The top 20 most commonly prescribed medications for 2006.

The purpose of this article is to review the top 20 most commonly prescribed medications in the United States for 2006. (1) Drugs included in this article are ranked according to the total number of prescriptions dispensed, based on a survey of U.S. prescription drugs dispensed at retail pharmacies in the United States (Table I). This data was compiled and reported by Verispan, VONA, via a health care audit that assessed data from the pharmaceutical industry. (2)

According to IMS Health, the global pharmaceutical market grew 7.0 percent with sales estimates at $683 billion dollars for 2006. U.S. prescription drug sales experienced an 8.3 percent increase, compared to a 5 percent increase observed in the previous year. Total prescription drug sales for 2006 are estimated at $274.9 billion U.S. dollars. (3) The best-selling brand name drug for this 12-month period was Lipitor, which has remained the leader in sales ranking for the past six years. (3)

Increased prescription sales volume is attributed to growth of the aging population and the introduction of the Medicare Part D prescription drug benefit program. This drug program has increased drug coverage to those who were previously uninsured as well as to the underinsured. Participation in and reimbursement by Medicare Part D have provided a tremendous benefit to the senior population. (3) This is evidenced by the fact that as of June 2006, 38 million Medicare beneficiaries had some form of prescription drug coverage. The Center for Medicare and Medicaid Services requires that Medicare Part D provide substantial reimbursement for six of the most highly utilized classes of medications by seniors: antidepressants, anti-psychotics, anticonvulsants, anti-retrovirals, anti-neo-plastics and immunosuppressant medications. Sales of these six classes of medications accounted for one-fifth of U.S. pharmaceutical sales in 2006. Prescriptions dispensed through a Medicare Plan D program accounted for 17 percent of all retail prescriptions. (3)

In 2006, generic drugs accounted for half of the volume of U.S. pharmaceutical product sales. Fifteen of the top 20 drugs dispensed through Medicare Plan D were generics. By the end of 2006, generics accounted for 63 percent of all dispensed prescriptions. In 2006, the number of prescriptions dispensed for generics increased by 13 percent, with a resultant 22 percent increase in sales of these medications. Many therapeutic areas experienced tremendous growth in sales due to new generic drugs, including lipid regulators, antidepressants, and inhaled nasal steroids. A number of other therapeutic classes experienced below-market average sales of leading brand name drugs, due to the emergence of generic competitors as well as a switch to over-the-counter (OTC) status. These classes included proton pump inhibitors, antihistamines, platelet aggregation inhibitors and antidepressants. Some high-volume generic sales included $911 million for simvastatin (generic Zocor), $902 million for clopidogrel (generic Plavix) and $480 million for sertraline (generic Zoloft). (3)

Of the leading therapeutic classes in sales, lipid regulators continue to predominate, with sales increases of 7.5 percent, estimated at $35.2 billion. These sales continue to increase, due to the introduction of new drugs, such as Crestor and Vytorin, and despite the loss of the patents of the brand name drugs Zocor and Pravachol. New generic equivalents, as well as the growing demand for drugs in this therapeutic class by Medicare Plan D participants, will continue to promote the use of these medications. (3)

Oncologics, or cancer drugs, experienced the highest growth among all of the top therapeutic classes, with sales increases of 20.5 percent, estimated at $34.5 billion. Cancer drug innovation is a focus of new drug development aimed at creating more effective therapies that improve cancer treatment and disease outcomes. (3) Respiratory drugs were the third-largest therapy class in terms of sales, with a 10 percent increase in growth, estimated at $24.6 billion. (3)

The oral side effects of the medications discussed in this article are found in Table II. Readers are cautioned that all of the drugs described in this article possess additional drug interactions, warnings and precautions that are not discussed within the context of this article. Every effort has been made to focus this review on applications to dental and dental hygiene practice. The author recommends that all oral health care professionals use a standard drug reference text to review all of a patient's medications prior to initiating treatment. (4-6) In addition, dentists must look up each drug taken by their patients prior to prescribing any additional medications to ensure drug compatibility and patient safety.

Cardiovascular Drugs

As in previous years, the cardiovascular drugs continue to dominate the top 20 list, with 8 out of the top 20 of 2006. Trends in cardiovascular drug use reflect the ongoing risks associated with heart disease among Americans. (7-9) Several new cardiac drugs enter the list this year that contain two drugs in one pill to improve patient compliance.

Cholesterol-Lowering Medications

Lipitor remains the leading brand name prescription drug in the United States according to sales (Table I). (1) Both Lipitor and Zocor belong to the class of medications known as the HMG-CoA reductase inhibitors, commonly referred to as the "statins."

Statin drugs inhibit the enzyme HMG Co-A reductase, the rate-limiting step in cholesterol synthesis. By targeting the liver, drugs in this class decrease the synthesis of cholesterol and increase the breakdown of existing LDL cholesterol. Because statin drugs reduce cholesterol levels in two ways, these drugs remain the drugs of choice for reducing cholesterol over all other classes of cholesterol-lowering medications. Therapeutic benefits of statin drugs include plaque stabilization, improved coronary artery endothelial function, inhibition of platelet thrombus formation and anti-inflammatory effects. Statin drugs can also increase plasma HDL levels in some patients, thus further lowering risk for coronary heart disease. (4-6) Lipitor is also approved for the primary prevention of cardiovascular disease, specifically to reduce the risk of myocardial infarction (MI) and stroke in patients without evidence of heart disease, but who possess multiple risk factors and/or type 2 diabetes. Zocor is also approved for the secondary prevention of MI and stroke in patients who have or are at high risk for coronary heart disease. (4)

Statin drugs are generally well tolerated, but they are associated with rare negative adverse drug effects that are experienced by approximately 10 percent of users. These adverse effects are of significance to dental professionals. First, statin users may experience elevated liver enzymes; therefore, liver function tests are performed on a regular basis to monitor these effects. Elevated liver enzymes may dictate the need for discontinuation of statin drug therapy. Dental professionals should ask their patients when they last had a liver function test performed and should note the results of the test in the treatment record. Patients who have not been tested within the last three months should be referred back to their physicians for routine follow-up testing and evaluation. Abnormalities in liver function generally return to normal upon discontinuation of the drug. (4-6)

Second, statin drugs are associated with rhabdomyolysis, a condition characterized by muscle weakness and deterioration. Often, a patient will complain of muscle aches or cramping, pain in the hips or buttocks, or leg fatigue when standing for long periods of time. Patients who report these symptoms should be referred back to their physicians for further evaluation. Risk for rhabdomyolysis with acute renal failure is dose-related, and increases with the concurrent use of other cholesterol-lowering medications (gemfibrozil, fibric acid derivatives, and niacin >1 gram/day) or with concurrent use of potent liver CYP3A3/4 inhibitors. These enzyme inhibitors include the macrolide antibiotics (e.g., erythromycin, clarithromycin) and the azole antifungals (itraconazole, ketoconazole). Ingesting large quantities of grapefruit juice with statins may also produce this effect. (4)

Atorvastatin (Lipitor) may increase the effects of levothyroxine (Synthroid), digoxin and ethinyl estradiol. Alcohol should be avoided in patients taking statin drugs. (4)

Vytorin is a combination antilipemic medication that contains ezetimibe (Zetia) and simvastatin (Zocor) in one pill. This medication is indicated for the treatment of high cholesterol in addition to dietary modification. Ezetimibe, the only drug in its class, inhibits the absorption of cholesterol along the brush border of the small intestine. By reducing dietary cholesterol, there is a resultant decrease in hepatic cholesterol stores. This drug also increases cholesterol clearance from the blood, causing reductions in LDL cholesterol, total cholesterol and triglycerides, and increased HDL levels. There are no oral complications associated with this medication. Overall, Vytorin is well tolerated; however, side effects similar to those associated with Zocor may be observed with Vytorin. (4)

Beta-Blocker

Beta-blockers are indicated for the treatment of hypertension and angina. They may be used off-label to manage the symptoms of alcohol withdrawal, certain types of arrhythmias, migraine headache prophylaxis and anxiety. (4-6) Beta-blockers are more effective in Caucasians than in African Americans, and in younger persons than in the elderly. (7)

Drugs in this class decrease the workload of the heart by decreasing arterial pressure, which decreases venous return, which decreases preload and myocardial oxygen demand. Decreased cardiac oxygen demand decreases the symptoms of angina. Beta-blockers also decrease cardiac output, as well as the rate and force of contraction. (7) Beta-blockers also have been shown to decrease risk for second heart attack in patients with a history of MI. These drugs also reduce the incidence of sudden cardiac death following MI. Oral health care professionals should note that patients who have survived a heart attack are taking beta-blockers.

Metoprolol (Lopressor, ToproI-XL) is a cardioselective beta-blocker that preferentially blocks beta 1 receptors found in the heart. Cardioselective beta-blockers are useful in patients with hypertension who also have impaired pulmonary function, as they eliminate the unwanted bronchoconstrictor effects caused by nonselective beta-blockers (e.g., propranolol) on the beta 2 receptors in the lungs. Thus, cardioselective beta-blockers are the drugs of choice for patients with chronic obstructive pulmonary diseases, such as asthma. (10)

Cardioselective beta-blockers antagonize beta 1 receptors at doses 50-100 times less than those required to block beta 2 receptors. Cardioselectivity is most pronounced at low doses and is lost at high doses. Nonselective beta-blockers decrease glycogenolysis and glucagon secretion, which may result in pronounced hypoglycemia after insulin injection; therefore, cardioselective agents also are preferred for insulin-dependent diabetics. (10)

Dental professionals are reminded that in the presence of a beta-blocker, epinephrine no longer lowers diastolic blood pressure nor stimulates the heart; however, its vaso-constrictive action, mediated by alpha receptors, remains unimpaired. (10) Nonselective beta-blockers enhance the pressor response to epinephrine, resulting in hypertension and bradycardia, an action that has not been reported with the cardioselective beta blockers. (4,11) Therefore, local anesthetics containing epinephrine as a vasoconstrictor can be safely used in patients taking metoprolol (Toprol XL), as well as other cardioselective beta-blockers (e.g., atenolol). (4,11-13)

Dental professionals are cautioned that the total amount of vasoconstrictor that can be safely administered to a patient is dependent upon the cardiovascular status of the patient. (13) For patients with heart disease, total epinephrine dosage is limited to 0.04 mg, which is the equivalent of two local anesthetic cartridges containing 1:100,000 epinephrine. (13) The prudent practitioner always takes the patient's blood pressure prior to administering local anesthetic agents to avoid complications related to uncontrolled hypertension. When epinephrine is necessary for dental treatment in patients with cardiovascular disease, it is always wise to administer the least amount of epinephrine for clinical efficacy at the lowest concentration possible. (13)

Patients often do not know whether their beta-blocker is cardioselective or not; therefore, oral health professionals must look up these medications prior to administering local anesthetics containing epinephrine. Helpful clues can be found in the patient's medical history, as cardioselective agents are preferred in patients who also have insulin-dependent diabetes, asthma or chronic obstructive pulmonary disorder (COPD) as comorbidities.

Beta-blockers decrease the effects of sulfonylureas (oral hypoglycemics), and may mask the tachycardia from hypoglycemia caused by insulin or oral hypoglycemics. The effects of beta-blockers are decreased with aluminum salts, calcium salts, barbiturates, NSAIDS, penicillins, rifampin and salicylates. (4) Beta-blockers may slow the metabolism of lidocaine, which may lead to lidocaine toxicity. Limit the dose of lidocaine to the lowest amount needed to produce the desired effect. (5)

Beta-blockers cause many unwanted side effects, including fatigue, sleep disturbances and sexual dysfunction. Many men suddenly stop taking their medication because of impotence. This behavior is important for dental professionals to understand because beta-blockers should never be stopped suddenly, as the patient may develop spontaneous rebound hypertension. When the drug is discontinued, it should be tapered off gradually, to avoid arrhythmias and dangerous hypertension. Many male patients will report to their dental professionals that they have decided to stop taking their medication without any explanation. It is important to do follow-up questioning of the patient and to refer the patient back to the physician. Taking blood pressure is critical in this instance, as administering epinephrine to a patient with undetected hypertension can lead to significant consequences. (4)

Calcium Channel Blocker 

Amlodipine (Norvasc) is a calcium channel blocker indicated for the treatment of hypertension and angina. Drugs in this class inhibit calcium ions from entering voltage-sensitive channels within vascular smooth muscle and the myocardium during depolarization. This action results in relaxation of vascular smooth muscle, which vasodilates coronary and peripheral arterioles and lowers blood pressure. Vasodilation decreases vascular resistance and improves blood flow to the heart, increasing oxygen delivery to the myocardium, thus relieving the symptoms of angina. Calcium channel blockers are also used to relieve coronary artery spasm in patients with variant angina. Drugs in this class are effective in treating hypertension in patients with angina, asthma, diabetes and peripheral vascular disease. They are effective agents for the management of hypertension in African Americans. (7) Amlodipine is now found in combination drugs, such as Caduet (amlodipine with atorvastatin), and Lotrel (amlodipine with the ACE inhibitor benazepril), to help improve compliance for patients with several types of cardiovascular problems. (4-6)

Calcium channel blockers are associated with gingival hyperplasia, although the incidence of this adverse drug event with amlodipine occurs in less than 1 percent of users. (14,15) Gingival hyperplasia, should it occur, disappears when the drug is discontinued. While oral hygiene cannot prevent gingival hyperplasia from occurring, good plaque control can limit the extent and severity of the overgrowth. (14,15) Some patients may also report xerostomia with use of amlodipine. (4-6)

Levels of amlodipine may be increased by the systemic azole antifungals, clarithromycin, doxycyline and erythromycin. The antihypertensive effects of both calcium channel blockers and beta-blockers may be compromised in patients who take nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen or indomethacin, for longer than three weeks. (4-6,16,17) In dentistry, NSAIDS are typically prescribed for short-term use only, for pain and swelling associated with infection or following invasive procedures. Short-term use of NSAIDS is not associated with this drug interaction. However, because many NSAIDS are available in over-the-counter (OTC) formulations, patients may be causing this drug interaction unknowingly. Oral health professionals should always assess blood pressure in patients taking antihypertensive medications who also routinely take NSAIDS on a long-term basis (e.g., for chronic pain) to assess if blood pressure is being adequately controlled.

Antiplatelet Agent

Clopidogrel (Plavix) is used as an antithrombotic for the prevention of myocardial infarction, stroke and vascular death in patients with atherosclerosis. Plavix was developed for use for patients who are unable to tolerate the adverse gastrointestinal effects of aspirin, and has recently replaced ticlopidine (Ticlid) as the drug of choice for patients who are allergic or intolerant to aspirin. (18) Evidence supports that both clopidogrel and ticlopidine are more effective than aspirin in preventing stroke and other serious vascular events in patients who are at high risk. (19)

Plavix inhibits platelet aggregation by affecting the ADP-dependent activation of the glycoprotein IIb/IIIa complex. Glycoprotein IIb/IIIa is a receptor on the platelet for adhesive proteins. Drugs that produce inhibition at this receptor site target the final common pathway for platelet adhesion, activation and aggregation. Plavix prevents fibrinogen from binding to this receptor site, thereby reducing platelet adhesion and aggregation. (4)

Plavix has been shown to reduce the combined risk of myocardial infarction, ischemic stroke or vascular death by 8.7 percent. (22) Adverse drug reactions with Plavix are similar to those with aspirin in terms of neutropenia, thrombocytopenia and incidence of hemorrhagic events. There is a lower incidence of intracranial and gastrointestinal bleeding with Plavix as compared to aspirin. Rash occurs more frequently with use of Plavix versus aspirin, but the rashes are mild and transient. (22)

Plavix interferes with the metabolism of many medications, and dental professionals are urged to consult a drug reference guide prior to prescribing any medications to ensure compatibility. This type of interaction includes NSAIDS, which may result in a toxicity reaction. Taking Plavix with aspirin and other NSAIDS may increase the risk for GI bleeding. Concurrent use of Plavix with other antiplatelet agents or anticoagulants further increases the risk for bleeding. Atorvastatin (Lipitor) and the macrolide antibiotics (e.g., erythromycin, clarithromycin) may decrease the effects of Plavix. It is important to note that many herbal supplements also demonstrate antiplatelet effects and thus increase the risk for bleeding; concurrent use of these supplements may produce an additive bleeding risk in patients taking Plavix. (12)

Like aspirin, this drug produces irreversible effects that last for the life of the platelet. Patients can receive routine dental procedures, including oral prophylaxis, without altering the dose of the drug. (20,21) The American Dental Association Council on Scientific Affairs has stated that antiplatelet and anticoagulant medications rarely need to be discontinued prior to most dental procedures. The decision to temporarily stop the medication must be made carefully and in conjunction with the patient's physician. In general, the risk for thromboembolic events is higher than the risk of inducing an uncontrollable bleeding event in the dental office; therefore, the risk to the patient is almost always greater than the perceived benefit of reducing bleeding risk. Bleeding in the dental office can be controlled with a variety of hemostatic agents. However, if the patient must undergo an elective surgery or invasive surgical procedure, and the antiplatelet effects of Plavix pose too great of a bleeding risk to the patient, the drug must be discontinued for seven days prior to the surgery. It must be emphasized that the decision to discontinue the drug must be made based on a thorough medical evaluation and consultation with the patient's prescribing physician. (21-24)

Angiotensin II Receptor Blocker

A new cardiac drug enters the top 20 list this year: valsartan (Diovan). Diovan is indicated for the treatment of essential hypertension and heart failure, and is used to reduce mortality in patients with left ventricular dysfunction after an MI. (4) Drugs in this class are alternatives to the popular ACE inhibitors (e.g., lisinopril or Zestril/Prinivil) used to treat hypertension, and are associated with fewer side effects. Diovan causes pharmacologic effects similar to ACE inhibitors by producing vasodilation and blocking the secretion of aldosterone, which decreases salt and water retention and thus lowers blood pressure. (4,10) Angiotension II receptor blockers also reduce kidney damage associated with diabetes, which makes them favorable drugs for the treatment of hypertension in patients with diabetes. (10)

Dental professionals should carefully monitor patients taking Diovan, especially during the early stages of drug therapy, as the drug may produce significant hypotension, placing patients at risk for orthostatic hypotension when arising from the dental chair. The systemic antifungal drug ketoconazole (Nizoral) should be avoided in patients taking this medication, as it may decrease the effects of the Diovan. (4)

Hormone

Levothyroxine (Synthroid) is used for the treatment of hypothyroidism and the suppression of thyroid stimulating hormone (TSH) from the pituitary gland. The drug is well tolerated and has no oral side effects. However it may increase the effects of oral anticoagulants (warfarin), increasing the risk for bleeding. When taken together, toxicity may occur for both levothyroxine and the tricyclic antidepressants (e.g., Elavil). Antacids containing aluminum and magnesium, iron, bile acid sequestrants used to lower cholesterol (colestipol, cholestyramine) and the ulcer medication sucralfate (Carafate) all decrease the absorption of levothyroxine. Certain seizure medications (phenytoin, phenobarbital and carbamazepine) and the TB medication rifampin (Rifadin) decrease serum levels of levothyroxine. Levothyroxine may decrease the effect of oral sulfonylureas (oral hypoglycemics). (4-6)

Gastrointestinal Medications

Three of the top 20 medications are popular GI medications that belong to the class of proton pump inhibitors: esomeprazole (Nexium), lansoprazole (Prevacid) and pantoprazole (Protonix). These prescription drugs bind to the proton pump in parietal cells of the stomach to reduce gastric acid secretion. They also neutralize gastric acid after it has been released and protect the gastric mucosa from damage. Recently, these drugs were approved to prevent and treat stomach ulcers associated with the use of NSAIDS. (4-6,10)

Nexium is a second-generation prescription drug that replaced omeprazole (Prilosec), which went over-the-counter in 2004. Nexium is indicated for the short-term treatment of erosive esophagitis and for the treatment of gastroesophageal reflux disease (GERD). It is also used in conjunction with an antibiotic to treat duodenal ulcer disease caused by Helicobacter pylori. Gastrointestinal side effects are common and include nausea, constipation, diarrhea and abdominal pain. Nexium also produces xerostomia, which is reversible upon discontinuation of the drug. Nexium increases the levels of some benzodiazepines (e.g., diazepam [Valium], midazolam [Versed], triazolam [Halcion] and carbamazepine [Tegretol]). Proton pump inhibitors may decrease the absorption of antiretroviral medications, iron salts and the systemic azole antifungals. (4-6)

Prevacid is indicated for the short-term treatment of active duodenal ulcers, maintenance therapy for healed ulcers, and as a part of treatment for duodenal ulcers caused by Helicobacter pylori. It is also used for the short-term relief of symptoms of GERD. Patients who take NSAIDS long-term may be placed on Prevacid to reduce the risk of GI ulceration that occurs as a side effect of NSAID therapy. This drug offers good long-term acid protection, has a slow onset of action and offers limited relief for nocturnal heartburn. Gastrointestinal side effects and drug interactions of Prevacid are similar to those caused by Nexium. Patients taking Prevacid may experience xerostomia and taste alteration. Other oral side effects occur in less than 1 percent of users, and include candidiasis and stomatitis. (4-6,25)

Protonix is indicated for the treatment and maintenance of healing erosive esophagitis caused by GERD and for the reduction of daytime and nighttime heartburn associated with GERD. It is also used for the management of a variety of hypersecretory conditions. Currently, this drug is investigational for the treatment of peptic ulcer disease and active bleeding ulcers, and as a part of treatment for Helicobacter pylori infection. Protonix shares a similar GI adverse events profile with Nexium and Prevacid. Adverse oral effects occur in less than 1 percent of users. (4-6) Protonix increases the effects of some selective serotonin reuptake inhibitors (SSRIs), some oral hypoglycemics, phenytoin and warfarin. Like other drugs in this class, Protonix decreases the absorption of many medications, including ampicillin, iron salts, antiretroviral medications and the systemic azole antifungals. The effects of Protonix can be reduced by CYP2C19 inducers such as carbamazepine (Tegretol) and phenytoin. (4-6)

Respiratory Drugs

Montelukast (Singulair) is a leukotriene-receptor antagonist used for the prevention and treatment of asthma, and for the relief of symptoms of seasonal allergies. This drug occupies receptor sites, which prevents leukotrienes from producing their unwanted bronchoconstrictor effects, airway edema and inflammation. This drug can be used in children and adults and offers an excellent alternative to steroids in mild or early forms of asthma. However, this drug cannot be used to reverse an acute asthma attack, and patients should be encouraged to carry their rescue bronchodilators (albuterol) with them to reverse acute bronchoconstriction. The chewable tablet form of this drug contains phenylalanine, a consideration for patients with phenylketonuria. Many seizure medications decrease the effects of Singulair. (4-6)

Advair Diskus is a combination medication that contains a beta 2 adrenergic agonist (salmeterol) with an inhaled corticosteroid (fluticasone). This inhaled drug is indicated for the maintenance of asthma and COPD associated with chronic bronchitis. It is important to note that Advair Diskus is not a substitute for a fast-acting inhaler (e.g., albuterol) for the management of acute asthma attacks. The bronchodilator salmeterol has a slower onset and a longer duration of action than albuterol, and is therefore not appropriate for use during acute respiratory distress. The corticosteroid component is used to reduce the inflammation and mucosal secretions associated with respiratory diseases, which helps to reduce the work of breathing. (4-6,10)

Serious complications are associated with use of this medication, including adverse cardiovascular events, seizure disorders, diabetes, glaucoma, hyperthyroidism, hepatic impairment and adrenal suppression. Dental professionals should use caution when administering other sympathomimetic drugs (e.g., epinephrine) to patients taking this medication, as they may experience increased heart rate and blood pressure, which increases risk for arrhythmias and seizures. There are multiple drug interactions associated with this medication. Clarithromycin and the systemic antifungals (itraconazole, ketoconazole) may increase the levels of both fluticasone and salmeterol. Sympathomimetics enhance the adverse effects of salmeterol. Antifungal agents may decrease the metabolism of corticosteroids, prolonging their effects."

The oral complications associated with Advair Diskus include oral candidiasis of the mouth and pharynx, oral discomfort/pain and taste alteration. (4) Patients who use inhalers often complain of taste alteration and tooth staining, which are typically caused by residual drug left in the mouth following inhalation. Patients should be instructed to rinse the mouth thoroughly after using their inhalers, and to expectorate after rinsing, to avoid increasing the systemic absorption of the drug. Good oral hygiene can also help to minimize any staining. (5)

One prescription antihistamine is also included on the top 20 list for 2006: cetirizine (Zyrtec). Zyrtec is an H1 receptor blocker used for the treatment of perennial and seasonal allergic rhinitis and for the management of other allergic symptoms. Zyrtec produces sedation as a side effect, and anticholinergic medications and CNS depressants, including alcohol, will increase this sedative effect. Like all antihistamines, xerostomia is a common oral complication that is typically experienced following the first dose. Other oral side effects include stomatitis, loss of taste, taste alteration and tongue discoloration. (4-6)

Sedative Hypnotic

Zolpidem (Ambien) is used for the short-term treatment of insomnia, and treatment is generally limited to 7-10 days. Zolpidem has no anticonvulsant or muscle-relaxing properties like the benzodiazepine drugs (e.g., Valium): it merely acts as a sedative hypnotic agent on the benzodiazepine receptor family. This drug typically does not produce withdrawal effects and produces very little tolerance, although there is some degree of risk for withdrawal following abrupt discontinuation of the drug. (4,7)

Dosage for adult patients should not exceed 10 mg taken immediately before bedtime. Elderly patients take a reduced dose of 5 mg. This drug should be used with caution in patients with depression. Side effects include heart palpitations, CNS effects of dizziness and lightheadedness, abnormal dreams and daytime drowsiness. Some users may experience GI side effects including nausea, diarrhea, constipation and xerostomia.

Concurrent use of drugs that inhibit CYP3A4, such as ciprofloxacin, doxycycline, erythromycin, clarithromycin and the systemic azole antifungal drugs may increase the serum levels of Ambien. Ambien causes CNS depression and may impair physical activities and mental acuity. Use of any other drugs, including alcohol, that act centrally may produce an additive CNS depression. This drug should be used only after an evaluation to determine the cause of the sleep disturbance and should be avoided in patients with sleep apnea and/or a history of sedative-hypnotic abuse. (4-6) Recent reports of adverse events associated with Ambien include complex behavior disorders, such as sleepwalking and sleep-driving, as well as hallucinations, increased depression and suicidal tendencies. (26)

Antidepressants

Two SSRIs appear on the top 20 list for 2006: escitalopram (Lexapro) and sertraline (Zoloft). SSRIs increase synaptic levels of serotonin by blocking its reuptake back into the presynaptic neuron, which results in elevated mood, improved sleep and an improved sense of satiety after eating.

Zoloft is approved for depression, obsessive-compulsive disorder (OCD), panic disorders, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD) and social anxiety disorder (SAD). (4,5) Lexapro is approved for the treatment of major depressive disorders and generalized anxiety disorders (GAD). (4,5)

There are many drug interactions associated with the SSRIs, making prescribing difficult for patients with multiple comorbidities. A drug reference should always be consulted prior to prescribing any additional medications to ensure compatibility. SSRIs should not be used with other antidepressants, especially the MAOIs, an older class of antidepressants, as concomitant use increases the risk for severe reactions, including serotonin syndrome and death. Serotonin syndrome is characterized by hyperthermia, muscle rigidity, altered mental status, agitation and autonomic instability (e.g., hypertension). (4) MAOIs must be discontinued for a minimum of two weeks prior to starting an SSRI, or the SSRI must be stopped for a minimum of five weeks before starting an MAOI.

Caution must be used in patients with liver or kidney impairments, those taking CNS depressants (e.g., alcohol) and during pregnancy. Recently, the FDA changed the labeling requirements for the SSRIs to state an increased risk for suicide among children and adolescents taking these drugs. SSRIs cause agitation and other emotional reactions as known side effects, and following the initiation of medication, family members, friends and caregivers of patients taking these medications should watch for signs of suicidal tendency or other associated negative risk behaviors. These behaviors include but are not limited to anxiety, agitation, panic attacks, hostility, aggression, irritability, impulsiveness, insomnia and mania. Patients exhibiting these symptoms should be referred back to their physicians for evaluation. Patients should not suddenly discontinue their medications; discontinuation should occur in gradual, tapered increments. (4) These drugs should not be used as monotherapy for patients with bipolar disorder, as a shift towards mania may occur. (4) Zoloft is not approved for use in children under the age of six, but is approved for the treatment of obsessive-compulsive disorder in children over the age of six. (4)

Use of SSRIs with NSAIDS, aspirin and other drugs that alter platelet function or coagulation increases the risk for bleeding. Dental professionals should be aware of this important adverse drug effect and should monitor their patients carefully for signs of increased bleeding. (4)

Zoloft may increase the effects of certain drugs of significance to dentistry including amphetamines, bupropion (Wellbutrin, Zyban), certain benzodiazepines, lidocaine, tricyclic antidepressants and warfarin. Concurrent use of lithium increases the risk for kidney damage, which should not be of significance as Zoloft is not FDA approved for the treatment of bipolar disorder. Zoloft may decrease the levels or effects of codeine, hydrocodone, oxycodone and tramadol. (4)

CYP3A4 inhibitors increase the effects of Lexapro, including the systemic azole antifungals, ciprofloxacin, clarithromycin, erythromycin and doxycycline. CYP3A4 inducers decrease the effects of Lexapro, including certain anticonvulsants (carbamazepine, phenobarbital, phenytoin) and nafcillin (a penicillin antibiotic). Alcohol, other CNS depressants, St. John's wort and other herbals that may increase CNS depression should be avoided with these SSRI medications. (4) Use of Lexapro with tramadol (UItram) increases the risk for seizures. (5)

A third, and similar antidepressant to the SSRIs also appears on the top 20 list: venlafaxine (Effexor XR), which is a serotonin/norepinephrine reuptake inhibitor. Effexor XR is indicated for the treatment of major depressive disorder, generalized anxiety disorder, social anxiety disorder and panic disorder. Currently, it is investigational for OCD, hot flashes, neuropathic pain and ADHD. (4) Many drug interactions are associated with this medication. Risk for serotonin syndrome increases with concurrent use of MAOIs, serotonin agonists, SSRIs, trazodone and tricyclic antidepressants. Levels of Effexor are increased with the use of systemic azole antifungals, clarithromycin, doxycycline and erythromycin. Patients should be told to avoid drinking alcohol due to an increased risk for CNS depression. Herbal medications, such as valerian, St. John's wort, SAMe, kava kava and tryptophan should be avoided due to risk for serotonin syndrome and/or excessive sedation. Dental hygienists should carefully monitor blood pressure in patients taking Effexor, as the drug produces a sustained increase in diastolic blood pressure and heart rate as a side effect. (4)

All antidepressants cause xerostomia, and symptoms generally appear quickly after the initiation of drug therapy. Patients taking these drugs may also complain of taste alteration, and as previously discussed, may use a variety of products in an attempt to mask the aftertaste. Dental professionals should watch these patients for signs of caries related to xerostomia and the excessive intake of sugar-containing mints and gum. Patients taking the SSRIs may also demonstrate bruxism: drugs in this class are thought to stimulate increased involuntary movements. (27) Drug-induced bruxism will manifest with multiple clinical signs in patients who previously did not show signs or symptoms; patients who already clench and grind their teeth will show increased symptoms of occlusal trauma, such as fractured restorations and teeth and/or orofacial pain. Patients should be evaluated for occlusal trauma and treated and/or referred as necessary.

Bisphosphonates

Alendronate (Fosamax) is used for treatment and prevention of osteoporosis in postmenopausal women and treatment of osteoporosis in males. Other indications include Paget's disease and the treatment of glucocorticoid-induced osteoporosis in men and women with low bone mineral density. (4-6)

The bisphosphonate drugs are the best bone-building drugs on the market and have a high binding affinity for bone hydroxyapatite. Once bound, drugs in this class become structurally incorporated into the bone and produce the greatest bone density increases of all available osteoporosis therapies. Bisphosphonates increase bone mineral density, and decrease bone resorption and turnover by inhibiting osteoclast formation and activity. (28) Bone density increases are generally greatest within the first year of therapy. Fosamax has been shown to decrease risk for future fractures of the hip and spine.

One limitation of the bisphosphonate drugs is their poor oral bioavailability. Drugs in this class must be taken on an empty stomach, usually first thing in the morning, with a minimum of six to eight ounces of water to facilitate moving the drug through the esophagus and to assist with absorption from the stomach and into the bloodstream. Patients must also remain upright for at least 30 minutes following ingestion to help prevent erosive esophagus, a negative adverse event associated with these medications.

The greatest side effect associated with Fosamax is hypocalcemia, which occurs in approximately 18 percent of users and is generally transient and mild in severity. Hypophosphatemia, another frequent complication, affects about 10 percent of users, and is also transient and mild. Patients may also complain of nausea and diarrhea when using Fosamax. Postmarketing reports include rare GI events of oropharyngeal ulceration, abnormal taste, esophagitis and esophageal perforation. (4,5) GI complications may be reduced by using once per week dosing of Fosamax versus daily dosing regimens.

It is important to remind patients to take their Fosamax with water only, as all food and beverages interfere with absorption; food decreases absorption by 40 percent, and coffee and orange juice decrease oral bioavailability by as much as 60 percent. Dairy products decrease absorption through calcium binding. Caffeine also may reduce efficacy. (4)

Oral medications also interfere with absorption, and patients should wait at least 30 minutes after ingesting Fosamax to take any of their other prescription medications. Multivalent cations, including calcium and antacids, and iron, may reduce absorption by as much as 60 percent, so the 30-minute waiting period applies to supplements as well. This is especially important, as many patients with osteoporosis may need to take supplemental calcium and vitamin D if their dietary intake is inadequate. (4)

There is growing interest in the number of reported cases of jaw osteonecrosis associated with dental treatment in patients receiving bisphosphonate medications. This adverse oral reaction has been primarily observed with the injectable bisphosphonate drugs pamidronate disodium (Aredia) and zoledronic acid (Zometa) in cancer patients who were receiving these drugs as a part of their therapy. Most of the reported cases have been associated with tooth extractions, and many of these patients had signs of local infection, including osteomyelitis. (29-34)

Signs and symptoms of oral bone necrosis include pain, swelling, gingival infections, loosening of teeth, poor gingival healing, numbness in the jaw, a feeling of heaviness in the jaw, drainage and exposed bone. (30)

Manufacturers of these drugs and FDA urge dental professionals to perform an examination and to provide preventive dental services to patients prior to initiating medical treatment with the bisphosphonates, especially for patients with known risk factors. Osteonecrosis has multiple known risk factors including the diagnosis of cancer, chemotherapy, use of corticosteroids and radiation therapy. Existing comorbidities, such as anemia, coagulopathies, infection, existing dental disease and poor oral hygiene increase risk. ADA recommends that all invasive procedures be performed prior to administration of IV bisphosphonates as part of cancer therapy. For patients currently undergoing bisphosphonate therapy, invasive dental procedures should be avoided whenever possible. For patients who develop jaw osteonecrosis while on bisphosphonates, dentists are cautioned that dental surgery may exacerbate the condition. (30) For these patients, a medical consultation is warranted.

Conclusion

Dental hygienists play an important role in reviewing the patient's pharmacologic history as a component of the comprehensive health history review. As medication use can increase risks associated with providing dental hygiene care, identifying potential risks during the health history review is an essential risk reduction strategy that prevents medical emergencies and ensures patient safety. Understanding the oral side effects of commonly prescribed medications allows the dental hygienist to make appropriate product recommendations to improve the patient's oral health and function.

References

(1.) The top 200 prescriptions for 2006 by number of US prescriptions dispensed. Available at www.rxlist.com/script/main/hp.asp. Accessed Sep. 1, 2007.

(2.) Verispan, VONA. Available at www.advanstarhealthcare.com. Accessed Sep. 15, 2007.

(3.) IMS Health. Available at www.imshealth.com. Accessed Sep. 15, 2007.

(4.) Wynn RL, Meiller TF, Crossley H. Drug information handbook for dentistry, 12th ed. Hudson: Lexi-Comp, Inc.; 2006.

(5.) Pickett FA, Terezhalmy GT. Dental drug reference with clinical implications. Baltimore: Lippincott Williams & Wilkins; 2006.

(6.) Gage T, Pickett F. Mosby's dental drug reference, 7th ed. St. Louis: Mosby; 2005.

(7.) Chobanian AV, Bakris GL, Black HR, et al.: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC report. J Am Dent Assoc 2003; 289: 2560-72. Erratum in: J Am Dent Assoc 2003; 290: 197.

(8.) Grudy SM, Cleeman JI, Bairey Merz CN, et al.: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227-39.

(9.) Mosca L, Appel LJ, Benjamin EJ, et al.: Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004; 109: 672-93.

(10.) Harvey RA, Champe PC, Howland RD, Mycek MJ. Lippincott's reviews: pharmacology, 3rd ed. Baltimore: Lippincott Williams & Wilkins, 2006.

(11.) Foster CA, Aston SJ: Propranolol-epinephrine interaction: a potential disaster. Plast Reconstr Surg 1983; 72(1):74-8.

(12.) Wynn RL: Epinephrine interactions with beta blockers. Gen Dent 1994; 42(1): 16, 18.

(13.) Malamed SF: Handbook of local anesthesia, 5th ed. St. Louis: Mosby; 2004.

(14.) Jorgensen MG: Prevalence of amlodipine-related gingival hyperplasia. J Periodontol 1997; 68(7): 676-8.

(15.) Wynn RL: An update on calcium channel blocker-induced gingival hyperplasia. Gen Dent 1995; 43(3): 218-22.

(16.) Wong DG, Spence JD, Lamki L, et al.: Effect of nonsteroidal anti-inflammatory drugs on control of hypertension of beta-blockers and diuretics. Lancet 1986; 1(8488): 997-1001.

(17.) Wynn RL: Dental nonsteroidal anti-inflammatory drugs and prostaglandin-based drug interactions--part two. Gen Dent 1992; 40(2): 104,106,108.

(18.) Wynn RL, Bergman SA. Drugs and herbal remedies that affect blood clotting. Gen Dent. 2002; 50: 484-88, 490.

(19.) Hankey GJ, Sudlow CLM, Dunbabin DW. Thienopyridine derivatives or to prevent stroke and other serious vascular events in patients at high risk for vascular disease? A systematic review of the evidence from randomized trials. Stroke. 2000; 31: 1779-84.

(20.) Little JW, Miller CS, Henry RG, McIntosh BA. Antithrombotic agents: implications in dentistry. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 93: 544-51.

(21.) Jeske AH, Suchko GD, ADA Council on Scientific Affairs and Division of Science, et al.: Lack of a scientific basis for routine discontinuation of oral anticoagulation therapy before dental treatment. J Am Dent Assoc 2003; 134(11): 1492-7.

(22.) Daniel NG, Goulet J, Bergeron M, et al.: Antiplatelet drugs: is there a surgical risk? J Can Dent Assoc 2002; 68(11): 683-7.

(23.) Scully C, Wolff A: Oral surgery in patients on anticoagulant therapy, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 93(1): 57-64.

(24.) Wynn RL: CIopidogrel (Plavix): dental considerations of an antiplatelet drug. Gen Dent 2001; 49(6): 564-8.

(25.) Byrne BE: Gastrointestinal drugs. In: Ciancio SC (ed.). ADA guide to dental therapeutics, 4th ed. Chicago, ADA Publishing Co., Chapter 16: 455-512, 2006.

(26.) United States Food and Drug Administration. Medwatch: Ambien. Available at: www.fda.gov/medwatch/SAFETY/2007/Mar_PI/Ambien_PI.pdf Accessed Sep. 15, 2007.

(27.) Gerber PE, Lynd LD: Selective serotonin reuptake inhibitor-induced movement disorders. Ann Pharmacother 1998; 32(6): 692-8.

(28.) Rodan GA: Mechanisms of action of bisphosphonates. Ann Review Pharmacol Toxicol 1998; 38: 375-88.

(29.) U.S. Food and Drug Administration. Medwatch. Available at www.fda. gov/medwatch/SAFETY/2004/safety04.htm. Accessed Sep. 30, 2005.

(30.) American Dental Association. Osteonecrosis of the jaw. Available at www.ada.org/prof/resources/topics/osteonecrosis.asp. Accessed Sep. 15, 2007.

(31.) Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62: 527-34.

(32.) Migliorati CA, Casiglia J, Epstein J, et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 2005; 136: 1658-68.

(33.) Ruggiero S, Gralow J, Marx RE, et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Prac 2006; 2: 7-14.

(34.) Pickett FA. Bisphosphonate-associated osteonecrosis of the jaw: a literature review and clinical practice guidelines. J Dent Hyg 2006; 3:10-10(1).

By Ann Eshenaur Spolarich, RDH, PhD

Ann Eshenaur Spolarich, RDH, PhD, is a licensed dental hygienist, consultant and physiologist, and specializes in the care of geriatric and medically complex patients. She is a clinical associate professor at the USC School of Dentistry where she teaches Pharmacology in the Department of Dental Hygiene; and teaches Pharmacology at the Arizona School of Dentistry and Oral Health, and in the Department of Audiology at the Arizona School of Health Sciences. She is a clinical instructor on the Dean's Faculty at the University of Maryland Dental School. She is the current chair of the ADHA Council on Research. She practices dental hygiene part-time in Arizona and Maryland.

Table I. The top 20 most commonly prescribed medications of 2006
ranked by total number of prescriptions dispensed. (1)

 Drug Name          Manufacturer               Therapeutic category

 1. Lipitor         Pfizer Inc.                HMG CoA Reductase
                                               inhibitor

 2. Toprol-XL       AstraZeneca                Cardioselective beta
                                               blocker

 3. Norvasc         Pfizer Inc.                Calcium channel
                                               blocker

 4. Synthroid       Abbott                     Hormone

 5. Lexapro         Forest                     Selective serotonin
                                               reuptake inhibitor

 6. Nexium          AstraZeneca                Proton pump inhibitor

 7. Singulair       Merck & Co., Inc.          Leukotriene-receptor
                                               antagonist

 8. Prevacid        TAP Pharmaceutical         Proton pump inhibitor
                    Products, Inc.

 9. Ambien          Sanofi-Synthelabo          Non-benzodiazepine
                                               hypnotic

10. Zoloft          Pfizer Inc.                Selective serotonin
                                               reuptake inhibitor

11. Advair Diskus   GlaxoSmithKline            Beta 2 adrenergic
                                               agonist with inhaled
                                               corticosteroid

12. Zyrtec          Pfizer Inc.                Antihistamine (H1
                                               receptor blocker)

13. Effexor XR      Wyeth-Ayerst               Antidepressant
                                               (serotonin/
                                               norepinephrine
                                               reuptake inhibitor)

14. Fosamax         Merck & Co., Inc.          Bisphosphonate

15. Plavix          Sanofi-Synthelabo, Inc.    Antiplatelet agent

16. Protonix        Wyeth Pharmaceuticals      Proton pump inhibitor

17. Vytorin         Merck/Schering-Plough      Antilipemic agent
                    Pharmaceuticals            with HMG CoA
                                               Reductase inhibitor
18. Zocor           Merck & Co., Inc.          HMG CoA Reductase
                                               inhibitor

19. Diovan          Novartis Pharmaceuticals   Angiotensin II
                                               receptor blocker

20. Lotrel          Novartis Pharmaceuticals   Calcium channel
                                               blocker with ACE
                                               inhibitor

Table II. Oral side effects associated with the 20 most common
prescribed drugs of 2006. (4-6)

Drug            Xerostomia   Candida   Altered   Vomiting
                                        taste
Lipitor
Toprol-XL           x
Norvasc             x                     x
Synthroid
Lexapro             x                               x
Nexium              x
Singulair
Prevacid
Ambien              x                     x
Zoloft              x
Advair Diskus                   x         x
Zyrtec              x                     x
Effexor XR          x                     x
Fosamax
Plavix
Protonix
Zocor                                     x
Vytorin                                   x
Diovan
Lotrel

Drug               Tongue       Stomatitis    Gingival
                discoloration                hyperplasia
Lipitor
Toprol-XL
Norvasc                                           x
Synthroid
Lexapro
Nexium
Singulair
Prevacid
Ambien
Zoloft
Advair Diskus
Zyrtec                x             x
Effexor XR
Fosamax
Plavix
Protonix
Zocor
Vytorin
Diovan
Lotrel                                            x

Drug                Oral         Bruxism
               discomfort/pain
Lipitor
Toprol-XL
Norvasc
Synthroid
Lexapro                             x
Nexium
Singulair
Prevacid
Ambien
Zoloft                              x
Advair Diskus         x
Zyrtec
Effexor XR
Fosamax
Plavix
Protonix
Zocor
Vytorin
Diovan
Lotrel