These actions explain its wide range of effects, including allergy relief, sedation, anticholinergic side effects, local anesthesia, anti-inflammatory activity, and potential pro-apoptotic effects in cancer cells 12345689+1 MORE.
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