Chapter 15: Cardiovascular Drugs

Chapter 15: Cardiovascular Drugs
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 15 Outline Cardiovascular Drugs
Dental implications of cardiovascular disease Cardiac glycosides Antiarrhythmic agents Antianginal drugs Antihypertensive agents Antihyperlipidemic agents Drugs that affect blood coagulation

Cardiovascular Drugs Haveles (p. 186) Cardiovascular disease refers to diseases of the heart and blood vessels Includes hypertension, angina pectoris, coronary artery disease, cerebrovascular accident, and congestive heart failure (CHF) A leading cause of death in the United States 25% of the top 200 drugs are in this group

Dental Implications of Cardiovascular Disease
Haveles (p. 187) Contraindications to treatment Vasoconstrictor limit Infective endocarditis Cardiac pacemakers Periodontal disease and cardiovascular disease

Contraindications to Treatment
Haveles (p. 187) (Box 15-1) Acute or recent myocardial infarction (MI) (within the preceding 3 to 6 months) Unstable or recent onset of angina pectoris Uncontrolled CHF Uncontrolled arrhythmias Significant, uncontrolled hypertension

Vasoconstrictor Limit
Haveles (p. 187) The majority of cardiovascular patients should benefit from the use of epinephrine in the local anesthetic agent The amount and effect of epinephrine administered must be weighed against the fact that discomfort can cause the release of endogenous epinephrine Limiting the dose to the cardiac dose (0.04 mg) may be warranted in a few severely affected patients

Infective Endocarditis
Haveles (p. 187) When a risk of producing infective endocarditis exists, prophylactic antibiotics should be prescribed, if warranted by the dental procedure being performed

Cardiac Pacemakers Haveles (p. 187) A cardiac pacemaker is an electrical device implanted in a patient’s chest to regulate the heart rhythm If not appropriately shielded, some electrical devices used in dentistry may interfere with pacemaker activity Consult with physician may be appropriate before treatment

Periodontal Disease and Cardiovascular Disease
Haveles (p. 187) Research has found a relationship between periodontal disease and both cardiovascular disease and stroke An inherited phenotype, MO, is under both genetic and environmental influences, placing the patient at increased risk for severe periodontal disease, insulin-dependent diabetes mellitus, atherosclerosis, and emboli production cont’d… Will the reader understand the MO phenotype?

Periodontal Disease and Cardiovascular Disease
Monocytes in these patients secrete abnormally high levels of cytokines, including prostaglandin (PG)E2, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α, all of which are associated with both periodontal and cardiovascular disease An increase in dietary intake of fat leads to an increase in low-density lipoproteins (LDL, bad cholesterol), which are known to upregulate the destructive monocyte response

Cardiac Glycosides Haveles (pp ) CHF Digitalis glycosides

Heart Failure Haveles (pp ) (Fig. 15-1) In CHF, the heart does not provide adequate cardiac output Blood accumulates in the failing ventricle(s), the ventricle(s) enlarges and finally becomes ineffective as a pump Left side failure backs into pulmonary circulation (lungs) leading to edema, dyspnea and orthopnea Right side failure causes systemic congestion, leading to peripheral edema with fluid accumulation evidenced by pitting edema (pedal edema)

Digitalis Glycosides Pharmacologic effects Uses Adverse reactions
Haveles (pp ) Pharmacologic effects Uses Adverse reactions Management of the dental patient taking digoxin Other drugs cont’d…

Digitalis Glycosides Haveles (p. 188) The most common type of drug used in the treatment of CHF Not considered first-line therapy digoxin (Lanoxin) is used as the prototype

Pharmacologic Effects of Digitalis Glycosides
Haveles (p. 188) Increases force and strength of contraction of the myocardium (positive inotropic effect) Allows the heart to do more work without increasing the use of oxygen The heart becomes more efficient, and cardiac output increases cont’d…

Pharmacologic Effects of Digitalis Glycosides
In CHF, the heart rate is increased due to increased sympathetic action resulting from decreased carbon monoxide (CO) As digoxin increases CO, sympathetic tone is decreased, with a decrease in heart rate Digoxin also reduces edema that occurs with CHF The size of the heart is reduced as excess blood volume is removed via the kidneys Digoxin can affect automaticity, conduction velocity, and refractory periods of different parts of the heart in different ways Is carbon monoxide correct?

Uses of Digitalis Glycosides
Haveles (p. 188) Most common usage is treatment of CHF Also used for atrial arrhythmias, including atrial fibrillation (AF) and paroxysmal atrial tachycardia (PAT) A recent trial found digoxin did not reduce mortality; for this reason use of digoxin is decreasing Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and β-adrenergic blockers are used more often

Adverse Reactions of Digitalis Glycosides
Haveles (pp ) Narrow therapeutic index: slight changes in dose, absorption, or metabolism can trigger toxic symptoms Gastrointestinal (GI): signs of toxicity include anorexia, nausea, vomiting, copious salivation Arrhythmias: if sufficient overdose is given (note: digitalis is used to treat arrhythmias, its toxicity can cause them) Neurologic: signs of toxicity include headache, drowsiness, and visual disturbances cont’d…

Adverse Reactions of Digitalis Glycosides
Oral: increased salivation is associated with digoxin toxicity Dental drug interactions: interaction with sympathomimetics can increase chances of arrhythmias; in severe cardiac disease, the epinephrine dose may be limited to the cardiac dose (0.04 mg) Erythromycin and tetracycline can increase toxicity of digoxin in some patients

Management of the Dental Patient Taking Digoxin
Haveles (p. 189) (Box 15-2) Watch for overdose side effects such as nausea, vision changes, and copious salivation Use epinephrine with caution to minimize arrhythmias Monitor pulse to check for bradycardia Tetracycline and erythromycin can increase digoxin levels (in approximately 10% of patients)

Other Drugs ACEIs: now first-line therapy for CHF
Haveles (p. 189) (Note: these are not cardiac glycosides) ACEIs: now first-line therapy for CHF ARBs: for patients who cannot tolerate ACEIs; also first-line therapy β-Adrenergic blockers Vasodilators: hydralazine and isosorbide dinitrate Diuretics: to relieve edema Aldosterone antagonists

Antiarrhythmic Agents
Haveles (pp ) Automaticity Action potential Arrhythmias Antiarrhythmic agents Adverse reactions Dental implications cont’d…

Haveles (p. 189) Arrhythmias may result from abnormal impulse generation or abnormal impulse conduction Cardiac diseases such as myocardial anorexia, arteriosclerosis, and heart block can produce arrhythmias Antiarrhythmic agents are used to prevent arrhythmias

Automaticity Haveles (pp ) (Fig. 15-2) Cells of cardiac muscles have an intrinsic rhythm called automaticity The sinoatrial (SA) node in right atrium has the fastest rate of depolarization and directs other cells of the heart It is innervated by both the parasympathetic and sympathetic nervous system It signals the atrioventricular (AV) node, which sends signals through the bundle of His to Purkinje fibers and ventricles

Action Potential Haveles (p. 190) (Fig. 15-2) Electrical excitation from the nerve produces movement of ions across the membrane, generating an action potential Visualized as an electrocardiogram (ECG) A relationship exists between the action potential and the ECG tracing

Arrhythmias Haveles (p. 190) Arrhythmias are divided into supraventricular (atrial) and ventricular types May result in tachycardia or bradycardia of supraventricular or ventricular parts of the heart May result from ectopic foci “emergent leaders” that preempt the SA or AV nodal rate

Haveles (pp ) (Tables 15-1, 15-2) Placed in four groups designated by numeral I through IV according to mechanism of action Subsets of these Roman numerals use capital letters (A, B, C) cont’d…

Antiarrhythmic agents work by depressing parts of the heart that are beating abnormally They may decrease the velocity of depolarization, decrease impulse propagation, and inhibit aberrant impulse propagation cont’d…

Haveles (p. 191) Digoxin: although digoxin is not included in the other groups of antiarrhythmics, it is used to treat some arrhythmias Shortens the refractory period of atrial and ventricular tissues while prolonging the refractory period and diminishing the conduction velocity in the Purkinje fibers

Adverse Reactions of Antiarrhythmic Agents
Haveles (p. 191) Antiarrhythmic agents have a narrow therapeutic index and are difficult to manage Only used for patients with arrhythmias that prevent the proper functioning of the heart

Classification and Mechanism of Action of the Antiarrhythmic Agents
Haveles (p. 191) (Table 15-1) Class IA sodium (Na+) channel blocker (medium) Quinidine, procainamide, disopyramide Class IB Na+ channel blocker (fast) lidocaine Class IC Na+ channel blocker (slow) Flecainide, encainide, propafenone cont’d…

Classification and Mechanism of Action of Antiarrhythmic Agents
Class II β-blockers Propranolol, esmolol, acebutolol, sotalol Class III potassium (K+) channel blockers Bretylium and d-sotalol (non–β-blocking enantiomer) Class IV calcium channel blockers (CCBs) Verapamil, diltiazem

Management of Dental Patients Taking Antiarrhythmic Agents
Haveles (p. 191) (Table 15-2) All: Check for abnormal or extra beats when taking blood pressure and pulse AF: pt. on warfarin-check international normalized ratio (INR) Amiodarone: liver toxicity, blue skin, photosensitivity CCBs: gingival enlargement Disopyramide: anticholinergic xerostomia Procainamide: reversible lupus-like syndrome, 25%-30%, central nervous system (CNS) depression xerostomia Quinidine: nausea, vomiting, diarrhea; cinchonism with large doses; atropine-like effect, xerostomia Phenytoin: gingival enlargement β-Blockers, nonspecific: interaction with epinephrine

Antianginal Drugs Angina pectoris Nitroglycerin (NTG)-like compounds
Haveles (pp ) Angina pectoris Nitroglycerin (NTG)-like compounds CCBs β-Adrenergic blocking agents Ranolazine Dental implications Prevention of an anginal attack MI

Angina Pectoris Haveles (pp ) Characterized by pain or discomfort in the chest radiating to the left arm and shoulder Pain can also radiate to neck, back, and lower jaw Jaw pain may be confused with a toothache Occurs when coronary arteries do not supply enough oxygen to the myocardium cont’d…

Angina Pectoris Haveles (pp ) (Table 15-3) At one time, NTG-like compounds were the only drugs that could relieve the symptoms Today, β-adrenergic blockers and CCBs have added a new dimension The effect of these drugs is to reduce the workload of the heart Oxygen requirement of myocardium is reduced, relieving painful symptoms

Nitroglycerin-Like Compounds
Haveles (pp ) (Box 15-3) NTG is by far the most often used nitrate for management of acute anginal episodes Also to prevent anginal attacks induced by stress or exercise

Mechanism of Nitroglycerin-Like Compounds
Haveles (p. 192) NTG is a vasodilator Releases free nitrite ion and nitric oxide Nitric oxide activates guanylyl cyclase and increases cyclic guanosine monophosphate (cGMP), producing relaxation of vascular smooth muscle throughout the body By reducing workload on the heart, NTG decreases the oxygen demand cont’d…

Mechanism of Nitroglycerin-Like Compounds
Amyl nitrite is a volatile agent in a closed container It is administered by crushing the container and inhaling the fumes Sublingual (SL) NTG is available as an SL tablet (Nitrostat) or spray used sublingually (Nitroingual) SL isosorbide dinitrate is also effective for an acute anginal attack One of the NTG products should be in the dental office emergency kit; the patient should bring their NTG to each appointment Is Nitroingual the correct spelling?

Adverse Reactions of Nitroglycerin-Like Compounds
Haveles (p. 193) Most reactions are caused its effect on vascular smooth muscle Severe headaches are often reported Flushing, hypotension, light-headedness, and syncope can also result SL NTG can produce a localized burning or tingling

Significant Drug Interactions and Contraindications
Haveles (p. 193) Phosphodiesterase 5 (PDE5) inhibitors include sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) The administration of any of these drugs with doses of any nitrate is contraindicated The combination can cause dangerously low blood pressure

Storage of Nitroglycerin-Like Compounds
Haveles (p. 193) NTG is degraded by heat and moisture but not by light Tablets should be stored in the original dark-brown glass container If opened it should be discarded between 3 and 6 months NTG spray is effective until its expiration date Long-acting NTG-like products are available for long-term prophylaxis of anginal attacks Dose forms include tablets and topical products cont’d…

Storage of Nitroglycerin-Like Compounds
With long-term regular use, tolerance develops Prophylactic nitrates should be given with an 8- to 12- hour “vacation” every day The mononitrate dose form requires a 7-hour “vacation” daily

Examples of Antianginal Preparations
Haveles (pp ) (Table 15-3) Acute attacks Nitrites Amyl nitrite Short-acting nitrates NTG (Nitrostat) (Nitrolingual) isosorbide dinitrate cont’d…

Examples of Antianginal Preparations
Prophylactic use Long-acting nitrates NTG (Nitro-Bid) (Nitro Dur, Minitran) isosorbide dinitrate (Isordil, Sorbitrate-DSC) isosorbide mononitrate (Imdur, Ismo, Monoket) pentaerythritol tetranitrate (Peritrate) β-Blockers Propranolol CCBs* (See Box 15-4) verapamil (Calan, Isoptin) nifedipine (Procardia)

Calcium Channel Blocking Agents
Haveles (pp ) (Table 15-4) Mechanism of action of CCBs for treatment of angina is related to inhibition of movement of calcium during the contraction of cardiac and vascular smooth muscle Vasodilation and a decrease in peripheral resistance results, decreasing the work of the heart CCBs are also used in treatment of cardiac arrhythmias and hypertension Adverse effects include dizziness, weakness, constipation, and hypotension Nifedipine is associated with gingival enlargement and dysgeusia

β-Adrenergic Blocking Agents
Haveles (p. 194) Used in the treatment of angina (as well as hypertension) Block the beta response to catecholamine stimulation reducing both chronotropic and inotropic effects Net result is a reduced myocardial oxygen demand Adverse effects include bradycardia, CHF, headache, dry mouth, blurred vision, and unpleasant dreams

ranolazine (Ranexa) A new drug for treatment of chronic angina
Haveles (p. 194) A new drug for treatment of chronic angina Exact mechanism of action is unknown Should only be used in patients that have not responded to long-acting nitrates, CCBs, and β-blockers

Dental Implications Treatment of an acute anginal attack
Haveles (p. 194) Treatment of an acute anginal attack Prevention of anginal attack MI

Treatment of an Acute Anginal Attack
Before administering NTG, the dental team should make sure the patient has not used a PDE5 inhibitor within the past 24 hours; if such is the case, call 911 The patient’s personal NTG tablets or spray should be available Long-acting nitrates and topical products are not useful for the treatment of an acute anginal attack cont’d…

Treatment of an Acute Anginal Attack
For acute emergencies, the office should have a supply of SL NTG The patient should be seated Three tablets or doses of spray, each 5 minutes apart If the anginal attack is not stopped, the patient should be taken to the emergency room

Prevention of Anginal Attack
Haveles (p. 194) Two methods to prevent an acute anginal attack include pretreatment with either an anxiolytic agent or SL NTG Anxiolytics: an antianxiety agent, or anxiolytic (benzodiazepine) may be prescribed to allay anxiety and prevent an acute anginal attack NTG: premedicating an anxious patient with SL NTG can reduce the chance of an attack

Myocardial Infarction
Haveles (p. 194) An anginal attack not relieved by three doses of SL NTG may be experiencing an MI If the patient who has not been previously diagnosed as having angina experiences chest pain, he or she should be taken to an emergency room for diagnosis Any patient with an anginal attack not relieved by NTG should go to the hospital emergency room

Antihypertensive Agents
Haveles (pp ) Patient evaluation Treatment of hypertension Diuretic agents β-Adrenergic blocking agents CCBs Angiotensin-related agents Renin inhibitors α1-Adrenergic blocking agents Other antihypertensive agents Management of the dental patient taking antihypertensive agents cont’d…

Haveles (pp ) (Box 15-4) Hypertension is the most common cardiovascular disease (28.6% of Americans) Even blood pressure within the formerly “normal” range is associated with an increase in morbidity and mortality Eventually, elevated blood pressure damages internal organs More likely to have kidney and heart disease and cardiovascular problems cont’d…

Haveles (pp. 195, 197) (Table 15-5) Hypertension is divided into categories based on the cause or progression of the disease Essential (idiopathic, primary): from an unknown cause, 85% to 90% of patients Secondary: cause can be identified and associated to a disease process of endocrine or renal system (10% of patients) Malignant: high or rapidly rising blood pressure, develops in about 5% of patients with primary or secondary hypertension

Patient Evaluation Three objectives Haveles (p. 195)
To assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and treatment To reveal identifiable causes of hypertension To assess for the presence or absence of target-organ damage or cardiovascular disease

Treatment of Hypertension
Haveles (pp. 195, 197) (Fig. 15-4; Table 15-6) A stepped-care approach as blood pressures become greater than 140/90 or less than 130/80 mm Hg in patients with diabetes or chronic kidney disease Lifestyle modification: stage 1 or stage 2 and everyone Weight reduction, physical activity, a diet rich in fruits and vegetables, reduced contents of saturated and total fats, sodium restriction Initial drug choices: once diagnosed with stage 1 or stage 2 hypertension Sex, race, presence of diabetes or hyperlipidemia, and renin activity are taken into consideration cont’d…

Treatment of Hypertension
Haveles (pp. 195, 199) (Box 15-5) The Big Five antihypertensive groups Diuretics β-Blockers CCBs ACEIs ARBs

Diuretic Agents for Hypertension
Haveles (pp ) (Fig. 15-6) The three major types of diuretics are found Thiazides (-like) diuretics Loop diuretics Potassium-sparing diuretics

Thiazide Diuretics Haveles (pp. 197, ) Among the most common agents for treatment of hypertension hydrochlorothiazide (HCTZ) is the most commonly used thiazide Many patients with stage 1 hypertension are treated solely with HCTZ

Mechanism of Action of Thiazide Diuretics
Haveles (pp. 197, 199) (Table 15-8) The exact mechanism by which thiazide diuretics lower blood pressure has not been determined Initially inhibit sodium reabsorption from the distal convoluted tubule and part of the ascending loop of Henle of the kidney Water and chloride ions passively accompany the sodium, producing diuresis Potassium excretion is also increased

Adverse Reactions of Thiazide Diuretics
Haveles (pp ) (Table 15-9) Common adverse reactions include hypokalemia (secondary to sodium-potassium exchange) and hyperuricemia (inhibits uric acid secretion) Hyperglycemia, hyperlipidemia, hypercalcemia, and anorexia are other side effects Hyperuricemia is of special concern if the patient has gout cont’d…

Adverse Reactions of Thiazide Diuretics
Oral adverse reactions include xerostomia and, rarely, oral lichenoid eruptions indistinguishable from lichen planus Nonsteroidal antiinflammatory drugs (NSAIDs) can reduce the antihypertensive effect of the thiazide diuretics Thiazides can cause hypokalemia and can sensitize the myocardium to developing arrhythmias The potential for arrhythmias is exacerbated in patients taking digoxin, especially if digitalis toxicity is present Epinephrine also has arrhythmic potential; limit to cardiac dose when patient is taking thiazide diuretics and digitalis toxicity may be present

Examples of Thiazide Diuretics
Haveles (p. 196) (Box 15-4) chlorothiazide (Diuril) hydrochlorothiazide (HCTZ, Esidrix)

Loop Diuretics The “strong cousins of thiazides”
Haveles (p. 200) The “strong cousins of thiazides” furosemide (Lasix) is the most commonly used loop diuretic Acts on the ascending limb of the loop of Henle and has some effect on the distal tubule Inhibits reabsorption of sodium with concurrent loss of fluids cont’d…

Loop Diuretics Side effects include hypokalemia and hyperuricemia
Used in management of hypertensive patients with CHF Can be used when rapid diuresis is desired

Examples of Loop Diuretics
Haveles (p. 196) (Box 15-4) bumetanide (Bumex) furosemide (Lasix) torsemide (Demadex)

Potassium-Sparing Diuretics
Haveles (p. 200) “Puny” diuretics with “potassium-catching” ability (weak diuretic action) Spironolactone: competitively antagonizes the action of aldosterone Result is sodium excretion through diuresis and loss of fluid volume Triamterene: interferes with potassium-sodium exchange in the distal and cortical collecting tubules and the collecting duct by inhibiting sodium-potassium adenosine triphosphate (ATPase)

Examples of Potassium-Sparing Diuretics
Haveles (p. 196) (Box 15-4) amiloride (Midamor) spironolactone (Aldactone) triamterene (Dyrenium) eplerenone (Inspra)

Potassium Salts Potassium salts are not cardiac drugs
Haveles (p. 200) Potassium salts are not cardiac drugs Lack of potassium caused by diuretics must be managed, often with potassium supplementation The most common adverse reaction relates to the GI tract; includes nausea and abdominal discomfort Patients taking calcium salts should be questioned about their use of diuretics

β-Adrenergic Blocking Agents for Hypertension
Haveles (pp ) β-Adrenergic blockers are frequently used to treat hypertension β1-receptor stimulation is associated with increased heart rate, cardiac contractility, and AV conduction β2-receptor stimulation causes vasodilation of skeletal muscle and bronchodilation in pulmonary tissues β-Adrenergic blockers inhibit these actions cont’d…

Haveles (pp. 196, 201) (Box 15-4) Nonselective β-adrenergic blocking drugs such as propranolol, block both β1- and β2-receptors In usual doses selective β-adrenergic blocking drugs such as metoprolol, block β1-receptors more than β2-receptors (β1 > β2 ) At larger doses, the selectivity disappears Pindolol and acebutolol have partial agonist activity and cause some beta stimulation while blocking catecholamine action cont’d…

Haveles (pp ) β-Adrenergic blockers lower blood pressure by decreasing cardiac output Side effects: bradycardia, mental depression, and decreased sexual ability CNS effects: confusion, hallucinations, dizziness, and fatigue have been reported GI tract effects: diarrhea, nausea, and vomiting Can produce xerostomia (very mild) or worsen a patient’s lipid profile May exacerbate asthma, angina, or peripheral vascular disease

Dental Drug Interactions of β-Adrenergic Blocking Agents
Haveles (p. 201) Nonselective β-blockers can have a drug interaction with epinephrine May have a two- to fourfold increase in vasopressor response resulting in hypertension In patients with cardiovascular disease or higher blood pressure, the amount of epinephrine given to patients taking nonspecific β-blockers should be limited to the cardiac dose unless blood pressure monitoring accompanies the use of larger doses Usual doses can be given to patients taking specific β-blockers or α- and β-blockers

α- and β-Adrenergic Blocking Drug for Hypertension
Haveles (p. 201) Labetalol is a nonselective β-adrenergic receptor blocking drug that also has α-receptor blocking activity Reduces peripheral resistance through its α-blocking action

Examples of β-Adrenergic Blocking Agents for Hypertension
Haveles (p. 196) (Box 15-4) β-Adrenergic blockers atenolol (Tenormin) betaxolol (Kerlone) bisoprolol (Zebeta) metoprolol (Lopressor) (Toprol-XL) nadolol (Corgard) propranolol (Inderal [LA]) timolol (Blocadren) cont’d…

Examples of β-Adrenergic Blocking Agents for Hypertension
β-Blockers with intrinsic sympathomimetic activity acebutolol (Sectral) penbutolol (Levatol) pindolol (Visken) β-Blockers with α-blocking activity carvedilol (Coreg) labetalol (Normodyne, Trandate)

Calcium Channel Blocking Agents for Hypertension
Haveles (pp ) Many CCBs end in the suffix -dipine Used to treat hypertension and other cardiac conditions such as arrhythmias and angina

Mechanism of Calcium Channel Blocking Agents
Haveles (p. 201) Inhibit the movement of extracellular calcium ions into cells, including vascular smooth-muscle and cardiac cells Produces vasodilation, which produces coronary vasodilation and reverses vasospasms By producing systemic vasodilation CCBs reduce the afterload on the heart Useful in treatment of both angina pectoris and hypertension cont’d…

Mechanism of Calcium Channel Blocking Agents
At least four types of calcium channels (L, T, N, and P) have been discovered Current CCBs are all of the L type The decrease in transmembrane calcium current results in relaxation of vascular smooth-muscle cells and a reduction in cardiac contractility and conduction

Pharmacologic Effects of Calcium Channel Blocking Agents for Hypertension
Haveles (p. 201) Smooth muscle: vascular smooth muscle is relaxed and dilation of coronary and peripheral arteries and arterioles occur, reducing preload Cardiac muscle: may reduce heart rate, decrease myocardial contractility (negative inotropic effect), and slow AV nodal conduction

Adverse Reactions of Calcium Channel Blocking Agents
Haveles (pp ) Extensions of pharmacologic effects CNS: can produce excessive hypotension, which can cause dizziness and lightheadedness, headache GI: nausea, vomiting, and constipation Cardiovascular: bradycardia and edema Other: shortness of breath due to pulmonary edema has been reported

Oral Manifestations of Calcium Channel Blocking Agents
Haveles (p. 202) Include xerostomia, dysgeusia, gingival enlargement On discontinuation of the CCB, the gingival enlargement usually reverts to normal tissue and does not reappear If not, gingivectomy or gingivoplasty may be required

Dental Drug Interactions of Calcium Channel Blocking Agents
Haveles (p. 202) carbamazepine (Tegretol) is used for trigeminal neuralgia Diltiazem and verapamil may increase serum levels of carbamazepine, resulting in toxicity Both nausea and constipation, side effects of CCBs, could be additive with side effects produced by NSAIDs (nausea) and opioids (constipation)

Examples of Calcium Channel Blocking Agents
Haveles (p. 196) (Box 15-4) CCBs diltiazem (Cardizem [SR], Dilacor [XR]) verapamil (Isoptin [SR], Calan [SR]) Dihydropyridines amlodipine (Norvasc) felodipine (Plendil) isradipine (DynaCirc) nicardipine (Cardene [SR]) nifedipine (Procardia [XL], Adalat [CC]) nisoldipine (Sular)

Angiotensin-Related Agents
Haveles (pp ) Two types of drugs whose mechanism involves angiotensin ACEIs ARBs

Angiotensin-Converting Enzyme Inhibitors
Haveles (pp ) ACEIs prevent the conversion of angiotensin I to angiotensin II ACEI drugs are commonly used as antihypertensives Many ACEIs end in -pril

Mechanism of Angiotensin-Converting Enzyme Inhibitors
Haveles (p. 202) (Fig. 15-7) The renin-angiotensin-aldosterone system adjusts the quantity of sodium and water retained (circulatory volume) and the peripheral resistance (blood vessels) When the kidney senses a decrease in blood pressure or flow it releases renin Renin catalyzes the conversion of angiotensinogen (inactive precursor) to angiotensin I ACE converts angiotensin I to angiotensin II ACE is the enzyme blocked by ACEIs cont’d…

Mechanism of Angiotensin-Converting Enzyme Inhibitors
Angiotensin II produces vasoconstriction and stimulates the adrenal cortex to release aldosterone, facilitating water retention By blocking these events, blood pressure is lowered

Adverse Reactions of Angiotensin-Converting Enzyme Inhibitors
Haveles (pp ) (Box 15-6) The most common adverse reactions are related to the cardiovascular system and the CNS Cardiovascular: hypotension has produced dizziness, lightheadedness, and fainting Tachycardia and chest pain have been noted CNS: side effects may include dizziness, insomnia, fatigue, and headache cont’d…

Haveles (pp ) (Box 15-6) GI: nausea, vomiting, and diarrhea can occur Respiratory: an increase in upper respiratory symptoms, including a dry, hacking cough can occur It occurs because the ACE also inactivates bradykinin, a potent stimulator of allergic reactions cont’d…

Allergic-like reactions Angioedema: swelling of the extremities, face, lips, mucous membranes, tongue, glottis, or larynx can occur Rash Other: because teratogenicity can cause fetal and neonatal morbidity and mortality, ACEIs should not be given to women who could be or become pregnant

Oral Adverse Reactions of Angiotensin-Converting Enzyme Inhibitors
Haveles (pp ) Dysgeusia: an altered sense of taste is reported in about 6% of patients taking captopril Usually reversible after a few months, even with continued drug treatment Autoimmune oral lesions: lichenoid or pemphigoid reactions may produce oral manifestations May have a photosensitivity factor

Dental Drug Interactions of Angiotensin-Converting Enzyme Inhibitors
Haveles (p. 203) The antihypertensive effectiveness of ACEIs is reduced by administration of the NSAIDs Chronic administration for several days may result in an increase in the patient’s blood pressure ACEIs may be used alone or in combination with a β-blocker, thiazide diuretic, or CCB

Examples of Angiotensin-Converting Enzyme Inhibitors for Hypertension
Haveles (p. 196) (Box 15-4) benazepril (Lotensin) captopril (Capoten) enalapril (Vasotec) fosinopril (Monopril) lisinopril (Zestril, Prinivil) moexipril (Univasc) perindopril (Aceon) quinapril (Accupril) ramipril (Altace) trandolapril (Mavik)

Angiotensin Receptor Blockers
Haveles (p. 203) ARBs attach to the angiotensin II receptor and block the effect of angiotensin II losartan (Cozaar) is the prototype losartan a high affinity and selectivity for the AT1-receptor It blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II An increase in plasma renin level follows

Adverse Reactions of Angiotensin Receptor Blockers
Haveles (p. 203) ARBs are more specific than ACEIs and may be expected to have fewer adverse reactions CNS: effects can include dizziness, fatigue, insomnia, and headache Upper respiratory infections occur more often in patients taking losartan GI: losartan can produce diarrhea Pain: both muscle cramps and leg and back pain have been reported with losartan Angioedema can occur, rarely Teratogenicity can occur if losartan is administered to pregnant women

Dental Drug Interactions of Angiotensin Receptor Blockers
Haveles (p. 203) NSAIDs may antagonize the antihypertensive effect of losartan by inhibiting renal prostaglandin synthesis or causing sodium and fluid retention

Examples of Angiotensin Receptor Blockers
Haveles (p. 196) (Box 15-4) candesartan (Atacand) eprosartan (Tevetan) irbesartan (Avapro) losartan (Cozaar) olmesartan (Benicar) telmisartan (Micardis) valsartan (Diovan)

Renin Inhibitors Haveles (p. 203) aliskiren (Tekturna): the first of a new class of drugs approved by the U.S Food and Drug Administration for treatment of hypertension Works by binding to renin which then reduces the levels of angiotensin I, angiotensin II, and aldosterone

α1-Adrenergic Blocking Agents for Hypertension
Haveles (p. 204) The adrenergic blockers include the α-blockers and β-blockers previously described Two α-receptor subtypes have been identified, α1 and α2

Mechanism of α1-Adrenergic Blocking Agents for Hypertension
α1-Receptors, located on postsynaptic receptor tissues, produce vasoconstriction and increase peripheral resistance when stimulated α1-Blocking agents produce peripheral vasodilation in the arterioles and venules that decreases peripheral vascular resistance α1-Adrenergic blockers result in a reduction in urethral resistance and pressure, bladder outlet resistance, and urinary symptoms Used in management of older men who have an enlarged prostate gland

Adverse Reactions of α1-Adrenergic Blocking Agents for Hypertension
Haveles (p. 204) Orthostatic hypotension: can result in dizziness or syncope CNS: α1-adrenergic blockers can cause CNS depression, producing either drowsiness or excitation and headache Cardiovascular: tachycardia, arrhythmias, and palpitations can occur Peripheral edema is another side effect

Dental Drug Interactions of α1-Adrenergic Blocking Agents for Hypertension
Haveles (p. 204) (Box 15-7) NSAIDs, especially indomethacin, can reduce antihypertensive effect of the α1-blockers Inhibit renal prostaglandin synthesis or cause sodium and fluid retention cont’d…

Dental Drug Interactions of α1-Adrenergic Blocking Agents for Hypertension
Haveles (p. 204) (Box 15-7) Epinephrine: sympathomimetics can increase the antihypertensive effect of doxazosin α1-Blockers prevent α1-agonist effects (vasoconstriction) of epinephrine, leaving the β1-agonist and β2-agonist effects (vasodilation) to predominate Can result in severe hypotension and reflex tachycardia

Uses of α1-Adrenergic Blocking Agents for Hypertension
Haveles (p. 204) Both doxazosin and terazosin are indicated for the management of benign prostatic hypertrophy (BPH) in addition to the treatment of hypertension

Examples of α1-Receptor Antagonists (Blockers) for Hypertension
Haveles (p. 196) (Box 15-4) doxazosin (Cardura) prazosin (Minipress) terazosin (Hytrin)

Other Antihypertensive Agents
Haveles (p. 204) These antihypertensive agents are used less often than those previously described because they generally have more or less tolerated adverse reactions Clonidine Other centrally acting antihypertensive agents Guanethidine Reserpine Hydralazine

clonidine (Catapres) Haveles (p. 204) A CNS-mediated (centrally acting) antihypertensive drug that reduces peripheral resistance through a CNS-mediated action on the α-receptor Stimulation of presynaptic central α2-adrenergic receptors results in decreased sympathetic outflow Reduces heart rate, cardiac output, and total peripheral resistance May be administered orally or by transdermal patch

Adverse Reactions of Clonidine
Haveles (p. 204) Include a high incidence of sedation and dizziness Rapid elevation of blood pressure has occurred with abrupt discontinuation CNS depressants employed in dental conscious-sedation techniques may contribute to postural hypotension when used in a patient taking clonidine

Oral Effects of Clonidine
Haveles (p. 204) A high incidence of xerostomia (40%), parotid gland swelling, and pain Another side effect is dysgeusia

Other Centrally Acting Antihypertensive Agents
Haveles (pp ) Two other centrally acting antihypertensive agents are also available methyldopa (Aldomet) and guanabenz (Wytensin) Adverse effects and indications are similar to clonidine May be combined with diuretics in essential hypertension management

guanethidine (Ismelin)
Haveles (pp. 198, ) (Fig. 15-5) Severe adverse reactions severely limits its use Blocks the release of norepinephrine from the sympathetic nerve endings Also depletes the amount of norepinephrine stored in synaptic vesicles Reduces sympathetic nervous system tone and decreases blood pressure Causes severe postural and exertional hypotension

Reserpine Depletes norepinephrine from the sympathetic nerve endings
Haveles (p. 205) Depletes norepinephrine from the sympathetic nerve endings Adverse effects include diarrhea, bad dreams, sedation, and even psychic depression leading to suicide Aggravates peptic ulcers

hydralazine (Apresoline)
Haveles (p. 205) Acts directly on arterioles to reduce peripheral resistance (vasodilation) At the same time a rise in heart rate and output occurs Propranolol is often administered concurrently to reduce the tachycardia and increased cardiac output Side effects include cardiac arrhythmias, angina, headache, and dizziness The drug of choice for treatment of a pregnant hypertensive woman

Management of the Dental Patient Taking Antihypertensive Agents
Haveles (p. 205) (Box 15-8) Check for xerostomia and its management If taking a CCB, check for gingival enlargement Check blood pressure before each appointment Avoid dental agents that add to side effects such as opioids If on diuretics, check for symptoms of hypokalemia, which may exacerbate arrhythmias from epinephrine If taking an ACEI, check for symptoms of neutropenia cont’d…

Management of the Dental Patient Taking Antihypertensive Agents
Haveles (p. 205) Adverse reactions Xerostomia Dysgeusia Gingival enlargement Orthostatic hypotension Constipation Central nervous system sedation

Antihyperlipidemic Agents
Haveles (pp ) 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors Niacin Cholestyramine Gemfibrozil Dental Implications cont’d…

Haveles (p. 205) Hyperlipidemia and hyperlipoproteinemia are elevations of plasma lipid concentrations above accepted normal values These metabolic distortions include elevations in cholesterol and/or triglycerides and are associated with the development of arteriosclerosis Many different types of hyperlipoproteinemias may result in elevations of chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), or combinations of these cont’d…

Foam cells, more prevalent in uncontrolled diabetes, become filled with cholesterol esters Accumulation of esters leads to deposition of lipids in arteries Collagen and fibrin also accumulate, occluding the vessels Atherosclerosis can lead to coronary artery disease, myocardial infarction, and cerebral artery disease Endothelium over the plaques activates platelets leading to formation of thrombi and clinical symptoms cont’d…

Haveles (p. 205) Cholesterol and other plasma lipids are carried in the blood as protein complexes to make them more soluble in plasma LDLs carry the greatest concentration of cholesterol and are considered to be the most dangerous High-density lipoproteins (HDLs) carry the least cholesterol and are considered to be beneficial cont’d…

Haveles (pp ) (Table 15-12) The first line of treatment is increasing exercise and decreasing saturated fat and cholesterol from the diet Drug therapy of hyperlipoproteinemia is directed at lowering the level of LDL cholesterol Some are more specific for cholesterol and some are more specific for triglycerides Drugs include bile acid-binding resins, niacin, gemfibrozil, and HMG CoA reductase inhibitors

3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
Haveles (p. 206) Often called “statins” because generic names end in that suffix lovastatin (Mevacor) is an example They lower cholesterol levels by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis

Adverse Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
Haveles (p. 206) GI complaints, myositis, skin rash, impotence, hepatotoxicity, blurred vision, and lens opacities Myositis results in complaints of muscle pain Can increase anticoagulant effect of warfarin

Inhibitors of Intestinal Absorption of Cholesterol
Haveles (pp ) ezetimibe (Zetia): works by inhibiting intestinal absorption of cholesterol Currently comes in combination with simsvastin to treat cholesterol from two different mechanisms of action Side effects include fatigue, abdominal pain, and diarrhea Should “simsvastin” be “simvastatin” ?

Niacin Overview Haveles (p. 207)
A B vitamin: in large doses, lowers cholesterol levels by inhibiting the secretion of VLDLs without accumulation of triglycerides in the liver At larger doses, commonly produces cutaneous flushing and a sensation of warmth after each dose This is blocked by pretreatment with aspirin or ibuprofen Hyperuricemia, allergic reactions, cholestasis, and hepatotoxicity have been reported

Dental Implications of Niacin
Haveles (p. 207) Hypotension may occur as a result of vasodilation

Cholestyramine Haveles (p. 207) Bile acid–binding resins lower cholesterol because cholesterol is a precursor required for the synthesis of new bile acids When the resins bind with bile acids, they produce an insoluble product lost through the GI tract Bile acids use up cholesterol, thereby reducing cholesterol levels cont’d…

Cholestyramine Adverse reactions relate to the GI tract and include constipation and bloating Patients often abandon their use

gemfibrozil (Lopid) Haveles (p. 207) Used to treat hyperlipidemias, especially when triglycerides are elevated Increases lipolysis of triglycerides, decreasing lipolysis in adipose tissue, and inhibiting secretion of VLDLs from the liver cont’d…

Gemfibrozil Adverse reactions
Can promote gallstone formation (cholelithiasis) Taste perversion and hyperglycemia have been reported

Dental Implications of Antihyperlipidemic Agents
Haveles (p. 207) Patients who take antihyperlipidemic agents have a higher risk of atherosclerosis and are at increased risk for cardiovascular emergencies (not because of the drug but because of the condition for which the drug is prescribed) GI and liver abnormalities are side effects associated with many of these drugs

Examples of Antihyperlipidemic Agents
Haveles (p. 206) (Table 15-10) HMG-CoA reductase inhibitors (statins) atorvastatin (Lipitor) fluvastatin (Lescol) lovastatin (Mevacor) pravastatin (Pravachol) simvastatin (Zocor) Bile acid sequestrants cholestyramine (Questran, Prevalite) colestipol (Colestid) cont’d…

Examples of Antihyperlipidemic Agents
Haveles (p. 206) (Table 15-10) Miscellaneous clofibrate (Atromid-S) ezetimibe (Zetia) ezetimibe/simvastin (Vytorin) nicotinic acid (Niacin) fibrates fenofibrate (Lipidil-DSC, Tricor) gemfibrozil (Lopid) Should “simvastin” be “simvastatin” ?

Drugs that Affect Blood Coagulation
Haveles (pp ) Anticoagulants Hemostasis Warfarin Heparin Clopidogrel Ticlopidine Streptokinase and alteplase Dipyridamole Pentoxifylline Drugs that increase blood clotting

Anticoagulants Drugs that interfere with coagulation Haveles (p. 207)
Administered in an attempt to prevent clotting Examples of indications for warfarin (Coumadin) are after a MI or thrombophlebitis

Hemostasis Haveles (pp ) (Fig. 15-8) Designed to prevent loss of blood after injury to a blood vessel Thromboplastin; factors V, VII, and X; and calcium ions form prothrombin, thrombin, and finally fibrinogen and fibrin Fibrin, along with vascular spasms, platelets, and red blood cells quickly forms the clot cont’d…

Hemostasis If the blood vessel’s interior remains smooth, circulating blood does not clot If internal injury to the vessel occurs and a roughened surface develops, intravascular clotting will take place Many factors required in the clotting process are synthesized in the liver Prothrombin (II) and factors VII, IX, and X require vitamin K for synthesis Warfarin antagonizes vitamin K and interferes with the synthesis of four clotting factors to produce an anticoagulant effect cont’d…

Hemostasis Intravascular clots can form in certain diseases
Clots or thrombi may break off, forming emboli that lodge in the smaller vessels of major organs such as the heart, brain, and lungs Anticoagulant therapy attempts to reduce intravascular clotting If the dose is too large, hemorrhage may occur If the dose is too small, the danger of embolism remains

Warfarin (Coumadin) Haveles (pp ) An oral anticoagulant that blocks the γ-carboxylation of glutamate residues in the synthesis of factors VII, IX, and X, prothrombin (II), and endogenous anticoagulant protein C Prevents the metabolism of the inactive vitamin K epoxide back to its active form The pharmacologic effect is delayed when therapy begins and ends cont’d…

Warfarin (Coumadin) Haveles (p. 208) (Fig. 15-9) Monitoring: the effect of warfarin is monitored using the INR A function of the prothrombin time (PT) of the patient, PT of control, and the international sensitivity index (ISI) The target INR for most indications is between 2 and 3, it can range from 1 to 4 cont’d…

Warfarin (Coumadin) Haveles (p. 208) Adverse reactions: the most common adverse effects are various forms of bleeding Look for petechial hemorrhages on the hard palate Ecchymoses can occur, even without trauma

Warfarin-Aspirin Interaction
Haveles (p. 208) (Table 15-11) Patients taking warfarin should not be given aspirin or aspirin-containing products, bleeding episodes or fatal hemorrhages can result Aspirin causes hypoprothrombinemia and alters platelet adhesiveness Can irritate the gastrointestinal tract Aspirin and warfarin compete for the same plasma protein-binding site Increases the proportion of free (unbound) warfarin in the blood

Warfarin-Acetaminophen Interaction
Haveles (p. 209) A statistically significant association was found between acetaminophen use and the abnormal elevation of the INR Toxicity has not been proved

Warfarin-Antibiotics Interaction
Haveles (p. 209) (Table 15-12) Antibiotics can potentiate the effect of warfarin Antibiotics reduce the bacterial flora in the GI tract that normally synthesize vitamin K This results in a decrease in vitamin K absorbed Because warfarin also inhibits vitamin K–dependent factors, an added anticoagulant effect occurs This interaction does not have a chance to develop when antibiotics are used before a dental procedure

Management of the Dental Patient Taking Warfarin
Haveles (p. 209) (Box 15-9) Bleeding: consult with physician regarding PT or INR Analgesics: aspirin is contraindicated unless the patient is taking one aspirin daily for its anticoagulant effect

Heparin Haveles (pp ) One of the most commonly used anticoagulant agents for hospitalized patients Administered by injection; not used orally Used after MI, stroke (embolism), or thrombophlebitis When heparin is started, warfarin is also begun An overdose of heparin is antagonized by protamine sulfate

clopidogrel (Plavix) Haveles (p. 210) An inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation Indicated for patients with recent history of MI or stroke, established peripheral arterial disease, and for patients with acute coronary artery syndrome Side effects include thrombotic thrombocytopenia purpura (TTP) and increased bleeding

ticlopidine (Ticlid) Haveles (p. 211) An irreversible inhibitor of ADP-induced platelet aggregation, which results in increased bleeding time Indicated to decrease thrombotic stroke in patients with previous stroke Used in patients who are intolerant of aspirin Major side effect is neutropenia

streptokinase (Streptase, Kabikinase) and alteplase (tPA, Activase)
Haveles (p. 211) Enzymes, called “clotbusters” are sometimes used in the therapy of deep vein thrombosis, arterial thrombosis, pulmonary embolism, and acute coronary artery thrombosis associated with myocardial infarction Called thrombolytic drugs because they promote conversion of plasminogen to plasmin, the natural clot-resolving enzyme

dipyridamole (Persantine)
Haveles (p. 211) Used to prolong the life of platelets in patients with prosthetic heart valves Artificial valves cause premature death of platelets due to their mechanical effect (trauma) on blood cells passing through the valves

pentoxifylline (Trental)
Haveles (p. 211) Improves blood flow by its hemorheologic effect Lowers blood viscosity and improves flexibility of red blood cells Indicated for claudication (limping) produced by chronic occlusive artery disease of the limbs Side effects include cardiovascular and gastric symptoms

Drugs that Increase Blood Clotting
Haveles (p. 211) Hemostatic Agents (fibrinolytic inhibitors) Aminocaproic acid (EACA) and tranexamic acid (Cyklokapron) are similar to the amino acid lysine, and they inhibit plasminogen activation Adverse effects include intravascular thrombosis, hypotension, and abdominal discomfort Used in the treatment of hemorrhage after surgery

Chapter 15: Cardiovascular Drugs

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Chapter 15: Cardiovascular Drugs

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