Dental Pharmacology

DR. SWAPNIL BORKAR POST GRADUATE STUDENT

DEPARTMENT OF PERIODONTICS & ORAL IMPLANTOLOGYS.D.K.S DENTAL COLLEGE

NAGPUR

Introduction To Pharmacology

Pharmacology is the science that deals with the study of drugs and their interaction with the living systems.

The useful and toxic effects of many plant and animal product were known to man in ancient time. The earliest writing on drugs are the Egyptian Medical papyrus (1600 BC) . The largest of them Ebers Papyrus lists some 800 preparations.

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Though medicine developed simultaneously in several countries the spread of knowledge was limited because of poorly developed communication across the world.

India’s earliest pharmacological writing are form the ‘Vedas’. An ancient Indian physician Charaka and then Sushuruta and Vagbhata, described many herbal preparations included in Ayurveda (meaning the science of life). Indians practiced vaccination as early as 550 BC.

Various other traditional systems of medicine were practiced in different parts of the world- like

Homeopathy , Unani Siddh system Allopathy

Thus several systems of medicine were introduced of which only a few survived.

By the end of 17th century the importance of experimentation, observation and scientific methods of study became clear.

Francois Magendie and Claude Bernard popularized the use of animal experiments to understand the effects of drugs. simultaneous development of the other branches of science viz. botany, zoology, chemistry and physiology helped in the better understanding of pharmacology

GENERAL DEFINITIONS  A. Pharmacology is the study of the interaction of chemicals with living systems.  B. Drugs are chemicals that act on living systems at the chemical (molecular) level.  C. Medical pharmacology is the study of drugs used for the diagnosis, prevention, and treatment of disease.

D. Toxicology is the study of the untoward effects of chemical agents on living systems. It is usually considered an area of pharmacology.  

E. Pharmacodynamic properties of a drug describe the action of the drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.  F. Pharmacokinetic properties describe the action of the body on the drug, including absorption, distribution, metabolism, and excretion. Elimination of a drug may be achieved by metabolism or by excretion.

G. Chemotherapy is the use of chemicals for the treatment of infections. The term now also includes the use of chemical compounds to treat malignancies.

INTRODUCTION TO PHARMACODYNAMICS

Concentration-Response.

A fundamental principle of pharmacology is that a relationship exists between the concentration of a drug at its site of action and its beneficial or toxic action.

The reliance of pharmacodynamic effects upon drug concentration provides the key link between pharmacokinetics and pharmacodynamics for it is the action of the body upon a drug that determines its concentration at its site of action.

Properties of Drug Receptors.

Most receptors are proteins (eg, enzymes, hormone and neurotransmitter receptors); in addition, some DNA and RNA molecules serve as drug binding targets.

A successful receptor must distinguish between different ligands.

That is, it must bind selectively to certain ligands. In many cases, drugs bind to a site on a protein that normally binds to an endogenous small molecule or protein.

C. Types of Drug-Receptor Interactions.When a drug activates a receptor that it binds to,

the drug is an agonist.Most agonists mimic the effects of small

molecules or proteins that serve as endogenous regulators of the receptor to which the drug binds.

Pharmacologic antagonists have the opposite effect. That is, they prevent the effect of endogenous agonists on the function of the receptor. Most of the time, a pharmacologic antagonist binds to the same site as an agonist and competes with the agonist for binding to a critical site on the receptor. Pharmacologic antagonists have two important properties.1. In the absence of an agonist, they do not elicit a biologic response.2. The effects of a competitive pharmacologic antagonist can be overcome by adding more agonist.

Graphical Representation of Concentration-Effect Relationships.

The relationship between drug concentration and receptor binding, and drug concentration and pharmacodynamic effect can best be understood through the use of graphical representations.

INTRODUCTION TO PHARMACOKINETICS

Pharmacokinetics concerns the effects of the body on the administered drug. It can be pictured as the processes of absorption, distribution, and elimination. Elimination includes both metabolism and excretion. All of these processes involve movement of drug molecules through various body compartments and across the barriers separating those compartments.

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Absorption of Drugs.

Drugs usually enter the body at sites remote from the target tissue and are carried by the circulation to the intended site of action.

Before a drug can enter the bloodstream, it must be absorbed from its site of administration. The rate and efficiency of absorption differs depending on the route of administration.

Figure 1.1 Schematic representation of drug absorption, distribution, metabolism, and elimination.

1. Oral (swallowed).

Maximum convenience but may be slower and less complete than parenteral routes.

Dissolution of solid formulations (eg, tablets) must occur first. The drug must survive exposure to stomach acid.

This route of administration is subject to the first pass effect (metabolism of a significant amount of drug in the gut wall and the liver, before it reaches the systemic circulation).

2. Sublingual (under the tongue)

Permits direct absorption into the systemic venous circulation thus avoiding the first pass effect.

May be fast or slow depending on the physical formulation of the product.

Nitroglycerin is administered by this route in the treatment of angina.

3. Rectal (suppository)Same advantage as sublingual routelarger amounts are feasible.Useful for patients who cannot take oral medications (eg, because of nausea and vomiting).

4. Intramuscular. Absorption is sometimes faster and more complete than after oral administration. Large volumes (eg, 5 - 10 mL) may be given.Requires an injection.Generally more painful than subcutaneous injection. Vaccines are usually administered by this route.

5. Subcutaneous.

Slower absorption than intramuscular. Large volumes are not feasible. Requires an injection. Insulin is administered by this route.

6. Inhalation.

For respiratory diseases, this route deposits drug close to the target organ; when used for systemic administration (e.g., nicotine in cigarettes, inhaled general anesthetics) it provides rapid absorption because of the large surface area available in the lungs.

7. Topical. Application to the skin or mucous membrane of

the nose, throat, airway, or vagina for a local effect.It is important to note that topical drug

administration can result in significant absorption of drug into the systemic circulation.

Drugs used to treat asthma are usually administered this way.

8. Transdermal.

Application to the skin for systemic effect. Transdermal preparations generally are patches that stick to the skin and are worn for a number of hours or even days.

To be effective by the transdermal route, drugs need to be quite lipophilic.

Nicotine is available as a transdermal patch for those who are trying to stop cigarette smoking.

9. Intravenous.

Instantaneous and complete absorption (by definition, 100%); potentially more dangerous because the systemic circulation is transiently exposed to high drug concentrations

Distribution of Drugs.

The distribution of drugs from the site of absorption, through the bloodstream and to the target tissue depends upon:

1. The blood flow to the tissue is important in the rate of uptake of a drug.Tissues that receive a high degree of blood flow (eg, brain, kidney) have a fast rate of uptake whereas tissues with a low degree of blood flow (eg, adipose tissue) accumulate drug more slowly.

2. Solubility of the drug in the tissue. Some tissues, eg, brain, have a high lipid content and dissolve a higher concentration of lipophilic agents

3. Binding of the drug to macromolecules in the blood or tissue limits their distribution.

4. The ability to cross special barriers.

Many drugs are poorly distributed to the brain and the testis because these tissues contain specialized capillaries (the smallest type of blood vessel).

The endothelial cells that line these capillaries form a blood-brain barrier and a blood-testis barrier by preventing the movement of hydrophilic molecules out of the blood and into the tissue, and by actively pumping lipophilic molecules out of the endothelial cell and into the blood.

Of special concern is the ability of drugs to distribute to breast milk in lactating women, and the ability of drugs to cross the placenta and affect the developing fetus.

A number of drugs are known to be teratogens (drugs that cause abnormal fetal development) and should be avoided in pregnancy.

Women taking drugs that are considered unsafe for infants and that achieve appreciably high concentrations in breast milk should not breast-feed their infants

C. Elimination of Drugs.

The rate of elimination (disappearance of active drug molecules from the bloodstream or body) is almost always related to termination of pharmacodynamic effect.

There are two major routes of elimination:

1. Excretion.The most common route for drug excretion is through

the kidney and out of the body in the urine. To be excreted by the kidney, drugs need to be reasonably hydrophilic so that they will remain in the fluid that becomes the urine. Patients with impaired kidney function usually have a reduced ability to eliminate hydrophilic drugs. To avoid excessively high drug concentrations in these patients, we will need to reduce their dosages or give dosages less frequently. A few drugs enter the bile duct and are excreted in the feces.

Metabolism.

The action of many drugs, especially lipophilic compounds, is terminated by enzymatic conversion, or metabolism, to biologically inactive derivatives.

In most cases, the enzymatic conversion forms a more hydrophilic compound that can be more readily excreted in the urine.

Most of the enzymes that catalyze drug-metabolizing reactions are located in the gastrointestinal tract and the liver.

Some drugs inhibit drug-metabolizing enzymes and thus cause drug-drug interactions when co-administered with drugs that depend upon metabolism for elimination.

Sources of Drugs :Natural

Plant – atropine , morphine quinine , digoxin

Animal –insulin , heparin , gonadotropin

Minerals- magnesium sulphate , aluminium hydroxide ,iron , sulphur

Micro organism – obtain from sum bacteria or fungi we thus havepenicillin, chephalosporins , tetracycline's

(text book of pharmacology 2ed edition)

Humans :

Immunoglobulin's from blood growth hormones from anterior pituitary chorionic gonadotropins from urine of pregnant

women.

Synthetic :

Quniolones omeprazole neostigmine

(text book of pharmacology 2ed edition)

Dental Pharmacology INTRODUCTION 

Rapid progress in dental pharmacotherapeutics requires that clinicians constantly update their knowledge of new drugs, drug interactions and useful therapeutic trends These drugs play a useful role in the treatment of ulcerations, inflammations, xerostomia and bleeding during gingival retraction.

They also help in reducing dentinal hypersensitivity during vital tooth preparation and increasing the gingival resistance against infections.

Local Anesthetics

LA are the drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain, in a restricted area of the body.

These drugs act by excessive stimulation followed by depression (Bennett, 1984a).

To work efficiently, the dental local anesthetics should have some requirements (Haas, 2002) such as:

• High intrinsic activity, which ensures complete anesthesia for all dental treatment• Rapid onset• Adequate duration of anesthesia (30 to 60 min for standard dental treatment)• Low systemic toxicity• High efficacy-toxicity ratio• Low overall incidence of serious adverse effects

Chemically local anesthetics are classified asEsters

cocaineprocainetetracainebenzocuaine

Amide typeslignocainmepivacainbupivacainetidocaine

(text book of pharmacology 2ed edition)

Local anesthetics containing vasoconstrictor agents are to be used with caution in patients with

Pheochromocytoma uncontrolled or unstable angina cardiac arrhythmias Congestive heart failure Hyperthyroidism diabetes.

(Bennett, 1984c)

The local adverse effects

If allergic reactions occur,

The immediate treatment is intravenous injection of 0.01 ml per kilogram body weight adrenaline,supplemented by antihistamine agents such as 10 to 20 mg chorpheniramine, or 50 mg hydroxyzine or promethazine hydrochloride (Ball, 1999).

Topical anesthetics

are used in the oral cavity to provide pain relief at needle insertion site and over ulcerations.

Topical anesthetic agents can also provide someform of relief in patients exhibiting gagging during theimpression procedure.

Glycerine, lanolin, petrolatum, mineral oil, sodium carboxymethylcellulose, propylene glycol andpolyethylene glycol are used as vehicles for topicalAnesthetics (Adriani and Zepernick, 1964).

Vasoconstrictors

Vasoconstrictors are used in dentistry either as components of the local anesthetic syringe or for application with gingival retraction cords.

These agents do not produce coagulation of blood but act by constricting blood vessels.

Examples of vasoconstrictors accepted by the Council on Dental Therapeutics includeEpinephrine (1:200,000/1:100,000/1:50,000),Levonordefrine (1:20,000) Norepinephrine (1:30,000). Epinephrine is the vasoconstrictor of choice for use in dentistry (Felpel, 1999).

It restricts the blood supply to the area by decreasing the size of blood capillaries thereby decreasing hemorrhage and fluid seepage.

It is advisable to use low concentration epinephrine (0.01%) for gingival retraction due to its superior effect in keeping the gingival sulcus relatively dry during the impression procedure(Csillag et al., 2007).

Antiseptics

Antiseptics are drugs that are applied on the body surfaces to prevent infection by killing or inhibiting the growth of pathogenic bacteria either by oxidation of bacterial protoplasm ordenaturation of bacterial proteins including enzymes

(Tripathi, 2008a).

Amongst the various types of antiseptics available, chlorhexidine a biguanide, is one of the most commonly used.

First Generation Phenols Quaternary Ammonium compounds Metallic ions Sanguinaris

Second Generation Bis biguanides

Third Generation Delmopinol

Classification of Chemical Plaque Control agents

a) Phenols (Triclosan): It’s a phenol derivative which is synthesized used as a topical antimicrobial agent with a broad spectrum of action including against both gram -ve and gram +ve bacteria.It also has specific action against mycobacterium and candida species.

Mechanism of Action:

Triclosan acts on cytoplasmic membrane and induce leakage of cellular contents which leads to bacteriolysis and Cell death.

Triclosan is induced in toothpaste to prevent plaque formation.It is used along with zinc citrate or its polymer gantrez to

enhance its retention in the oral cavity.It also inhibits prostaglandins and leukotriens thereby it

reduces the degree of inflammation.

Metallic ions:These are Zn -ions and Cu -ions.It acts by reducing the glycolytic activity in bacteria and hence delays bacterial growth.

Quaternary Ammonium Compounds:These are Benzathonium Chloride, Benzallenium Chloride and Cetylpyredinum. These are cationic antiseptics and surface active agents which are effective against gram +ve organisms.

Mechanism of action:Positively charged molecule reacts with negatively

charged cell membrane phosphates and thereby disrupting the bacterial cell wall structure.

The side effects staining and enhanced calculus formation it also causes burning sensation and desquamation.

Sanguinare:

Sanguinare chloride is currently used in both mouth rinses and toothpaste.

It is an extract from blood root plant Sanguinare candensis.

It is an benzophenanthredine alleloid. Mechanism of action is not known. It is most effective against gram positive organisms.

Second generation

Bisbiguanides:

isbiguanides posses anti plaque activity including Chlorhexidine, Alexidine and Octenidine.

The antiplaque properties of chlorhexidine are unsurpassed by other agents.

It has much greater and more prolonged effects than other antiseptics.( Joyston-Bechal 1993)

The digluconate of chlorhexidine (1: 6 – Di 4 – chlorphenyl – diguanidohexane) is a synthetic antimicrobial drug which is effective in vitro against both gram positive and gram negative bacteria including aerobes, anaerobes, yeast and fungi.

( Eley B. 1999)

Mechanism of action: Prevents pellicle formation by blocking acidic groups of salivary glycoprotein’s thereby reducing glycoprotein adsorption on to tooth surface. Prevents adsorption of bacterial cell wall on tooth surface. Prevents binding of mature plaque

Antibacterial action of Chlorhexidineconsits of two actions, i.e., bacteriostatic at low concentration and bactericidal at high concentration.

Bacteriostatic action at low concentration is mainly due to the negative energy of the bacterial cell wall reacts with positive energy chlorhexidine molecule. This alter the integrity of cell membrane and Chlorhexidine binds to inner membrane phospholipids and increases permeability. This leads to the vital elements leaks out resulting in bacterial cell death.

Bactericidal Action is due to the higher concentration of chlorhexidine. This cause progressive greater damage of membrane and the larger molecular weight compounds loss and coagulation and precipitation of cytoplasm.The Free CHX molecules enter the cell and coagulate proteins and vital cell activity ceases and cause resultant cell death.

It has shown that 0.2% CHX mouth rinses will prevent development of experimental gingivitis, it has been shown that Chlorhexidine is more effective in preventing plaque accumulation on a clean tooth surface than in reducing pre existing plaque deposits.( Joyston‐Bechal S,1993)

The adverse effects brown staining of tooth and restorationloss of taste sensationstenosis of parotid duct.

It affects the mucous membrane and tongue; and may be related to the precipitation of chromogenic dietary factors on teeth and mucus membrane. It is probable that one cationic group attaches chlorhexidine to the tooth and mucosal surface, which the other cationic group lyse the bacterial cell wall. Thus the cationic group can also attach dietary factors such as gallic acid derivatives found in some foods and beverages including tea, coffee and wines.

Essential oils (Listerine): It’s a combination of phenol related essential oil, thymol and methyl salicylate.It has shown to have moderate plaque inhibitory effect and antigingivitis effect.It has poor oral retention and has burning and bitter taste. (Mandel 1988)

Mechanism of Action:The action of phenol acid is cell wall disruption

and inhibition of bacterial enzyme.( McDonnell G 1999) The phenolic compound are also known to act as

scavengers of oxygen free radical and hence has an effect on leucocyte activity

Third generation Delmopinol : It’s a relatively new preparation which inhibits plaque growth and gingivitis.It interferes with plaque matrix formation and also reduces bacterial adhesion and adherence.It ceases binding of plaque to tooth, thus aiding the easy removal of plaque by mechanical procedures.It is indicated as a pre brushing mouth rinse.

Adverse effects staining of tooth and tongue taste disturbances mucosal soreness erosion

Steroids

Steroids play a role in the modulation of the inflammatory reaction by inhibitory activity affecting the production of mRNA and thus protein synthesis. Application of topical steroid preparations provides temporary relief of symptoms associated with inflammation and ulcerated lesions in the oral cavity such as recurrent apthous stomatitis.

These topical ointments include

Triamcinolone acetonide 0.1%Kenalog in OrabaseHydrocortisone acetate 1% Betamethasone dipropionate 0.05%.

Topical use of steroids is usually well tolerated but some patients may develop a secondary erythematous candidosis or pseudomembranous candidosis (thrush) if predisposing conditions like xerostomia,Systemic and/or topical use of antibioticscorticosteroid asthma inhalantsprostheses and cigarette smoking are present in them.

Even though clinical experience and laboratory studies haveshown systemic absorption of steroids to be insignificant through the oral mucosa but caution should be exercised when used in patients with

Diabetes Hypertension tuberculosis

(Savage and McCullough, 2005).

Analgesics

Analgesic agents are used for the management of pain

divided :

Nonopioid (non-narcotic)Acetaminophen (Paracetamol)Opioid (narcotic).

An important difference between the opioids and the nonopioid analgesic agents is their mechanism of action.

The action of the nonopioid analgesic agents is related to their ability to inhibit prostaglandin synthesis at the peripheral nerve endings whereas the opioids affect the amount of pain by depressing the central nervous system.

Text book of pharmacology 2ed edition

Opioid Analgesics

Opioid analgesics used in dentistry for oral administration are Codeine,Hydrocodone, Oxycodone andPentazocaine whereas Morphine, Meperidine and Fentanyl are usedparenterally .

Opioids are added tononopioids to manage pain that ismoderate to severe or that does notrespond to nonopioids alone. Opioidsdiffer from the nonopioids in that they have no ceiling effect. The onlydosing limitation is based on side effects (Felpel, 1997).

Non steroidal anti-inflammatory Drugs (NSAIDs’)

The NSAIDs constitute a heterogeneous group of drugs with clinically important analgesic, antipyretic and anti-inflammatory properties that rank intermediately between corticoids withanti-inflammatory properties on one hand, and major analgesics – opioids on the other (Poveda-Roda et al., 2007).

These agents differ from opioid analgesics in the following ways:

(1)there is a ceiling effect to the analgesia(2) they do not product tolerance or physicalDependence(3) they are antipyretic(4) they possess both anti-inflammatory as well as analgesic properties (Yagiela et al., 2004a).

Nonopioids are most effective in treating postprocedural pain when given before the procedure (or immediately following a short procedure), thus preventing the synthesis of prostaglandins that quickly follow the surgical insult.

Text book of pharmacology 2ed edition

Physical, chemical or mechanical stimuli in the form of tissue damage, hypoxia, immune processes, etc. induce arachidonic acid release and metabolization.

NSAIDs inhibit cyclooxygenase (COX) – the enzyme responsible for the transformation of arachidonic acid into prostaglandins and thromboxanes, which are substances generically referred to as eicosanoids.

These resulting metabolites (prostaglandins and thromboxanes) exert potent vasodilating action, resulting in increased vascular permeability, with the extravasation of fluids and white blood cells therby contributing to inflammation.

Consequently, the inhibition of cyclooxygenase synthesis exerts a clear anti-inflammatory effect (Poveda-Roda et al., 2007).

Out of the two forms (isoenzymes) of cyclooxygenase namely COX-1 and COX-2 the latter COX-2 appears to be more involved with synthesis of prostaglandins at sites of inflammation, whereas COX-1 is more involved at sites where adverse effects of NSAIDs are expressed, such as the GIT.

Therefore NSAIDs that have more selective inhibitory activity on COX-2 as opposed to COX- 1 would be expected to have a more favorable therapeutic index (Waldman et al., 1982).Celecoxib, Rofecoxib and Parecoxib are drugs showing selective COX-2 inhibitory action but these should be avoided in patients with moderate to severe hepatic damage.

Potential adverse effects of NSAIDs include

peptic ulcer disease gastrointestinal (GI) bleeding, GI perforation impaired renal function inhibition of platelet function.

Salicylates should be avoided in patients suffering from Ulcers, Asthma, Diabetes, Gout, Influenza and hypercoagulationstates.

Asprin and related salicylates are contraindicated for treatment in children and teenagers with viral infections, as it has been associated with hepatotoxicity and encephalopathy (Reye’s syndrome) (Waldman et al., 1982).

Ibuprofen, naproxen sodium, ketoprofen and asprin are currently approved by the food and drug administration for overthe counter (OTC) use.

These OTC drugs should not be used consecutively for over 10 days for pain and 3 days for fever (Yagiela et al., 2004b).

A 200 to 800 mg dose of ibuprofen should be considered as the first choice for management of acute inflammatory pain(Hargreaves and Abbott, 2005).

Acetaminophen (Paracetamol)

It has analgesic and anti-pyretic effects, and it is a weak inhibitor of the cyclo-oxygenase sub-groups COX-1 and COX-2. At therapeutic doses it does not inhibit prostaglandin in theperipheral tissues so there is very little, if any, anti-inflammatory action.

It is therefore not classified as an NSAID (Felpel, 1997).

Tolerance and dependence have not been reported, and Paracetamol does not cause the same gastric irritation or the other complications associated with aspirin and other NSAIDs (Seymour et al., 1999).

The usual recommended adult dose of Paracetamol is 500-1000mg every four to six hours (up to a maximum of 4000mg per day) (Therapeutic guidelines, 2002).

Combination drug therapyThe goal of combining analgesics with different mechanisms

of action is to use lower doses of the component drugs, thereby improving analgesia without increasing adverse effects(Mehlisch, 2002).

Patients with acute dental pain are best treated with NSAIDs oracetaminophen as the primary analgesic and the addition of a narcotic should be reserved for situations when additional analgesia is required.

Opioid and acetaminophen combination studies show that a combination is better than opioids or acetaminophen alone (Moore

et al., 1997).

Opioids such as codeine, hydrocodone and oxycodone combined with ibuprofen are superior to manage acute dental pain than ibuprofen alone (Po and Zhang, 1998).

The analgesic properties of aspirin, acetaminophen and ibuprofen have been seen to increase when combined with 65 to 100 mg caffeine.

Antimicrobials

Antibiotics are chemicals virtually always derived naturally with the exception of ulfonamides, fluoroquinolones and oxazolidinones.These drugs act on the microorganisms to effect theirviability hence they can be either bactericidal (inducing cell death) or bacteriostatic(preventing cell growth or replication) (Yagiela et al., 2004d).

Antibiotics with activity against a wide range of disease-causing bacteria are termed as broad-spectrum antibiotics.It also means that it acts against both Gram-positive and Gram-negative bacteria.

This is in contrast to a narrow-spectrum antibiotic which is effective against only specific families of bacteria.

tetracyclines and clindamycin are accepted by the Council on Dental therapeutics, ADA.

Other antibiotics appropriate for use in Dentistry includepenicillin,erythromycincephalosporins bacitracin (Felpel, 1997).

Oral infections are usually caused by aerobic gram-positive cocci (Staphylococcus aureus) and anaerobic microorganisms (Peptostreptococcus) and the use of antibiotics in dentistry is to either treat these or as a prophylaxis to prevent bacterial endocarditis that is caused by α hemolytic streptococci

Most acute oral infections respond well to one of the oral penicillin preparations.

adverse side effects, and allergic reactions. A true allergic reaction usually manifests as an irritating rash. Anaphylactoid reactions though rare, occur insusceptible patients within 30 seconds of an im inj.

Signs and symptoms of anaphylaxis include oral paresthesia cold hands feet Bronchospasm wheezing, circulatory collapse unconsciousness

Alternatives to penicillin include Erythromycin Cephalosporins Clindamycin, Tetracycline but Cephalosporins should not be used in a person with a history ofanaphylaxis, angioedema or urticaria with penicillins or ampicillin.

Erythromycin estolate Erythromycin ethylsuccinateContraindicatedliver dysfunction as they can cause cholestatic hepatitis.

Tetracyclines – avoided duringPregnancychildren below 8 years because permanent staining of deciduous and permanent teeth and retardation of bone growth may occur. gastrointestinal upsetHepatotoxicityNephrotoxicityphotosensitivity impaired calciumabsorption.

Similarly, quinolones should be avoided in children, pregnant or nursing women, and in epileptics (Felpel, 1997).

Antibiotic prophylaxis is recommended for dental procedurein patients with prosthetic cardiac valve, previous infective endocarditis, cardiac transplantation recipients who develop cardiac valvulopathy and during the first six months following any procedure to treat congenital heart disease (Prevention of infectiveendocarditis, 2007).

Antibiotic coverage for invasive dental procedures isrecommended in patients with poorly controlled or uncontrolled diabetes, infective endocarditis but not in those having orthopedic prosthesis placed over 2 years prior to the dental procedure.

Prophylactic use of antibiotics in conjunction with dental treatment should be avoided unless there is a clear indication since unwarranted overuse of antibiotics can lead to development of resistant strains of microorganisms (Barker, 1999).

Antibiotic prophylactic regimen for dental procedures inhigh risk patients

Antifungals

Oral moniliasis (thrush) is a fungal infection of the oral cavity caused by Candida albicans. C albicans can also colonize prosthetic devices like dentures.

Atleast 2 weeks of therapy are required for treating oral candidiasis. Nystatin (Mycostatin) is the most common drug used in dentistry and it can have a fungistatic or fungicidal effect depending on its dose.

A 2-3 ml (100,000 units/ ml) suspension or 1-2 lozenges (200,000 units each) may be used four to five times per day. Colonized dentures can be treated by soaking them in a nystatin solutionor applying an ointment (100,000/g) of nystatin to the tissue surface.

Clotrimazole (Mycelex), a fungistatic can be used in a dose of 10 mg troches dissolved in the mouth five times a day

Since Nystatin and Clotrimazole are not appreciably absorbed from the gastrointestinal tract, the topical route is preferred for their administration.

Oral Fluconazole (Diflucan) in a dose of 50 to 100 mg/day and Itraconazole (Sporanox) 200mg/day are broad-spectrum antifungal agents that are effective in treating oropharyngeal and esophageal candidiasis (Yagiela et al., 2004e).

Antianxiety Drugs

Antianxiety agents are used in clinical dentistry for premedication in an apprehensive patients pending operative procedure like Implant surgery. Antianxiety agents are known to summate with Anestheticsopioid analgesicsAntidepressantssedative-hypnoticsalcohol to cause excessive CNS depression (Yagiela et al, 2004f)hence should be prescribed with caution.Benzodiazepines such as

Diazepam (Valium),Lorazepam (Ativan)and Alprazolam (Xanax)

Antihistamines such as Hydroxyzine (Vistaril) Promethazine (Phenergan)

are the preferred anxiolytics for use in dentistry.

They should preferably have a rapid onset and a short duration of action.

Diazepam (2-10mg),Lorazepam (2-6 mg) Alprazolam (0.25-1.5mg) have a 12-24 hour duration of actionwhereas antihistamines in a dose of 25-100mg have a 4-6 hour duration of action.

The use of Benzodiazepines is contraindicated in patients with psychosis,acute narrow-angle glaucomaliver disease.

Centrally Acting Muscle Relaxants

These are drugs that reduce skeletal muscle tone without altering consciousness.

They are used in chronic spastic conditions and acute muscle spasms of the temporomandibular joint.

These drugs usually cause slight sedation hence caution is to beexercised regarding operation of motor vehicles.

These drugs have a potential for abuse and dependence hence prolonged administration and abrupt stoppage is to be avoided (Stanko, 1990).

DefinitionAccording To ADA council on dental “a dentifrice is a substance use with a toothbrush for the purpose of cleaning the accessible surfaces of the teeth”.

Webster described the term dentifrice as derived from (Latin) dens (tooth) fricare (to rub)Came into English in 1558.

Dorland described it as a preparation for cleaning and polishing the teeth.

Functions of a toothpaste (in conjunction with toothbrush):

Minimizing build up of plaque. Strengthening teeth against caries. Cleaning teeth by removing stains. Removing tooth debris. Freshening the mouth.

Composition:

Dentifrices have been prepared in several physical forms

- Pastes - Powder - Liquid - gel

Powder dentifrices : abrasive, detergents, Flavoringsweetening agents.

Paste dentifrices: contain the above plus binders,preservative ,humectant,water

Composition

The polishing or abrasive agent(25-50 %): An ideal abrasive is one that cleans well with no

damage to the tooth surface and provides a high polish that can prevent or delay the reaccumalation of stains and deposits.

Abrasives by volume are the single largest components of a dentifrice.

Abrasive agent has two purposes: Firstly, its mild abrasive action helps to eliminate

plaque from the teeth, hence reducing plaque build up.

Secondly, the abrasive agent removes stained pellicle from the teeth, polishes the surfaces, restores the natural luster and enhances enamel whiteness

Abrasive agent must be chosen very carefully, so that there is no scratching or damaging the enamel or the much softer underlying dentine.

In particular attention is paid to the size of the particles and their shape and hardness.

The abrasive system should be insoluble, inert nontoxic and preferably white.

Commonly used abrasive materials include calcium carbonate, dicalciurn phosphate dihydrate, alumina and silicas.

In gel toothpaste, the abrasive system is usually a special porous silica that becomes transparent when blended into the gel system.

The binder or thickener(1-2%): The binder or thickener controls the stability and

consistency of a toothpaste, and also affects the ease of dispersion of the paste in the mouth.

Choice of the correct binder and concentration is critical to ensure that the product can be readily squeezed from the tube and yet have a good appearance when it is on the toothbrush.

Commonly used thickeners can be divided into two classes –

Water soluble- carrageenates, alginates and sodium carboxymethylcellulose.

Water insoluble - magnesium aluminum silicate, sodium magnesium silicate and colloidal silica.

The surfactant agent /detergent (1-3%):

Purposes:

1. To Lower surface tension.2. Penetrate and loosen surface deposits and stains.3. Emulsify debris for easy removal by toothbrush.

The surfactant agent provides the foam that causes the removal of food debris and aids dispersion of the product in the mouth.

Early dentifrices actually used soap, but mild synthetic detergents are now universally used to give better taste, foam and product stability.

The detergent used most widely by all major manufacturers is sodium lauryl sulfate.

Sodium lauryl sulfate also has anti microbial properties and thus helps to preserve the toothpaste during manufacture and use.

It also has a rapid antimicrobial effect on oral flora, which adds to the overall plaque-inhibiting properties of the toothpaste.

Another positive role sodium lauryl sulfate has is to help to solubilize key ingredients such as flavors and certain anti-microbial agents.

Surfactant used should fulfill the following criteria:

Non toxic Neutral in reaction Active in acid or alkaline media. Stable Compatible with other dentifrice ingredients. No distinctive flavor Have foaming characteristics.

Examples : 1. Synthetic detergents2. Sodium lauryl sulfate 3. Sodium and lauryl sarcosinate

The humectant :

A humectant is a material that helps to reduce the loss of moisture from a preparation.

In toothpaste, the humectant minimizes plug formation in tube nozzles and improves the texture and feel of the product in the mouth.

It can also act as a sweetening agent.

Examples are: glycerin, sorbitol and polyethylene glycol. Glycerin and sorbitol are the humectants used most often .

The flavoring agents

The choice of flavor is very important. It renders the product pleasant to use and should

leave a fresh taste in the mouth after use. Types of flavor : peppermint oil, spearmint oil and

wintergreen (methyl salicylate). Others - wintergreen, aniseed, lemon oil and

eucalyptus are also usually added to improve the acceptability of the flavor and to add individual notes to the flavors - important in medicinal formulations

Uses of flavor:1. To make dentifrice desirable2. To make other ingredients that may have a less

pleasant flavor

Water (20-30%):

Most important of the remaining ingredients.

Serves as vehicle to deliver ingredients of toothpaste.

Deionized or distilled water is utilized

Preservatives (0.05-0.5%):

Most dentifrice humectants and some organic binders are susceptible to attack by microorganisms or molds.

Hence preservatives such as dichlorophene benzoate, p-hydroxy benzoate, formaldehyde or paraben

Others: Titanium dioxide to whiten the preparation

Therapeutic agents (0.4 – 1.0 %)

Toothpaste is an excellent vehicle for delivering oral health benefits and hence many therapeutic agents are added.These include

Anti caries agents Anti plaque agents Anti tartar agents Anti sensitivity agents.

Therapeutic agents and their mechanism of action:

ANTI-CARIES AGENTS

1. Fluoride: Fluoride is considered to be the most effective caries-inhibiting agent, and almost all toothpastes today contain fluoride in one form or the other.

Most common form - sodium fluoride(NaF).

Mono-fluoro-phosphate (MFP) Stannous fluoride (SnF) are also used.

The fluoride amount in toothpaste is usually between 0.10-0.15 %.

Toothpastes are the main vehicle for fluoride.

Three main theories considering the positive action of fluoride in the prevention Of caries:

1. It is claimed that fluoride, incorporated into the enamel during tooth development in the form of fluorhydroxyapatite (FAP), reduces the solubility of the apatite .

2. It is also suggested that fluoride has antibacterial actions. In an acidic environment, if fluoride is present, hydrogen fluoride (HF) is formed .

3. Today the most important anti-caries effect is claimed to be due to the formation of calcium fluoride (CaF2) in plaque and on the enamel surface during and after rinsing or brushing with fluoride. CaF2 serves as a fluoride reservoir .

2. XYLITOL

Xylitol is a sugar alcohol that cannot be fermented by oral microorganisms.

It is considered to be a cariostatic agent since it can inhibit the carbohydrate metabolism in different oral microorganisms .

The inhibitory effect on glycolysis has been related to the uptake of xylitol via a constitutive fructose specific PTS system and subsequent intracellular accumulation of xylitol-5-phosphate. Such a mechanism leads to reduced acid formation from glucose, and a reduction in the streptococcus mutans content in both plaque and saliva

3. Calcium/Phosphate:

Calcium and phosphate supplementation in a toothpaste will increase the concentration of these ions in the oral cavity.

This has been reported to improve remineralization and increase fluoride uptake.

4.Sodium Bicarbonate: Several studies have shown that bicarbonate is one of the salivary components that potentially modifies the formation of caries. It increases the pH in saliva, and in this way creates a hostile environment for the growth of aciduric bacteria. Sodium bicarbonate can also change the virulence of the bacteria that cause tooth decay

ANTI-CALCULUS AGENTS

Of the anti-calculus agents, the crystal growth inhibitors have been most extensively tested clinically. These agents act by delaying dental plaque calcification, thereby promoting plaque removal with normal tooth brushing

1.Pyrophosphate:

Inhibit the formation of supragingival dental calculus.

Added as tetrasodium pyrophosphate, tetrapotassium pyrophosphate or disodium pyrophosphate.

It has been shown that pyrophosphate has high affinity to hydroxyapatite (HA) surfaces, probably by an interaction with Ca+ in the hydration layer, reduces their protein-binding capacity.

It also has the ability to inhibit calcium

phosphate formation. It is therefore conceivable that pyrophosphate introduced in the oral cavity through dentifrices may affect pellicle formation.

P-O-P bond of pyrophosphate is susceptible to enzymatic hydrolysis by plaque and salivary phosphatases, and the effect may thus be of limited duration in the oral cavity .

Tartar control dentifrices that contain pyrophosphate incorporate phosphates inhibitors that prolong the activity of pyrophosphate in the mouth.

. Zinc:

Zinc has anti-calculus effect due to its anti-plaque properties, but in addition it is thought to influence calculus formation by inhibiting crystal growth

ANTI-DENTINE HYPERSENSITIVITY AGENTSAlthough the condition is referred to as "dentine

hypersensitivity" it isn't really the dentine that is sensitive. The sensitivity of dentine is caused by fluid-filled tubules in communication with the pulp.

Potassium salts:Potassium ions are thought to act by blocking

action potential generation in intradental nerves. It is claimed that potassium salts increase the

concentration of potassium ions around the pulpal nerves, and thereby depolarizes the nerve. This can inhibit a nerve response from different stimuli .

The exact mechanism by how potassium desensitises dentine is yet to be elucidated.

ANTI-APHTOUS AGENTS

Aminoglucosidase and Glucose oxidase:

Enzymatic toothpastes do not contain detergents like SLS because the detergent can denaturate the enzymes.

SLS may induce adverse effects in oral soft tissues and increases the frequency of ulcers in patients suffering from recurrent aphthous ulcers (RAU). Enzyme toothpastes can therefore be an alternative for patients suffering from RAU .

Use of a dentifrice containing the combination of the enzymes aminoglucosidase and glucose oxidase has a positive, inhibiting effect on RAU.

The ulcers were generally reported to be smaller and less painful, to have a shorter healing time and the frequencies of aphthous ulcers episodes were decreased.

WHITENING AGENTS

Whitening toothpastes do not lighten the colour of the tooth structure; they simply remove surface stains with abrasives or special chemical or polishing agents, or prevent stain formation.

1. Abrasives: An abrasive is required for the effective removal of

a discoloured pellicle. Abrasives provide a significant whitening benefit,

particularly on smooth surfaces. limited use for areas along the gum line and

interproximally . Coarse abrasives in toothpates can damage the

dental tissue.

2.Dimethicones:

Dimethicones are versatile substances that ranges from low molecular weight polydimethylsiloxane fluids to high molecular weight polymers that are gum-like in nature. They cause a smooth surface on the tooth that prevents stain formation.

3. Papain: Papain is a sulfahydryl protease consisting of a

single polypeptide chain, extracted from the Carica papaya plant. It is able to hydrolyse peptide bonds, and can also catalyse the transfer of an acyl group. It is used in toothpastes as an non-abrasive whitening agent

4. Sodium bicarbonate: Dentifrices containing high concentrations of

sodium bicarbonate are more effective in removing intrinsic tooth stain than those not containing sodium bicarbonate

ANTI-HALITOSIS AGENTSZinc:

Halitosis originates mainly from the oral cavity and is due to the retention of anaerobic, Gram-negative bacteria.

These bacteria use sulphur containing amino acids as substrates in their production of volatile sulphur-containing compounds (VSC).

VSC have a distinctly unpleasant odour even in low concentrations Zinc inhibits the production of VSC in the oral cavity by interacting with sulphur in the amino acids or their metabolism.

Zinc can be retained in the oral cavity for approximately 2-3 hours after tooth brushing by binding to acidic substances on the oral mucosa, in the saliva or on bacterial surfaces.

Astringents

Astringents are the substances that precipitate proteins, but do not penetrate cells, thus affecting the superficial layer of mucosa only.

They toughen the surface by making it mechanically stronger and decrease exudation.

Astringents may be administered by retraction cords already impregnated with the agent or by applying them to cotton pellets.Examples Alum aluminum chloride zinc chloride (8-20%) tannic acid

Styptics are the concentrated form of astringents.

They cause superficial and local coagulation.

Some of the examples are ferric chloride and ferric sulfate.

Aluminum chloride and Ferrous sulfate are preferred astringents amongst prosthodontists because they cause minimum tissue damage (Rosenstiel, 2006a).

Hemostatic Agents

Hemostatic agents are used in dentistry for hemorrhage control and wound protection (Mc Bee and Koerner, 2005).

These are drugs which arrest more serious bleeding from cut orlacerated capillaries and arterioles.

Some of the examples are:I. Thrombin- It is prepared from mammalian pro-thrombin, acts by

accelerating the clotting of blood. It is available in powder form and mixed with saline.It should be applied locally and never injected.

II. Gel Foam- It is also known as gelatin sponge and is available as a powder or porous sheet.The hemostatic properties of absorbable gelatin sponge can beimproved by soaking it in a thrombin solution before application

(Felpel, 1999).

Sialogogues

Xerostomia may result from disease states (Sjogren's syndrome, rheumatoid arthritis, diabetes insipidus, pernicious anemia), from radiation, as a side effect of a wide variety ofdrugs, or from natural aging.

Sialogogues are the agents which activate muscarinic cholinergic receptors of the parasympathetic nervous system to increase salivary flow in patients with xerostomia (Tripathi, 2008b).

All commercially available preparations have a limited duration of action, making frequent application necessary.

Agents such as sugar free gum or candies and lozenges containing citric acid sorbitol, mannitol or xylitol may be recommended.

According to Boucher, making a conscious effort of consuming at least eight glasses of water, juice or milk daily is the most important measure to relieve dry mouth

(Zarb and Bolender, 2004a).

Pilocarpine have been reported as potentially effective sialogogues for xerostomic patients in a study on patients with dry mouth following cancer therapy

(Gorsky et al., 2004).

Carboxy methyl cellulose based artificial saliva demonstrated moderate effects in reducing dry mouth related symptoms with more significant effects appearing in patients whose residualsecretory potency was severely compromised

(Oh et al., 2008).

Anti-sialogogues

These agents are used to decrease salivary secretion by cholinergic antagonist action.

They decrease salivary secretion by inhibiting the action of myo-epithelial cells in the salivary glands thus producing a dry field.

examples of anti-sialogouges, Methantheline

Propantheline (synthetic atropine derivatives)with Propantheline being 5 times more potent.

Clonidine (0.2mg) an antihypertensive drug has been found to be as effective as methantheline (50 mg) in reducing salivary flow (Wilson et al., 1984). For the desired reduction in salivary flow, the oral administration of atropine, scopolamine, or methantheline and propantheline should precede the clinical procedure by 1to 2 h, half to 1 h, or one-halfan hour, respectively.

Medications with anti sialogogic effect include (Rosenstiel et al., 2006b);

probanthine (7.5 to 15 mg), robinul (1 to 2 mg), saltropine (0.4 mg) and antipasbentyl (10 to 20 mg).

Anticholinergic drugs are contraindicated in patients with glaucoma, prostatic hypertrophy, severe gastrointestinal disorders (ulcerative colitis, obstructive disease, intestinal atony), and myasthenia gravis (Felpel, 1999).

Gum PaintsGum paints are the combination of antiseptics and

tanning agents which precipitate proteins but do not penetrate cells thereby affecting only the superficial layer making it mechanically stronger and decreases exudation. They have germicidal, fungicidal, anesthetic and healing properties. When applied, they provide a soothing, cooling and an astringent effect. All these preparations contain Choline salicylate Tannic acid Cetrimide, Thymol Camphor, Cinnamon oil Iodine Alum (hydrated potassium aluminumsulfate).

‘Zingisol’ containing 2% Zinc Sulfate is used to control bleeding gums.

The patient is advised to apply 3-4 drops on finger and massage 3-4 times a day.

‘Sensoform’ gum paint (Warren) contains tannic acid, glycerine and potassium iodide and is applied on affected area several times with the cotton applicator for the treatment of stomatitis, inflammation and bleeding gums.

It also decreases sensitivity and increases gingival resistance against infections.

‘Stolin’ gum paint (dr. reddy’s)15ml contains cetrimide 0.1 % w/v tannic acid 2 % w/vzinc chloride 1 % w/v.

‘Sensorok’ gum astringent with zinc sulfate is used for gum massage 2-3 times daily

Denture Cleansers

It must be emphasized that improper care of dentures can have detrimental effects on the health of the denture supporting tissues. Maintenance of adequate denture hygiene is essential to minimize and eliminate adverse tissue reactions.

It must be an integral component of post insertion patient care (Zarb and Bolender, 2004b).

Following are the requirements of an ideal denture cleanser:- Should be non toxic- Easy to remove and harmless to the patient- Be able to dissolve the denture deposits such as calculus- Exhibit bacteriocidal and fungicidal effect- Should have long shelf life and inexpensive- Harmless to the denture base materials, denture teeth as well as soft liners

Commonly available denture cleansers are available in powder and tablet form and include:

a) Oxygenating cleansers- overnight immersion of dentures in alkaline peroxide solution is a safe and effective method.

b) Hypochlorite cleansers- immersion of the dentures in a solution of one part of 5% sodium hypochlorite in three parts of water followed by light brushing is advisable.

c) Dilute mineral acids.

d) Abrasive powders and pastes.

e) Enzyme containing minerals (proteases).

Commercially available denture cleansers includeKleenex, Stain Away, Polident, Triclean, Efferdent

Denture Adhesives

Denture adhesives augment the same retentive mechanisms already operating when a denture is worn.

They consist of keraya gum,tragacanth,sodium carboxyl methyl cellulose,polyethylene oxide,flavouring agents,antimicrobial agents plasticizers

They enhance retention through optimizing interfacial forces by increasing the adhesive and cohesive properties and viscosity of the medium lying between the denture and the basal seat and eliminating voids between the denture base and the basal seat

(Zarb and Bolender, 2004c).

Oral Protective Agents

These agents are finely powdered, inert and insoluble.They afford physical protection to the mucous membrane thus are used for apthous ulcers and gingival inflammation.

All these gel preparations should be applied 2-3 times daily.The Lignocaine based preparations contain

Lignocaine hydrochloride, Benzalkonium and Choline salicylate. Examples are Dentogel,Dologel and Emergel.

Dentasep, Dentonex-M, Maghex-M and Metrogyl DG gel are examples of metronidazole and chlorhexidine preparations. Oraguard B and Mucopain are gels containing Benzocaine as the active ingredient. Petroleum jelly is also used successfully as an oral protective agent

DemulcentsThese are inert substances which sooth the inflamed and denuded mucosa by preventing contact with air or irritants in the surrounding.

They can be applied as thick colloidal and viscid solutions in water. Commonly used agents are Gum AcaciaGum Tragacanth.

These are used as suspending agents for indiffusible powders, emulsifying agents for oils and in lozenges.

Glycerin (50-75%) in water acts as a popular vehicle for gum paint (Tripathi, 2008c).

CONCLUSION

All the pharmacological agents mentioned are used either before commencement of the treatment, during the treatment or at the post treatment duration.

Therefore, a dentist should have sound knowledge of the benefits and drawbacks of these agents in achieving the desired results