45: Antiplaque and Antigingivitis Agents

CHAPTER 45 Antiplaque and Antigingivitis Agents*

The periodontium, which is responsible for the retention of teeth in the maxilla and mandible, consists of four different tissue types. Cementum and alveolar bone are the hard tissues to which the fibrous periodontal ligament anchors the tooth into the skeleton, and the gingiva is the covering tissue of the periodontium (Figure 45-1). The gingiva is a unique body tissue because it allows the penetration of calcified tissue (i.e., teeth) into an intact mucosa, while protecting the underlying periodontal tissues. The buildup of infectious organisms on these structures give rise to some of the most common diseases in humans.

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FIGURE 45-1 Photomicrograph of periodontium.

(Courtesy Dr. Rudi Melfi, The Ohio State University.)

The accumulation of microorganisms on the tooth surface along the gingival margin can alter the structure and function of the gingiva, inducing an oral inflammatory reaction; clinically, this is known as gingivitis.64 During adolescence, the occurrence of gingivitis is almost universal, and in adulthood, it affects approximately 50% of the population.2 Because of the frequent appearance of gingivitis, this disease remains a principal concern for the dentist, as it can be converted to other, more destructive forms of periodontal disease.64 The prevention or cure of gingivitis is of particular interest to dentists.

Dental caries is another common oral disease the prevalence of which varies in regard to the tooth surface and age of the individual.25 Although caries is a worldwide problem associated with dental plaque and refined carbohydrates, some individuals, particularly individuals in lower educational, lower socioeconomic, and older age groups, are at greater risk.25

The most common method of eliminating gingivitis or preventing dental caries is by the mechanical removal of the microorganisms found in dental plaque via tooth brushing and flossing. Effective mechanical removal of plaque is a tedious, time-consuming process, however, which is affected by an individual’s gingival architecture, tooth position, dexterity, and motivation. Consequently, incomplete removal of dental plaque by mechanical means allows for the induction and continued progression of gingivitis and dental caries. Pharmacologic agents that prevent or reduce plaque can aid the dentist by effectively preventing or eliminating these diseases. The development of safe, effective, topically applied anti-infective agents would help in the maintenance of healthy hard and soft tissues. This chapter examines the relationship of the unique pharmacokinetic characteristics of common antiplaque and antigingivitis agents and drugs available in mouth rinses and dentifrices to manage dental plaque.

RATIONALE FOR BIOFILM DRUG THERAPY

Many different types of materials accumulate on teeth. The most ubiquitous and important deposit is dental plaque or dental biofilm. Dental biofilm consists primarily of microorganisms in an organized matrix of organic and inorganic components.85 Bacteria account for at least 70% of the mass of the biofilm; 1 mm3 of dental biofilm contains more than 100 million bacteria consisting of more than 400 different species.41,69 The organic matrix of biofilm consists of polysaccharide, protein, and lipid components, whereas the inorganic matrix is primarily composed of calcium and phosphorus ions.85

The dental biofilm found above the gingival margin of the tooth is called supragingival, and the dental biofilm found below the gingival margin (i.e., in the gingival sulcus or pocket) is called subgingival. Dental biofilm has been considered to be a common denominator in caries and periodontal diseases. This concept is a gross oversimplification, however, because there are different types of bacteria, some of which may be cariogenic, some of which may be periodontopathic (with subsets leading to different forms of periodontal diseases), and some of which may be relatively innocuous and cause only low-grade dental disease.

Gingivitis is due principally to the accumulation and retention of dental biofilm coronal to the gingival margin.45,62 The accumulation of supragingival biofilm is also a prime influence in the development of the subgingival biofilm.16 As undisturbed biofilm matures, it changes in composition and becomes more complex. A bacterial succession occurs whereby microorganisms associated with gingival health (i.e., gram-positive rods and cocci) are replaced by microorganisms associated with gingivitis (i.e., gram-negative cocci and rods) and spiral-shaped organisms and spirochetes. As a consequence of the change in microflora, inflammation-induced changes in the gingiva cause an increase in epithelial cell turnover and connective tissue degradation, resulting in anatomic changes that tend to deepen the gingival sulcus causing a gingival pocket to form.37 This change in gingival architecture and the subgingival environment provides a new and better protected niche for bacteria to grow. Here, they are continually bathed by exudate from the gingival crevice and end products from the supragingival biofilm. Control of supragingival biofilm also has a profound influence on the developing composition of periodontitis-associated subgingival biofilm.37

Dental caries is a chronic disease that is characterized by the progressive decalcification of tooth structure. The biofilm contains bacterial species (e.g., Streptococcus mutans) that convert refined carbohydrates to lactic acid and other acids.103 These acids can dissolve tooth mineral, resulting in a subsurface lesion initially and a cavity if the process continues over time. The unimpeded progress of dental caries can penetrate the enamel or cementum and progress through the dentin to the dental pulp. When the dental pulp is affected, a pulpitis develops resulting in tooth pain (i.e., toothache).

Some current commercially available therapeutic measures for control of biofilms include agents that act directly on the microflora and agents that interfere with bacterial attachment or the mechanical removal of the biofilm or both. Discussion of mechanical techniques is beyond the scope of this chapter, but excellent comprehensive reviews on mechanical plaque control can be found elsewhere in the dental literature.15,29

PHARMACOKINETICS OF THE ORAL CAVITY

The therapeutic outcome of topically applied agents used to control oral infections depends on the characteristics of drugs that take advantage of the unique physiologic and anatomic circumstances found in the oral cavity. This section is a broad overview of important oral pharmacokinetic principles.

Absorption

The vascularity of the oral cavity, combined with a thin epithelial lining in some areas, allows for the absorption of drugs at a rapid rate.43,94 Nonionized drugs, such as nitroglycerin, take advantage of these tissue characteristics and diffuse rapidly across the oral mucosa into the bloodstream. In contrast to most drugs, for which the principal objective is to introduce the agent into the bloodstream rapidly, the goal of oral topical agents is to be retained in the oral cavity for as long as possible.35 Rapid oral absorption can lead to toxic effects elsewhere in the body and a significant reduction of the free drug in the oral cavity. In most instances, the drugs used to restrain plaque levels are highly ionized and are generally unable to penetrate the oral mucosa.

IDEAL PROPERTIES OF ANTIPLAQUE AGENTS

The pursuit of an ideal agent to reduce dental biofilms has been an ongoing search in dentistry for centuries.107 In 1890, Willoughby D. Miller, an American dental surgeon, stated in his now-famous book, The Micro-Organisms of the Human Mouth, that “we ought to be able by means of properly chosen antiseptic material … to prevent as well as arrest microbial-induced diseases in the oral cavity.”67 Since that time, numerous antiplaque mouth rinses have been introduced to the public, many with dubious claims, and only more recently have dentists been able to prescribe therapeutically effective agents. Considering that the average time a person spends mechanically removing plaque from teeth is approximately 37 seconds,106 having a “chemical” toothbrush would be a great benefit to improve oral health.

The principal properties of an ideal antiplaque agent include efficacy, stability, low clearance, safety, and taste (Box 45-1). An antiplaque agent must be able to suppress meaningfully or eliminate specific pathogens with no untoward local or systemic side effects. It should not allow the overgrowth of opportunistic organisms or encourage the development of resistant organisms. When used, it should be slowly released over time in the oral cavity with continued antimicrobial effect. The agent should be stable at room temperature and have a color and taste that is pleasing to the consumer. Last but not least, it should be relatively inexpensive to purchase. No such perfect antiplaque agent exists today.

The myriad claims regarding antiplaque efficiency of drugs has led the American Dental Association (ADA) Council on Scientific Affairs19 to develop guidelines for testing the long-term efficacy of chemotherapeutic products for control of supragingival dental plaque and gingivitis. The requirements of these guidelines are summarized in Box 45-2 and have been adopted, in some cases with modifications, by the U.S. Food and Drug Administration (FDA), the Canadian Dental Association, and the British Dental Association. To be considered acceptable, a product should be tested in at least two, independently conducted, 6-month clinical trials in populations that represent individuals for whom the product is intended.

The Council on Scientific Affairs has set a mean estimated proportionate reduction in gingival inflammation across two studies of no less than 20% for establishing definite improvement (i.e., clinical significance) of mean gingivitis scores when measured against a masked placebo agent. This last requirement is important because participants in studies that use a placebo agent often show improvement simply because they are in a dental study; have had their teeth, plaque, and gingiva examined; and subsequently are more dentally aware. The Council also recommends that, in addition to measuring plaque quantitatively by any of the traditional indexes, investigators should obtain microbiologic samples from several supragingival sites and should characterize the oral flora in a control group and in the test group. In evaluating the efficacy of a chemotherapeutic agent on gingivitis, the Council recommends that subjective scoring of gingiva, based on tissue color or estimated degree of swelling, and objective measures, such as extent of gingival bleeding on probing or the amount of crevicular fluid flow, should be made.

ANTIPLAQUE AND ANTIGINGIVITIS AGENTS

Bis-biguanides

The bis-biguanides, chlorhexidine and alexidine, are cationic agents with fungicidal activity and bactericidal action against gram-positive and gram-negative organisms. Chlorhexidine is a chlorophenyl biguanide (Figure 45-3) that has been used as the acetate and, more commonly, the gluconate salt (which is more soluble) in mouth rinses, gels, and dentifrices for control of plaque and gingivitis. It binds to anionic groups on the bacterial surface, probably the phosphate groups of teichoic acid in gram-positive bacteria and the phosphate groups of lipopolysaccharides in gram-negative bacteria. When the bis-biguanide binds to the organism, the cell’s membrane becomes permeable, allowing the cytoplasmic contents to leak. At higher concentrations, chlorhexidine causes precipitation of cytoplasmic proteins. By virtue of their cationic properties, the bis-biguanides also bind electrostatically to hydroxyapatite of teeth, to acquired pellicle, to plaque, and to buccal mucosa.

In one of the earliest studies on the dental applications of chlorhexidine, Schroeder91 showed a 73% reduction of supragingival calculus plaques formed on carrier foils in short-term (3-day) tests. Subsequently, Löe and Rindom Schiøtt61 showed that chlorhexidine was the most effective antiplaque and antigingivitis agent that had been tested until that time. In short-term trials with an experimental gingivitis model, a twice-daily rinse with 0.2% chlorhexidine gluconate completely prevented accumulation of plaque and the onset of gingivitis. These observations have been confirmed in numerous trials in humans and animals. Chlorhexidine mouth rinse in this experimental model prevented the development of white-spot lesions associated with incipient caries.63

The efficacy of chlorhexidine mouth rinse as an antiplaque/antigingivitis agent is dose-dependent in the range of 0.03% to 0.2%.6,55 The volume and frequency of use and the concentration are important in determining the clinical response.57 Although no significant difference in response was found between a 0.2% and a 0.12% chlorhexidine mouth rinse when administered in a 15-mL dose twice daily (delivering a total of 60 mg and 36 mg of the agent),92 a significant difference in response was found between a 0.2% and a 0.1% chlorhexidine mouth rinse when administered in a 10-mL dose twice daily (providing 40 mg and 20 mg of the agent).6 Additional factors, such as bioavailability of the formulation, may also affect the dose response.

Long-term use (6 months) of chlorhexidine mouth rinses has shown plaque reduction and significant prevention of gingivitis in children57 and adults.38 In a short-term study (21 days), 0.12% chlorhexidine mouth rinse used twice daily was clearly effective in reducing plaque (62% to 99%) compared with placebo, whereas rinsing with a phenolic compound containing essential oils, or sanguinarine with zinc chloride, resulted in no significant reduction in plaque.95 The chlorhexidine rinse was superior to the other agents in its ability to maintain optimal gingival health during the entire 3 weeks the mouth rinses were used. Similarly, a 0.2% chlorhexidine rinse was approximately twice as effective as a sanguinarine rinse in a 19-day nonbrushing study in which plaque and gingivitis scores were assessed.70 Fluoride (100 ppm), when combined with chlorhexidine (0.12%), does not interfere with the antiplaque/antigingivitis activity of a mouthwash.49 The ADA Council on Scientific Affairs has accepted a mouth rinse containing 0.12% chlorhexidine gluconate as a safe and effective adjunct to brushing and flossing and regular professional care in helping prevent and reduce supragingival plaque and gingivitis.18

Chlorhexidine rinses occasionally produce some undesirable side effects, the most conspicuous being the development of yellow-brown stains on the teeth, anterior restorations, and the dorsum of the tongue. Although the stain is extrinsic, it cannot be removed by brushing with a normal toothpaste; mechanical polishing is necessary for its removal. Chlorhexidine also tends to promote supragingival calculus formation. A few individuals have had mucosal desquamation and soreness. Solutions containing bis-biguanides have a disagreeable, bitter taste that requires masking by compatible flavoring agents to be palatable. Some patients have a persistent aftertaste or disturbed taste sensation.

Extensive safety testing of the short-term and long-term effects of these compounds shows extremely low levels of toxicity locally and systemically. The low toxicity is a result of the poor absorption of chlorhexidine by the oral cavity and gastrointestinal tract, resulting in a limited amount entering the bloodstream. When chlorhexidine directly contacts mammalian connective tissue cells, there is usually a harmful effect. In cell culture, chlorhexidine can adversely affect gingival fibroblast attachment to root surfaces.14 Protein production in human gingival fibroblasts was reduced at chlorhexidine concentrations that would not normally affect cell proliferation.65 Such findings corroborate earlier studies showing delayed wound healing in standardized mucosal wounds after rinsing with a 0.5% chlorhexidine solution.8 No teratogenic or reproductive changes have been found.

Bis-biguanides are effective as antiplaque and antigingivitis agents. They should not be used prophylactically, but as therapeutic agents for patients with active disease. This use requires proper diagnosis and supervised care until the disease is controlled. In the United States, these agents are for prescription use only. Chlorhexidine mouth rinses can serve as an important adjunct to regular oral hygiene for short-term application, particularly in the healing phase after periodontal surgery, oral surgery, and insertion of immediate dentures and for the treatment of acute necrotizing ulcerative gingivitis.55 Chlorhexidine rinses can also be used for intermittent short-term application three to four times a year to prevent repeated denture stomatitis, limit plaque and gingivitis in patients with dental implants, and suppress the salivary titers of S. mutans in patients with high caries activity. Finally, long-term use of such a mouth rinse on a daily, weekly, or biweekly basis may benefit special patients with agranulocytosis, leukemia, hemophilia, thrombocytopenia, kidney disease, bone marrow transplantation, or acquired immunodeficiency syndrome (AIDS); patients being treated with cytotoxic or immunosuppressive drugs or radiation therapy; and patients who are physically handicapped or mentally retarded (Box 45-3).

Investigators have tested more intensive, professionally applied antimicrobial treatment with varnishes containing high concentrations of chlorhexidine compounds: 5%, 10%, 20%, and 40%.54,82-84,86-89 The goals were to suppress S. mutans for an extended period, to prevent the increase of S. mutans normally accompanying placement of fixed orthodontic appliances, and possibly to eliminate them from the mouth. In these studies, S. mutans was successfully suppressed and in some cases eliminated for up to 22 months. There was no long-term effect on Actinomyces species or Streptococcus sanguis, however. A 40% chlorhexidine varnish, applied to exposed root surfaces of patients who had had periodontal surgery, was as effective as a fluoride varnish in preventing root caries.87

Bis-biguanides are useful adjuncts in the treatment of periodontal disease or rampant caries. They are not a panacea or magic bullet; in the absence of conventional therapeutic and preventive measures, bis-biguanides alone have been unable to cure periodontal disease or prevent caries.

Nonionic Bisphenols

Triclosan is a broad-spectrum antimicrobial compound whose chemical name is 2,4,4′-trichloro-2′-hydroxydiphenyl ether (Figure 45-4).90 Originally, triclosan was used extensively in soaps, antiperspirants, and cosmetic toiletries as a germicide.90 Currently, triclosan has been incorporated into toothpaste and mouth rinse because of its wide spectrum of antimicrobial effects, anti-inflammatory actions, and only modest toxicity.66

Triclosan is active against a broad range of oral gram-positive and gram-negative bacteria.90 The antibacterial actions of triclosan were originally thought to affect cell membrane integrity by binding to membrane targets and interfering with transport mechanisms.90 More recent work has shown that the effects of triclosan in bacteria occur by inhibiting the enzyme enoyl-acyl carrier protein redu/>

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Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 45: Antiplaque and Antigingivitis Agents
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