Cardiovascular

Cardiovascular Drugs and Dental Considerations

This paper provides current information on the pharmacologic management of cardiovascular diseases. It also describes the drugs used to treat five common cardiovascular disorders -- heart failure, coronary artery disease, atrial fibrillation, hypertension and unstable angina -- and lists their dental implications. This information can be used to monitor patients for potential adverse drug reactions and drug interactions and to provide an information base for medical consultation.

This paper describes the drugs used to treat five common cardiovascular disorders: heart failure, coronary artery disease, atrial fibrillation, hypertension, and unstable angina. For each condition, a discussion of the drugs used in the management of that condition is provided. The drugs are also listed in Tables 1 through 5. Some of the listings are redundant because the drugs are used to treat more than one cardiovascular disorder. As a convenience to the reader, each table has been constructed as a stand-alone listing of drugs for the given disorder. The dental implications of these drugs are listed in Tables 6 and 7. Each of these two tables is a consolidation of the drugs from Tables 1 through 5. Table 6 describes the more frequent cardiovascular, respiratory, and central nervous system adverse reactions that may be seen in the dental patient. Table 7 describes the effects on dental treatment reported for these drugs. It is suggested that the reader use Tables 6 and 7 to check for potential effects that could occur in medicated cardiovascular dental patients. It is the purpose of this paper to provide the most current information on the pharmacologic management of cardiovascular diseases. This information can then be used to monitor patients for potential adverse drug reactions and drug interactions and to provide an information base for medical consultation.

Drugs to Treat Heart Failure

Heart failure is a condition in which the heart is unable to pump sufficient blood to meet the needs of the body. It is caused by impaired ability of the cardiac muscle to contract or by an increased workload imposed upon the heart. The most significant underlying cause of heart failure is coronary artery disease. Other contributory causes are hypertension, diabetes, idiopathic dilated cardiomyopathy, and valvular heart disease. It is estimated that heart failure affects approximately 5 million Americans.¹ The New York Heart Association functional classification is regarded as the standard measure to describe the severity of a patient’s symptom.² Class I is characterized by having no limitation of physical activity. There is no dyspnea, fatigue, palpitations or angina with ordinary physical activity. There is no objective evidence of cardiovascular dysfunction. Class II includes those patients having slight limitation of physical activity. These patients have fatigue, palpitations, dyspnea, or angina with ordinary physical activity but are comfortable at rest. There is evidence of minimal cardiovascular dysfunction. Class III is characterized with marked limitation of activity. Less than ordinary physical activity causes fatigue, palpitations, dyspnea, or angina; but patients are comfortable at rest. There is objective evidence of moderately severe cardiovascular function. Class IV is characterized by the inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest, and any physical activity undertaken increases discomfort. There is objective evidence of severe cardiovascular dysfunction.

Drug Classes and Agents for Treatment

Drug classes and the specific agents used to treat heart failure are listed in Table 1. Angiotensin converting enzyme inhibitors reduce left ventricular volume and filling pressure and decrease total peripheral resistance. They induce cardiac output modestly and induce natriuresis. These ACE inhibitors are usually used in all patients with heart failure if no contraindication or intolerance exists. This group of drugs is considered the cornerstone of treatment, and they are used routinely and early if pharmacologic treatment is indicated.

Diuretics increase sodium chloride and water excretion resulting in reduction of preload, the degree of tension on the cardiac muscle when it begins to contract. By reducing preload, the diuretics relieve symptoms of pulmonary congestion associated with heart failure. They may also reduce myocardial oxygen demand. The thiazides, the loop diuretics, and the potassium-sparing agents are all useful in reducing preload by way of their diuretic actions. See Table 1 for a list of the specific diuretics.

Digitalis glycosides have been used in the treatment of heart failure for more than 200 years. Digitalis drugs increase cardiac output by a direct positive inotropic action on the myocardium. Inotropic action is defined as the contractile force of the cardiac muscle. This increased cardiac output results in decreased venous pressure, reduced heart size, and diminished compensatory tachycardia.

Beta-adrenergic receptor blocking drugs (beta blockers) are used in the treatment of heart failure because they reduce the number of deaths. A meta-analysis of randomized clinical trials showed that the beta blockers significantly reduced all causes of mortality, with carvedilol (Coreg) showing the greatest efficacy.³ The overall risk of death was reduced by more than 30 percent. The beta blockers used to treat heart failure are listed in Table 1.

Other drugs used in the treatment of heart failure are referred to as supplemental agents. The direct-acting vasodilators reduce excessive vasoconstriction and the workload of the failing heart. The catecholamines and phosphodiesterase inhibitors are alternative agents with positive inotropic effects. The catecholamines and phosphodiesterase inhibitors are effective for short-term therapy and have not been demonstrated to prolong life during long-term therapy. The names of these supplemental drugs are found in Table 1.

Drugs to Treat Coronary Artery Disease

Coronary artery disease is the cause of about half of all deaths in the United States.⁴ CAD has been shown to correlate to the levels of plasma cholesterol and/or triacylglycerol-containing lipoprotein particles. Secondary prevention of CAD focuses on therapies to reduce morbidity and mortality in patients clinically documented to have the disease. In contrast, primary prevention focuses on averting the development of CAD. Lipid-lowering and cardioprotective drugs provide significant risk-reducing benefits in the secondary prevention of CAD. Reducing total and low-density cholesterol levels primarily through the inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase by the statin drugs significantly improves survival. Cardioprotective drug therapy includes antiplatelet/anticoagulant agents to inhibit platelet adhesion, aggregation and blood coagulation; beta blockers to lower heart rate, contractility and blood pressure; and the ACE inhibitors to lower peripheral resistance and workload. See Table 2 for a listing of these drugs.

Drugs to Treat Atrial Fibrillation

Atrial fibrillation is an arrhythmia characterized by multiple electrical activations in the atria resulting in scattered and disorganized depolarization and repolarization of the myocardium. Atrial contraction can lead to an irregular and rapid rate of ventricular contraction. The prevalence of atrial fibrillation within the U.S. population ranges from 1 percent to 4 percent,^5,6 with the incidence of the disease increasing with age. It is often associated with rheumatic valvular disease and nonvalvular conditions including coronary artery disease and hypertension. Coronary artery disease is present in about one-half of the patients with this form of arrhythmia. Atrial fibrillation is a major risk factor for systemic and cerebral embolism. It is thought that thrombi develop as a result of stasis in the dilated left atrium and are dislodged by sudden changes in cardiac rhythm.⁷ About 10 percent of all strokes in patients older than 60 are caused by atrial fibrillation.⁷

The cornerstones of drug therapy for atrial fibrillation are the restoration and maintenance of normal sinus rhythm through the use of anti-arrhythmic drugs; ventricular rate control through the use of beta blockers, digitalis drugs or calcium channel blockers; and stroke prevention through the use of anticoagulants.⁸ Therapy for atrial fibrillation also includes the management of arrhythmias by cardiac pacemaker and ablation therapy.

Antiarrhythmic Drugs

Cardiac rhythm is conducted through the sinoatrial and atrioventricular nodes, bundle branches, and Purkinje fibers. Electrical impulses are transmitted within this system by opening and closing of sodium and potassium channels. Antiarrhythmic drugs are classified by which channel they act upon, a classification known as Vaughn Williams after the author of the paper describing them.⁹ The so-called Class I agents act primarily on sodium channels, and the Class III agents act on the potassium channels. In addition, there are subclassifications within the Class I agents according to effects of the drug on conduction and refractoriness within the Purkinje and ventricular tissues. Class IA agents show moderate depression of conduction and prolongation of repolarization; Class IB agents show modest depression of conduction and shortening of repolarization; Class IC agents show marked depression of conduction and mild or no effect on repolarization. Class IA and IC agents are effective in the treatment of atrial fibrillation. Class IB agents are not used to treat atrial fibrillation but are effective in treating ventricular arrhythmias. This class includes lidocaine and phenytoin. Table 1 lists the drugs and the categories used to treat atrial fibrillation. Class II drugs are the beta-adrenergic blocking drugs and Class IV are the calcium channel blockers.

Restoring and Maintaining Normal Sinus Rhythm

Cardioversion induced by drugs can usually restore sinus rhythm in patients with atrial fibrillation. Class IA drugs (disopyramide, procaineamide, quinidine), Class IC drugs (flecainide, propafenone), and Class III antiarrhythmics (amiodarone) are all effective in restoring normal sinus rhythm. Success rates may vary greatly and are complicated by the high rate of spontaneous conversion.^10,11 The drugs used for pharmacologic conversion are also used to maintain sinus rhythm.

Ventricular Rate Control

It is accepted practice to treat patients with medication when the resting ventricular rate exceeds 110 beats per minute. Digoxin, calcium channel blockers, and beta-adrenergic blockers are used in the regulation of the ventricular rate. Digoxin increases the vagal tone to the atrioventricular node, calcium channel blockers slow the atrioventricular nodal conduction, and the beta-adrenergic blocking drugs decrease the sympathetic activation of the atrioventricular nodal conduction.

Stroke Prevention

Reports from stroke prevention trials indicate that patients with atrial fibrillation incurred a 4 percent annual risk of stroke if not treated.¹² Also, patients with heart failure or coronary heart diseases were three times more likely to have a stroke than those without risk factors. Anticoagulation therapy with warfarin reduced the stroke risk by 64 percent.¹² Warfarin was found to be more effective than aspirin in all age groups in the Stroke Prevention in Atrial Fibrillation II Trial.^13,14 To achieve optimal levels of anticoagulation with the lowest incidence of bleeding, the International Normalized Ratio is usually maintained between 2 and 3.^15-17 For patients younger than 60 with atrial fibrillation and no other risk factors, no anticoagulant therapy is needed. Aspirin in the amount of 325 mg daily is recommended for those older than 60.⁷

Drugs to Control Hypertension

In the United States, almost 50 million adults 25 to 74 years of age have hypertension. Hypertension is defined as systolic blood pressure ≥ 140 mm Hg, and/or diastolic pressure of > 90 mm Hg.¹⁸ People having blood pressure above normal are considered at increased risk of damage to the heart, kidney, brain, and eye that results in premature morbidity and mortality.¹⁹ Individuals with high normal blood pressure (systolic blood pressure of 130 to 139 mm Hg and diastolic blood pressure of 85 to 89 mm Hg) should be monitored and encouraged to reduce blood pressure by nondrug measures, including weight control, restriction of sodium and alcohol, and participation in an exercise program.¹⁸ Stage 1 hypertension is blood pressure of 140 to 159/90-99 mm Hg. If the desired blood pressure is not achieved with nondrug measures within six months in patients with Stage 1 hypertension without target organ disease and/or clinical cardiovascular disease, pharmacologic therapy is suggested.¹⁸

The suggested initial goals of drug therapy are the maintenance of an arterial pressure of ≤140/90 mm Hg with concurrent control of other modifiable cardiovascular risk factors.¹⁸ Further reduction to 130/85 mm Hg should be pursued if cardiovascular and cerebrovascular function is not compromised. The Hypertension Optimal Treatment randomized trial using patients 50 to 80 years of age found that the lowest incidence of major cardiovascular events and the lowest risk of cardiovascular mortality occurred at a mean achieved diastolic blood pressure of 82.6 and 86.5 mm Hg respectively.²⁰ The classes of medications used for the treatment of hypertension include:

* Diuretics;

* Beta-adrenergic receptor blocking agents (beta blockers);

* Alpha ₁-adrenergic receptor blocking agents (alpha ₁ blockers);

* Agents that have both alpha and beta adrenergic blocking properties (alpha/beta blockers);

* ACE inhibitors;

* Angiotensin II receptor blockers;

* Calcium channel blocking agents; and

* Supplemental agents such as central-acting alpha ₂ - adrenergic receptor agonists and direct acting peripheral vasodilators.

Table 4 lists the drug categories and representative agents used to treat hypertension.

Current Thinking Regarding Antihypertensive Drug Selection

Medications in the first eight categories in Table 4 were held to be equally effective in two large scale studies reported in the New England Journal of Medicine and the Journal of the American Medical Association,^21,22 and it was determined that any of the medications could be used initially for monotherapy. According to the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,¹⁸ diuretics or beta blockers are recommended as initial therapy for uncomplicated hypertension. If a diuretic is selected as initial therapy, a thiazide diuretic is preferred in patients with normal renal function. If necessary, potassium replacement or concurrent treatment with a potassium-sparing agent may prevent hypokalemia. Loop diuretics are used in patients with impaired renal function or who cannot tolerate thiazides. Diuretics are well-tolerated and inexpensive. They are considered the drugs of first choice for treating isolated systolic hypertension in the elderly.¹⁸

Beta blockers are the agents of choice in patients with coronary artery disease or supraventricular arrhythmia and in young patients with hyperdynamic circulation.

Beta blockers are alternatives for initial therapy and are more effective in white patients than in black patients. Beta blockers are not considered first choice drugs in elderly patients with uncomplicated hypertension.

The beta blocking drug carvedilol also selectively blocks alpha ₁ receptors and has been shown to reduce mortality in hypertensive patients.

Alpha ₁ adrenergic blocking agents can be used as initial therapy. The alpha ₁ blocking agent prazosin and related drugs have an added advantage in treating hypertensive patients with coexisting hyperlipidemia since they seem to have beneficial effects on lipid levels. Selective blockade of the post synaptic alpha ₁ receptors by prazosin and related agents reduces peripheral vascular resistance and systemic blood pressure. In addition, all alpha ₁ adrenergic blocking agents relieve symptoms of benign prostatic hyperplasia.

ACE inhibitors are the preferred drugs for patients with coexisting heart failure. They are useful in initial therapy in hypertensive patients with kidney damage or diabetes mellitus with proteinuria, and in white patients.¹⁸ No clinically relevant differences have been found among the available ACE inhibitors.²³ They are well-tolerated by young, physically active patients and the elderly. The most common adverse effect of the ACE inhibitors is dry cough. Angiotensin II receptor blockers produce hemodynamic effects similar to ACE inhibitors while avoiding dry cough.²⁴ These agents are similar to the ACE inhibitors in potency and are useful for initial therapy.

The calcium channel blocking agents are effective as initial therapy in both black and white patients and are well-tolerated by the elderly. These agents inhibit entry of calcium ion into cardiac cells and smooth muscle cells of the coronary and systemic vasculature. Nifedipine (Procardia) and amlodipine (Norvasc) are more potent as peripheral vasodilators than diltiazem (Cardizem). Long-acting formulations of the calcium channel blockers have been shown to be very safe despite some earlier reports that short acting calcium channel blockers were associated with a 60 percent increase in heart attacks among hypertensive patients given a short-acting calcium antagonist.²⁵

Supplemental antihypertensive agents include the centrally acting alpha-₂ agonists and direct-acting vasodilators. These agents are less commonly prescribed for initial therapy because of the impressive effectiveness of the other drug groups. Clonidine (Catapres) lowers blood pressure by activating inhibitory alpha ₂ receptors in the central nervous system, thus reducing sympathetic outflow. It lowers both supine and standing blood pressure by reducing total peripheral resistance. Hydralazine (Apresoline) reduces blood pressure by directly relaxing arteriolar smooth muscle. Hydralazine is given orally for the management of chronic hypertension, usually with a diuretic and a beta blocker.

Drugs to Treat Unstable Angina Pectoris

Numerous physiologic triggers can initiate the rupture of plaque in coronary blood vessels. Rupture leads to the activation, adhesion, and aggregation of platelets and the activation of the clotting cascade, resulting in the formation of occlusive thrombus. If this process leads to complete occlusion of the artery, then acute myocardial infarction with ST-segment elevation occurs. Alternatively, if the process leads to severe stenosis and the artery remains patent, then unstable angina occurs. Triggers that induce unstable angina include physical exertion, mechanical stress due to an increase in cardiac contractility, pulse rate, blood pressure, and vasoconstriction.

Unstable angina accounts for more than 1 million hospital admissions each year.²⁶ In 1989, Braunwald devised a classification system for angina according to the severity of the clinical manifestations.²⁷ These manifestations are defined as acute angina while at rest (within the 48 hours before presentation), subacute angina while at rest (within the previous month but not within the 48 hours before presentation), or new onset of accelerated (progressively more severe) angina. The system also classifies angina according to the clinical circumstances in which unstable angina develops, defined as either angina in the presence or absence of other conditions such as fever, hypoxia, tachycardia, thyrotoxicosis, and whether or not ECG abnormalities are present. Recently, the term "acute coronary syndromes" has been used to describe the range of conditions that includes unstable angina, non-Q-wave myocardial infarction, and Q-wave myocardial infarction.

Pharmacologic therapy to treat the syndrome of unstable angina includes antiplatelet drugs, antithrombin therapy and conventional antanginal therapy with beta blockers, nitrates, and calcium channel blockers. These drug groups and selected agents are listed in Table 5.

Antiplatelet Drugs

Aspirin reduces platelet aggregation by blocking platelet cyclooxygenase through irreversible acetylation. This action prevents the formation of thromboxane A₂. A number of studies have confirmed that aspirin reduces the risk of death from cardiac causes and fatal and nonfatal myocardial infarction by approximately 50 percent to 70 percent in patients presenting with unstable angina.²⁸ Ticlopidine is a second-line alternative to aspirin in the treatment of unstable angina and is also used as adjunctive therapy with aspirin to prevent thrombosis after placement of intracoronary stents. Ticlopidine blocks ADP-mediated platelet aggregation. Clopidogrel inhibits platelet aggregation by affecting the ADP-dependent activation of the glycoprotein IIb/IIIa complex. Clopidogrel is chemically related to ticlopidine but has fewer side effects than ticlopidine.

Platelet glycoprotein IIb/IIIa receptor antagonists. Antagonists of glycoprotein IIb/IIIa, a receptor on the platelet for adhesive proteins, inhibit the final common pathway involved in adhesion, activation, and aggregation. There are three classes of inhibitors. One class is murine-human chimeric antibodies of which abciximab is the prototype. The other two classes are the synthetic peptide forms (e.g., eptifibatide) and the synthetic nonpeptide forms (e.g., tirofiban). These agents have been used to treat unstable angina in combination with heparin and aspirin to significantly reduce the incidence of death or myocardial infarction.

Antithrombin Drugs

Unfractionated heparin in combination with aspirin is used to treat unstable angina. Unfractionated heparin consists of polysaccharide chains that bind to antithrombin III and cause conformational change that accelerates the inhibition of thrombin and factor Xa by antithrombin III. Unfractionated heparin is, therefore, an indirect thrombin inhibitor. Unfractionated heparin can only be administered intravenously. Low-molecular-weight heparins have a more predictable pharmacokinetic profile than the unfractionated heparin and can be administered subcutaneously. These heparins have a mechanism of action and use similar to unfractionated heparin.

The direct antithrombins decrease thrombin activity in a manner independent of any actions on antithrombin III. One such direct antithrombin is lepirudin, also known as recombinant hirudin. This agent is a highly specific direct thrombin inhibitor with each molecule capable of binding to one molecule of thrombin and inhibiting its thrombogenic activity. Direct antithrombins are used for the prevention or reduction of ischemic complications associated with unstable angina.

Warfarin (Coumadin) elicits its anticoagulant effect by interfering with the hepatic synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X. Although warfarin appears to be somewhat effective after myocardial infarction in preventing death or recurrent myocardial infarction, its effectiveness in the treatment of acute coronary syndrome is questionable. Combination therapy with aspirin and heparin followed by warfarin has resulted in reduction of recurrent angina, myocardial infarction, death or all three at 14 days as compared to aspirin alone.²⁹ Another study, however, failed to show any additional benefit from a combination of aspirin and warfarin compared to aspirin alone in the treatment of acute coronary syndrome.³⁰

Conventional Antianginal Therapy (Beta Blockers, Nitrates, Calcium Channel Blockers)

Current thinking is that there is a definite link between unstable angina and acute myocardial infarction. In this regard, beta blockers are currently recommended as first-line agents in all acute coronary syndromes.²⁸ A meta analysis of studies involving 4,700 patients with unstable angina demonstrated a 13 percent reduction in the risk of myocardial infarction among patients treated with beta blockers. The various preparations of beta blockers appear to all have equal efficacy.²⁸ The effects of beta blockers are thought to be due to their ability to decrease myocardial oxygen demand.

Nitrates, such as nitroglycerin, are widely used in the management of unstable angina. Nitrates elicit a number of effects, including a reduction in oxygen demand, arteriolar vasodilation, augmentation of collateral coronary blood flow, and reduction in the frequency of coronary vasospasm. Intravenous nitroglycerin is one of the first line therapies for unstable angina because of the ease of dose titration and the rapid resolution of effects. Continuous nitrate therapy with oral and transdermal patch preparations has resulted in tolerance to the beneficial effects of nitrates. A six- to eight-hour daily nitrate-free interval will minimize the tolerance phenomenon. Also, supplemental use of vitamin C appears to prevent nitrate tolerance.³¹ The different nitrate preparations used to treat unstable angina are listed in Table 5.

Calcium channel blockers such as nifedipine, verapamil, and diltiazem cause coronary vasodilation and reduced blood pressure. Because of these actions, the calcium channel blockers were thought to be a drug group that could be effective in the treatment of unstable angina. However, a meta analysis of studies in which patients with unstable angina were treated with calcium channel blockers found no effect of the drugs on the incidence of death or myocardial infarction.²⁸ More recently, it has been shown that treatment with diltiazem and verapamil may result in increased survival and reduced rates of reinfarction in patients with acute coronary syndrome. Current thinking suggests that calcium channel blockers should be used in patients in whom beta blockers are contraindicated or those with refractory symptoms after treatments with aspirin, nitrates or beta blockers. The different calcium channel blockers used to treat unstable angina are listed in Table 5.

Author

Richard L. Wynn, PhD, is a professor at the University of Maryland Dental School

References

1. American Heart Association, Heart and stroke facts: 1996 statistical supplement. National Center of the American Heart Association, Dallas, 1996, p 15.

2. The Criteria Committee of the American Heart Association, New York City Affiliate, 1994 revisions to classification of functional capacity and objective assessment of patients with diseases of the heart. Circulation 90:644-5, 1994.

3. Heidenreich PA, Lee TT, Massie BM, Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trails. J Am Coll Cardiol 30: 27-34, 1997.

4. Libby P, Molecular basis of the acute coronary syndromes. Circulation 91:2844-50, 1995.

5. Albers GW, Atwood JE, et al. Stroke prevention in nonvalvular atrial fibrillation. Ann Intern Med 115: 727-36, 1991.

6. Cairns JA, Connolly SJ, Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 84:469-81, 1991.

7. Morley J, Marinchak R, et al, Atrial fibrillation, anticoagulation and stroke. Am J Cardiol 77:38A-44A, 1996.

8. Pritchett EL, Management of atrial fibrillation. N Eng J Med 326:1264-71, 1992.

9.Vaughn Williams EM, A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 24:129-47, 1984.

10. Sopher SM, Camm AJ, Atrial fibrillation: maintenance and sinus rhythm versus rate control. Am J Cardiol 77:24A-37A, 1996.

11. Gilligan DM, Ellenbogen KA, Epstein AE, The management of atrial fibrillation. Am J Med 101:413-21, 1996.

12. Golzari H, Cebul RD, Bahler RC, Atrial fibrillation: restoration and maintenance of sinus rhythm and indications for anticoagulation therapy. Ann Intern Med 125:311-23, 1996.

13. Atrial Fibrillation Investigators, Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449-57, 1994.

14. Stroke prevention in atrial fibrillation investigators, Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation. Stroke prevention in atrial fibrillation II study. Lancet 343:687-91, 1994.

15. Hylek EM, Skates SJ, et al. An analysis of the lowest effective intensity of prophylactic coagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 335:540-6, 1996.

16. Stroke prevention in atrial fibrillation investigators, Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: stroke prevention in atrial fibrillation III randomized clinical trial. Lancet 348:633-8, 1996.

17. The European Atrial Fibrillation Trial Study Group, Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 333:5-10, 1995.

18. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Ann Intern Med 157:2413-46, 1997.

19. Kannel WB, Blood pressure as a cardiovascular risk factor. J Am Med Assoc 275:1571- 6, 1996.

20. Hansson L, Zanchetti A, et al, Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 351:1755-62, 1998.

21. Materson BJ, Reda DJ, et al, Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Eng J Med 328:914-21, 1993.

22. Neaton JD, Grimm RH Jr, et al, Treatment of Mild Hypertension Study. Final results. Treatment of mild hypertension Study Research Group. J Am Med Assoc 270:713-24, 1993.

23. Leonetti G, Cuspidi C, Choosing the right ACE inhibitor, a guide to selection. Drugs 49: 516-35, 1995.

24. Kaplan NM, Perspectives on the new JNC VI guidelines for the treatment of hypertension. Formulary 32:1224-31, 1997.

25. Furberg CD, Psaty BM, Meyer JV, Nifedipine: Dose-related increase in mortality in patients with coronary heart disease. Circulation 92:1326-31, 1995.

26. Graves E, National Hospital Discharge Survey. Annual survey 1996. Series 13, no. 4. National Center for Health Statistics, Washington, DC, 1998.

27. Braunwald E, Unstable angina: a classification. Circulation 80:410-4, 1989.

28. Yeghiazarians Y, Braunstein JB, et al, Unstable angina pectoris. New Eng J Med 342:101-14, 2000.

29. Cohen MC, Adams PC, et al, Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users: primary end points analysis from the ATACS trial. Circulation 89:81-8, 1994.

30. Coumadin Aspirin Reinfarction Study (CARS) Investigators, Randomised double-blind trail of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 350:389-96, 1997.

31. Bassenge E, Fink N, et al, Dietary supplement with vitamin C prevents nitrate tolerance. Am J Cardiol 77:24C-30C, 1996.

32. United States Pharmacopeial Dispensing Information, Therapeutic monograph, atrial fibrillation. In, USPDI volumes I and II update. The United States Pharmacopeial Convention Inc, Rockville, MD, December 1998:2118-40.

33. United States Pharmacopeial Dispensing Information, Therapeutic monograph, atrial fibrillation. In: USPDI volumes I and II update. The United States Pharmacopeial Convention Inc, Rockville, MD, April 1998: 630-45.

34. United States Pharmacopeial Dispensing Information, Therapeutic monograph, atrial fibrillation. In, USPDI volumes I and II update. The United States Pharmacopeial Convention Inc, Rockville, MD, November 1998, 1954-82..

35. United States Pharmacopeial Dispensing Information, Drug information for the health care professional, volume I, ed. 19. The United States Pharmacopeial Convention Inc, Rockville, MD, 1999.

To request a printed copy of this article, please contact/Richard L. Wynn, PhD, Dental Department of Pharmacology, University of Maryland, 666 W. Baltimore St., Baltimore, MD 21201 or e-mail at rlw001@dental.umaryland.edu

Table 1. Drugs Used to Treat Heart Failure

Angiotensin converting enzyme (ACE) inhibitors*

Benazepril (Lotensin)

Captopril (Capoten)

Enalapril (Vasotec)

Fosinopril (Monopril)

Lisinopril (Prinivil)

Perindopril (Aceon)

Quinapril (Accupril)

Ramipril (Altace)

Trandolapril (Mavik)

Diuretics

Thiazides

Hydrochlorothiazide (Hydrodiuril)

Loop diuretics

Furosemide (Lasix)

Potassium-sparing agents

Amiloride and hydrochlorothiazide (Moduretic)

Spironolactone (Aldactone)

Spironolactone and hydrochlorothiazide (Aldactizide)

Triamterene and hydrochlorothiazde (Dyazide)

Digitalis glycosides

Digoxin (Lanoxin)

Digitoxin

Beta-adrenergic receptor blocking drugs

Bisoprolol (Zebeta)

Carvedilol (Coreg)

Labetolol (Normodyne, Trandate)

Metoprolol (Lopressor)

Supplemental agents

Direct-acting vasodilators

Hydralazine (Apresoline)

Nitroglycerin

Sodium nitroprusside (Nitropress)

Catecholamines

Dobutramine (Dobutrex)

Dopamine

Phosphodiesterase inhibitors

Amrinone (Inocor)

Milrinone (Primacor)

Regarded as the cornerstone of treatment of heart failure and should be used routinely and early in all patients.

From USPDI volumes I and II update, December 1998 (32)

Table 2. Drugs Used in the Treatment of Coronary Artery Disease

Reduction of total and low-density cholesterol levels

HMG-CoA reductase inhibitors

Fluvastatin

Lovastatin

Pravastatin

Simvastatin

Atorvastatin

Cerivastatin

Fibrate group

Gemfibrozil

Clofibrate

Bile acid resins

Cholestyramine

Colestipol

Nicotinic acid

Cardioprotective drug therapy

Antiplatelet/anticoagulant agents

Aspirin

Ticlopidine

Clopidogrel

Warfarin

Beta -adrenergic receptor blockers

Metoprolol

Atenolol

Propranolol

Angiotensin Converting Enzyme (ACE) inhibitors

Captopril

Enalapril

Ramipril

Lisinorpil

Fosinopril

Table 3. Drugs Indicated for the Treatment of Atrial Fibrillation *

Class I Antiarrhythmic Agents

Disopyramide (Norpace) (I A)

Flecainide (Tambocor) (I C)

Procainamide (Pronestyl) (I A)

Propafenone (Rythmol) (I C)

Quinidine (I A)

Class II Antiarrhythmic Agents (Beta-adrenergic Blocking Drugs)

Cardioselective (beta ₁ – receptor block only)

Acebutolol (Sectral)

Atenolol (Tenormin)

Betaxolol (Kerlone)

Metoprolol (Lopressor)

Noncardioselective (beta ₁ and beta ₂ – receptor block)

Nadolol (Corgard)

Penbutolol (Levatol)

Pindolol (Visken)

Propranolol (Inderal)

Timolol (Blocadren)

Class III Antiarrhythmic Agents

Amiodarone (Cordarone)

Class IV Antiarrhythmic Agents (Calcium Channel Blocking Agents)

Diltiazem (Cardizem)

Verapamil (Calan)

Miscellaneous Agents

Digitalis

Anticoagulants

Warfarin (Coumadin)

Aspirin

From USPDI volumes I and II update, April 1998 (33)

Table 4. Drug Categories and Representative Agents for the Treatment of Hypertension *

Diuretics

Thiazide-type

hydrochlorothiazide (HCTZ)

Loops

furosemide (Lasix)

Potassium-sparing

triamterene (Dyrenium)

Potassium-sparing combinations

triamterene/HCTZ (Dyazide)

Beta blockers

Cardioselective beta blockers

atenolol (Tenormin)

Noncardioselective beta blockers

propranolol (Inderal)

Alpha ₁ blocker

prazosin (Minipress)

Alpha/Beta blocker

carvedilol (Coreg)

Angiotensin-converting enzyme (ACE) inhibitors

lisinopril (Prinivil)

enalapril (Vasotec)

Angiotensin-converting enzyme inhibitors/diuretic combination

captopril and HCTZ (Capozide)

Angiotensin II receptor blockers

candesartan (Atacand)

losartan (Cozaar)

Calcium channel blocking agents

amlodipine (Norvasc)

nifedipine (Procardia)

diltiazem (Cardizem)

Supplemental agents

Central-acting alpha ₂-agonist

clonidine (Catapres)

Direct-acting peripheral vasodilator

hydralazine (Apresoline)

From USPDI volumes I and II update, November 1998 (34)

Table 5. Drugs Used to Manage Unstable Angina

Antiplatelet drugs

aspirin

ticlopidine (Ticlid)

clopidogrel (Plavix)

glycoprotein IIb/IIIa receptor antagonists

abciximab (ReoPro)

eptifibatide (Integrilin)

tirofiban (Aggrastat)

Antithrombin drugs

Indirect thrombin inhibitors

unfractionated heparin (Heparin)

low molecular-weight heparin (Enoxaparin)

Direct thrombin inhibitors

lepirudin (Hirudin)

Dicumarols

warfarin (Coumadin)

Conventional antianginal drugs

Beta blockers

atenolol (Tenormin)

bisoprolol (Zebeta)

carteolol (Cartrol)

nadolol (Corgard)

propranolol (Inderal)

Nitrates

erythrityl tetranitrate (Cardilate)

isosorbide tetranitrate (Diltrate – SR, Isordil)

isosorbide mononitrate (Imdur)

nitroglycerin (sublingual tablets, oral tablets, sublingual spray, transdermal patch)

pentaerythritol tetranitrate (Duotrate, Peritrate)

Calcium channel blockers

diltiazem (Cardizem)

nifedipine (Procardia, Adalate)

verapamil (Calan)

Table 6. Cardiovascular/Respiratory/Nervous System Effects Caused by Drugs Used for Cardiovascular Disorders

Alpha ₁ blocker -- prazosin (Minipress): More frequent: orthostatic hypotension, dizziness; Less frequent: heart palpitations; Rare: angina.

Alpha/Beta blocker -- carvedilol (Coreg): More frequent: bradycardia, postural hypotension, dizziness; Rare: A-V block, hypertension, hypotension, palpitations, vertigo, nervousness, asthma.

Angiotensin-converting enzyme (ACE) inhibitors

benazepril (Lotensin): Less frequent: dizziness, insomnia, headache; Rare: hypotension, bronchitis.

captopril (Capoten): Less frequent: tachycardia, insomnia, transient cough, dizziness, headache; Rare: hypotension

enalapril (Vasotec): Less frequent: chest pain, palpitations, tachycardia, syncope, dizziness, dyspnea; Rare: angina pectoris, asthma

fosinopril (Monopril): Less frequent: orthostatic hypotension, dizziness, cough headache; Rare: syncope, insomnia.

lisinopril (Prinivil): Less frequent: hypotension, dizziness; Rare: angina pectoris, orthostatic hypotension, rhythm disturbances, tachycardia,

perindopril (Aceon): Less frequent: headache, dizziness, cough (incidence > women 3:1); Rare: hypotension.

quinapril (Accupril): Less frequent: hypotension, dizziness, headache, cough; Rare: orthostatic hypotension, angina, insomnia.

ramipril (Altace): Less frequent: tachycardia, dizziness, headache, cough; Rare: hypotension.

trandolapril (Mavik): Less frequent: tachycardia, headache, dizziness, cough (more frequent in women); Rare: hypotension.

Angiotensin-converting enzyme inhibitors/diuretic combination -- captopril and HCTZ (Capozide): Less frequent: tachycardia, palpitations, chest pain, dizziness; Rare: hypotension

Angiotensin II receptor blockers

Candesartan (Atacand): Less frequent: chest pain, flushing; Rare: myocardial infarction, tachycardia, angina, palpitations, dyspnea.

Losartan (Cozaar): Less frequent: hypotension without reflex tachycardia, dizziness; Rare: orthostatic hypotension, angina, A-V block (second degree), CVA, palpitations, tachycardia, sinus bradycardia, flushing, dyspnea.

Antiplatelet/anticoagulant agents

Aspirin, ticlopidine, clopidogrel, warfarin: no cardiorespiratory or nervous system effects reported.

Abciximab ( ReoPro): More frequent: hypotension, pain; Less frequent: bradycardia

Eptifibatide (Integrilin): More frequent: hypotension, bleeding.

Tirofiban (Aggrastat): More frequent: bleeding; Less frequent: bradycardia, dizziness, headache.

Beta blockers

Acebutolol (Sectral): Less frequent: chest pain, bradycardia, hypotension, dizziness, dyspepsia, dyspnea; Rare: ventricular arrhythmias

Atenolol (Tenormin): Less frequent: bradycardia, hypotension, chest pain, dizziness, dyspepsia, dyspnea; Rare: ventricular arrhythmias

Betaxolol (Kerlone): Less frequent: bradycardia, palpitations, dizziness; Rare: chest pain

Bisoprolol (Zebeta): More frequent: lethargy; Less frequent: hypotension, chest pain, bradycardia, headache, dizziness, insomnia, cough

Labetolol (Normodyne, Trandate): Less frequent: orthostatic hypotension, dizziness, nasal congestion; Rare: bradycardia, chest pain

Metoprolol (Lopressor): More frequent: dizziness; Less frequent: bradycardia, heartburn, wheezing; Rare: chest pain, confusion.

Nadolol (Corgard): More frequent: bradycardia; Less frequent: dizziness, dyspepsia, wheezing; Rare: congestive heart failure, orthostatic hypotension, confusion, paresthesia.

Penbutolol (Levatol): Less frequent: congestive heart failure, dizziness; Rare: bradycardia, chest pain, hypotension, confusion.

Pindolol (Visken): More frequent: dizziness; Less frequent: congestive heart failure, dyspnea.

Propranolol (Inderal): More frequent: bradycardia; Less frequent: congestive heart failure, dizziness, wheezing; Rare: chest pain, hypotension, bronchospasm.

Timolol (Blocadren): Less frequent: bradycardia, dizziness, dyspnes; Rare: chest pain, congestive heart failure

Calcium channel blocking agents

Amlodipine (Norvasc): Less frequent: palpitations, dizziness, dyspnea; Rare: hypotension, bradycardia, arrhythmias

Diltiazem (Cardizem): Less frequent: bradycardia, dizziness; Rare: dyspepsia, paresthesia, tremor.

Nifedipine (Procardia): More frequent: flushing, dizziness; Less frequent: palpitations, hypotension, dyspnea; Rare: tachycardia, syncope

Verapamil (Calan): Less frequent: bradycardia, congestive heart failure, hypotension; Rare: chest pain, hypotension.

Class I antiarrhythmics

Disopyramide (Norpace): More frequent: exacerbation of angina pectoris, dizziness; Less frequent: hypotension, hypertension, tachycardia, dyspnea; Rare: syncope, flushing, hyperventilation.

Flecainide (Tambocor): More frequent: dizziness, dyspnea; Less frequent: palpitations, chest pain, tachycardia, tremor; Rare: bradycardia, nervousness, paresthesia.

Procainamide (Pronestyl): Less frequent: tachycardia, dizziness, lightheadedness; Rare: hypotension, confusion, disorientation.

Propafenone (Rythmol): More frequent: dizziness; Less frequent: palpitations, angina, bradycardia, loss of balance, dyspepsia, dyspnea; Rare: paresthesia

Qunidine: Less frequent: hypotension, syncope, lightheadedness, wheezing; Rare: confusion, vertigo, angina, edema.

Class III antiarrhythmics

Amiodarone (Cordarone): More frequent: dizziness, tremor, paresthesia, dyspnea; Less frequent: congestive heart failure, bradycardia, tachycardia; Rare: hypotension.

Digitalis glycosides

digoxin; digitoxin: Rare: atrial tachycardia, sinus bradycardia, ventricular fibrillation, vertigo

Diuretics

Thiazide-type Rare: hypotension

Loops: More frequent: orthostatic hypotension, dizziness

Potassium -sparing: Less frequent: hypotension, bradycardia, dizziness; Rare: flushing

Potassium-sparing combinations: Rare: dizziness

HMG-CoA reducatase inhibitors

Atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin: Less frequent: headache, dizziness

Nitrates

Nitroglycerin drugs: More frequent: postural hypotension, flushing, headache, dizziness; Rare: reflex tachycardia, bradycardia, arrhythmias.

Supplemental drugs for heart failure

Hydralazine (Apresoline): More frequent: tachycardia, headache; Less frequent: hypotension, nasal congestion; Rare: edema, dizziness

Sodium nitroprusside: Less frequent: palpitations, headache

Dobutamine (Dobutrex): Less frequent: tachycardia, chest pain; Rare: headache, dyspnea.

Amrinone (Inocor): Less frequent: arrhythmia, chest pain.

Milrinone (Primacor) More frequent: arrhythmias; Less frequent: chest pain;

Supplemental antihypertensives

Central-acting alpha ₂-agonists; clonidine (Catapres): More frequent: dizziness; Less frequent: orthostatic hypotension, nervousness/agitation; Rare: palpitations, tachycardia, bradycardia, congestive heart failure

Direct-acting; hydralazine (Apresoline): More frequent: tachycardia, headache; Less frequent: hypotension, nasal congestion; Rare: edema, dizziness

From information found in professional package insert for individual agent or the USPDI³⁵

More frequent = > 10 percent incidence; less frequent = 1 percent to 10 percent; rare = < 1 percent incidence.

Table 7. Cardiovascular Drugs: Dental Drug Interactions and Effects on Dental Treatment *

Any drug known to cause skin allergy is likely to cause a mouth allergy as well.

Alpha ₁ blocker

Prazosin (Minipress): Significant orthostatic hypotension a possibility; monitor patient when getting out of dental chair; significant dry mouth in up to 10% of patients.

Alpha/Beta blocker

Carvedilol (Coreg): See nonselective beta blockers.

Angiotensin-converting enzyme (ACE) inhibitors

The NSAID indomethacin reduces the hypotensive effects of ACE inhibitors. Effects of other NSAIDs such as ibuprofen not considered significant.

Angiotensin-converting enzyme inhibitors/diuretic combination

Captopril and HCTZ (Capozide): No effect or complications on dental treatment reported.

Angiotensin II receptor blockers

No effect or complications on dental treatment reported.

Beta blockers

Cardioselective beta blockers; i.e. atenolol (Tenormin): No effect or complications on dental treatment reported. Noncardioselective beta receptor blockers: Any of the noncardioselective beta blockers ( i.e. nadolol, penbutolol, pindolol, propranolol, timolol) may enhance the pressor response to vasoconstrictor epinephrine resulting in hypertension and reflex bradycardia. Although not reported, it is assumed that similar effects could be cause with levonordefrin (Neo-Cobefrin). Use either vasoconstrictor with caution in hypertensive patients medicated with noncardioselective beta adrenergic blockers.

Calcium channel blocking agents

Cause gingival hyperplasia in approximately 1 percent of the general population taking these drugs. There have been fewer reports with diltiazem and amlodipine than with other CBs such as nifedipine. The hyperplasia will usually disappear with cessation of drug therapy. Consultation with the physician is suggested.

Antiplatelet/anticoagulant agents

Aspirin may cause a reduction in the serum levels of NSAIDs if they are used to manage post-operative pain; clopidogrel: if a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 7 days prior to surgery; warfarin: signs of warfarin overdose may first appear as bleeding from gingival tissue; consultation with prescribing physician is advisable prior to surgery to determine temporary dose reduction or withdrawal of medication; eptifibatide: bleeding may occur while patient is medicated with eptifibatide; platelet function is restored in about 4 hours following discontinuation;

Class I antiarrythmics

Disopyramide: Increased serum levels and toxicity with erythromycin. High incidence of anticholinergic effect manifested as dry mouth and throat. Flecainide: No effects or complications on dental treatment reported. Procainamide: systemic lupus-like syndrome has been reported resulting in joint pain and swelling, pains with breathing, skin rash. Propafenone: >10 % experience significantly reduced salivary flow; taste disturbance, bitter or metallic taste. Qunidine: secondary anticholinergic effects may decrease salivary flow, especially in middle age and elderly patients. Known to contribute to caries, periodontal disease and oral candidiasis.

Class III antiarrythmics

Amiodarone: Bitter or metallic taste has been reported.

Digitalis glycosides

Digitalis: Use vasoconstrictor with caution due to risk of cardiac arrhythmias. Sensitive gag reflex induced by digitalis drugs may cause difficulty in taking dental impressions. Erythromycin and tetracyclines may increase digitalis serum levels.

Diuretics

Thiazide-type: Many diuretics are known to reduce salivary flow. Monitor for xerostomia. Loops: NSAIDs may increase chloride and tubular water reuptake to counter-act loop type diuretics. Many diuretics are known to reduce salivary flow. Monitor for xerostomia. Potassium-sparing: Many diuretics are known to reduce salivary flow. Monitor for xerostomia. Potassium-sparing combinations: Many diuretics are known to reduce salivary flow. Monitor for xerostomia.

HMG-CoA reductase inhibitors

Concurrent use of erythromycin and some of the statin drugs may result in rhabdomyolysis.

Nitrates

No effects or complications on dental treatment reported.

Supplemental drugs for heart failure

Amrinone, milrinone: no effects or complications on dental treatment reported.

Supplemental antihypertensives

Central-acting alpha ₂-agonists; clonidine (Catapres): Greater than 10% of patients experience significant dry mouth. Hydralazine (Apresoline): No effect or complications on dental treatment reported.

From Drug Information Handbook for Dentistry, 5^th ed. RL Wynn, TF Meiller, HL Crossley, Lexi-Comp, Inc, Hudson (Cleveland), 1999-2000.