Pharmacology of benzydamine hydrochloride

Introduction

Pain and inflammation are the consequences of sore throat, dental and oral procedures, infections, ulcers and head and neck chemotherapy/radiotherapy, and their management is of fundamental importance to avoid distress in patients. Benzydamine hydrochloride (Figure 1) is a topical indolic nonsteroidal anti-inflammatory drug, endowed with analgesic and anesthetic activity, and with antimicrobial (including both gram-positive and gram-negative bacteria) and antifungal properties (targeting Candida albicans and non-albicans strains), used in odontostomatology, otorhinolaryngology, and gynecology for its properties. This molecule has a lipophilic nature, showing high affinity with cell membranes and exhibiting membrane stabilization properties, resulting in local anesthesia, an effect related also to the interaction of the drug with cationic channels. Unlike other non-steroidal anti-inflammatory drugs, benzydamine hydrochloride is a weak inhibitor of cyclooxygenase or lipoxygenase and consequently its primary mechanisms of action are not related to arachidonic acid metabolism and do not affect the biosynthesis of the inflammation mediators prostanoids, prostacyclin, thromboxane and leukotrienes. Benzydamine hydrochloride is able to inhibit the production of pro-inflammatory cytokines, with consequent analgesia. Moreover, benzydamine hydrochloride is able to inhibit leukocyte-endothelial interactions and platelet aggregation.[1]

Pharmacology of benzydamine hydrochloride

Pharmacokinetics of benzydamine hydrochloride

Benzydamine hydrochloride has high lipid solubility in the unionized form, but low protein-binding capacity, and is consequently taken up by cells with high efficiency. Benzydamine hydrochloride is metabolized mainly by conjugation, dealkylation andoxidation, with benzydamine N-oxide as the major metabolite.[2] Benzydamine hydrochloride is characterized by a high volume of distribution and a relatively low systemic clearance. Plasma drug concentrations of oral and oromucosal/buccal/intraoral benzydamine hydrochloride reach a peak rapidly and decline with a half-life of about 13 h. Less than 20% of the drug results to be bound to plasma proteins.[3] The systemic absorption of benzydamine hydrochloride through the skin and non-specialized mucosae is relatively low compared to oral and oromucosal/buccal/intraoraladministration, thereby limiting unrequired systemic exposure to this drug and the potential for any systemic side-effect.

The mechanisms of action of benzydamine hydrochloride [1]

Benzydamine hydrochloride shares some properties with other NSAIDs, but exhibits also some distinctive characteristics. Among others, it may exert an anti-inflammatory activity by decreasing the release of pro-inflammatorycytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), but not IL-6 and IL-8, without affecting the production of anti-inflammatory molecules, such as IL-10 and IL-1 receptor antagonist (IL-1ra). At lower concentrations (3–30 μmol/L), this drug is also able to inhibit leukocyte-endothelial interactions, while at concentration of 10–100 μmol/L, benzydamine hydrochloride may stabilize the mucosal membrane by virtue of its general high affinity for membranes, and may inhibit the release of azurophilic granules from neutrophils, rich in serine proteases, further contributing to its anti-inflammatory effects. In addition, the anti-inflammatory activity of benzydamine hydrochloride is exerted also through the inhibition of monocyte migration stimulated by different classes of chemotactic factors and associated to a blockage of ERK and p38 MAPK pathways. Benzydamine hydrochloride also reduces the histamine-induced vasodilation and vascular permeability. Benzydamine hydrochloride shows antithrombotic activity and the inhibition of the collagen induced aggregation appears to be rather selective vs. other NSAIDs. Finally, benzydamine hydrochloride is a weak inhibitor of cyclooxygenase and lipoxygenase, and needs high concentrations to inhibit effectively prostaglandin and thromboxane biosynthesis. Consequently, the primary mechanisms of benzydamine hydrochloride of action are not related to arachidonicacid metabolism and do not affect the biosynthesis of the inflammation mediators prostanoids, prostacyclin, thromboxane and leukotrienes.

Benzydamine hydrochloride has also anti-microbial properties, supporting its anti-inflammatory activity when applied to the mouth. It proved to be effective in growth inhibition of Candida albicans and non-albicans strains, with minimal inhibitory concentrations ranging from 12.5 to 50.0 μg/mL, and with cytotoxic activity at higher concentration, through a membrane-damaging action, consistently with the lipophilic properties of this drug. A very recent study confirmed the effectiveness of benzydamine hydrochloride on Candida albicans inhibition through the impairment of its adhesion, biofilm formation, regrowth and persistence in vitro. Benzydamine hydrochloride proved to be effective also against gram-negative and gram-positive bacteria in vitro within a few minutes from exposure, at concentrations equal to or lower than those generally used to exert an anti-inflammatory action.

Conclusions

Pain and inflammation are the consequences of sore throat, dental and oral procedures, infections, ulcers and HNC chemotherapy/radiotherapy, and their management is of fundamental importance to avoid distress in patients. Benzydamine hydrochloride proved to besafe and efficient in pain relief, and novel properties and formulations are currently under investigation with promising results and new interesting perspectives for this well-established drug. Further detailed information can be found in Reference 1.

References

[1] Ferrer-Montiel A. Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action. F1000Res. 2025;13:350. Published 2025 May 22. doi:10.12688/f1000research.144067.2

[2] Baldock GA, Brodie RR, Chasseaud LF, et al.: Pharmacokinetics ofbenzydamine after intravenous, oral, and topical doses tohuman subjects. Biopharm. Drug Dispos. 1991; 12(7): 481–492.

[3] Chasseaud LF, Catanese B: Pharmacokinetics of benzydamine.Int. J. Tissue React. 1985; 7(3): 195–204.

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