Journal of Clinical Medicine Review Conceptual Model for Using Imidazoline Derivative Solutions in Pulpal Management Robert S. Jones Division of Pediatric Dentistry, Department of Developmental & Surgical Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] Abstract: Alpha-adrenergic agonists, such as the Imidazoline derivatives (ImDs) of oxymetazoline and xylometazoline, are highly effective hemostatic agents. ImDs have not been widely used in dentistry but their use in medicine, specifically in ophthalmology and otolaryngology, warrants consideration for pulpal hemostasis. This review presents dental healthcare professionals with an overview of ImDs in medicine. ImD solutions have the potential to be more effective and biocompatible than existing topical hemostatic compounds in pulpal management. Through a comprehensive analysis of the pharmacology of ImDs and the microphysiology of hemostasis regulation in oral tissues, a conceptual model of pulpal management by ImD solutions is presented. Keywords: hemostasis; alpha-adrenergic agonists; imidazoline; oxymetazoline; nasal; dental pulp; mucosa; apexogenesis; pulpotomy; direct pulp cap; dentistry 1. Overview Citation: Jones, R.S. Conceptual The purpose of this review is to formulate a conceptual model on the potential man- Model for Using Imidazoline agement of pulpal tissue by imidazoline derivatives (ImDs) based on a review of the Derivative Solutions in Pulpal literature that examines the hemostatic properties and mechanistic actions of these com- Management. J. Clin. Med. 2021, 10, 1212. https://doi.org/10.3390/ pounds in other human tissues. Commercial ImDs are formulated in solution with an- jcm10061212 timicrobial preservatives in order to act as ‘parenteral topical agents’ and used to manage ophthalmic inflammation, nasal congestion, and to control bleeding during otolaryngology Academic Editor: Rosalia surgery [1,2]. While systematic reviews of IMDs in medicine are published [3–5] this critical Maria Leonardi review proposes an advancement in dental pulpal management by examining the pharma- cology and biochemistry of ImDs, which have been largely understudied for direct dental Received: 2 February 2021 application [6–9]. ImD solutions that also contain antimicrobial preservatives may be more Accepted: 11 March 2021 effective and biocompatible than existing topical hemostatic compounds in dentistry. These Published: 15 March 2021 medicinal parenteral topical compounds have potential in pulpal management procedures such as a direct pulp cap, managing an exposure in a permanent tooth with an immature Publisher’s Note: MDPI stays neutral root (e.g., apexogenesis), and a primary tooth pulpotomy. with regard to jurisdictional claims in published maps and institutional affil- 2. Imidazoline Derivatives iations. There are several different medically useful ImDs compounds such as oxymetazoline, xylometazoline, naphazoline, and tetrahydrozoline (also known as tetryzoline). These ImDs are synthetic, noncatecholamines that can act as alpha adrenergic agonists. The root imidazoline ring makes them distinct from catecholamines such as epinephrine, nore- Copyright: © 2021 by the author. pinephrine, and phenylephrine (Figure1). Oxymetazoline and xylometazoline are nearly Licensee MDPI, Basel, Switzerland. identical in chemical structure with oxymetazoline having an additional hydroxyl group This article is an open access article substitution. Naphazoline and tetrahydrozoline are nearly identical with the imidazoline distributed under the terms and bound to a polycyclic aromatic naphthalene. ImDs are commonly formulated in hydrochlo- conditions of the Creative Commons ride (HCL) salts which are light/heat stable, soluble in water, and nonreactive when mixed Attribution (CC BY) license (https:// with other compounds such as local anesthetics, alcohol, and antimicrobial preservatives. creativecommons.org/licenses/by/ 4.0/). J. Clin. Med. 2021, 10, 1212. https://doi.org/10.3390/jcm10061212 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 12 J. Clin. Med. 2021, 10, 1212 2 of 11 when mixed with other compounds such as local anesthetics, alcohol, and antimicrobial preservatives. FigureFigure 1.1. Catecholamines(a) epinephrine with and a Imidazoline root benzene Derivatives. ring (b) oxymetazoline (a) epinephrine has withan imidazoline a root benzene ring in- ring (bcorporated) oxymetazoline into the has benzene an imidazoline ring structure ring incorporated (c) tetrahydrozoline into the benzene (also known ring structure as tetryzoline) (c) tetrahydro- has an zolineimidazoline (also known ring bound as tetryzoline) to a polycyclic has an imidazolinearomatic naphthalene. ring bound to a polycyclic aromatic naphthalene. 3.3. PharmacologyPharmacology andand UseUse ImDsImDs are are sympathomimetic sympathomimetic compounds compounds that that directly directly act act on on alpha-adrenergic alpha-adrenergic receptors recep- withintors within the sympathetic the sympathetic nervous nervous system system [10]. ImDs [10]. mimic ImDs catecholamines, mimic catecholamines, norepinephrine norepi- andnephrine epinephrine, and epinephrine, but are more but are selective more toselective alpha( αto)-1 alpha( andα alpha()-1 andα)-2 alpha( postα synaptic)-2 post syn- re- ceptorsaptic receptors [11]. ImDs [11]. have ImDs very have little very to little no β to-adrenergic no β-adrenergic agonist agonist or antagonist or antagonist activity activity that stimulatesthat stimulates systemic systemic effects effects within within heart heart and lung and tissuelung tissue [12]. ImDs, [12]. ImDs, such as such oxymetazoline as oxymeta- andzoline xylometazoline, and xylometazoline, have a have high affinitya high affinity for α-1a for subtype α-1a subtype receptors receptors that are that ubiquitous are ubiq- inuitous the nasal in the mucosa nasal mucosa and also and bind also to bind less to common less commonα-2 receptors α-2 receptors within within the tissue the tissue [11]. ImDs[11]. ImDs have similarhave similar effects effects within corneawithin vesselscornea [vessels13]. The [13]. immediate The immediate local effect local is vascular effect is smoothvascular muscle smooth contraction muscle contraction (vasoconstriction) (vasoconstriction) in pre-capillary in arteriolespre-capillary and post-capillaryarterioles and venulespost-capillary [14]. In venules the case [14]. of nasalIn the congestion, case of nasal vasoconstriction congestion, vasoconstriction reduces tissue reduces edema tissue and improvesedema and nasal improves airway nasal flow (decongestant)airway flow (decongestant) [4]. Topical ocular [4]. Topical application ocular of ImDsapplication reduces of eyeImDs redness reduces (conjunctivitis) eye redness (conjunctivitis) [15]. ImDs, such [15]. as ImDs, oxymetazoline such as oxymetazoline and xylometazoline, and xylomet- can alsoazoline, be used can toalso improve be used tissue to improve visualization tissue by visualization controlling hemostasis by controlling for reduction hemostasis based for surgery,reduction grafting based procedures,surgery, grafting and prosthetic procedures placement, and prosthetic in otolaryngology placement [ 2in,16 otolaryngol-] (Table1). ogy [2,16] (Table 1). Table 1. Commercially Available Solutions of Imidazoline Derivatives (ImDs) 1. 1 CompoundTable 1. Commercially Primary Uses Available Solutions USA Availability of Imidazoline Surgical Derivatives Hemostasis (ImDs) . Duration (h) 0.05% OxymetazolineCompound HCL Nasal CongestionPrimary Uses USA Yes Availability Surgical Yes Hemostasis Duration 8 (h) 0.1%0.05% Xylometazoline Oxymetazoline HCL HCL NasalNasal Congestion Congestion NoYes YesYes 8 8 0.02% Naphazoline HCL Conjunctivitis Yes No 4 0.1% Xylometazoline HCL Nasal Congestion No Yes 8 0.1% Tetrahydrozoline HCL Conjunctivitis Yes No 4 0.02% Naphazoline HCL Conjunctivitis Yes No 4 1 Micromedex (IBM). ImDs are available globally with some country specific regulations (USA shown). 0.1% Tetrahydrozoline HCL Conjunctivitis Yes No 4 1 Micromedex (IBM). ImDs are available globally with some country specific regulations (USA shown). 4. Efficacy 4. EfficacyOxymetazoline and xylometazoline activity have considerably longer duration of activity (8 h versus 1 h) than other sympathomimetics, such as epinephrine and phenyle- Oxymetazoline and xylometazoline activity have considerably longer duration of ac- phrine [17]. Oxymetazoline and xylometazoline are the most effective vasoconstrictor tivity (8 h versus 1 h) than other sympathomimetics, such as epinephrine and phe- agents during ear, nose, and throat surgical procedures and can be delivered pre- and intra- nylephrine [17]. Oxymetazoline and xylometazoline are the most effective vasoconstrictor operatively [18,19]. While this surgical use is an off-label application [2], oxymetazoline agents during ear, nose, and throat surgical procedures and can be delivered pre- and and xylometazoline are approved and widely available as over-the-counter medications intra-operatively [18,19]. While this surgical use is an off-label application [2], oxymeta- for multi-dose nasal congestion due to the reduction in local upper airway edema via sympathomimeticzoline and xylometazoline vasoconstriction are approved [4]. Naphazoline and widely available and tetrahydrozoline as over-the-counter are found medi- in approvedcations for ophthalmic multi-dose topical nasal congestion solutions. Theydue to are the rarely reduction used for in local hemostasis