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Angiotensin-Converting Enzyme (ACE) InhibitorsNonproprietary Names Benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, ACE inhibitors block the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) by inhibiting the angiotensin-converting enzyme (ACE). Reducing the production of angiotensin II also decreases the generation of aldosterone, thereby decreasing sodium and fluid retention. In addition, ACE inhibitors produce vasodilation by blocking bradykinin degradation and increasing prostaglandin E and prostacyclin production, thus reducing the vascular resistance against which the heart pumps (afterload). ACE inhibitors also reduce angiotensin-mediated left ven- ACE inhibitors should be used in all patients with symptomatic systolic dysfunction HF (EF < 40%) or asymptomatic patients with an EF < 35%, unless contraindicated.1,6 ACE inhibitors can also be considered for patients at high risk for developing HF (ACC/AHA Stage A), such as those with coronary artery disease, hypertension or diabetes.1 ACE inhibitors are recommended for most HF patients with PSF, although mortality benefits have not been demonstrated in this patient population.
ACE inhibitors have no adverse effects on lipids or glucose.3 In asymptomatic systolic dysfunction HF patients, ACE inhibitors slow the progression to overt HF. In patients with symptomatic systolic dysfunction HF, ACE inhibitors reduce symptoms and mortality. These agents also increase survival in post-myocardial infarction (MI) patients with sys- ACE inhibitors reduce left ventricular hypertrophy, which may be a precipitating factor in HF Renovascular disease, severe renal impairment (especially in patients with one kidney or with bilateral renal artery stenosis), volume-depleted patients, history of angioedema while on an ACE inhibitor†, pregnancy†, hypotension (SBP < 80 mmHg)† COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
A N G I O T E N S I N - C O N V E RT I N G E N Z Y M E I N H I B I T O R S Dry cough (up to 10–20%)‡, hyperkalemia, hypotension (especially with first dose and if sodium- or volume-depleted)§, taste disturbances, rash (especially at high doses of captopril; may be transient), headache, dizziness (especially with first dose and concurrent diuretics), renal insufficiency Rare: neutropenia, agranulocytosis, proteinuria, glomerulonephritis, angioedema30 Current heart failure guidelines recommend the use of agents and doses that have been sub- stantiated in clinical trials. Doses should be titrated to the lower of either the target dose or the • Adverse effects: light-headedness, dizziness, cough • Tests: blood pressure, renal function (creatinine, BUN)¶, serum potassium levels ACC/AHA, American College of Cardiology/American Heart Association; BUN, blood urea nitrogen; EF, ejection fraction; HF, heart failure; PSF, preserved systolic function; SBP, systolic blood pressure * Consult the product monographs for a full list of indications, contraindications, warnings, precautions, adverse effects and drug ‡ Tolerance to the cough develops in many patients.
§ If symptomatic hypotension persists, consider separating the dose of ACE inhibitor from other medications that can lower ¶ When an ACE inhibitor is initiated, an increase in serum creatinine levels of up to 30% may be observed. Treatment can be continued if the rise in serum creatinine stabilizes at less than 30%, although careful monitoring is recommended.6 COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
A N G I O T E N S I N I I R E C E P T O R B L O C K E R S Angiotensin II Receptor Blockers (ARBs)Nonproprietary Names Candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan ARBs block the binding of angiotensin II to Type 1a and 1b angiotensin receptors (AT1a and AT1b, respectively). Blocking AT1a and AT1b receptors produces vasodilation and decreases aldosterone secretion, renal tubular sodium reabsorption and sympathetic activation. ARBs should be used in patients who cannot tolerate an ACE inhibitor, particularly those experiencing an ACE inhibitor-induced cough.6,7 ARBs can also be used in combination with an ACE inhibitor when beta-blockers are contraindicated or not tolerated (despite careful treatment initiation and titration).6 Addition of an ARB should be considered for HF patients who remain symptomatic or require hospital- ization despite receiving an ACE inhibitor and a beta-blocker.6 ARBs should be considered for patients at high risk for developing HF (ACC/AHA Stage A), such as those with coronary artery disease, hypertension or diabetes.1 ARBs are associated with a lower incidence of cough than ACE inhibitors because ARBs do not increase levels of bradykinin or substance P.3 ARBs may be useful in reducing hospitalizations in Renovascular disease, pregnancy†, angioedema with prior ACE inhibitor use (it is unclear whether patients who have developed angioedema with ACE inhibitors can use ARBs safely) Hyperkalemia (similar incidence to ACE inhibitors), cough (lower incidence than ACE inhibitors), hypotension (especially with first dose and if sodium- or volume-depleted)‡, hyperuricemia, renal Rare: angioedema, neutropenia, thrombocytopenia, leukopenia30 COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
A N G I O T E N S I N I I R E C E P T O R B L O C K E R S Current heart failure guidelines recommend the use of agents and doses that have been substanti- ated in clinical trials. Doses should be titrated to the lower of either the target dose or the highest • Adverse effects: light-headedness, dizziness • Tests: blood pressure, renal function (creatinine, BUN), serum potassium levels ACC/AHA, American College of Cardiology/American Heart Association; ACE, angiotensin-converting enzyme; BUN, blood urea nitrogen; HF, heart failure; PSF, preserved systolic function * Consult the product monographs for a full list of indications, contraindications, warnings, precautions, adverse effects and ‡ If symptomatic hypotension persists, consider separating the dose of ARB from other medications that can lower blood pressure.
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Bisoprolol (cardioselective), carvedilol (alpha-blocking properties), metoprolol (cardioselective) In general, beta-blockers decrease cardiac output, sympathetic outflow from the brain, renin release and norepinephrine release.1 There are two types of beta receptors: beta and beta . Blocking beta receptors decreases heart rate, contractility and renin release. Blocking beta receptors causes bron- choconstriction, peripheral vasoconstriction and impaired glycogenolysis.
Cardioselective beta-blockers have an increased affinity for beta receptors, primarily those in the heart and kidneys. Cardioselectivity is lost at higher doses. Non-cardioselective beta-blockers block beta receptors in the heart and kidney and block beta receptors in the lungs, liver, pan- Beta-blockers with alpha-blocking properties block beta and alpha receptors. The alpha- blocking activity causes vasodilation, partially attenuating the cardiac depressant properties of Beta-blockers should be used in all systolic dysfunction HF patients with an EF < 40% due to their benefits in reducing morbidity and mortality.6 Patients should be stabilized with no changes in their diuretic or ACE inhibitor dose for at least 2 weeks before starting a beta-blocker. Dose titrations must occur very slowly with close follow-up (especially in those with NYHA class III or IV HF). Beta-blockers can also be used in HF patients with PSF, particularly those with concomitant Note: Although bisoprolol, carvedilol and metoprolol have been extensively studied in the treatment of HF, some of the older beta- blockers, such as propranolol and oxprenolol, have been associated with several reports of HF deterioration. It is not yet clear if the benefits of beta-blockers in HF are a class effect, or which specific properties of these agents (vasodilation, cardioselectivity, intrinsic sympathomimetic activity [ISA]) are beneficial. Therefore, only bisoprolol, carvedilol or metoprolol should be used in COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
Beta-blockers reduce morbidity and mortality in HF when used in addition to ACE inhibitors. In low doses, beta-blockers may maintain or improve ventricular filling in patients with diastolic Bronchospastic disease† (beta-blockers are contraindicated in asthma or in patients with a reactive airway component to their COPD; most COPD patients can tolerate a beta-blocker but must start with low doses and be evaluated carefully), second- or third-degree heart block†, depression, dia- betes (types 1 and 2; may mask or prolong symptoms of insulin-induced hypoglycemia‡), systolic dysfunction HF with low cardiac output, overt HF (acutely hospitalized patients with NYHA class IV symptoms at rest)†, peripheral vascular disease or Raynaud’s disease, bradycardia, hypotension Decreased heart rate, fatigue, insomnia, decreased exercise tolerance, rebound hypertension and tachycardia (if abruptly discontinued), erectile dysfunction (more common with non-cardioselective beta-blockers such as propranolol; less common with cardioselective beta-blockers), impaired peripheral circulation, changes in lipid profiles (may not be clinically significant), first-dose hypoten- COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
Current heart failure guidelines recommend the use of agents and doses that have been sub- stantiated in clinical trials. Doses should be titrated to the lower of either the target dose or the • Adverse effects: reduced energy level, reduced exercise tolerance, light-headedness, dizziness, sexual dysfunction, signs and symptoms of worsening heart failure¶ ACE, angiotensin-converting enzyme; COPD, chronic obstructive pulmonary disease; EF, ejection fraction; HF, heart failure; NYHA, New York Heart Association; PSF, preserved systolic dysfunction; SBP, systolic blood pressure * Consult the product monographs for a full list of indications, contraindications, warnings, precautions, adverse effects and ‡ Most patients with diabetes can tolerate beta-blockers; often, the survival benefits of therapy outweigh the risks of adverse effects.
§ Not available in Canada at the time of authoring. In practice, immediate-release metoprolol is often used in lieu of metoprolol CR/XL (initial dose = 6.25–12.5 mg BID; target dose = 100 mg BID), although studies supporting the use of immediate-release ¶ Patients should be made aware that they may experience symptoms of HF, such as dyspnea, swelling of the ankles and fatigue, when starting a beta-blocker. If symptoms are severe, the dose may need to be decreased for a couple of weeks then increased again. Patients should begin to feel better after 2–3 months (once the titration phase is complete). COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
C A L C I U M C H A N N E L B L O C K E R S Calcium Channel Blockers (CCBs)Nonproprietary Names Dihydropyridines (DHP): amlodipine, felodipine, nifedipine Non-dihydropyridines (non-DHP): diltiazem, verapamil In general, CCBs relax cardiac and smooth muscle by blocking calcium channels. Verapamil and diltiazem decrease heart rate, slow AV nodal conduction (diltiazem < verapamil) and depress cardiac contractility (i.e., they have a negative inotropic effect).
Dihydropyridine CCBs do not have nodal blocking properties. They cause peripheral vasodilation CCBs are not recommended for the treatment of systolic dysfunction HF. Amlodipine or felodipine may be preferred in patients with systolic dysfunction HF who require a CCB for another indication (e.g., hypertension, angina), as these agents have not been shown to worsen HF.
Verapamil and diltiazem can be used for the treatment of HF with PSF.6,7 In patients with diastolic dysfunction (i.e., HF with PSF), verapamil and diltiazem may help reduce myocardial hypertrophy and provide symptom relief in patients with hypertrophic cardiomyopathy.10 Some patients may need to start therapy in the hospital, as significant deterioration can occur. Second- or third-degree heart block (non-DHP)†, systolic dysfunction HF (except amlodipine and felo- dipine)†, angina/myocardial infarction (immediate-release nifedipine may cause acute hypotension) COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
C A L C I U M C H A N N E L B L O C K E R S Dihydropyridines: dizziness, flushing, headache, peripheral edema, mood changes, erectile dysfunction, gingival hypertrophy, gastrointestinal complaints, increased mortality (short-acting agents), increased frequency, intensity or duration of angina (short-acting agents) Diltiazem, verapamil: decreased heart rate, AV block, systolic dysfunction HF, anorexia, gingival hyperplasia (verapamil), peripheral edema, hypotension, flushing, headache, erectile dysfunction, nausea or headache (diltiazem), constipation (verapamil)10 • Adverse effects: hypotension, peripheral edema (DHP), flushing (DHP), headache (DHP), signs • Tests: heart rate (especially with diltiazem and verapamil), blood pressure AV, atrioventricular; HF, heart failure; PSF, preserved systolic function * Consult the product monographs for a full list of indications, contraindications, warnings, precautions, adverse effects and COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
Digoxin increases heart contractility (mildly positive inotropic effect), slows the heart rate (by increasing vagal tone), improves diastolic ventricular filling and reduces neurohumoral activation.
Digoxin can be used in patients with systolic dysfunction HF who continue to experience moderate to severe symptoms despite using standard HF medications (i.e., ACE inhibitors, beta-blockers, ARBs and diuretics). Digoxin can also be used in HF patients with concomitant atrial fibrillation or atrial flutter, when beta-blockers fail to control the ventricular rate or cannot be used.1,6 Digoxin has been shown to reduce the rate of hospitalization (not mortality) in patients with Ventricular fibrillation, hypokalemia, decreased renal function, second- or third-degree heart block Digoxin toxicity (nausea, vomiting, anorexia, cardiac arrhythmias, palpitations, fatigue, confusion, depression, visual disturbances [hazy vision, photophobia, colour vision disturbances]), decreased Digoxin is generally dosed from 0.125–0.25 mg per day in heart failure. Low initial doses should be used in the elderly, and doses should be reduced in those with renal impairment. Doses that maintain trough (8–12 hours post-dose) serum digoxin levels < 1.28 nmol/L (< 1 ng/mL) achieve optimal benefits with a lower risk of side effects.6 • Adverse effects: signs of digoxin toxicity • Tests: heart rate, digoxin levels†, serum potassium levels‡ ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; AV, atrioventricular; HF, heart failure * Consult the product monograph for a full list of indications, contraindications, warnings, precautions, adverse effects and † Digoxin has a narrow therapeutic index. Digoxin levels are used to monitor for toxicity, although the correlation between digoxin levels and toxicity is poor.
‡ Potassium levels should generally be maintained between 4 and 5 mmol/L to prevent toxicity.
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D I U R E T I C S ( L O O P A N D T H I A Z I D E ) Diuretics (Loop and Thiazide)Nonproprietary Names Loop diuretics: bumetanide, ethacrynic acid, furosemide Thiazide diuretics: chlorthalidone, hydrochlorothiazide, indapamide, metolazone (thiazide-like) Diuretics remove peripheral and pulmonary fluid and congestion, thus reducing HF symptoms.
Loop diuretics reduce sodium reabsorption in the ascending loop of Henle and in the distal renal tubules, causing increased excretion of water, sodium, chloride, magnesium, potassium and calcium.
These are the most potent diuretics.
Thiazide diuretics reduce sodium reabsorption in the distal tubules, causing increased excretion of sodium, water and potassium. Metolazone has intermediate potency between hydrochlorothiazide Diuretics are used to treat HF symptoms due to sodium and water retention; effects on mortality have never been studied with diuretics. All patients with fluid retention should receive a diuretic.
Once fluid status has returned to ‘normal’ (i.e., euvolemia), the diuretic dose can be decreased; diuretic therapy should be continued to prevent recurrence of fluid retention.1 A loop diuretic is recommended for most patients with heart failure and congestive symptoms.1,6 Thiazide diuretics (most commonly metolazone) may be added in patients with persistent fluid retention despite using a high-dose loop diuretic.7 Diuretics should be used cautiously in HF with PSF.6,7 Note: Potassium-sparing diuretics (e.g., amiloride, triamterene) have weak diuretic effects and are not used for alleviating COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
D I U R E T I C S ( L O O P A N D T H I A Z I D E ) Diuretics produce symptomatic benefits more rapidly than other HF medications (within hours or Loop diuretics are the most potent diuretics and are useful in patients with poor renal function (GFR < 30 mL/min), ascites and hypercalcemia. A synergistic effect occurs when a thiazide diuretic (usually metolazone) is used in combination with a loop diuretic. Hypovolemia†, severe hypokalemia†, dyslipidemia‡, diabetes‡, gout General: hypovolemia, increased serum lipids‡, dose-dependent hyperglycemia‡, potential Loop diuretics: hypokalemia (minimized by using low doses), hypomagnesemia, hypocalcemia, increased photosensitivity in some patients, lipid abnormalities (less than thiazide diuretics), glucose changes (less than thiazide diuretics), ototoxicity at higher doses Thiazide diuretics: similar to loop diuretics, with the exception of hypocalcemia (thiazides reduce renal calcium excretion and have been associated with hypercalcemia) Once congestive symptoms have cleared, the lowest possible diuretic dose that yields stable signs and symptoms should be used.6 Diuretics should generally be taken in the morning; additional doses (e.g., patients on twice-daily dosing) should not be taken late in the day (i.e., not later than 4:00 pm) to minimize nocturia-related sleep disruptions.7 • Adverse effects: light-headedness, dizziness, fluid status • Tests: urine output, blood pressure, serum electrolyte levels, renal function (creatinine, BUN) BUN, blood urea nitrogen; GFR, glomerular filtration rate; HF, heart failure; PSF, preserved systolic function * Consult the product monographs for a full list of indications, contraindications, warnings, precautions, adverse effects and ‡ High-dose diuretics (with the exception of indapamide) may worsen lipid and blood glucose levels; this occurs less often with loop diuretics than thiazide diuretics. Controversy exists regarding the clinical significance of these effects. COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
Spironolactone is an aldosterone antagonist and thus decreases sodium and water retention. Although it is a mild potassium-sparing diuretic, it is used in HF because of its effects on aldosterone. These effects appear to attenuate some of the detrimental HF compensatory mechanisms.6 Spironolactone is recommended for carefully-selected patients with severe systolic dysfunction HF (EF < 30%; NYHA class IIIb–IV) who remain symptomatic despite the use of other recommended treatments at optimal doses (i.e., ACE inhibitors, beta-blockers, ARBs, diuretics).6 The concurrent use of an ACE inhibitor, ARB and spironolactone is not recommended unless the patient is under careful supervision (e.g., in a HF clinic) due to the risk of life-threatening hyperkalemia.1 Low-dose spironolactone (12.5–25 mg daily) has demonstrated mortality benefits in patients with Hypovolemia, hyperkalemia†, renal insufficiency† Spironolactone is used at very low doses as an aldosterone antagonist in the treatment of severe heart failure. The recommended initial dose is 12.5 mg once daily, titrated to a target dose of • Adverse effects: light-headedness, dizziness, fluid status, breast enlargement/tenderness (men) • Tests: serum potassium levels, renal function (creatinine, BUN) ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BUN, blood urea nitrogen; EF, ejection fraction; HF, heart failure; NYHA, New York Heart Association * Consult the product monograph for a full list of indications, contraindications, warnings, precautions, adverse effects and COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
Isosorbide dinitrate (a long-acting nitrate) Hydralazine dilates arteries, reducing blood pressure and therefore the pressure against which the heart has to work (afterload). Isosorbide dinitrate primarily dilates veins, which decreases venous return (preload), decreases left ventricular congestion and lowers blood pressure.
Hydralazine, in combination with isosorbide dinitrate, can be used as add-on therapy (to standard treatment) in patients of African descent who have systolic dysfunction HF.6 In addition, combination hydralazine/isosorbide dinitrate can be used in patients who do not tolerate other recommended therapies (i.e., ACE inhibitors, ARBs or beta-blockers).6 The combination of hydralazine and isosorbide dinitrate has been shown to improve systolic dysfunction HF symptoms and survival compared with placebo in clinical trials (V-HeFT I).24 ACE inhibitors, however, were significantly more efficacious than hydralazine/isosorbide dinitrate in Hydralazine: systemic lupus erythematosus (SLE)†, severe tachycardia†, high-output heart failure† COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.
Hydralazine: postural hypotension, tachycardia, palpitations, flushing, transient nausea, headache§, SLE, erectile dysfunction; rarely used alone due to reflex tachycardia Nitrates: flushing, headache§, postural hypotension, tolerance/tachyphylaxis Current heart failure guidelines recommend the use of agents and doses that have been sub- stantiated in clinical trials. Doses should be titrated to the lower of either the target dose or • Adverse effects: light-headedness, dizziness, orthostatic hypotension, tolerance¶ ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; HF, heart failure; V-HeFT, Vasodilator Heart Failure Trial.
* Consult the product monographs for a full list of indications, contraindications, warnings, precautions, adverse effects and ‡ The combination of hydralazine and isosorbide dinitrate is generally not well tolerated; in clinical trials, the drop-out rate § Patients usually develop tolerance to the headache after several weeks of therapy. Mild analgesics, such as acetaminophen, can be used to manage the headache in the meantime. If patients continue to have headaches, consider discontinuing the vasodilator.3 ¶ When hydralazine is used with nitrates for heart failure, a nitrate-free period is not necessary.24 COPYRIGHT 2006 APOTEX INC. ALL RIGHTS RESERVED.

Source: http://www.sound-decisions.ca/ce-essentials/hf/PDF_Files/medications.pdf