(Modified from Lilley LL, Harrington S, Snyder JS: Pharmacology and the nursing process, ed. 5, St. Louis, 2007, Mosby. In Mosou K, Snipe K: Pharmacology for pharmacy technicians. St. Louis, 2009, Mosby.)

Arrhythmia is an abnormal conduction of the heart, may be an atrial or ventricular problem. Ventricular arrhythmias are more serious than atrial. Electrolytes should be checked and corrected if abnormal. Some patients require mechanical treatment: defibrillator; current models may have a pacemaker. Patients should know which type of defibrillator they have and when it was placed in their body.

A. Atrial: arrhythmia occurring in the atria

1. Atrial fibrillation (Afib): most common supraventricular arrhythmia, overall incidence approximately 2% (older than 75 years old, incidence may be as high as 10%); extremely active and disorganized atrial activation leads to loss of atrial contraction and lower ventricular contraction and response.

a) Acute treatment: If the patient is considered hemodynamically unstable, give electrical cardioversion or medication; If the patient is considered hemodynamically stable, use electrical cardioversion or medication; may require chronic treatment

b) Chronic treatment: medication to maintain cardioversion; warfarin (Coumadin) to prevent potential coagulation problems

2. Atrial flutter (Aflutter): less frequent than Afib, similar in consequences and treatment; difference is that there are rapid beats, but atrial activation is normal; it is a disorder of atrial pulse formation, most commonly resulting from localized atrial reentry or ectopic focus in lower part of right atrium.

B. Ventricular: arrhythmia occurring in the ventricle

1. Ventricular tachycardia (Vtach): most commonly encountered life-threatening arrhythmia; episode usually constituted by at least three successive ventricular ectopic beats >100/min; QRS complex is wide. Usually a regular rhythm; conduction from ventricle to atria may occur, resulting in retrograde atrial depolarization. Coronary artery disease with MI is the most common structural heart disease predisposing to Vtach; symptoms palpitations, breathlessness, lightheadedness, angina, syncope.

a) Hemodynamically unstable: electrical cardioversion

b) Hemodynamically stable: chemical cardioversion; can start lidocaine, procainamide, bretylium, amiodarone

2. Ventricular fibrillation (Vfib): chaotic ventricular rhythm; no organized electrical activity, no ventricular contraction, patient requires immediate medical attention to prevent death; any structural, toxic, or metabolic derangement adversely affecting ventricular repolarization may predispose patient to Vfib; immediate electrical cardioversion necessary or use medical cardioversion

a) Correct reversible causes (e.g., hypomagnesemia, hypokalemia). If occurring within the first 72 hours of an acute MI and not associated with increased risk of recurrence, chronic drug therapy is not required.

b) Other: mechanical defibrillator implanted and/or chemical prophylaxis

C. Antiarrhythmic therapies (Vaughan Williams antiarrhythmic classification)

1. Class I: inhibit fast sodium channels

a) Class Ia: prolong ventricular refractoriness and QT interval

(1) Quinidine: suppress symptomatic atrial premature depolarizations and complex ventricular ectopy, convert Afib to sinus rhythm and prevent recurrence, terminate and prevent paroxysmal supraventricular tachycardia (PSVT), may prevent recurrence of sustained Vtach or Vfib in some patients.

(2) Procainamide: same effects as quinidine on automaticity, conduction, and refractoriness; major metabolite: N-acetylprocainamide (NAPA) has class III action; may be as effective as lidocaine in acute termination of sustained Vtach

(3) Disopyramide: slows conduction and prolongs refractoriness; similar to procainamide and quinidine

b) Class Ib: less potent sodium channel blockers; shorten action potential duration and refractoriness

(1) Lidocaine: effective in management of Vtach, especially in setting of acute MI, not to be used as prophylaxis when patient has an MI

(2) Mexiletine: similar to lidocaine, but has less-potent antiarrhythmic activity; can be used alone or with class Ia medication; has not been shown to be effective in preventing recurrence of sustained life-threatening ventricular arrhythmias when used alone

(3) Tocainide: alone or with class Ia drugs for treatment of ventricular arrhythmias; not shown effective in preventing recurrences of sustained life-threatening ventricular arrhythmias

(4) Phenytoin: primarily used for treatment of digoxin-induced ventricular and supraventricular arrhythmias

(5) Moricizine: combined effect of class Ia/Ib; may be used to treat ventricular arrhythmias; not shown to be effective in preventing recurrences of sustained life-threatening ventricular arrhythmias

c) Class Ic: potent sodium channel blockers; slow conduction with little effect on repolarization

(1) Flecainide: may be more effective than other class I agents in management of Afib, flutter, and PSVT

(2) Propafenone: chemical structure is similar to flecainide’s, but has type Ic and moderate beta-adrenergic antagonism; used similar to flecainide

2. Class II: blocks beta-adrenergic receptor sites

a) Beta-adrenergic antagonists (beta blockers): bind at catecholamine receptor sites; decrease automaticity and prevent re-entrant arrhythmias involving the atrioventricular (AV) node; may favorably alter myocardial oxygen supply versus demand and by blunting tissue response to catecholamines

3. Class III: impact potassium channels and prolong repolarization; prolong action potential duration and repolarization to a greater extent than they depress conduction velocity

a) Amiodarone: prolongs repolarization and refractoriness in atrial and ventricular tissue; slows sinus rate and prolongs AV nodal conduction; alpha and beta antagonist; can reduce systemic vascular resistance and mean arterial blood pressure (BP). Potent antiarrhythmic effective for a number of arrhythmias. Prevents recurrence of sustained Vtach or Vfib in <60% patients; full suppression takes 4–6 weeks

b) Bretylium: has important interactions with the autonomic nervous system; prolongs action potential duration and refractoriness in Purkinje fibers and ventricular muscle; affects peripheral adrenergic nerve terminals (initially causes abrupt release of norepinephrine, then prevents further release and reuptake); main use is in treatment of Vtach and Vfib

c) Sotalol: patients should stay in hospital for 3 days when initiating and if dose is changed; decreases frequency and duration of nonsustained Vtach in <40% of patients; prevents recurrence of sustained Vtach and Vfib in 70% of patients; prevents recurrence of symptomatic AFib and flutter

d) Ibutilide: for chemical cardioversion of AFib and flutter; prolongs atrial and ventricular refractory period; minimal effect on conduction

4. Class IV: selectively blocks slow calcium channels; sinoatrial (SA) and AV nodes depend on slow channel activity; induces a concentration-dependent depression in phase 4 depolarization and prolonged refractoriness = depressed automaticity and slowed conduction

a) Calcium channel antagonists

(1) Verapamil: slows ventricular response in AFib and atrial flutter, slows or abolishes SVT using AV node for re-entrant circuit

(2) Diltiazem: similar to verapamil; shorter half-life.

b) Purinergic agonists

(1) Adenosine: inhibits sinus node automaticity, shortens atrial refractory period duration, depresses AV node conduction, prolongs AV node refractoriness; not effective in converting atrial flutter, AFib, or Vtach to sinus rhythm, but may allow diagnosis

c) Digitalis glycosides

Caution: antiarrhythmics may cause arrhythmias; agents may cause more than one action

(1) Digoxin: control resting ventricular rate in Afib or atrial flutter in the setting of left ventricular dysfunction and heart failure; may be useful as adjunctive therapy in combination with calcium-channel blocker (CCB) or beta blocker (BB) for rate control of chronic Afib

d) Warfarin (Coumadin)

(1) Anticoagulation: prevent potential clotting due to abnormal blood flow, aspirin may be used in patients at high risk of complications from warfarin therapy

V. Lipid Disorders

A. Lipoproteins

1. Clusters of lipids associated with proteins that serve as transport vehicles for lipids in the lymph and blood

2. Lipoproteins are distinguished by size and density. Each contains different amounts and kinds of lipids and proteins.

a) Chylomicrons are made by intestinal cells and transport fatty acids from intestines to muscle and other energy using tissues by lipoprotein lipase.

b) Very low-density lipoproteins (VLDLs) are made by the liver and contain large amounts of triglyceride. They are similar to chylomicrons because they transport fatty acids to cells.

c) Intermediate density lipoproteins (IDLs) result from the loss of fatty acids from VLDLs. They are taken up by the liver or remain in the circulation and are converted to low-density lipoproteins (LDL).

d) LDL the “bad” cholesterol that delivers cholesterol from liver to cells.

e) HDL the “good” cholesterol that are made by the liver to scavenge or collect excess cholesterol from cells, including atherosclerotic plaques.

B. Hyperlipidemias

1. Primary hyperlipidemias: familial disease

2. Suspected in people with very high levels of cholesterol (>300 mg/dL) or triglycerides (>1000 mg/dL)

3. Secondary hyperlipidemias are due to other factors such as diet, exercise, medications, diabetes, alcohol intake, hypothyroidism, primary biliary cirrhosis.

C. Laboratory tests to measure lipids

1. Total cholesterol

2. Triglycerides

3. Glycerol kinase reaction assays

F. National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) Guidelines

2. Moderately high risk patients

a) Two or more risk factors (10-year risk 10%–20%)

b) Goal: LDL cholesterol <130 mg/dL

3. Moderate-risk patients

a) Two or more risk factors (10-year risk <10%)

b) Goal: LDL cholesterol <160 mg/dL

4. Low-risk patients

a) None or one risk factor

b) Goal: LDL cholesterol <160 mg/dL

c) If LDL cholesterol is ≥160 mg/dL consider therapeutic lifestyle changes (TLC)

d) If LDL cholesterol is ≥190 mg/dL consider TLC and possible drug therapy

e) If LDL cholesterol is 160–189 mg/dL consider TLC and drug therapy

G. Nondrug therapy

1. Weight control

2. Smoking cessation

3. Limit intake of saturated fat

4. Blood pressure control

H. Drug therapy

1. Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins)

a) Examples

(1) Lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), rosuvastatin (Crestor)

b) Method of action

(1) Decrease LDL, triglyceride, and total cholesterol

(2) Inhibits HMG-CoA reductase

(3) Selective, reversible, competitive inhibition

(4) HMG-CoA converts to mevalonic acid, a precursor of cholesterol

c) Indications

(1) Hyperlipoproteinemia

d) Caution

(1) Patients who consume substantial amounts of alcohol

(2) Patients with active liver disease

(3) Patients with unexplained persistent elevations in serum aminotransferase concentrations

(4) Contraindication: absolute liver disease, pregnancy, lactating women, women of childbearing age who may conceive during therapy, hypersensitivity to medication

e) Interactions

(1) Immunosuppressants such as cyclosporine may increase serum concentrations of atorvastatin, thereby increasing the risk of myopathy.

(2) Concurrent use of fibrates with HMG-CoA reductase inhibitors may increase the risk of myopathy and rhabdomyolysis.

(3) Systemic azole-derivative antifungals (e.g., itraconazole) may decrease the CYP 450 metabolism of HMG-CoA reductase inhibitors. If systemic antifungal treatment is needed, statin is usually discontinued during the course of antifungal treatment.

(4) Select systemic macrolides (e.g., erythromycin, clarithromycin) may decrease the CYP 450 metabolism isoenzymes of HMG-CoA reductase inhibitors. If systemic macrolide treatment is needed with one of these drugs, statin is usually discontinued during the course of the macrolide treatment.

(5) Simvastatin, lovastatin, and atorvastatin are major substrates of CYP 3A4.

(6) Fluvastatin is a major susbstrate of CYP 2C9.

(7) Grapefruit juice may inhibit metabolism of HMG-CoA reductase inhibitors by CYP3A4; therefore high dietary intakes of grapefruit juice should be avoided.

2. Fibrates

a) Examples

(1) Clofibrate (Atromid-S), gemfibrozil (Lopid), fenofibrate (TriCor, others)

b) Method of action

(1) Hydrolyze triacylglycerol and VLDL

(2) Causes increased removal of triacylglycerol and VLDL from plasma

(3) Triglycerides reduced

(4) Little to no change in LDL

(5) Possible increase in HDL

(6) Greater effect seen with gemfibrozil than clofibrate

c) Indications

(1) Hypertriglyceridemia

(2) Dyslipidemia (high triglycerides [TG], low HDL cholesterol)

d) Caution

(1) Should be discontinued if response is not observed within 3 months

(2) None has shown beneficial effect on cardiovascular mortality

(3) None is considered first-line choice

(4) Patients with a history of hepatic or renal dysfunction, peptic ulcer disease, or gallbladder disease

(5) Contraindicated: known hypersensitivity to medication, pregnancy, lactation

e) Interactions

(1) Fibrates may increase effects of coumanin anticoagulants; monitor international normalized ratio (INR)

(2) Gemfibrozil may increase the serum concentrations of repaglinide and cause severe hypoglycemia.

(3) Concurrent use with HMG-CoA reductase inhibitors may increase the risk of myopathy and rhabdomyolysis.

(4) Gemfibrozil is a strong inhibitor of CYP 2C8, 2C9, and 2C19.

f) Toxicity and side effects

(1) Leukopenia

(2) Acute muscular syndrome (acute flu-like syndrome)

(3) Cholelithiasis (increased cholesterol excretion in bile)

(4) Arrhythmias

(5) Reversible increased liver function tests

(6) Nausea, abdominal pain, epigastric pain, dyspepsia

(1) Inhibits lipolysis in adipose tissue, decreasing free fatty acids

(2) Prevents liver from forming VLDL

(3) Prevents VLDL from forming LDL, the “bad cholesterol”

(4) Increases HDL, the “good cholesterol”

(5) May reverse some endothelial cell dysfunction

c) Indications

(1) Hypercholesterolemia, niacin deficiency, pellagra

d) Caution

(1) Patients with diabetes

(2) Liver dysfunction, history of jaundice

(3) Gallbladder disease

(4) Gout

(5) Peptic ulcer disease

(6) Hypersensitivity to niacin, niacinamide

e) Interactions

(1) Nicotinic acid may increase the effects of ganglionic blocking drugs.

(2) May increase the adverse effects of HMG-CoA reductase inhibitors.

f) Toxicity and side effects (not tolerated by many patients)

(1) Flushing: especially the face and neck (tolerance may build), may be less with sustained-release, may pretreat with aspirin

(2) Other: pruritus, sensation of burning, stinging or tingling of skin, nausea, bloating, flatulence, hunger pains, vomiting, heartburn, diarrhea, hypotension, dizziness, tachycardia, syncope, headache, hyperglycemia

(3) Long-term use: rash, hyperpigmentation, liver impairment

4. Bile acid binding resins

a) Examples

(1) Cholestyramine (Questran), colestipol (Colestid)

b) Method of action

(1) Bind bile acids and bile salts in small intestine

(2) Bound complex is excreted in feces

(3) Liver increases conversion of cholesterol to bile acids

(4) Intracellular cholesterol levels decrease

(5) Increased uptake of LDL in liver

(6) May see increase in HDL

c) Indications

(1) Hypercholesterolemia (adjunct)

d) Caution

(1) GI dysfunction (constipation)

(2) Patients with phenylketonuria: flavored Colestid granules contain aspartame, which is converted to phenylalanine

e) Interactions

(1) Bile acid resins may bind to numerous medications and reduce absorption; recommend separating 1 hour before or 4 hours after other medications

f) Toxicity and side effects

(1) GI: constipation, fecal impaction, hemorrhoids, abdominal pain, distention, bloating, flatulence, nausea, vomiting, diarrhea, anorexia, dyspepsia, heartburn, biliary colic, indigestion (tolerance may develop to flatulence and bloating)

(2) Hyperchloremic acidosis or increased urinary calcium excretion

5. Ezetimibe

a) Examples

(1) Zetia, also found in combination with simvastatin (Vytorin)

b) Method of action

(1) Inhibits absorption of cholesterol at the brush border of the small intestine

(2) Decreases transport of cholesterol to liver

(3) Decreases total, LDL, and triglycerides

(4) Increases HDL

c) Indications

(1) Hypercholesterolemia (adjunct)

d) Caution

(1) Hepatic or renal impairment

(2) Contraindications: active liver disease

e) Interactions

(1) Concurrent use of ezetimbide with fibrates may increase risk of cholelithiasis

(2) Bile acid sequestrants may decrease ezetimibe bioavailability

f) Toxicity and side effects

(1) Upper respiratory tract infection, headache, myalgia

(2) Increased liver transaminases with HMG-CoA reductase inhibitors

(3) Possible association between the use of simvastatin and ezetimbe and increased incidence of cancer.

VI. Congestive Heart Failure

CHF represents a complex clinical syndrome characterized by abnormalities of left ventricular function and neurohormonal regulation. It may be caused by multiple underlying diseases such as CHD, atherosclerosis, rheumatic fever, cardiomyopathy, valve disorders, ventricular failure, left or right-sided failure, hypertension, prolonged drug or alcohol addiction, diabetes, or previous heart attack.

B. New York Heart Association functional classification

1. Class I: Physical activity is not limited

2. Class II: Some limitation with physical activity; comfortable at rest

3. Class III: Marked limitation with physical activity

4. Class IV: Unable to be physically active without discomfort

6. Sedentary lifestyle

7. High dietary sodium intake

D. Signs and symptoms

1. Tachycardia

2. Decreased exercise tolerance

3. Shortness of breath

a) Orthopnea (dyspnea that occurs from lying flat)

4. Peripheral and pulmonary edema

5. Cardiomegaly

E. Goals of therapy

1. Meet oxygen requirements of the body

2. Reduce symptoms and improve quality of life

3. Reduce hospitalization

4. Gradual exertion programs

G. Drug therapy (Figure 10-3)

1. Cardiac glycosides (e.g., digoxin)

a) Increases force of myocardial contractility

b) Increases cardiac output

c) Increases cardiac efficiency

d) Decreases heart rate

e) Decreases cardiac size

2. Diuretics

a) Controls fluid retention and improves symptoms rapidly

b) Should be prescribed to all patients with evidence of fluid retention

c) Do not use alone in patients with heart failure

3. Drugs

a) Loop diuretics (e.g., furosemide)

b) Aldosterone antagonists with spironolactone or eplerenone may be added to loop diuretics to enhance diuresis and minimize potassium loss

c) Oral metolazone, spironolactone, or intravenous chlorothiazide can be added as a second diuretic agent when diuretic response is inadequate

(1) Metolazone is the drug of choice in refractory patients with advanced renal failure

4. Vasodilators

a) Used in patients who remain symptomatic after administration of diuretics and digitalis

b) Useful in patients with dilated left ventricle, normal or increase systemic blood pressure, increased systemic vascular resistance, or valvular regurgitation

c) Venous dilators: nitrates

d) Arterial vasodilators: hydralazine and minoxidil

5. Beta blockers (e.g., Carvedilol, metoprolol)

a) Positive actions

(1) Decreases myocardial oxygen consumption demand by decreasing heart rate

(2) Decreases blood pressure, thereby decreasing afterload and preload

b) Negative actions

(1) Decreases cardiac contractility

6. ACE inhibitors/ARB

a) Reduces afterload and preload; reduces workload on the heart

b) Generates positive cardiac inotropy

c) Slows progression of left ventricular dysfunction in CHF (ACE inhibitors)

d) Used for chronic CHF

Figure 10-3 Algorithm for digoxin therapy for heart failure.

(Modified from Morris S, Hatcher HF, Reddy DK: Digoxin therapy for heart failure: An update, American Family Physician, August 15, 2006. Available at: http://www.aafp.org/afp/20060815/613.html.)

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