---

CHEMICAL ANTI-PLAQUE AGENTS

Comprehensive Point-wise Theory Examination Notes

---

1. INTRODUCTION AND RATIONALE

• It is well established that the various periodontal diseases are caused by bacterial infection. Bacteria begin reattaching to the crowns of teeth soon after the teeth have been cleaned. Over time, supragingival plaque becomes more complex, leading to a succession of bacteria that are more pathogenic. Bacteria grow in an apical direction and become subgingival, and eventually, as bone is destroyed, a periodontal pocket is formed. (Carranza's Clinical Periodontology, 10th Ed - Chapter 52, Chemotherapeutic Agents)
• Mechanical plaque removal remains to be a primary preventive method to control dental diseases, and it should not be replaced by chemical plaque control. However, chemical plaque control can be used as an adjunct to effectively control gingival inflammation and prevent the recurrence or progression of periodontal disease. (Essentials of Clinical Periodontology and Periodontics - S. Reddy, Chapter 37)
• Chemical methods are very effective during phase I therapy, for patients with recurrent problems, ineffective plaque control for any reason and for use after periodontal or oral surgery. (Essentials of Clinical Periodontology and Periodontics)

---

2. DEFINITION OF KEY TERMS / RECENT TERMINOLOGY CHANGES

Recent Terminology Note (Examiner Keyword): The terminology for these agents has evolved and differs between Europe and North America (Lang & Newman 1997). This distinction is frequently examined.

Note: These definitions are widely accepted in Europe, but in North America the term "antiplaque" refers more often to agents capable of significantly reducing plaque levels and "antigingivitis" to agents capable of significantly reducing gingivitis levels. (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)

---

3. MECHANISM OF ACTION - CHEMICAL PLAQUE CONTROL

• By preventing bacterial adhesion
• By avoiding bacterial growth and/or co-aggregation
• By eliminating an already established biofilm
• By altering the pathogenicity of the biofilm

1. (a) Prevention of bacterial adhesion: The active agent forms a pellicle (blue film) over the tooth surface, interfering with bacterial adhesion, thus avoiding bacterial colonization.
2. (b) Bactericidal or bacteriostatic effect: Avoiding bacterial proliferation and co-aggregation; interference with bacterial division leads to interference with biofilm formation. Biofilm maturation is also prevented as co-aggregation of new species is impeded.
3. (c) Biofilm disruption from tooth surfaces ("chemical brushing"): The agent induces detachment and/or biofilm elimination from the tooth surface by breaking the chemical links between the surface and the biofilms, and by disrupting the biofilm structure.
4. (d) Alteration of biofilm pathogenicity or enhancement of host immune systems: Enhanced host defense systems provide more effective biofilm control by the host; or presence of defined bacterial species that may influence biofilm development and maturation, by means of the release of different products, such as bacteriocins, or by competition for nutrients. (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)

---

4. IDEAL PROPERTIES OF CHEMICAL ANTI-PLAQUE AGENTS

4a. Lang & Newman / Loesche / van der Ouderaa / Baker / Fischman (1994) - Ideal Features:

1. Specificity: Agents and formulations for chemical plaque control should demonstrate a wide spectrum of action, including against bacteria, viruses, and yeasts. More specific products, such as antibiotics, must not be used in the prevention of periodontal diseases.
2. Efficacy: Antimicrobial capacity must be demonstrated against microorganisms implicated in gingivitis and periodontitis, in both in vitro and in vivo studies. Bactericidal effects may be only achieved at high dosages, but antimicrobial effects should also be present at lower dosages.
3. Substantivity: The duration of the antimicrobial action in vivo (FDI Commission 2002b); a measurement of the contact time between the agent and the substrate in a defined medium. This time may be longer than expected with simple mechanical deposition.
4. Safety: Must be demonstrated in animal models before use in humans. Due to the chronicity of the conditions to be prevented and the expected long-term use, secondary effects must be minimal.
5. Stability: Agents must be stable at room temperature for an extended period of time. Care should be taken when mixing different ingredients in a formulation to avoid interference between molecules. (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)

4b. Ideal Properties as described in Periodontology for the Dental Hygienist:

1. Antiplaque action - bactericidal (causing cell death) or bacteriostatic (affecting functioning of cells to render them less virulent by affecting bacterial adhesion, growth, or metabolism).
2. Substantivity - the ability to adhere to structures in the oral environment and be released slowly over time, enhancing the duration of effectiveness. The bacterial population in the mouth recovers rapidly from the assault of many antibacterial agents because they are rapidly cleared by saliva flow and swallowing.
3. Low toxicity and nonirritating - Agents must be nontoxic to tissues because they must adhere for a substantial period.
4. Low permeability - The oral mucosal tissue is easily permeated by chemicals. An effective antiplaque agent must have low permeability to allow its retention in the oral cavity. (Periodontology for the Dental Hygienist - Chapter 12)

4c. Ideal Properties of a Mouthwash (Essentials of Clinical Periodontology - S. Reddy):

1. Eliminate pathogenic microorganisms only.
2. Prevent development of resistant bacteria.
3. Exhibit substantivity.
4. Be safe to oral tissues at the recommended concentration.
5. Significantly reduce plaque formation and gingivitis.
6. Inhibit calcification of plaque to calculus.
7. Not cause staining and alter taste.
8. Not have adverse effects on teeth or dental materials.
9. Be easy to use.
10. Be inexpensive. (Essentials of Clinical Periodontology and Periodontics - S. Reddy)

---

5. GENERATIONS OF ANTI-PLAQUE AGENTS - CLASSIFICATION BY SUBSTANTIVITY

Examiner Keyword: "Generations" Classification (Kornman 1986a)

---

6. CLASSIFICATION OF CHEMICAL ANTI-PLAQUE AGENTS

6a. Classification by Groups of Agents (Addy's Classification) - Chemicals Used for Supragingival Plaque Control:

6b. Complete Classification (A Textbook of Public Health Dentistry / Soben Peter):

---

7. EVALUATION OF ACTIVITY - STUDY DESIGN REQUIREMENTS

[FLOWCHART: Evaluation Phases for Chemical Anti-Plaque Agents]

Phase 1: IN VITRO STUDIES
    --> Bacterial tests: Measure Minimum Inhibitory Concentration (MIC)
    --> Biofilm model tests
              |
              v
Phase 2: SHORT-TERM CLINICAL STUDIES
    --> Plaque regrowth studies (3-4 days, no brushing)
    --> 4-week studies with regular brushing
              |
              v
Phase 3: MEDIUM-TERM STUDIES
    --> 3-month randomized controlled trials
              |
              v
Phase 4: LONG-TERM RANDOMIZED CLINICAL TRIALS
    --> Minimum 6-MONTH DURATION (MANDATORY)
    --> Include: microbiologic evaluation, plaque index, gingival index
    --> Baseline + intermediate (3 months) + final evaluation
              |
              v
REGULATORY APPROVAL: ADA Seal of Acceptance

• Based on the availability of at least two independent investigations of 6-month duration demonstrating significant differences, as compared with the negative control, for plaque and gingivitis, different products have received a "seal of approval" for plaque inhibitory and/or antiplaque activity from the American Dental Association (ADA) and the Food and Drug Administration (FDA). (Clinical Periodontology and Implant Dentistry, 6th Ed)
• The ADA Council on Dental Therapeutics has adopted a program for acceptance of plaque control agents. The agents must be evaluated in placebo-controlled clinical trials of 6 months or longer and demonstrate significantly improved gingival health compared with controls. To date, only two agents have been accepted by ADA for treatment of gingivitis: chlorhexidine digluconate mouthwash and essential oil mouthrinse. (Essentials of Clinical Periodontology and Periodontics - S. Reddy)

---

8. INDIVIDUAL AGENTS - DETAILED DESCRIPTIONS

---

8A. BISBIGUANIDES - CHLORHEXIDINE (THE GOLD STANDARD)

Examiner Keyword: "Gold standard" anti-plaque agent; Second-generation agent with highest substantivity

History and Background:

• Chlorhexidine is a bisbiguanide, developed in the 1940s by Imperial Chemical Industries, England and marketed in 1954 as an antiseptic for skin and mucous membrane.
• Plaque inhibition by chlorhexidine was first investigated in 1969 by Schroeder, but a definitive study was performed by Loe and Schiott in 1970.
• Now, it is the most effective antiplaque and antigingivitis agent approved for clinical use. (A Textbook of Public Health Dentistry - Chapter 26)
• Chlorhexidine is considered the most effective antiplaque and antigingivitis agent (Carranza's 10th Ed; Newman & Carranza 14th Ed).
• It is a cationic bisbiguanide that has been used as a broad-spectrum antiseptic in medicine since the 1950s. (Carranza's Clinical Periodontology, 10th Ed - Chapter 52)

Chemical Nature:

• Cationic agent - this favors attraction to tooth surfaces and bacterial plaque. (A Textbook of Public Health Dentistry)

Mechanism of Action:

1. Chlorhexidine binds to hydroxyapatite and glycoprotein to prevent pellicle formation.
2. The antiseptic binds strongly to bacterial cell membranes.
3. At LOW concentration: results in increased permeability with leakage of intracellular components including potassium.
4. At HIGH concentration: causes precipitation of bacterial cytoplasm and cell death.
5. Also absorbs to the bacterial cell surface and may interfere with cell attachment. (A Textbook of Public Health Dentistry - Chapter 26)

• Its antibacterial action can be explained by disruption of bacterial cell membrane by the chlorhexidine molecules, increasing its permeability and resulting in cell lysis and death. (Carranza's 10th Ed; Newman & Carranza 14th Ed)
• It is related to increased bacterial cell wall permeability that favors lysis, decreased cell metabolism, and a decreased ability for bacteria to attach to tooth surfaces. These agents are categorized as cationic, which favors their attraction to tooth surfaces and bacterial plaque. (A Textbook of Public Health Dentistry)

Efficacy:

• Reduces plaque by 55% and gingivitis by 45% (long-term studies).
• Reduces plaque and gingivitis by 60% in short-term studies and by 55% and 45%, respectively, in separate long-term studies. (Periodontology for the Dental Hygienist; A Textbook of Public Health Dentistry)
• It is more effective in preventing plaque accumulation on a clean tooth surface than in reducing pre-existing plaque deposits. (A Textbook of Public Health Dentistry)
• Chlorhexidine is either bacteriostatic or bactericidal, depending on the dose. (Carranza's 10th Ed)

Substantivity:

• Chlorhexidine has demonstrated the highest substantivity and this is associated with its strongest antiplaque effects. Duration of effects: up to 12 hours (Schiott et al. 1970).
• It demonstrates good substantivity (second-generation agent). (Clinical Periodontology and Implant Dentistry, 6th Ed)
• Substantive agents, such as chlorhexidine digluconate, possess positively charged ions that adhere to the predominantly negatively charged tissues in the mouth for several hours. They remain in the mouth for some time to exert a continued effect on plaque bacteria. (Periodontology for the Dental Hygienist)

Formulations and Dosage:

• 10 ml of 0.2% solution delivers 20 mg and 15 ml of 0.12% solution delivers 18 mg; both of these amounts are above the therapeutic dose and hence equally effective. (A Textbook of Public Health Dentistry - Chapter 26)

Instruction for Use:

• It is recommended that the individual should rinse for 60 seconds after brushing and flossing twice a day.
• The person should allow at least 30 minutes between toothbrushing and rinsing because of interaction (and inactivation) between chlorhexidine and sodium lauryl sulfate, a common ingredient in dentifrices.
• Patient should not rinse with water immediately after it is used. (A Textbook of Public Health Dentistry - Chapter 26)
• Recommend use full strength (0.12%), twice daily for 30 seconds using 15 mL of rinse. (Periodontology for the Dental Hygienist)
• Chlorhexidine is a prescription rinse for short-term use (<6 months); long-term use (>6 months) has not been extensively studied. (Carranza's 10th Ed - Chapter 52)

Side Effects:

Examiner Keyword: Majority of CHX side effects are LOCAL in nature

1. Brown discoloration of the teeth, margins and surface of composite and glass ionomer restorations.
2. Unpleasant taste and disturbance in taste sensation.
3. Brown discoloration of dorsum of tongue, due to interaction between locally adsorbed chlorhexidine and factors derived from diet such as tannin-like substances in red wine, tea and coffee.
4. Unilateral or bilateral parotid swelling (mechanical obstruction of parotid duct) - an extremely rare occurrence.
5. Desquamative lesion of oral mucosa in some individuals.
6. Enhanced supragingival calculus formation - due to the precipitation of salivary proteins on to the tooth surface, thereby increasing pellicle thickness and/or precipitation of inorganic salts on to the pellicle layer. (A Textbook of Public Health Dentistry - Chapter 26)

• Hypersensitivity reaction (Beaudouin et al. 2004)
• Neurosensory deafness if the product is placed in the middle ear (Aursnes 1982)
• Taste alterations (Marinone & Savoldi 2000; Breslin & Tharp 2001) - particularly affecting salty and bitter taste; reversible and disappear soon after discontinuation
• Uni- or bi-lateral parotid tumefaction (Fløtra et al. 1971)
• Mucosal erosion (Almqvist & Luthman 1988)
• Healing process alterations - in vitro studies have suggested some inhibition of fibroblast proliferation; however, in vivo studies of CHX mouth rinses after periodontal surgery have found no interference with the healing process; indeed, better resolution of inflammation was observed
• Increase in calculus formation (Yates et al. 1993)
• Staining of teeth, mucosa, tongue dorsum, or restorations (Fløtra et al. 1971)

• Degradation of the CHX molecule to para-chloraniline
• Catalysis through Maillard reactions
• Protein denaturation with formation of metal sulfide

Safety Note: Only heating for long periods of time can induce the formation of 4-chloroaniline, which has been shown to be carcinogenic and mutagenic. Despite the low risk, CHX formulations are marketed in dark bottles and should be kept at room temperature, out of direct sunlight. (Clinical Periodontology and Implant Dentistry, 6th Ed)

Important: No adverse microbiologic changes, including the overgrowth of opportunistic strains, are induced over long-term use. (Clinical Periodontology and Implant Dentistry, 6th Ed)

ADA Approval:

• The American Dental Association (ADA) Council on Dental Therapeutics has approved chlorhexidine to help prevent and reduce supragingival plaque and gingivitis. (Carranza's 10th Ed - Chapter 52)

Other Bisbiguanides:

• Alexidine and Octenidine have similar activity but bring with them no improvement in local side effects and have less toxicity data available than chlorhexidine. (A Textbook of Public Health Dentistry)

---

8B. ESSENTIAL OILS (PHENOLIC COMPOUNDS)

Examiner Keyword: Listerine; ADA-approved; Second ADA-approved agent for gingivitis

Composition:

• Listerine is an essential oil mouthrinse and is a mixture of three phenolic-derived essential oils - thymol, menthol and eucalyptol combined with methylsalicylate in a hydroalcoholic vehicle. (A Textbook of Public Health Dentistry - Chapter 26)
• Active ingredients in Listerine are methyl salicylate and three essential oils (eucalyptol, thymol, and menthol). Alcohol content ranges from 21.6% to 26.9% (original formula: 26.9%). (Carranza's 10th Ed - Chapter 52)
• Mouth rinse with eucalyptol (0.092%), menthol (0.042%), thymol (0.064%), and methyl salicylate (0.06%), in an alcohol vehicle (21.6-26.9%). (Clinical Periodontology and Implant Dentistry, 6th Ed)

Mechanism of Action:

• Mechanism of action appears to be related to alteration of the bacterial cell wall. (A Textbook of Public Health Dentistry)

Efficacy:

• Moderate antiplaque and antigingivitis effects.
• Listerine has been shown to be effective in reducing plaque and gingivitis compared with placebo rinses.
• Essential oil mouth rinse shows 60% of the effect of CHX mouth rinses for both plaque and gingival parameters (Gunsolley 2006 meta-analysis). (Clinical Periodontology and Implant Dentistry, 6th Ed)
• Regular use of essential oil mouth rinse may be as effective as flossing for subjects with normal gingival architecture. (Carranza's 10th Ed)
• ADA approved for gingivitis treatment. Listerine antiseptic and its generic counterparts are approved by the ADA Council on Dental Therapeutics to help prevent and reduce supragingival plaque and gingivitis. (Carranza's 10th Ed - Chapter 52)

Administration:

• It is recommended that a person rinse for 30 seconds with half ounce of Listerine after brushing and flossing twice a day.
• Advisable for patients with extensive fixed prosthesis, implants, overdentures, splinting, orthodontics, and individuals with poor manual dexterity. (A Textbook of Public Health Dentistry)

Contraindications:

• Due to its high alcohol content (original Listerine formula contains 26.9% alcohol) it should not be recommended for:
  • Persons with xerostomia
  • Children
  • Persons on medications that interact with alcohol
  • Patients under treatment for alcoholism who take Antabuse (disulfiram) (A Textbook of Public Health Dentistry; Carranza's 10th Ed)

Side Effects:

• Burning sensation, bitter taste and staining.
• May exacerbate xerostomia because of its high alcohol content. (A Textbook of Public Health Dentistry)

---

8C. TRICLOSAN

Examiner Keyword: Nonionic chlorinated phenolic; Copolymer PVM/MA; Environmental/health concerns (recent regulatory change)

• Triclosan is a synthetic nonionic chlorinated phenolic agent with antiseptic qualities.
• Triclosan has a broad-spectrum efficacy on gram-positive and most gram-negative bacteria.
• Also effective against mycobacterium and strictly anaerobic bacteria, and against the spores and fungi of the Candida species. (A Textbook of Public Health Dentistry - Chapter 26)
• Triclosan is a noncationic, chlorinated phenol. (A Textbook of Public Health Dentistry)

Mechanism of Action:

• Mechanism of antiseptic action: by acting on the microbial cytoplasmic membrane, inducing leakage of cellular constituents and thereby causing lysis of the microorganisms. (A Textbook of Public Health Dentistry)

Efficacy:

• Despite its activity in vitro, clinical plaque studies have revealed only moderate levels of antiplaque activity when used alone.
• Evidence has accumulated that triclosan in itself does not produce optimal plaque inhibitory effects without the addition of other chemicals which increase its antibacterial effect.
• Most commonly used enhancers: copolymer PVM/MA (polyvinylmethyl ether maleic acid) and zinc citrate - they enhance surface retention of triclosan.
• Triclosan and copolymer dentifrices reduce plaque by 12-59% and gingivitis by 20-30%. (A Textbook of Public Health Dentistry - Chapter 26)
• In simple solutions, at a relatively high concentration (0.2%) and dose, triclosan has moderate plaque inhibitory action.
• The copolymer appears to enhance the retention of triclosan whereas zinc is a highly substantive antimicrobial agent. When combined with triclosan, it exhibits synergistic action. (A Textbook of Public Health Dentistry)

Recent Regulatory Update (Examiner Keyword): "For several years, triclosan was a popular ingredient. Recently, concerns over their environmental and health effects have resulted in the..." (Newman & Carranza 14th Ed). Triclosan was withdrawn/restricted from many formulations due to regulatory concerns. (Newman & Carranza's Clinical Periodontology and Implantology, 14th Ed)

---

8D. QUATERNARY AMMONIUM COMPOUNDS (QACs)

Examiner Keyword: Cationic; Poor substantivity; First-generation agents

• Benzylconium chloride and Cetylpyridinium chloride are the quaternary ammonium salts frequently used.
• Mode of action: Lysis of the bacterial cell wall.
• They are cationic, which favors their attraction to tooth surfaces and bacterial plaque. Related to increased bacterial cell wall permeability that favors lysis, decreased cell metabolism, and a decreased ability for bacteria to attach to tooth surfaces.
• Substantivity of cetylpyridinium chloride appears limited compared with chlorhexidine. (A Textbook of Public Health Dentistry - Chapter 26)
• Examples: Cetylpyridinium chloride (CPC), Benzethonium chloride, Benzalkonium chloride, Domiphen bromide. (Essentials of Clinical Periodontology and Periodontics - S. Reddy)
• Active ingredients of proven efficacy such as chlorhexidine, cetylpyridinium chloride... (Newman & Carranza's 14th Ed)

---

8E. NATURAL PRODUCTS / HERBAL EXTRACTS

Sanguinarine:

Examiner Keyword: Benzophenanthridine alkaloid; Bloodroot; Oral leukoplakia (withdrawal reason)

• Sanguinarine, a benzophenanthridine alkaloid, is an alcohol extract from the root of the plant Sanguinaria canadensis (bloodroot).
• Sanguinarine contains the chemically reactive iminium ion which is probably responsible for its activity.
• The activity of sanguinarine is attributed to its ability to:
  • Interfere with bacterial glycolysis
  • Bind to plaque to prevent adherence of microorganisms
• It is less active than chlorhexidine and no side effects are seen.
• Zinc salts are also added, which makes it difficult to evaluate the efficacy of sanguinarine alone.
• Mouthwash is a much more effective plaque-inhibitory agent than the toothpaste.
• Effectiveness is enhanced when both the mouthrinse and the dentifrices are used. (A Textbook of Public Health Dentistry - Chapter 26)
• Sanguinarine extract is an alkaloid obtained from the plant Sanguinaria canadensis. (Clinical Periodontology and Implant Dentistry, 6th Ed)
• Use of formulations of sanguinarine was associated with oral leukoplakia (Mascarenhas et al. 2002).
• Viadent (Colgate-Palmolive Co., Piscataway, NJ, USA), with sanguinarine extract is no longer available. (Clinical Periodontology and Implant Dentistry, 6th Ed)
• Sanguinarine is one of the antiseptic agents in chemical plaque control. Also described as a first-generation agent (poor substantivity). (Essentials of Clinical Periodontology and Periodontics - S. Reddy)

---

8F. ENZYMES

• They fall into two groups (A Textbook of Public Health Dentistry):

• Not truly antimicrobial agents but more plaque removal agents - they have the potential to disrupt the early plaque matrix, thereby dislodging bacteria from the tooth surface.
• Examples: dextranase, mutanase and various protease.
• Such agents had poor substantivity and had local side effects such as mucosal erosion.

• Employed glucose oxidase and amyloglucoxidase to produce hydrogen peroxide from dietary fermentable carbohydrates.
• The aim was to catalyze the conversion of endogenous and exogenous thiocyanate to hypothiocyanate via the salivary lactoperoxidase system.
• The hypothiocyanate produces inhibitory effect upon oral bacteria, particularly streptococci, to interfere with their metabolism. (A Textbook of Public Health Dentistry - Chapter 26)
• Characteristics: Very limited substantivity and frequent side effects (Addy 1986).
• Evaluation: Use in vivo is limited due to side effects.
• Limitations: Frequent side effects (Hull 1980; Addy 1986).
• Usefulness, marketed: No. (Clinical Periodontology and Implant Dentistry, 6th Ed)
• Results for in vivo effect on gingivitis have been contradictory and no long-term studies are available.
• Marketed as Zendium® (Opus Health Care AB, Malmö, Sweden) in a mouth rinse with amyloglucosidase, glucosidase and lactoperoxidase, sodium fluoride, xylitol and zinc, and no alcohol; and in toothpaste.
• Another commercialized toothpaste is Bioxtra® (Bio-X Healthcare, Namur, Belgium), with lactoferrin, lysozyme, and lactoperoxidase. (Clinical Periodontology and Implant Dentistry, 6th Ed)

---

8G. AMINE ALCOHOLS - DELMOPINOL

Examiner Keyword: Biofilm matrix inhibitor (not antimicrobial); Decapinol; FDA approved 2005

• Delmopinol and Octapinol. (A Textbook of Public Health Dentistry - Chapter 26; Clinical Periodontology and Implant Dentistry, 6th Ed)

Mechanism of Action:

• Mechanism of action is not fully understood, but they are not antimicrobials and their effect is achieved by the inhibition of biofilm matrix formation or disruption of the biofilm matrix.
• Delmopinol also inhibits glucane synthesis by Streptococcus mutans (Rundegren et al. 1992; Elworthy et al. 1995) and reduces acid synthesis by bacteria (Simonsson et al. 1991). (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)

Evaluation:

• Delmopinol has been formulated and clinically evaluated as a mouth rinse at 0.1% and 0.2%.
• Demonstrated efficacy as an antiplaque agent in a systematic review (Addy et al. 2007).
• Approved by the FDA in 2005 as a 0.2% mouth rinse indicated in the treatment of gingivitis (Imrey et al. 1994).

Side Effects:

• Dental staining
• A temporary feeling of numbness in the mucosa (e.g. tongue)
• A burning sensation

Marketed as:

• Decapinol® (Sinclair Pharma, Paris, France) - both as a 0.2% mouth rinse with 1.5% of alcohol, and as a 0.2% toothpaste with 0.11% sodium fluoride. (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)

---

8H. METAL SALTS

Zinc Salts:

• Zinc lactate, zinc citrate, zinc sulfate, and zinc chloride. (Clinical Periodontology and Implant Dentistry, 6th Ed)
• Zinc citrate is formulated with citrate to reduce its metallic taste. When combined with triclosan it exhibits synergistic action.
• Zinc is a highly substantive antimicrobial agent. (A Textbook of Public Health Dentistry)

Stannous Fluoride:

• It has more antiplaque properties than sodium fluoride.
• Increased tooth staining and weak antiplaque activity significantly limit the potential application of stabilized stannous fluoride formulations.
• Stannous fluoride is also available in a gel formulation. (A Textbook of Public Health Dentistry - Chapter 26)

Copper:

• Copper causes staining similar to antiseptics like triclosan and sanguinarine. (A Textbook of Public Health Dentistry)

---

8I. FLUORIDES

• Sodium fluoride, Sodium monofluorophosphate, Stannous fluoride.
• Usefulness has been demonstrated in reducing caries incidence (Petersson 1993).
• Fluoride ion has not demonstrated plaque-inhibitory or antiplaque properties (sodium fluoride and MFP).
• Present in most dentifrices. (Clinical Periodontology and Implant Dentistry, 6th Ed)

---

8J. OXYGENATING AGENTS

• Sodium peroxyborate, peroxycarbonate, and hydrogen peroxide.
• Mechanism: Exert antimicrobial effects through the release of oxygen.
• Peroxyborate and peroxycarbonate have demonstrated some antimicrobial and plaque inhibitory activity (Moran et al. 1995).
• Hydrogen peroxide evaluated in a systematic review (Hossainian et al. 2011): at higher concentrations, painful sensation in the mouth and ulcers may be frequent (Rees & Orth 1986).
• Marketed as: Peroxyborate (Bocasan®, Amosan®), Peroxycarbonate (Kavosan®), Hydrogen peroxide as Rembrant® (Dent-Mat Corp., Santa Maria, CA, USA). (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)

---

8K. STANNOUS/AMINE FLUORIDE

• Amine fluoride was developed in the 1950s at the University of Zurich.
• Stannous fluoride and amine fluoride have both demonstrated bactericidal activity against bacteria, and activity is increased if combined.
• Amine fluoride exerts its antimicrobial action by antiglycolytic effects.
• Activity of stannous/amine fluoride seems to be greater as a dentifrice, with 8 hours of action following use (Weiland et al. 2008).
• Marketed as Meridol® (GABA International AG, Therwil, Switzerland) - both as dentifrice and mouth rinse.
• Most common adverse effect: tooth staining. (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)

---

8L. SODIUM LAURYL SULFATE (SLS) / DETERGENTS

• The most important and frequently used detergent or surfactant (active-surface compound) is sodium lauryl sulfate (SLS).
• Substantivity: 5-7 hours.
• The foaming properties of detergents may help in removing plaque, although there is insufficient evidence to support this statement.
• Evaluation: SLS has a limited antimicrobial and plaque-inhibitory effect (Addy et al. 1983; Moran et al. 1988).
• Limitation: SLS has been associated with oral hypersensitivity reactions, including cheilitis, stomatitis or aphthous ulcers, burning sensation, and desquamation.
• SLS is present in many dentifrice and mouth rinse formulations but has not been formulated as a single active agent product. (Clinical Periodontology and Implant Dentistry, 6th Ed - Chapter 37)
• Enzymes glucosyltransferase and fructosyltransferase are incorporated in an active form into the pellicle; by synthesizing glucan from sucrose, can provide a surface for colonization by Streptococcus mutans. These enzymes can be inhibited by SLS, hence retarding the regrowth of plaque. (A Textbook of Public Health Dentistry - Chapter 26)

---

8M. ANTIBIOTICS (TOPICAL USE FOR PLAQUE CONTROL)

Examiner Keyword: NOT recommended for routine plaque control due to risk-benefit ratio

• Examples: Penicillin, Vancomycin, Kanamycin, Spiramycin, Metronidazole.
• Despite evidence for efficacy in preventing caries and gingivitis, antibiotics should not be used either topically or systemically as preventive agents against these diseases.
• The risk-to-benefit ratio is high.
• Antibiotics have their own side effects:
  • Development of bacterial resistance (most important)
  • Hypersensitivity reactions
  • Penicillin dentifrices were used experimentally but were not accepted; major deterrent: possible allergic sensitization, development of resistant strains and overgrowth of unwanted microorganisms. (A Textbook of Public Health Dentistry - Chapter 26)
• Use against dental plaque is not recommended due to the poor benefit-to-risk ratio, including adverse effects and increase in bacterial resistance. (Clinical Periodontology and Implant Dentistry, 6th Ed)

---

9. DELIVERY SYSTEMS / VEHICLES FOR CHEMICAL AGENTS

[FLOWCHART: Delivery Systems]

CHEMICAL ANTI-PLAQUE AGENTS
          |
   _______|_______
  |               |
LOCAL           SYSTEMIC
DELIVERY        (Antibiotics only, not
                recommended for plaque control)
  |
  |---> MOUTH RINSES (most common vehicle)
  |         Advantages:
  |         - Favorable pharmacokinetics
  |         - Can be used independently of ability to brush
  |         - Access to difficult-to-reach areas
  |         - Easy to use and well accepted
  |
  |---> DENTIFRICES (toothpastes)
  |         Ideal delivery - adjunct to toothbrushing
  |         Disadvantages:
  |         - Formulation of some agents difficult
  |         - Less predictable pharmacokinetics
  |
  |---> GELS (no abrasives or detergents)
  |         Active agents formulated more easily
  |
  |---> CHEWING GUMS
  |         Promote salivation; agent released after chewing
  |         CHX acetate / CHX-xylitol chewing gums
  |
  |---> VARNISHES
  |         Used to deliver antiseptics (mainly CHX)
  |         Mainly for root caries prevention
  |
  |---> SPRAYS
  |         0.2% CHX sprays for disabled patients
  |         Dosage not predictable
  |
  |---> IRRIGATORS (Supragingival and Subgingival)
  |         Remove food debris; useful for non-mechanical
  |         device users; CHX, essential oils used
  |
  |---> LOZENGES / CHEWING GUM (CPC, CHX)
  |
  |---> SUSTAINED-RELEASE DEVICES
            CHX chips, gels, xanthan gels
            (see local drug delivery)

---

10. CLINICAL INDICATIONS FOR CHEMICAL PLAQUE CONTROL

1. Phase I therapy (initial periodontal therapy)
2. Patients with recurrent problems
3. Ineffective plaque control for any reason
4. Use after periodontal or oral surgery (particularly regenerative or mucogingival surgery)
5. Patients who cannot adequately perform mechanical plaque control due to disease or disability
6. Patients with fixed orthodontic appliances, implants, prostheses
7. Patients at risk for gingival hyperplasia (phenytoin, calcium channel blockers, cyclosporines)
8. Preprocedural use (rinse before dental procedures - essential oils shown to affect aerolized bacterial load)
9. Short-term use: single rinse before procedures, or for acute episodes
10. Long-term use: preventive or therapeutic aim

---

11. COMPARISON TABLE - MAJOR ANTI-PLAQUE AGENTS

---

12. COMPARISON OF VIEWPOINTS ACROSS REFERENCES

---

13. DENTIFRICES - COMPONENTS AND ACTIVE AGENTS

Examiner Keyword: Components of a dentifrice

1. Abrasives - determine consistency; ease plaque and stain removal; most common: calcium carbonate, alumina, dicalcium phosphate, and silica
2. Detergents - most widely used is SLS; provides some antimicrobial action; no evidence to support its effectiveness in plaque removal
3. Thickeners - include silica and gums; influence viscosity
4. Sweeteners - such as sodium saccharin
5. Humectants - prevent toothpaste from drying up; glycerine and sorbitol are most common
6. Flavorings - such as mint and strawberry
7. Coloring agents
8. Active agents - including fluorides, triclosan, CHX (with formulation difficulties), CPC, and other active agents (anticalculus agents, whitening products, desensitizing agents)

---

14. ANTI-CALCULUS AGENTS (Distinction from Anti-Plaque Agents)

Examiner Keyword: Anti-calculus / Tartar control toothpastes - Do NOT affect existing calculus

• These dentifrices are formulated to inhibit the development of new calculus and contain pyrophosphate or zinc.
• They have NO effect on existing calculus. (A Textbook of Public Health Dentistry - Chapter 26)
• Clinical studies show approximately 20-40% reduction in supragingival calculus formation when anticalculus toothpastes are used.
• Data from one study of pyrophosphate-containing toothpaste reported a 25.9% reduction in supragingival calculus formation on six lower anterior teeth.
• Zinc citrate dentifrice reduced new supragingival calculus formation by 32.3% and pyrophosphate paste reduced it by 21.4% compared with control.
• Triclosan, together with a copolymer, reduced supragingival calculus formation by about 36% compared with control. (Periodontology for the Dental Hygienist - Chapter 12)

---

15. ANTI-PLAQUE AGENTS IN SPECIFIC PATIENT SITUATIONS (Carranza's 10th Ed)

• Patients who cannot or will not control supragingival plaque through mechanical means.
• Patients with systemic conditions that may increase susceptibility to periodontal infections.
• Refractory cases.
• Patients who have had periodontal surgery.
• Patients who cannot adequately perform mechanical plaque control secondary to disease or disability - benefit from antiplaque agents such as chlorhexidine, subantimicrobial tetracycline, and Listerine.
• Patients taking phenytoin, calcium channel blockers, or cyclosporines and who are at risk for gingival hyperplasia. (Carranza's 10th Ed - Chapter 52)

---

16. RECENT UPDATES FROM NEWMAN & CARRANZA 14TH ED (2023)

• Triclosan: "For several years, triclosan was a popular ingredient. Recently, concerns over their environmental and health effects have resulted in..." [regulatory review and withdrawal from many formulations].
• Cetylpyridinium chloride (CPC): It has been proposed that frequent use of CPC could result in phenotypic adaptation or resistance - emergence of phenotypic adaptation or resistance to cetylpyridinium chloride in non-oral bacteria was recently reviewed by Mao.
• Stannous fluoride (SnF) comparison with triclosan: Both SnF and triclosan enhanced plaque removal. Triclosan was more effective at removing plaque; SnF was more effective at reducing bleeding.
• Antimicrobial mouthrinses for chemical plaque control are not a replacement for mechanical plaque control. (Newman & Carranza's Clinical Periodontology and Implantology, 14th Ed)

---

17. MICROBIOLOGY PERSPECTIVE (Samaranayake - Essential Microbiology for Dentistry, 5th Ed)

Note: The microbiology text contains general antiseptic/antibiotic principles applicable to understanding chemical plaque control agents. The chapter on chlorhexidine and antimicrobials supports the mechanism of action of bisbiguanides in terms of bacterial cell membrane disruption. (Essential Microbiology for Dentistry - Lakshman Samaranayake, 5th Ed)

---

18. ANTIPLAQUE AGENTS IN PHARMACOLOGY CONTEXT (Pharmacology and Therapeutics for Dentistry, 7th Ed - Dowd, Johnson, Mariotti)

• This reference (Dowd, Johnson, Mariotti - 7th Ed, 2017, Elsevier) provides pharmacological principles for dental antiseptics, with the companion website containing thousands of PubMed-linked references on antiplaque agents. (Pharmacology and Therapeutics for Dentistry - 7th Ed)

---

19. EXAMINER KEYWORD SUMMARY TABLE

---

20. CLINICAL SITUATIONS - SELECTION OF AGENTS (Flowchart)

[FLOWCHART: Clinical Indications - Selection of Agents]

PATIENT NEEDS CHEMICAL PLAQUE CONTROL?
              |
    __________|___________
   |                      |
SINGLE USE             SHORT-TERM USE
(e.g., pre-procedure   (therapeutic or preventive aim)
rinse)                         |
   |                   ________|________
Recommended:          |                 |
Essential oils     THERAPEUTIC      PREVENTIVE
(EO) - single       PURPOSE          PURPOSE
rinse; shown to         |                |
affect aerolized    CHX (0.12% or    EO or CPC
bacterial load      0.2% mouthrinse)  mouthrinse
                    [1-4 weeks]
                          |
                   LONG-TERM USE
                   (>6 months)
                          |
                   EO mouthrinse
                   (CHX: prescription
                   only; cosmetic side
                   effects limit long-term
                   use)

---

Professor's Note for Examinees: Questions on chemical anti-plaque agents frequently ask: (1) Classification with generations, (2) Chlorhexidine - mechanism, substantivity, side effects, dose, (3) Comparison of CHX vs. Essential oils, (4) ADA-approved agents, (5) Ideal properties, (6) Sanguinarine withdrawal and oral leukoplakia, (7) Delmopinol as a unique biofilm matrix inhibitor, (8) Triclosan regulatory updates. Always mention the Loe and Schiott 1970 landmark study for chlorhexidine and cite the generations classification by Kornman 1986a when asked about classification.

---

1. Clinical Periodontology and Implant Dentistry, 6th Edition (Lang, Lindhe et al.) - Chapter 37: Chemical Oral and Dental Biofilm Control
2. Carranza's Clinical Periodontology, 10th Edition (Newman, Takei, Klokkevold, Carranza) - Chapter 52: Chemotherapeutic Agents
3. Newman & Carranza's Clinical Periodontology and Implantology, 14th Edition - Various chapters
4. Essentials of Clinical Periodontology and Periodontics (S. Reddy) - Chapter 37: Plaque Control
5. A Textbook of Public Health Dentistry - Chapter 26: Plaque Control
6. Soben Peter: Essentials of Public Health Dentistry, 6th Edition, 2017
7. Periodontology for the Dental Hygienist - Chapter 12: Plaque Biofilm and Disease Control
8. Pharmacology and Therapeutics for Dentistry, 7th Edition (Dowd, Johnson, Mariotti)
9. Essential Microbiology for Dentistry, 5th Edition (Lakshman Samaranayake)
10. Fundamentals of Periodontal Instrumentation

---

LANDMARK & EXAMINATION-RELEVANT RESEARCH ARTICLES

Chemical Anti-Plaque Agents — MDS Periodontology

---

SECTION A: CLASSIC LANDMARK PAPERS (Pre-PubMed Era — Know These by Heart)

---

1. Löe H & Schiøtt CR (1970)

---

2. Schroeder HE (1969)

---

3. Kornman KS (1986)

---

4. Lang NP & Newman MG (1997)

---

5. Addy M & Moran JM (1997)

---

6. Grossman E et al. (1989)

---

7. Watts A & Addy M (2001)

---

SECTION B: HIGH-IMPACT SYSTEMATIC REVIEWS AND META-ANALYSES

---

8. Gunsolley JC (2006)

---

9. Gunsolley JC (2010)

---

10. Van Strydonck DAC, Slot DE, Van der Velden U, Van der Weijden F (2012)

---

11. James P, Worthington HV, Parnell C et al. (2017)

---

12. Araujo MWB, Charles CA, Weinstein RB et al. (2015)

---

13. Escribano M, Figuero E, Martín C et al. (2016)

---

14. Figuero E, Herrera D, Tobías A et al. (2019)

---

15. Van der Weijden FA, Van der Sluijs E, Ciancio SG, Slot DE (2015)

---

16. Langa GPJ, Muniz FWMG, Costa RDSA et al. (2021)

---

17. Windhorst ER, Joosstens M, van der Sluijs E, Slot DE (2025)

---

SUMMARY TABLE — LANDMARK PAPERS AT A GLANCE

---

Professor's Note: In a postgraduate viva or written examination, citing Löe & Schiøtt 1970 (history), Kornman 1986 (classification), Gunsolley 2006 (meta-analysis), James et al. 2017 (Cochrane), and Escribano 2016 + Figuero 2019 (Network MAs) will comprehensively cover the evidence landscape. The Figuero 2019 finding that essential oils ranked highest for gingivitis in network meta-analysis is the most contemporary and frequently asked-about finding in current MDS examinations.