Antiplaque Agents

ANTIPLAQUE AGENTS

Bisbiguanides

Chlorhexidine is a symmetrical cationic molecule that is most stable as a salt; the highly water-soluble diglu-conate is the most commonly used preparation. Be-cause of its cationic properties, it binds strongly to hy-droxyapatite (the mineral component of tooth enamel), the organic pellicle on the tooth surface, salivary pro-teins, and bacteria. Much of the chlorhexidine binding in the mouth occurs on the mucous membranes, such as the alveolar and gingival mucosa, from which sites it is slowly released in active form.

Pharmacokinetics

The rate of clearance of chlorhexidine from the mouth after one mouth rinse with 10 mL of a 0.2% aqueous so-lution follows approximately first-order kinetics, with a half-life of 60 minutes. This means that following appli-cation of a single rinse with a 0.2% chlorhexidine solution, the concentration of the compound exceeds the minimum inhibitory concentration (MIC) for oral streptococci (5 mg/mL) for almost 5 hours. The pro-nounced substantivity, along with the relative suscepti-bility of oral streptococci, may account for the great ef-fectiveness of chlorhexidine in inhibiting supragingival plaque formation.

Mechanisms of Action

Although chlorhexidine affects virtually all bacteria, gram-positive bacteria are more susceptible than are gram-negative organisms. Furthermore, Streptococcus mutans and Antinomies viscosus seem to be particularly sensitive. S. mutans has been associated with the forma-tion of carious lesions in fissures and on interproximal tooth surfaces and has been identified in large numbers in plaque and saliva samples of subjects with high caries activity.

Low concentrations of chlorhexidine are bacterio-static, while high concentrations are bactericidal. Bacteriostasis is the result of chlorhexidine binding to the negatively charged bacterial cell wall (e.g., lipo-polysaccharides), where it interferes with membrane transport systems. Oral streptococci take up sugars via the phosphoenolpyruvate-mediated phosphotrans-ferase (PEP-PTS) system. The PEP-PTS is a carrier-me-diated group translocating process in which a number of soluble and membrane-bound enzymes catalyze the transfer of the phosphoryl moiety of PEP to the sugar substrate with the formation of sugar phosphate and pyruvate. Chlorhexidine is known to abolish the activity of the PTS at bactericidal concentrations. High chlor-hexidine concentrations cause intracellular protein pre-cipitation and cell death. Despite its pronounced effect on plaque formation, no detectable changes in resist-ance of plaque bacteria were found in a 6-month longi-tudinal study of mouth rinses.

Clinical Uses

The previous routine treatment for cases of severe gin-gival disease consisted of calculus and plaque removal and oral hygiene instructions. Subsequent resolution of the gingival inflammation was largely dependent on daily plaque control by the patient. However, the use of a 0.1 to 0.2% chlorhexidine mouthwash supplementing daily plaque control will facilitate the patient’s effort to fight new plaque formation and to resolve gingivitis. Consequently, use of chlorhexidine is indicated in the following situations: in disinfection of the oral cavity be-fore dental treatment; as an adjunct during initial ther-apy, especially in cases of local and general aggressive periodontitis; and in handicapped patients.

Adverse Effects and Toxicity

The most conspicuous side effect of chlorhexidine is the development of a yellow to brownish extrinsic stain on the teeth and soft tissues of some patients. The discol-oration on tooth surfaces is extremely tenacious, and a professional tooth cleaning using abrasives is necessary to remove it completely. The staining is dose dependent, and variation in severity is pronounced between indi-viduals. This side effect is attributed to the cationic nature of the antiseptic. Desquamative soft tissue lesions have also been reported with use of drug concentrations exceeding 0.2% or after prolonged application. A fre-quently observed side effect is impaired taste sensation. It was reported that rinsing with a 0.2% aqueous solu-tion of chlorhexidine digluconate resulted in a signifi-cant and selective change in taste perception for salt but not for sweet, bitter, and sour.

In vitro, chlorhexidine can adversely affect gingival fibroblast attachment to root surfaces. Furthermore, protein production in human gingival fibroblasts is re-duced at chlorhexidine concentrations that would not affect cell proliferation. Such findings corroborate ear-lier studies showing delayed wound healing in stan-dardized mucosal wounds after rinsing with 0.5% chlorhexidine solution.

As an oral rinsing agent, to date chlorhexidine has not been reported to produce any toxic systemic effects. Since chlorhexidine is poorly absorbed in the oral cav-ity and gastrointestinal tract, little if any enters the bloodstream. A summary of chlorhexidine oral rinses is given in Table 42.1.

Nonionic Bisphenols

Triclosan is a broad-spectrum antimicrobial compound. It was originally used in soaps, antiperspirants, and cos-metic toiletries as a germicide. Today, triclosan is incor-porated into toothpaste because of its wide spectrum of antimicrobial activities and low toxicity.

Pharmacokinetics

Triclosan is retained in dental plaque for at least 8 hours, which in addition to its broad antibacterial prop-erty could make it suitable for use as an antiplaque agent in oral care preparations. However, the com-pound is rapidly released from oral tissues, resulting in relatively poor antiplaque properties as assessed in clin-ical studies of plaque formation. This observation is fur-ther corroborated by a poor correlation between mini-mal inhibitory concentration values generated in vitro and clinical plaque inhibitory properties of triclosan. Improvement of substantivity was accomplished by in-corporation of triclosan in a polyvinyl methyl ether maleic acid copolymer (PVM/MA, Gantrez). With the combination of PVM/MA copolymer and triclosan, the substantivity of the triclosan was increased to 12 hours in the oral cavity.

Mechanism of Action

Triclosan is active against a broad range of oral gram-positive and gram-negative bacteria. The primary target of its antibacterial activity is the bacterial cell mem-brane. High concentrations cause membrane leakage and ultimately lysis of the bacterial cell. 

Effects at lower concentration are more subtle. Triclosan has been shown to bind to cell membrane targets and inhibit en-zymes associated with the phosphotransferase and pro-ton motive force systems.

Clinical Effects

Triclosan plus copolymer is available in toothpaste. Commercially available dentifrice concentrations con-tain 0.3% triclosan and 2.0% PVM/MA copolymer. This product (Total) was tested in a large number of short-term controlled clinical trials, from which a statis-tically significant but clinically modest 15 to 20% plaque reduction was reported. The same toothpaste composi-tion also exhibited significant anticalculus properties. Typically, the reported reductions in calculus formation ranged from 25 to 35%. Finally, of considerable interest is the observation that triclosan inhibits gingivitis by a mechanism independent of its antiplaque activity. In a clinical study, minimal plaque effects accompanied an average 50% reduction in gingivitis. An explanation of this surprising effect stems from research conducted us-ing a gingival fibroblast cell culture model. These exper-iments revealed that triclosan could inhibit the IL-1-induced production of prostaglandin E₂.

Essential Oils

A mixture of essential oils consisting of thymol 0.06%, eucalyptol 0.09%, methyl salicylate 0.06%, and menthol 0.04% in an alcohol-based vehicle (26.9%) provides the plaque-inhibiting properties of rinsing agents such as Listerine.

Essential oils may reduce plaque levels by inhibiting bacterial enzymes and by reducing pathogenicity of plaque via reduction of the amount of endotoxin; the al-cohol is probably responsible for denaturing bacterial cell walls. The substantivity of Listerine appears to be quite low, and therefore, it must be used at least twice a day to be effective. A variety of clinical studies have demonstrated that Listerine is capable of reducing plaque and gingivitis over extended periods; however, the degree of reduction is variable. Listerine will reduce plaque and gingivitis anywhere from 14.9 to 20.8% and 6.5 to 27.7%, respectively (Table 42.1). Adverse reac-tions include a bitter taste and burning sensation in the oral cavity. Regular use of high-alcohol rinses can ag-gravate existing oral lesions and desiccate mucous membranes. In addition to Listerine, a huge number of American Dental Society (ADA) approved generic equivalents available over the counter.

Fluorides

Fluorides are widely used in caries prevention, for which they have been highly effective. Systemic administration of fluorides for caries prevention is available via drink-

ing water (1 mg/ L), tablets (0.25–1 mg), drops (0.125–0.5 mg), topical application by mouthwashes (200–1,000 mg/L), gels for home use (900 mg/kg) and professional use (9,000–19,000 mg/kg), and dentifrices (1,000 mg/kg). In contrast to the efficacy of fluorides in preventing car-ious lesions, these formulations have relatively poor an-tibacterial properties (Table 42.1). The weak therapeutic benefit of fluorides on gingivitis is due to a modest inhi-bition of glycolysis in plaque bacteria. Sodium fluoride, monofluorophosphate, and stannous fluoride are the compounds used in topically applied agents.

A few well-controlled clinical studies suggested a potential plaque-inhibiting effect for dentifrices con-taining stannous fluoride. However, these results were most likely due to the stannous ion rather than to fluoride; the positive charge of the stannous ion may in-terfere with bacterial membrane function, bacterial adhesion, and glucose uptake, thereby inhibiting the formation of plaque.

Mild tooth staining has been observed after use of stannous fluoride products. The ADA Council on Dental Therapeutics endorses fluorides for their caries-inhibiting effect but not for plaque inhibition.

Prebrushing Rinses

The topical application of a liquid rinse before brushing as an aid in the mechanical removal of supragingival plaque is a novel idea. Since the introduction of the first prebrushing rinse there has been a rapid increase in the number of generic products that claim to physically loosen or remove plaque. Prebrushing rinses usually contain a plethora of ingredients, and it is not known which constituent is the active chemical. It has been sug-gested that sodium lauryl sulfate acts as a detergent to dislodge or loosen the plaque on teeth (Table 42.1). When prebrushing rinses were tested against placebo rinses, prebrushing rinses appeared to have no effect on plaque reduction.