1

Heart Heart Failure Failure [HF][HF]

22

Definition of HFDefinition of HF• Heart failure is a complex clinical Heart failure is a complex clinical

syndrome that can result from any syndrome that can result from any structural or functional cardiac structural or functional cardiac disorder that impairs the ability of disorder that impairs the ability of the ventricle to fill with or eject the ventricle to fill with or eject blood blood

• As As a consequence the a consequence the heart fails to pump sufficient blood heart fails to pump sufficient blood to meet the body's metabolic needsto meet the body's metabolic needs. .

33

Cardiovascular consequences of heart failure.

44

Diagnosis of HF Diagnosis of HF [Signs and [Signs and symptoms]symptoms]

Venous Venous congestioncongestion

CardiacCardiac

CardiomegalyCardiomegaly

ArterialArterial

Peripheral Peripheral hypoperfusionhypoperfusion

DyspneaDyspnea

OedemaOedema

HypoxiaHypoxia

HepatomegalHepatomegalyy

Raised Raised venous venous pressurepressure

DilationDilation

TachycardiaTachycardia

RegurgitationRegurgitation

CardiomyopathyCardiomyopathy

Ischemia, Ischemia, arrhythmiasarrhythmias

FatigueFatigue

PallorPallor

Renal Renal impairmentimpairment

ConfusionConfusion

Circulatory Circulatory failurefailure

55

Hepatojugular refluxHepatojugular reflux

66

Investigations of HFInvestigations of HF

77

Investigations of HFInvestigations of HF

InvestigationInvestigationcommentcomment

Blood gas analysisBlood gas analysisTo assess respiratory gas exchangeTo assess respiratory gas exchange

Blood testBlood testPlasma BNP = likelihood of a diagnosis of HF = Plasma BNP = likelihood of a diagnosis of HF = screening testscreening test

Fasting blood glucose: for DMFasting blood glucose: for DM

Full blood count: for anemiaFull blood count: for anemia

Renal function tests:serum urea and creatinineRenal function tests:serum urea and creatinine

Liver function tests: AST, ALT enzymesLiver function tests: AST, ALT enzymes

Thyroid function tests: for thyrotoxicosisThyroid function tests: for thyrotoxicosis

88

Investigations of HFInvestigations of HF

InvestigationInvestigationcommentcomment

Chest radiography Chest radiography [ X-ray][ X-ray]

For: - enlarged cardiac shadowFor: - enlarged cardiac shadow

- consolidation in the lungs- consolidation in the lungs

ECG ECG [ electrocardiogra[ electrocardiography]phy]

For: arrhythmiasFor: arrhythmias

left or right ventricular hypertrophyleft or right ventricular hypertrophy

Abnormal ECG requires furhter Abnormal ECG requires furhter investigationsinvestigations

EchocardiographyEchocardiographyConfirmConfirm the diagnosis of heart failure the diagnosis of heart failure and any underlying cause e.g. valvular and any underlying cause e.g. valvular heart diseaseheart disease

99

DD of Dyspnea DD of Dyspnea [shortness of breath][shortness of breath]• Cardiac:Cardiac:

1.1. Heart failureHeart failure2.2. Angina: retrosternal pain radiates to arm and jaw-Angina: retrosternal pain radiates to arm and jaw-

pain ppt by exertion, relieved by restpain ppt by exertion, relieved by rest3.3. Pulmonary embolism: acute dyspnea- hemoptysis Pulmonary embolism: acute dyspnea- hemoptysis

diagnosed by pulmonay angiographydiagnosed by pulmonay angiography4.4. Pulmonary hypertension: Ausc.: accentuated 2Pulmonary hypertension: Ausc.: accentuated 2ndnd heart heart

sound- dullness in the 2sound- dullness in the 2ndnd intercostal space intercostal space• Other causes:Other causes:

1.1. Respiratory disease [ bronchitis]= longer in duration- Respiratory disease [ bronchitis]= longer in duration- normal heart and ECG exam.+ diffuse rhonchinormal heart and ECG exam.+ diffuse rhonchi

2.2. Anemia = CBC Anemia = CBC 3.3. Obesity =BMI and normal chest and heart Obesity =BMI and normal chest and heart

examinationexamination4.4. History of Drug intake: History of Drug intake: -blockers in asthmatic -blockers in asthmatic

patient- exacerbation of heart failure by patient- exacerbation of heart failure by -blockers, -blockers, NSAIDS, DiltiazemNSAIDS, Diltiazem

1010

DD of generalized edema DD of generalized edema

• Cardiac:Cardiac: occurs in the dependent parts of the occurs in the dependent parts of the body: ankle, sacral- bilateral pitting edema-edema body: ankle, sacral- bilateral pitting edema-edema of LL preceeds ascitesof LL preceeds ascites

• Renal:Renal: nephritic or nephrotic syndrome, first nephritic or nephrotic syndrome, first appears in eye lids and is associated with polyurea appears in eye lids and is associated with polyurea or oliguria-hematuriaor oliguria-hematuria

• Hepatic:Hepatic: edema of LL and ascites + features of edema of LL and ascites + features of liver cirrhosis: cirrhosis- splenomegaly- jaundiceliver cirrhosis: cirrhosis- splenomegaly- jaundice

• Nutritional:Nutritional: long history of inadequate diet or long history of inadequate diet or diarrhea. First in LL associated with features of diarrhea. First in LL associated with features of nutritional deficiency nutritional deficiency

• Drugs:Drugs: fluid retention from steroids, NSAIDs, fluid retention from steroids, NSAIDs, nifedipine and amlodipine [CCBs]nifedipine and amlodipine [CCBs]

1111

Goals and guidelines of Goals and guidelines of therapytherapy

• The ACC/AHA Task Force The ACC/AHA Task Force recommends that most patients recommends that most patients with HF should be routinely with HF should be routinely managed with managed with a combination of a combination of four types of drugsfour types of drugs::

• A Diuretic, A Diuretic, • An ACE Inhibitor, An ACE Inhibitor, • A A -adrenergic Blocker, -adrenergic Blocker, • And (Usually) Digitalis. And (Usually) Digitalis. • An Aldosterone Antagonist (E.G., Spironolactone) Is A An Aldosterone Antagonist (E.G., Spironolactone) Is A

Fifth Class Of Drug Recommended For Patients Fifth Class Of Drug Recommended For Patients With With Advanced HF.Advanced HF.

1212

Goals and guidelines of Goals and guidelines of therapytherapy

• The ultimate goalThe ultimate goal is to: is to:– prolong survival in individuals prolong survival in individuals

– and reduce mortality rates within and reduce mortality rates within the population of patients with HF. the population of patients with HF.

– Short of a heart transplant, none Short of a heart transplant, none of the treatment measures are of the treatment measures are

curative.curative.

1313

Main guidelines of Main guidelines of therapytherapy

• medical management of HF includes:medical management of HF includes:1.1. correction of correction of underlying disease statesunderlying disease states

(e.g., hypertension, ischemic heart disease, (e.g., hypertension, ischemic heart disease, arrhythmias, lipid disorders, anemia, or arrhythmias, lipid disorders, anemia, or hyperthyroidism)hyperthyroidism)

2.2. moderate moderate physical activityphysical activity3.3. immunization with immunization with influenza and influenza and

pneumococcal vaccines to reduce the risk pneumococcal vaccines to reduce the risk of respiratory infectionsof respiratory infections, and , and discontinuation of possible drug-induced causes. discontinuation of possible drug-induced causes.

4.4. A sodium-restricted diet and diuretics are A sodium-restricted diet and diuretics are required required if fluid retention is evident. if fluid retention is evident.

5.5. Amiodarone is indicated in the treatment of Amiodarone is indicated in the treatment of symptomatic symptomatic ventricular tachycardia and ventricular tachycardia and atrial fibrillation associated with HF.atrial fibrillation associated with HF.

1414

MANAGEMENTMANAGEMENT

OFOF

HEART FAILUREHEART FAILURE

1515

Physical ActivityPhysical Activity

• Edema can be minimized by use of Edema can be minimized by use of elastic stocks elastic stocks

• During acute exacerbations, During acute exacerbations, bed rest bed rest and restricted physical activityand restricted physical activity

• Renal perfusion is increased in the Renal perfusion is increased in the prone position, resulting in diuresisprone position, resulting in diuresis

1616

Sodium-Restricted DietSodium-Restricted Diet

• In patients with In patients with hypertension or hypertension or evidence of fluid retentionevidence of fluid retention, but is , but is not required in all patients. not required in all patients.

• Dietary sodium can be Dietary sodium can be reduced to reduced to 2 to 4 g of NaCl2 to 4 g of NaCl is more palatable is more palatable andand leads to better adherence leads to better adherence than a severely salt-restricted than a severely salt-restricted diet.diet.

1717

Drug Drug therapy therapy

of HFof HF

1818

Ion movements during the contraction of cardiac muscle. ATPase = adenosine triphosphatase.

1919

1-Diuretics in HF1-Diuretics in HF• are indicatedare indicated in patients with circulatory in patients with circulatory

congestion (pulmonary and peripheral congestion (pulmonary and peripheral edema) and/or cardiac distension (enlarged edema) and/or cardiac distension (enlarged heart on chest radiograph). heart on chest radiograph).

• They produce They produce symptomatic reliefsymptomatic relief more more rapidly than other drugs for HF. rapidly than other drugs for HF.

• However, However, monotherapy with diuretics monotherapy with diuretics is discouraged, is discouraged, diuretics should be diuretics should be combined with an ACE inhibitor and a β-combined with an ACE inhibitor and a β-blocker unless contraindications exist. blocker unless contraindications exist.

2020

1-Diuretics in HF1-Diuretics in HF

• By enhancing renal excretion of sodium By enhancing renal excretion of sodium and water, diuretics and water, diuretics diminish vascular diminish vascular volumevolume, thus relieving ventricular and , thus relieving ventricular and pulmonary congestion and decreasing pulmonary congestion and decreasing peripheral edema.peripheral edema.

• If diuresis is too vigorous, intravascular If diuresis is too vigorous, intravascular

volume depletion:volume depletion:– hypotensionhypotension– paradoxical decrease in CO paradoxical decrease in CO – Weight loss exceeding 1 kg/day is to be avoided Weight loss exceeding 1 kg/day is to be avoided

except in patients with except in patients with acute pulmonary edema.acute pulmonary edema.

2121

1-Diuretics in HF1-Diuretics in HF• Diuresis after Diuresis after IV administrationIV administration: :

– The onset of response after an IV injection of loop The onset of response after an IV injection of loop diuretics is 10 minutes or less, diuretics is 10 minutes or less,

– peaking within the first 30 minutes, peaking within the first 30 minutes,

– and usually abating within 2 hoursand usually abating within 2 hours. .

•Diuresis after oral Diuresis after oral administration:administration:– usually begins 30 to 90 minutes after the oral usually begins 30 to 90 minutes after the oral

administration of loop diureticsadministration of loop diuretics– it peaks within the first or second hourit peaks within the first or second hour– and lasts for 6 to 8 hours. and lasts for 6 to 8 hours.

2222

Monitoring Parameters Monitoring Parameters with Diuretics with Diuretics

•↓ ↓ CHF symptoms CHF symptoms • Weight loss not more than 1 Kg/day “ideal Weight loss not more than 1 Kg/day “ideal weight” achieved weight” achieved

Signs of volume depletion Signs of volume depletion •      HypotensionHypotension • CO: CO: Weakness;  , dizziness,    ↓ Urine Weakness;  , dizziness,    ↓ Urine outputoutput

2323

Aldosterone Antagonists (e.g., Aldosterone Antagonists (e.g., eplerenone and spironolactone)eplerenone and spironolactone)

• The Randomized Aldactone The Randomized Aldactone Evaluation StudyEvaluation Study Investigators Investigators found that found that ::1.1. protective effect of protective effect of spironolactonspironolactone was e was

related more to: a reduction in related more to: a reduction in aldosterone-induced vascular damage aldosterone-induced vascular damage and myocardial or vascular fibrosis than and myocardial or vascular fibrosis than to its diuretic effect.to its diuretic effect.

2.2. Similarly, with Similarly, with 25 to 50 mg of eplerenone25 to 50 mg of eplerenone: reduced : reduced mortality was observed in patients with left mortality was observed in patients with left ventricular dysfunction following a recent MIventricular dysfunction following a recent MI

3.3. NO EVIDENCENO EVIDENCE that the direct acting potassium that the direct acting potassium sparing diuretics sparing diuretics amiloride or triamterene exert a amiloride or triamterene exert a similar protective effect.similar protective effect.

2424

2-Angiotensin-Converting Enzyme 2-Angiotensin-Converting Enzyme InhibitorsInhibitors

• Drugs with Drugs with vasodilating propertiesvasodilating properties have have become a primary treatment modality of become a primary treatment modality of HF. HF.

• Arterial dilationArterial dilation provides symptomatic provides symptomatic relief of HF by decreasing arterial relief of HF by decreasing arterial impedance (afterload) to left ventricular impedance (afterload) to left ventricular outflow. outflow.

• Venous dilationVenous dilation decreases left ventricular decreases left ventricular congestion (preload). congestion (preload).

• The combination of these two properties The combination of these two properties providesprovides additive benefits to alleviate the additive benefits to alleviate the symptoms of HF and increase exercise symptoms of HF and increase exercise tolerance. tolerance.

2525

Angiotensin-Converting Enzyme Angiotensin-Converting Enzyme InhibitorsInhibitors

• ACE inhibitors are not only vasodilators but they also ACE inhibitors are not only vasodilators but they also favorably favorably modify cardiac remodelingmodify cardiac remodeling

• they have a they have a more tolerable side effect profilemore tolerable side effect profile..

• they they slow the rate of mortalityslow the rate of mortality in HF more than the in HF more than the hydralazine-nitrate combination hydralazine-nitrate combination

• These advantages, led ACC/AHA to recommend These advantages, led ACC/AHA to recommend ACE ACE inhibitors as the drugs of choice for initial therapy,inhibitors as the drugs of choice for initial therapy,

2626

2- Angiotensin-Converting 2- Angiotensin-Converting Enzyme InhibitorsEnzyme Inhibitors

• The 2001 ACC/AHA guidelines state: The 2001 ACC/AHA guidelines state: – ““ACE inhibitors ACE inhibitors should be prescribed to all patients should be prescribed to all patients

with HF due to left ventricular systolic dysfunctionwith HF due to left ventricular systolic dysfunction unless they have a contradiction to their use or unless they have a contradiction to their use or have been shown to be unable to tolerate treatment have been shown to be unable to tolerate treatment with these drugs. with these drugs.

– ACE inhibitors should not be prescribed without a ACE inhibitors should not be prescribed without a diuretic in patients with current or recent history of diuretic in patients with current or recent history of fluid retention.fluid retention. prescribers should ensure that the prescribers should ensure that the appropriate doses of diuretics before and during appropriate doses of diuretics before and during treatment with these drugs.”treatment with these drugs.”

• Their value in diastolic failure still is being Their value in diastolic failure still is being investigated. investigated.

2727

Effect of enalapril on the mortality of patients with congestive heart failure.

2828

2- The Angiotensin Receptor 2- The Angiotensin Receptor Blockers [ARBs]Blockers [ARBs]

• A related class of drugs are the angiotensin A related class of drugs are the angiotensin receptor inhibitors (candesartan [Atacand], receptor inhibitors (candesartan [Atacand], eprosartan [Teveten], irbesartan eprosartan [Teveten], irbesartan [Avapro], losartan [Cozaar], olmesartan [Avapro], losartan [Cozaar], olmesartan [Benicar], telmisartan [Micardis], and [Benicar], telmisartan [Micardis], and valsartan (Diovan).valsartan (Diovan).

•Advantages over ACEIsAdvantages over ACEIs• The receptor inhibitors offer theoretic The receptor inhibitors offer theoretic

advantages over ACE inhibitors by being:advantages over ACE inhibitors by being:– more specific for angiotensin II blockade more specific for angiotensin II blockade – with a lower risk of drug-induced coughwith a lower risk of drug-induced cough. .

2929

ARBsARBs• Mechanism of actionMechanism of action

• Block Ang II receptor type IBlock Ang II receptor type I

• Advantages over ACEIsAdvantages over ACEIs• Does not block type II angiotensin II receptors Does not block type II angiotensin II receptors

so maintain antiproliferative and VD effect so maintain antiproliferative and VD effect• Bradykinin is converted to kinins so no dry Bradykinin is converted to kinins so no dry

cough cough

Disadvantages against ACEIsDisadvantages against ACEIs• No action on type IV angiotensin II receptorNo action on type IV angiotensin II receptor

thrombotic tendencythrombotic tendency• No maintainance of bradykinin No maintainance of bradykinin no additional no additional

VDVD

3030

2-The Angiotensin Receptor 2-The Angiotensin Receptor blockers [ARBs]blockers [ARBs]

• Advantages of ACEIs over ARBsAdvantages of ACEIs over ARBs– More importantly, there is evidence that ACE More importantly, there is evidence that ACE

inhibitors have inhibitors have a more favorable effect on a more favorable effect on prevention of cardiac remodelingprevention of cardiac remodeling by unclear by unclear mechanisms. mechanisms.

– Currently, ARBs are reserved for use in Currently, ARBs are reserved for use in those who fail to tolerate ACE inhibitors those who fail to tolerate ACE inhibitors (e.g., angioedema or intractable cough) or (e.g., angioedema or intractable cough) or during pregnancy.during pregnancy.

3131

The Angiotensin Receptor The Angiotensin Receptor blockers [ARBs]blockers [ARBs]

• Clinical trials on ARBsClinical trials on ARBs– Preliminary results of clinical trials with Preliminary results of clinical trials with

several of the angiotensin-receptor several of the angiotensin-receptor blockers (ARBs) have been encouraging, blockers (ARBs) have been encouraging, but more data are needed relative to but more data are needed relative to their effects on restricting cardiac their effects on restricting cardiac remodeling and reducing mortalityremodeling and reducing mortality..

– There have been more clinical trials with There have been more clinical trials with losartan, losartan, but only valsartan has FDA but only valsartan has FDA approved labeling for treatment of approved labeling for treatment of HF.HF.

3232

Effects of angiotensin-converting enzyme (ACE) inhibitors

3333

Doses of ACEIs and ARBsDoses of ACEIs and ARBs

ACEIsACEIs

EnalaprilEnalapril

RamiprilRamipril

Target: 10-20 Target: 10-20 mg/twice dailymg/twice daily

Start: 2.5 mg/dayStart: 2.5 mg/day

Target : 10 mg/once Target : 10 mg/once dailydaily

Start: 2.5 mg/dayStart: 2.5 mg/day

1.1. First dose First dose hypotension may hypotension may occur. occur.

2.2. Adjust dose in Adjust dose in renal failurerenal failure

3.3. HyperkalemiaHyperkalemia

4.4. coughcough

ARBsARBs

ValsartanValsartan

CandesartanCandesartan

Target; 160 mg/ twice Target; 160 mg/ twice dailydaily

Start: 40 mg/dayStart: 40 mg/day

Target; 32 mg/ once Target; 32 mg/ once dailydaily

Start: 4-8 mg/dayStart: 4-8 mg/day

1.1. Comparable Comparable effectiveness effectiveness with ACEIswith ACEIs

2.2. Follow-up of Follow-up of renal functionrenal function

3.3. possibility of possibility of hyperkalemiahyperkalemia

3434

3-β-Adrenergic Blocking 3-β-Adrenergic Blocking AgentsAgents

• Cardiac adrenergic drive initially supports Cardiac adrenergic drive initially supports the performance of the failing heart, but the performance of the failing heart, but long-term activation of the sympathetic long-term activation of the sympathetic nervous system exerts deleterious effects nervous system exerts deleterious effects that can be antagonized by the use of β-that can be antagonized by the use of β-blockers.blockers.

• Extended release metoprolol (Toprol XL) Extended release metoprolol (Toprol XL) and carvedilol are FDA approved for use in and carvedilol are FDA approved for use in HF. HF.

3535

3-β-Adrenergic Blocking 3-β-Adrenergic Blocking AgentsAgents

• While some patients can initially have a temporary While some patients can initially have a temporary worsening of symptoms, worsening of symptoms, – continued use results in improved quality of life, continued use results in improved quality of life, – fewer hospitalizations, fewer hospitalizations, – and most importantly, longer survival. and most importantly, longer survival.

• The AHA/ACC guidelines state that β-blockers should The AHA/ACC guidelines state that β-blockers should be prescribed to all patients with stable HF due to be prescribed to all patients with stable HF due to left systolic dysfunction and with mild to moderate left systolic dysfunction and with mild to moderate symptoms unless they have a contraindicationsymptoms unless they have a contraindication to to their use or have been shown to be unable to their use or have been shown to be unable to tolerate treatment with these drugs. tolerate treatment with these drugs. Generally they Generally they are used in combination with diuretics and an ACE are used in combination with diuretics and an ACE inhibitor (with or without digoxin).inhibitor (with or without digoxin).

3636

Cumulative mortality in patients with heart failure treated using placebo or metoprolol

3737

3-β-Adrenergic Blocking 3-β-Adrenergic Blocking AgentsAgents

• β-Blockers are also an important β-Blockers are also an important part of the treatment part of the treatment of patients of patients with HF symptoms due to diastolic with HF symptoms due to diastolic failurefailure,.,. For these patients a For these patients a nonselective β-blocker like nonselective β-blocker like propranolol can be a therapy of propranolol can be a therapy of choice in selected patients by:choice in selected patients by:– slowing the HR slowing the HR

– allowing improved ventricular filling. allowing improved ventricular filling.

3838

4-Digitalis Glycosides 4-Digitalis Glycosides (Digoxin)(Digoxin)

• Mechanism of action: Digitalis Mechanism of action: Digitalis glycosides glycosides binds to and inhibits binds to and inhibits sodium-potassium (Na+-K+) sodium-potassium (Na+-K+) adenosine triphosphatase (ATPaseadenosine triphosphatase (ATPase) in ) in cardiac cells, decreasing outward cardiac cells, decreasing outward transport of sodium and increasing transport of sodium and increasing intracellular concentrations of intracellular concentrations of calcium within the cells. calcium within the cells. Calcium Calcium binding to the sarcoplasmic reticulum binding to the sarcoplasmic reticulum causes an increase in the contractile causes an increase in the contractile state of the heart.state of the heart.

3939

Mechanism of action of cardiac glycosides, or digitalis. ATPase = adenosine triphosphatase

4040

4- Digitalis Glycosides 4- Digitalis Glycosides (Digoxin)(Digoxin)

• Recent evidence suggests that even Recent evidence suggests that even at serum concentrations at serum concentrations belowbelow those those associated with positive inotropismassociated with positive inotropism

• , digoxin has beneficial autonomic , digoxin has beneficial autonomic effects by reducing sympathetic tone effects by reducing sympathetic tone and stimulating parasympathetic and stimulating parasympathetic (vagal) responses(vagal) responses. .

4141

4-Digitalis Glycosides 4-Digitalis Glycosides (Digoxin)(Digoxin)

• In addition to effects on contractility, digoxin In addition to effects on contractility, digoxin decreases the conduction velocity and decreases the conduction velocity and prolongs the refractory period of the prolongs the refractory period of the atrioventricular (AV) node. atrioventricular (AV) node.

• This AV node–blocking effect prolongs the PR This AV node–blocking effect prolongs the PR interval and is the basis for interval and is the basis for use of digoxin in use of digoxin in slowing the ventricular response rate in slowing the ventricular response rate in patients with patients with atrial fibrillation and other atrial fibrillation and other supraventricular arrhythmiassupraventricular arrhythmias..

•

4242

4- Digitalis Glycosides 4- Digitalis Glycosides (Digoxin)(Digoxin)

• In the past few years, In the past few years, several several studies have confirmed that studies have confirmed that

digoxindigoxin should be considered should be considered to improve the symptoms to improve the symptoms

and clinical status of patients and clinical status of patients with HF, with HF, in combination with in combination with

diuretics, an ACE inhibitor, diuretics, an ACE inhibitor, and a β-blocker.and a β-blocker.

4343

4- Digitalis Glycosides 4- Digitalis Glycosides (Digoxin)(Digoxin)

• Digoxin can be used Digoxin can be used earlyearly to reduce to reduce symptoms in patients who have symptoms in patients who have started, started, but not yet responded to, but not yet responded to, treatment with an ACE inhibitor and a treatment with an ACE inhibitor and a β-blocker. β-blocker.

• Alternatively, treatment with digoxin Alternatively, treatment with digoxin can be delayedcan be delayed until the patient's until the patient's response to an ACE inhibitor and β-response to an ACE inhibitor and β-blocker has been defined and used blocker has been defined and used only for those patients who remain only for those patients who remain symptomatic despite the other drugs. symptomatic despite the other drugs.

• Monotherapy with digoxin or in combination with only Monotherapy with digoxin or in combination with only a diuretic is no longer recommendeda diuretic is no longer recommended. .

4444

4- Digitalis Glycosides 4- Digitalis Glycosides (Digoxin)(Digoxin)

• Digoxin can also be considered in patients Digoxin can also be considered in patients with HF who also have chronic atrial with HF who also have chronic atrial fibrillation,fibrillation, although β-blockers may be although β-blockers may be more effective than digoxin in controlling more effective than digoxin in controlling the ventricular response, especially during the ventricular response, especially during exercise. exercise.

• the digitalis glycosides are not useful in the digitalis glycosides are not useful in diastolic HFdiastolic HF and, in fact, may worsen this and, in fact, may worsen this form of left ventricular dysfunction. form of left ventricular dysfunction.

4545

4- Digitalis Glycosides 4- Digitalis Glycosides (Digoxin)(Digoxin)

• Most clinicians prefer to use the brand Most clinicians prefer to use the brand name product (Lanoxin) with a high name product (Lanoxin) with a high bioavailability from other digoxin bioavailability from other digoxin preparations.preparations.

• Digoxin's rapid onset of action (30 to 60 minutes) Digoxin's rapid onset of action (30 to 60 minutes) corresponds with peak plasma levels. Maximum effects corresponds with peak plasma levels. Maximum effects from a single dose are observed 5 to 6 hours after drug from a single dose are observed 5 to 6 hours after drug administration, a time at which drug distribution in the administration, a time at which drug distribution in the body is complete. Digoxin has a steady-state volume of body is complete. Digoxin has a steady-state volume of distribution averaging 6.7 L/kg of lean body weight distribution averaging 6.7 L/kg of lean body weight (range, 4 to 9 L/kg). (range, 4 to 9 L/kg). New evidence indicates New evidence indicates therapeutic benefit and greater safetytherapeutic benefit and greater safety by by targeting serum concentrations in the range targeting serum concentrations in the range of 0.5 to 1.2 ng/mL of 0.5 to 1.2 ng/mL

4646

4-Digitalis Glycosides 4-Digitalis Glycosides (Digoxin)(Digoxin)

• Digoxin has a half-life (t½) of 1.6 to 2 days Digoxin has a half-life (t½) of 1.6 to 2 days (36 to 40 hours) and is characterized by (36 to 40 hours) and is characterized by first-order pharmacokinetics. first-order pharmacokinetics.

• With renal impairment, the half-life of With renal impairment, the half-life of digoxin is prolonged, reaching 4.4 days or digoxin is prolonged, reaching 4.4 days or more in total anuria. more in total anuria.

At a creatinine clearance of 100 mL/min, the percent eliminated At a creatinine clearance of 100 mL/min, the percent eliminated per day is 35%, whereas at a creatinine clearance of 0 (i.e., per day is 35%, whereas at a creatinine clearance of 0 (i.e., anuria), the percent eliminated per day is 14%, anuria), the percent eliminated per day is 14%,

4747

5-Other Vasodilating Drugs: 5-Other Vasodilating Drugs: Hydralazine and NitratesHydralazine and Nitrates

• Although ACE inhibitors have become the Although ACE inhibitors have become the vasodilator drug of choice, the first vasodilator drug of choice, the first vasodilators to be used in patients with HF vasodilators to be used in patients with HF were:were:– hydralazine and nitrates. hydralazine and nitrates. – Hydralazine (Apresoline)Hydralazine (Apresoline) is a potent arterial dilating is a potent arterial dilating

agent that provides symptomatic relief of HF by agent that provides symptomatic relief of HF by decreasing arterial impedance (afterload) to left decreasing arterial impedance (afterload) to left ventricular outflow. ventricular outflow.

– Nitrates (e.g., nitroglycerin [NTG], isosorbide Nitrates (e.g., nitroglycerin [NTG], isosorbide dinitrate, and isosorbide mononitrate)dinitrate, and isosorbide mononitrate) have venous have venous dilating properties that decrease left ventricular dilating properties that decrease left ventricular congestion (preload). congestion (preload).

– Used in combinationUsed in combination, these two agents have , these two agents have additive benefits in alleviating the symptoms of HF additive benefits in alleviating the symptoms of HF and increasing exercise tolerance. and increasing exercise tolerance.

4848

7-Other Inotropic Agents7-Other Inotropic Agents

• Previous doubt about the clinical Previous doubt about the clinical effectiveness of digitalis derivatives and effectiveness of digitalis derivatives and concern over their potential for toxicity concern over their potential for toxicity prompted a search for alternative positive prompted a search for alternative positive inotropic drugs. inotropic drugs. – IV Dopamine and dobutamineIV Dopamine and dobutamine, both of which are , both of which are

sympathomimetics, are commonly used in acute cardiac sympathomimetics, are commonly used in acute cardiac emergencies, but their use is limited by the need for emergencies, but their use is limited by the need for IVIV administration in cardiogenic shock.administration in cardiogenic shock.

– DopamineDopamine is more effective as an arterial is more effective as an arterial dilator, dilator, especially in the kidneyespecially in the kidney, whereas , whereas dobutaminedobutamine has more has more potent inotropic potent inotropic properties properties

–

4949

Other Inotropic AgentsOther Inotropic Agents

• Amrinone and milrinoneAmrinone and milrinone, nonsympathomimetic , nonsympathomimetic inotropes (phosphodiesterase inhibitorsinotropes (phosphodiesterase inhibitors), are associated ), are associated with an unacceptably with an unacceptably high incidence of side effects high incidence of side effects (thrombocytopenia and increased death rates) when given (thrombocytopenia and increased death rates) when given orally, orally, but are available in parenteral form for short-term but are available in parenteral form for short-term use in severe HFuse in severe HF via enzyme inhibition results in increased via enzyme inhibition results in increased cyclic AMP levels in myocardial cells and cyclic AMP levels in myocardial cells and thus enhances thus enhances contractilitycontractility. Their activity is not blocked by propranolol.. Their activity is not blocked by propranolol.

• • Because they are phosphodiesterase inhibitors, they also Because they are phosphodiesterase inhibitors, they also

act as act as vasodilatorsvasodilators. .

• All inotropes are relatively All inotropes are relatively contraindicated in diastolic HF.contraindicated in diastolic HF.

5050

Calcium Channel Calcium Channel BlockersBlockers

• Amlodipine (Norvasc), felodipine Amlodipine (Norvasc), felodipine (Plendil), isradipine (DynaCirc), nifedipine (Plendil), isradipine (DynaCirc), nifedipine (Adalat, Procardia), and nicardipine (Adalat, Procardia), and nicardipine (Cardene) are examples of calcium (Cardene) are examples of calcium antagonists antagonists with arterial vasodilating and with arterial vasodilating and antispasmodic properties. antispasmodic properties.

• They offer the theoretic advantage of They offer the theoretic advantage of being afterload-reducing agents in HFbeing afterload-reducing agents in HF, , but their applicability in systolic but their applicability in systolic dysfunction is diminished by negative dysfunction is diminished by negative inotropic effects. inotropic effects.

5151

Calcium Channel Calcium Channel BlockersBlockers

• Among these drugs, only amlodipine and Among these drugs, only amlodipine and felodipine have been documented to be felodipine have been documented to be safe in HF (i.e., do not make HF worse)safe in HF (i.e., do not make HF worse)

• Until more data are available, calcium Until more data are available, calcium channel blockers other than amlodipine channel blockers other than amlodipine and felodipine are contraindicated in and felodipine are contraindicated in patients with systolic dysfunction. patients with systolic dysfunction.

• On the other hand, On the other hand, the negative inotropic the negative inotropic effects of some calcium antagonists, effects of some calcium antagonists, especially that of verapamil (Calan, especially that of verapamil (Calan, Isoptin, Verelan), is an indication for use Isoptin, Verelan), is an indication for use in diastolic HF. in diastolic HF.

5252

HF caseHF case• A.J., a 58-year-old man, is admitted with a chief A.J., a 58-year-old man, is admitted with a chief

complaint of increasing complaint of increasing shortness of breath shortness of breath (SOB)(SOB) and an 8 kg weight gain. Two years and an 8 kg weight gain. Two years before admission, he noted the onset of before admission, he noted the onset of dyspnea on exertion (DOE) after 1 flight of dyspnea on exertion (DOE) after 1 flight of stairs, stairs, orthopnea, and ankle edemaorthopnea, and ankle edema. Since that . Since that time, his symptoms have progressed despite time, his symptoms have progressed despite intermittent hydrochlorothiazide (HCTZ) intermittent hydrochlorothiazide (HCTZ) therapy. Three weeks before admission, he therapy. Three weeks before admission, he noted the onset of episodic bouts of noted the onset of episodic bouts of paroxysmal paroxysmal nocturnal dyspnea (PND).nocturnal dyspnea (PND). Since then he only Since then he only has been able to sleep in a sitting position. A.J. has been able to sleep in a sitting position. A.J. notes a notes a productive cough, nocturia (2 to 3 productive cough, nocturia (2 to 3 times/night), and mild, dependent edematimes/night), and mild, dependent edema. .

5353

HF caseHF case• A.J.'s other medical problems A.J.'s other medical problems

include a long history of include a long history of heartburnheartburn; ; a 10-year history of a 10-year history of osteoarthritis, osteoarthritis, managed with various nonsteroidal managed with various nonsteroidal anti-inflammatory drugs (NSAIDs);anti-inflammatory drugs (NSAIDs); chronic headaches; and chronic headaches; and hypertension, which has been poorly hypertension, which has been poorly controlled with HCTZ and controlled with HCTZ and propranolol (Inderal).propranolol (Inderal). A strong A strong family history of diabetes mellitusfamily history of diabetes mellitus is is also present.also present.

5454

HF caseHF case• Physical examination reveals Physical examination reveals dyspenia, cyanosis, dyspenia, cyanosis,

and tachycardia.and tachycardia. A.J. has the following vital signs: A.J. has the following vital signs: BP, 160/100 mm Hg; pulse, 100 beats/min; and BP, 160/100 mm Hg; pulse, 100 beats/min; and respiratory rate, 28 breaths/minrespiratory rate, 28 breaths/min. He is 166 cm tall . He is 166 cm tall and weighs 78 kg. and weighs 78 kg. His neck veins are distended. On His neck veins are distended. On cardiac examination an S3 gallop is heardcardiac examination an S3 gallop is heard; point of ; point of maximal impulse (PMI) is at the sixth intercostal maximal impulse (PMI) is at the sixth intercostal space (ICS), 12 cm from the midsternal line (MSL). space (ICS), 12 cm from the midsternal line (MSL). His liver is enlarged and tender to palpation, and a His liver is enlarged and tender to palpation, and a positive hepatojugular reflux (HJR) is observedpositive hepatojugular reflux (HJR) is observed. He is . He is noted to have 3+ pitting edema of the extremities noted to have 3+ pitting edema of the extremities and sacral edema. Chest examination reveals and sacral edema. Chest examination reveals inspiratory inspiratory rales and rhonchi bilaterallyrales and rhonchi bilaterally..

5555

HF caseHF case• The medication history reveals the The medication history reveals the

following current medications: following current medications: – HCTZ (Hydrodiuril) 25 mg QD [one a day]; HCTZ (Hydrodiuril) 25 mg QD [one a day]; – propranolol (Inderal) 80 mg TID [3 times a day]; propranolol (Inderal) 80 mg TID [3 times a day]; – ibuprofen (Motrin) 600 mg QID [ 4 times a day]; ibuprofen (Motrin) 600 mg QID [ 4 times a day]; – ranitidine (Zantac) 150 mg HS [ before sleep at ranitidine (Zantac) 150 mg HS [ before sleep at

bed time]; and bed time]; and – Mylanta Double Strength 15 mL as needed up to Mylanta Double Strength 15 mL as needed up to

QID [used for an antacid and antiflatulent QID [used for an antacid and antiflatulent preparation ]. preparation ].

– He has no allergies and no dietary restrictions.He has no allergies and no dietary restrictions.

5656

HF caseHF case• Admitting laboratory values include the following:Admitting laboratory values include the following:

– hematocrit (Hct), 41.1% (normal, 40% to 45%); hematocrit (Hct), 41.1% (normal, 40% to 45%); – white blood cell (WBC) count, 5,300/mm3 (normal, 5,000 to white blood cell (WBC) count, 5,300/mm3 (normal, 5,000 to

10,000/mm3); 10,000/mm3); – Na, 132 mEq/L (normal, 136 to 144 mEq/L); Na, 132 mEq/L (normal, 136 to 144 mEq/L); – potassium (K), 3.2 mEq/L (normal, 3.5 to 5.3 mEq/L); potassium (K), 3.2 mEq/L (normal, 3.5 to 5.3 mEq/L); – chloride (Cl), 90 mEq/L (normal, 96 to 106 mEq/L); chloride (Cl), 90 mEq/L (normal, 96 to 106 mEq/L); – bicarbonate, 30 mEq/L (normal, 22 to 28 mEq/L); bicarbonate, 30 mEq/L (normal, 22 to 28 mEq/L); – magnesium (Mg), 1.5 mEq/L (normal, 1.7 to 2.7 mEq/L); magnesium (Mg), 1.5 mEq/L (normal, 1.7 to 2.7 mEq/L); – fasting blood sugar (FBS), 120 mg/dL (normal, 65 to 110 mg/dL); fasting blood sugar (FBS), 120 mg/dL (normal, 65 to 110 mg/dL); – uric acid, 8 mg/dL (normal, 3.5 to 7 mg/dL); uric acid, 8 mg/dL (normal, 3.5 to 7 mg/dL); – blood urea nitrogen (BUN), 40 mg/dL (normal, 10 to 20 mg/dL);blood urea nitrogen (BUN), 40 mg/dL (normal, 10 to 20 mg/dL);– serum creatinine (SrCr), 0.8 mg/dL (normal, 0.5 to 1.2 mg/dL); serum creatinine (SrCr), 0.8 mg/dL (normal, 0.5 to 1.2 mg/dL); – alkaline phosphatase, 120 U (normal, 40 to 80 U); and alkaline phosphatase, 120 U (normal, 40 to 80 U); and – aspartate aminotransferase (AST), 100 U (normal, 0 to 35 U). aspartate aminotransferase (AST), 100 U (normal, 0 to 35 U). – The chest radiograph shows cardiomegaly.The chest radiograph shows cardiomegaly.

5757

HF CASEHF CASE

•What What signs, symptoms, signs, symptoms, and laboratory and laboratory abnormalitiesabnormalities of HF does of HF does A.J. exhibit? A.J. exhibit?

5858

What are the therapeutic What are the therapeutic objectives in treating A.J.?objectives in treating A.J.?

• Cure is not a feasible therapeutic objective in Cure is not a feasible therapeutic objective in patients with any form of HF. patients with any form of HF.

• The immediate objective for A.J. is to:The immediate objective for A.J. is to:– provide provide symptomatic reliefsymptomatic relief as assessed by a as assessed by a

reduction in his complaints of SOB and PND, reduction in his complaints of SOB and PND, – an an improved quality of sleepimproved quality of sleep, , – and and increased exercise tolerance.increased exercise tolerance.

– Parameters used to measure success in Parameters used to measure success in meeting this objective include :meeting this objective include :• reduced peripheral and sacral reduced peripheral and sacral edemaedema, , • weight lossweight loss, , • slowing of the HR to <90 beats/min, slowing of the HR to <90 beats/min, • normalization of BPnormalization of BP

5959

Bed rest and a 3-g sodium diet were Bed rest and a 3-g sodium diet were ordered. Why should A.J. continue his ordered. Why should A.J. continue his diuretic therapy?diuretic therapy?

• Excessive volume increases the Excessive volume increases the workload of a compromised heart, workload of a compromised heart, and diuretics are an integral part of and diuretics are an integral part of therapy. therapy.

• This is especially true This is especially true if volume if volume overload is symptomatic (e.g., overload is symptomatic (e.g., pulmonary congestion)pulmonary congestion) as in A.J. as in A.J. Diuretics produce symptomatic Diuretics produce symptomatic improvement more rapidly than any improvement more rapidly than any other drug for HF.other drug for HF.

6060

Furosemide and Other Loop DiureticsFurosemide and Other Loop DiureticsIt is decided to begin a combination regimen of It is decided to begin a combination regimen of furosemide and an ACE inhibitor in A.J. What route, furosemide and an ACE inhibitor in A.J. What route, dose, and dosing schedule of furosemide should be dose, and dosing schedule of furosemide should be used?used?

• Furosemide is the most commonly used loop Furosemide is the most commonly used loop diuretic for HF because of diuretic for HF because of greater clinical greater clinical experience and low cost. experience and low cost.

• Typically, Typically, a patient's treatment is initiated a patient's treatment is initiated with with 20 to 40 mg of oral or IV furosemide20 to 40 mg of oral or IV furosemide given as a single dose and monitored for given as a single dose and monitored for responsivenessresponsiveness. If the desired diuresis is not . If the desired diuresis is not obtained, obtained, the dose can be increased in 40- the dose can be increased in 40- to 80-mg increments over the next several to 80-mg increments over the next several days to a total daily dose of 160 mg/daydays to a total daily dose of 160 mg/day, , usually divided into two doses.usually divided into two doses.

6161

Examine A.J.'s laboratory values . Can any of Examine A.J.'s laboratory values . Can any of the abnormal values be attributed to the the abnormal values be attributed to the HCTZ A.J. was taking? What is the significance HCTZ A.J. was taking? What is the significance of these abnormalities?of these abnormalities?

•Azotemia:Azotemia: – A.J. has an elevated BUN (40 mg/dL) but a A.J. has an elevated BUN (40 mg/dL) but a

normal serum creatinine (0.8 mg/dL). normal serum creatinine (0.8 mg/dL). Normally, a BUN-to-creatinine ratio of 10 Normally, a BUN-to-creatinine ratio of 10 to 20:1 is seen. Progressive renal failure to 20:1 is seen. Progressive renal failure is characterized by an elevation of both is characterized by an elevation of both BUN and creatinine., BUN and creatinine., A disproportionately A disproportionately elevated BUN relative to creatinine is elevated BUN relative to creatinine is indicative of prerenal azotemia due to indicative of prerenal azotemia due to poor renal perfusion occuring in HFpoor renal perfusion occuring in HF

6262

Examine A.J.'s laboratory values . Can any Examine A.J.'s laboratory values . Can any of the abnormal values be attributed to of the abnormal values be attributed to the HCTZ A.J. was taking? What is the the HCTZ A.J. was taking? What is the significance of these abnormalities?significance of these abnormalities?

• HyponatremiaHyponatremia (low serum sodium (low serum sodium concentration) reflects the dilutional concentration) reflects the dilutional effect of extra free water in the effect of extra free water in the plasma on sodium concentration. plasma on sodium concentration.

6363

Examine A.J.'s laboratory values . Can any Examine A.J.'s laboratory values . Can any of the abnormal values be attributed to of the abnormal values be attributed to the HCTZ A.J. was taking? What is the the HCTZ A.J. was taking? What is the significance of these abnormalities?significance of these abnormalities?

• Hypochloremic AlkalosisHypochloremic Alkalosis• A.J.'s low serum chloride of 90 mEq/L concurrent with A.J.'s low serum chloride of 90 mEq/L concurrent with

an elevated serum bicarbonate (total CO2) of 30 an elevated serum bicarbonate (total CO2) of 30 mEq/L signifies hypochloremia with a metabolic mEq/L signifies hypochloremia with a metabolic alkalosis. alkalosis.

• HypomagnesemiaHypomagnesemia• A.J.'s serum magnesium level is 1.5 mEq/L. This could A.J.'s serum magnesium level is 1.5 mEq/L. This could

either be a result of magnesium diuresis induced by either be a result of magnesium diuresis induced by his diuretic therapy or malabsorption secondary to his diuretic therapy or malabsorption secondary to binding of magnesium ions in the intestines by his binding of magnesium ions in the intestines by his antacids. antacids.

6464

Examine A.J.'s laboratory values . Can any Examine A.J.'s laboratory values . Can any of the abnormal values be attributed to of the abnormal values be attributed to the HCTZ A.J. was taking? What is the the HCTZ A.J. was taking? What is the significance of these abnormalities?significance of these abnormalities?

• HyperglycemiaHyperglycemia• A.J. has a fasting blood sugar of 120 mg/dL, which is A.J. has a fasting blood sugar of 120 mg/dL, which is

only slightly elevated and, It also could represent a only slightly elevated and, It also could represent a stress-related diabetic reaction. stress-related diabetic reaction.

• However, hyperglycemia and glucose intolerance However, hyperglycemia and glucose intolerance have been reported to occur during treatment with have been reported to occur during treatment with thiazide diuretics thiazide diuretics

• Because A.J. has a family history of diabetes, he Because A.J. has a family history of diabetes, he could be at increased risk. At this time A.J.'s blood could be at increased risk. At this time A.J.'s blood sugar needs further monitoring, but no specific sugar needs further monitoring, but no specific therapy is required.therapy is required.

6565

Examine A.J.'s laboratory values . Can any Examine A.J.'s laboratory values . Can any of the abnormal values be attributed to of the abnormal values be attributed to the HCTZ A.J. was taking? What is the the HCTZ A.J. was taking? What is the significance of these abnormalities?significance of these abnormalities?

• HyperuricemiaHyperuricemia– Increases of 1 to 2 mg/dL in uric acid levels are Increases of 1 to 2 mg/dL in uric acid levels are

common during thiazide administration.common during thiazide administration. – Most patients who develop elevated uric acid Most patients who develop elevated uric acid

levels during treatment with diuretic agents levels during treatment with diuretic agents remain asymptomatic and need not be treated. remain asymptomatic and need not be treated.

– Only those with uric acid levels persistently >10 Only those with uric acid levels persistently >10 mg/dL, as well as those with a history of gout or a mg/dL, as well as those with a history of gout or a familial predisposition, should be considered for familial predisposition, should be considered for treatment with urate-lowering agentstreatment with urate-lowering agents

6666

Examine A.J.'s laboratory values . Can any Examine A.J.'s laboratory values . Can any of the abnormal values be attributed to of the abnormal values be attributed to the HCTZ A.J. was taking? What is the the HCTZ A.J. was taking? What is the significance of these abnormalities?significance of these abnormalities?

• Liver FunctionLiver Function– A.J.'s elevated alkaline phosphatase A.J.'s elevated alkaline phosphatase

and AST probably are not indicative and AST probably are not indicative of any drug-related toxicity. of any drug-related toxicity. Although cholestatic jaundice has Although cholestatic jaundice has been reported with thiazide been reported with thiazide diuretics, the elevated liver function diuretics, the elevated liver function tests most likely are the result of tests most likely are the result of hepatic congestion from right-sided hepatic congestion from right-sided HF.HF.

6767

The physician gave A.J. one 1-g dose of magnesium sulfate The physician gave A.J. one 1-g dose of magnesium sulfate and three 20-mEq doses of potassium chloride IV. This and three 20-mEq doses of potassium chloride IV. This raised his serum magnesium to 2.0 and his potassium to 3.9 raised his serum magnesium to 2.0 and his potassium to 3.9 mEq/L. Should he receive prophylactic magnesium or mEq/L. Should he receive prophylactic magnesium or potassium supplementation? What is the best drug and potassium supplementation? What is the best drug and appropriate dose?appropriate dose?

• A fall in serum potassium concentration can be seen A fall in serum potassium concentration can be seen within hours of the first dose of a diuretic, and the within hours of the first dose of a diuretic, and the maximum fall usually is reached by the end of the maximum fall usually is reached by the end of the first week of treatment. When diuretics are stopped, first week of treatment. When diuretics are stopped, it can take several weeks for serum potassium to it can take several weeks for serum potassium to return to normal. return to normal.

• When dose of diuretic is to be increased and When dose of diuretic is to be increased and digitalis therapy is considered, potassium digitalis therapy is considered, potassium supplementation is warranted.supplementation is warranted.

6868

The physician gave A.J. one 1-g dose of magnesium The physician gave A.J. one 1-g dose of magnesium sulfate and three 20-mEq doses of potassium chloride sulfate and three 20-mEq doses of potassium chloride IV. This raised his serum magnesium to 2.0 and his IV. This raised his serum magnesium to 2.0 and his potassium to 3.9 mEq/L. Should he receive potassium to 3.9 mEq/L. Should he receive prophylactic magnesium or potassium prophylactic magnesium or potassium supplementation? What is the best drug and supplementation? What is the best drug and appropriate dose?appropriate dose?

• If potassium replacement is prescribed, only If potassium replacement is prescribed, only potassium chloridepotassium chloride (KCl) should be used (KCl) should be used because all potassium-wasting diuretics can because all potassium-wasting diuretics can cause hypochloremic alkalosis ; if the cause hypochloremic alkalosis ; if the chloride ion is not replaced, alkalosis and chloride ion is not replaced, alkalosis and hypokalemia will persist, even if large hypokalemia will persist, even if large quantities of potassium are given.quantities of potassium are given.

• Slow K and Kaon-Cl are usedSlow K and Kaon-Cl are used

6969

• It is difficult to predict the dose It is difficult to predict the dose of KCl that will be required to of KCl that will be required to maintain proper potassium maintain proper potassium balance. Many patients do well balance. Many patients do well with 20 mEq/day with 20 mEq/day

7070

• Would use of a potassium-sparing Would use of a potassium-sparing diuretic such as triamterene offer any diuretic such as triamterene offer any advantage over a potassium supplement advantage over a potassium supplement to prevent or treat hypokalemia? to prevent or treat hypokalemia?

• The potassium-sparing diuretics The potassium-sparing diuretics (amiloride and triamterene) may be more (amiloride and triamterene) may be more effective in preventing or correcting the effective in preventing or correcting the fall in serum potassium than potassium fall in serum potassium than potassium supplements. supplements.

7171

After a single 40 mg IV dose of furosemide, A.J. is After a single 40 mg IV dose of furosemide, A.J. is begun on 40 mg of furosemide each morning and KCl begun on 40 mg of furosemide each morning and KCl tablets 20 mEq BID. How should his therapy be tablets 20 mEq BID. How should his therapy be monitored?monitored?

• A.J. needs to be monitored for both an A.J. needs to be monitored for both an improvement in his HF and for side improvement in his HF and for side effects.effects.– Subjectively,Subjectively, the clinician should monitor for the clinician should monitor for

decreased pulmonary distress and an decreased pulmonary distress and an increased exercise tolerance, demonstrating increased exercise tolerance, demonstrating control of HF. control of HF.

– Objective monitoringObjective monitoring parameters for disease parameters for disease control include weight loss (ideal, 0.5 to 1 control include weight loss (ideal, 0.5 to 1 kg/day until ideal weight is achieved), a kg/day until ideal weight is achieved), a decrease in edema, flattening of neck veins, decrease in edema, flattening of neck veins, and disappearance of the S3 gallop and and disappearance of the S3 gallop and rales. Because A.J. has hypertension, his BP rales. Because A.J. has hypertension, his BP also requires monitoring with a goal to also requires monitoring with a goal to reduce to <120/80 mm Hg.reduce to <120/80 mm Hg.

7272

CaseCase• You are consulted on another patient whose You are consulted on another patient whose

initial history was similar to A.J.'s. After initial history was similar to A.J.'s. After nearly 2 years of relatively good HF control nearly 2 years of relatively good HF control on a regimen of 40 mg furosemide, 20 mg QD on a regimen of 40 mg furosemide, 20 mg QD lisinopril, 200 mg QD metoprolol extended lisinopril, 200 mg QD metoprolol extended release, and 0.125 mg QD digoxin, urinary release, and 0.125 mg QD digoxin, urinary output diminished about 1 week ago and output diminished about 1 week ago and edema increased significantly. Nonadherence edema increased significantly. Nonadherence to drug therapy and salt restriction was ruled to drug therapy and salt restriction was ruled out. The dose of furosemide was increased to out. The dose of furosemide was increased to 80 mg 2 days ago without much effect. 80 mg 2 days ago without much effect. Should the dose of furosemide be increased Should the dose of furosemide be increased further? Could another diuretic be added to further? Could another diuretic be added to the therapy?the therapy?

7373

AnswerAnswer• many patients develop a blunted diuretic many patients develop a blunted diuretic

response with continued therapy for response with continued therapy for unknown reasons or due to failure of its unknown reasons or due to failure of its transport to their site of action in case of transport to their site of action in case of HD. HD.

• Most clinicians Most clinicians choose a combination of choose a combination of metolazone plus furosemide or metolazone plus furosemide or bumetanidebumetanide based on demonstrated based on demonstrated value in the literature and clinical value in the literature and clinical experience. A small dose of metolazone experience. A small dose of metolazone (5 mg) is first added to the furosemide (5 mg) is first added to the furosemide therapy, doubling the dose of metolazone therapy, doubling the dose of metolazone every 24 hours until the desired diuretic every 24 hours until the desired diuretic response is achieved. response is achieved.

7474

• Vasodilators are first-line Vasodilators are first-line therapy, with digoxin being therapy, with digoxin being added in patients with either:added in patients with either:– supraventricular arrhythmiassupraventricular arrhythmias, , – failure to achieve symptomatic failure to achieve symptomatic

relief with vasodilators alone, relief with vasodilators alone, – or intolerable side effects from or intolerable side effects from

vasodilators.vasodilators.

Digoxin and ACEIs in HFDigoxin and ACEIs in HF

7575

Critics over digitalis useCritics over digitalis use

– However, critics raised concerns However, critics raised concerns that that symptom relief was less in symptom relief was less in patients with normal sinuspatients with normal sinus rhythm rhythm than in those with supraventricular than in those with supraventricular arrhythmias. The most vocal critics arrhythmias. The most vocal critics claimed that claimed that the risk of digitalis the risk of digitalis toxicity did not warrant using thistoxicity did not warrant using this class of drugs in patients with class of drugs in patients with normal sinus rhythm.normal sinus rhythm.

7676

• In the case of A.J., In the case of A.J., his physician his physician should be discouraged from starting should be discouraged from starting digoxin at this time. Instead, he digoxin at this time. Instead, he should be counseled to continue with should be counseled to continue with the already prescribed ACE inhibitor the already prescribed ACE inhibitor in addition to continuing the in addition to continuing the furosemide.furosemide.

• A strong argument can be made for A strong argument can be made for starting a β-blocker such as starting a β-blocker such as metoprolol or carvedilol now or metoprolol or carvedilol now or within the next few days. within the next few days.

• Based on your advice, A.J.'s doctor Based on your advice, A.J.'s doctor has decided to withhold digoxin and has decided to withhold digoxin and assess the response to just one drug assess the response to just one drug (i.e., the ACE inhibitor) for now.(i.e., the ACE inhibitor) for now.

7777

What ACEI drug is preferred?What ACEI drug is preferred?

• There does not seem to be a There does not seem to be a significant difference in side significant difference in side effects between agents. effects between agents. Based on these factors, no Based on these factors, no one drug is preferred over one drug is preferred over another.another.

7878

ACEIs versus ARBsACEIs versus ARBs

•when A.J. is not tolerating when A.J. is not tolerating enalapril, enalapril, discontinuation discontinuation of his enalapril and of his enalapril and initiation of valsartan is initiation of valsartan is justified. justified.

7979

Effect of ACEIs and ARBs Effect of ACEIs and ARBs on renal functionon renal function

• In the case of low-pressure or low-flow states, In the case of low-pressure or low-flow states, the renin-angiotensin-aldosterone system is the renin-angiotensin-aldosterone system is activated to maintain intraglomerular activated to maintain intraglomerular pressure. pressure. When patients with low-pressure When patients with low-pressure states are given ACE inhibitors or ARBs, the states are given ACE inhibitors or ARBs, the protective mechanism of efferent protective mechanism of efferent vasoconstriction is inhibited and renal vasoconstriction is inhibited and renal function can significantly and rapidly worsenfunction can significantly and rapidly worsen..

• Conversely, in patients Conversely, in patients with hypertensive with hypertensive renal diseaserenal disease, glomerular function actually , glomerular function actually can improve because the ACE inhibitors lower can improve because the ACE inhibitors lower afferent pressure and help protect the kidney. afferent pressure and help protect the kidney.

8080

Interaction between aspirin Interaction between aspirin and ACEIsand ACEIs

• Several studies suggest that:Several studies suggest that:– aspirin may attenuate the beneficial affects aspirin may attenuate the beneficial affects

of ACE inhibitors when given together in of ACE inhibitors when given together in patients with HF and other cardiovascular patients with HF and other cardiovascular disorders.disorders.

– The proposed mechanism is inhibition of The proposed mechanism is inhibition of prostaglandin formation by aspirin, thus prostaglandin formation by aspirin, thus counteracting the clinical effects of ACE counteracting the clinical effects of ACE inhibitors that rely in part on prostaglandins inhibitors that rely in part on prostaglandins to elicit their positive hemodynamic effects.to elicit their positive hemodynamic effects.

– The significance of this interaction is still The significance of this interaction is still being debated. being debated.

8181

-blockers in HF-blockers in HF• Returning to the case of A.J., we are now Returning to the case of A.J., we are now

6 weeks into his treatment, his regimen 6 weeks into his treatment, his regimen was changed to valsartan 40 mg BID in was changed to valsartan 40 mg BID in place of enalapril. After starting place of enalapril. After starting valsartan, his cough disappeared over valsartan, his cough disappeared over the next 7 to 10 days. During that same the next 7 to 10 days. During that same time, he noted more fatigue and time, he noted more fatigue and increased nighttime dyspnea. These increased nighttime dyspnea. These symptoms improved after his dose of symptoms improved after his dose of valsartan was increased incrementally to valsartan was increased incrementally to 80 mg BID. At the same time, his 80 mg BID. At the same time, his physician wants to reconsider the need physician wants to reconsider the need to start a β-blocker. to start a β-blocker. Is this a good time Is this a good time to start a β-blocker?to start a β-blocker?

8282

• the use of β-blockers is associated with a the use of β-blockers is associated with a consistent 30% reduction in mortality and a 40% consistent 30% reduction in mortality and a 40% reduction in hospitalizations in patients with HF.reduction in hospitalizations in patients with HF.

• The 2001 ACC/AHA guidelines state that because The 2001 ACC/AHA guidelines state that because metoprolol and carvedilol have been shown to metoprolol and carvedilol have been shown to reduce HF symptoms and reduce mortality, they reduce HF symptoms and reduce mortality, they should be prescribed to all patients with stable should be prescribed to all patients with stable HF due to left ventricular systolic dysfunction, HF due to left ventricular systolic dysfunction, unless there is a contraindication to their use.unless there is a contraindication to their use.

• They should be part of the primary treatment They should be part of the primary treatment plan, usually in combination with a diuretic, and plan, usually in combination with a diuretic, and ACE inhibitor and often with digoxin. ACE inhibitor and often with digoxin.

8383

• Another common misperception is that Another common misperception is that patients who have mild symptoms or who patients who have mild symptoms or who appear clinically stable on diuretics and appear clinically stable on diuretics and ACE inhibitors (with or without digoxin) do ACE inhibitors (with or without digoxin) do not require additional treatment.not require additional treatment.

• However, even these patients However, even these patients should should receive a β-blocker to slow the rate of receive a β-blocker to slow the rate of disease progression and reduce the risk of disease progression and reduce the risk of sudden death.sudden death.

8484

• Treatment with a β-blocker should be initiated Treatment with a β-blocker should be initiated at low doses, followed by gradual increments in at low doses, followed by gradual increments in dose every 1 to 2 weeks as tolerated by the dose every 1 to 2 weeks as tolerated by the patient. patient.

• Transient bradycardia, hypotension, and fatigue Transient bradycardia, hypotension, and fatigue are common during the first 24 to 48 hours when are common during the first 24 to 48 hours when β-blockers are first started or during subsequent β-blockers are first started or during subsequent incremental increases in dosage. incremental increases in dosage.

• Thus, patients should be monitored daily for Thus, patients should be monitored daily for changes in vital signs (pulse and blood pressure) changes in vital signs (pulse and blood pressure) and symptoms during this up-titration period. and symptoms during this up-titration period.

8585

• With β-blocker administration to With β-blocker administration to A.J. patient:A.J. patient:– Bradycardia, heart block and Bradycardia, heart block and

hypotension complications are hypotension complications are accompanied by dizziness, or accompanied by dizziness, or blurred vision can occurred blurred vision can occurred this this needs dose reduction of the β-needs dose reduction of the β-blocker and/or ACE inhibitor or blocker and/or ACE inhibitor or slower up titration may be slower up titration may be necessary. necessary.

8686

• Today, A.J.’s wife brought him to the ED because she Today, A.J.’s wife brought him to the ED because she could no longer care for him. His chief complaints could no longer care for him. His chief complaints are are weakness, dizziness, extreme SOB, and inability weakness, dizziness, extreme SOB, and inability to get out of bedto get out of bed. His weight has increased to 80 kg. . His weight has increased to 80 kg. His His BP is considerably lower at 128/83 mm Hg with a BP is considerably lower at 128/83 mm Hg with a postural drop to 112/75 mm Hg.postural drop to 112/75 mm Hg. Abnormal laboratory Abnormal laboratory values on admission are values on admission are BUN, 31 mg/dLBUN, 31 mg/dL and serum and serum creatinine, 1.4 mg/dL. His K is 4.3 mEq/dL. An ECG creatinine, 1.4 mg/dL. His K is 4.3 mEq/dL. An ECG shows a HR of 98 beats/min. His valsartan is held for shows a HR of 98 beats/min. His valsartan is held for 24 hours while he is diuresed with several 40- and 24 hours while he is diuresed with several 40- and 80-mg boluses of IV furosemide. 80-mg boluses of IV furosemide. The plan is to The plan is to reinstitute valsartan and to begin a digitalis reinstitute valsartan and to begin a digitalis glycoside. Is digitalis indicated for A.J.? What glycoside. Is digitalis indicated for A.J.? What digitalis preparation should be prescribed?digitalis preparation should be prescribed?

8787

Digoxin administration Digoxin administration to A.J. patientto A.J. patient• the ACC/AHA guidelines indicate that :the ACC/AHA guidelines indicate that :

– digoxin can be used early to reduce symptoms in digoxin can be used early to reduce symptoms in patients who have been started on, but not yet patients who have been started on, but not yet responded symptomatically to an ACE inhibitor or responded symptomatically to an ACE inhibitor or β-blocker. β-blocker.

– Alternatively, digoxin can be delayed until the Alternatively, digoxin can be delayed until the patient's response to ACE inhibitors and β-patient's response to ACE inhibitors and β-blockers has been defined and used only in blockers has been defined and used only in patients who remain symptomatic.patients who remain symptomatic.

– A.J. fits the latter situation and thus is a logical A.J. fits the latter situation and thus is a logical candidate for adding digoxin as a fourth candidate for adding digoxin as a fourth therapeutic intervention.therapeutic intervention. It could be argued that It could be argued that both a β-blocker and digoxin should have been both a β-blocker and digoxin should have been started at the onset of his treatment a year ago, started at the onset of his treatment a year ago, but A.J.'s physician was reluctant to make but A.J.'s physician was reluctant to make multiple interventions simultaneously.multiple interventions simultaneously.

8888

Digoxin administration Digoxin administration to A.J. patientto A.J. patient• Digoxin is also Digoxin is also prescribed routinely in prescribed routinely in

patients with HF and concurrent chronic patients with HF and concurrent chronic atrial fibrillation,atrial fibrillation, but β-blockers may be but β-blockers may be more effective in controlling the ventricular more effective in controlling the ventricular response, especially during exercise.response, especially during exercise.

• Digoxin should be avoided if the patient Digoxin should be avoided if the patient has significant sinus or atrioventricular has significant sinus or atrioventricular block, unless the block is treated with a block, unless the block is treated with a permanent pacemakerpermanent pacemaker. .

8989

Digoxin administration Digoxin administration to A.J. patientto A.J. patient• It should be used cautiously in It should be used cautiously in

patients taking other drugs that patients taking other drugs that can can depress sinus or AV nodal depress sinus or AV nodal functionfunction (e.g., amiodarone or β- (e.g., amiodarone or β-blockers), although patients blockers), although patients usually will tolerate this usually will tolerate this combination.combination.

9090

Gender difference in Gender difference in response to digoxinresponse to digoxin• increased risk of death among increased risk of death among

women taking digoxin is an women taking digoxin is an interaction between hormone-interaction between hormone-replacement therapy and digoxinreplacement therapy and digoxin. . Progesterone might increase Progesterone might increase serum digoxin levels by reducing serum digoxin levels by reducing digoxin renal tubular excretion. digoxin renal tubular excretion.

9191

LD and MD of digoxinLD and MD of digoxin

• A patient with normal renal function (t½ = A patient with normal renal function (t½ = 1.8 days) given a daily dose of 0.125 mg of 1.8 days) given a daily dose of 0.125 mg of digoxin will reach peak serum concentration digoxin will reach peak serum concentration in approximately 7 days. in approximately 7 days.

• The target therapeutic serum digoxin The target therapeutic serum digoxin concentration is 0.5 to 1.2 ng/mL (mean, concentration is 0.5 to 1.2 ng/mL (mean, 0.75 ng/mL). 0.75 ng/mL).

• smaller doses of digoxin are given to smaller doses of digoxin are given to patients with impaired excretion rates (e.g., patients with impaired excretion rates (e.g., those with renal failure, older patients)those with renal failure, older patients)

• No more therapeutic benefit from LD No more therapeutic benefit from LD not not used now used now

9292

Treatment options for various stages of heart failure. ACE = Angiotensin-converting enzyme; ARB = angiotensin receptor blockers.

9393

Drug interaction in HFDrug interaction in HF

ACEIs or ARBsACEIs or ARBsNSAIDsNSAIDs [ antagonism of [ antagonism of hypotension, increased hypotension, increased risk of renal impairment]risk of renal impairment]

Diuretics Diuretics [ enhancement of [ enhancement of hypotension, increased hypotension, increased risk of hyperkalemia with risk of hyperkalemia with K+-sparing diuretics]K+-sparing diuretics]

CyclosporinCyclosporin [ increased [ increased risk of hyperkalemia]risk of hyperkalemia]

LithiumLithium [ impairment of [ impairment of lithium excretion]lithium excretion]

9494

Drug interaction in HFDrug interaction in HF

DiureticsDiureticsNSAIDsNSAIDs [ decreased effect [ decreased effect of diuretics]of diuretics]

LithiumLithium [ impairment of [ impairment of lithium excretion]lithium excretion]

CarbamazepineCarbamazepine [ [ ↑ risk of ↑ risk of hyponatremia]hyponatremia]

-blockers-blockersAmiodaroneAmiodarone [↑ risk of [↑ risk of bradycardia]bradycardia]

Diltiazem, verapamilDiltiazem, verapamil [↑ risk of [↑ risk of bradycardia and heart block]bradycardia and heart block]

9595

Drug interaction in HFDrug interaction in HF

Digoxin Digoxin

Amiodarone, propafenone, Amiodarone, propafenone, quinidinequinidine [ ↑ digoxin level [ ↑ digoxin level need to halve MD of digoxin ]need to halve MD of digoxin ]

VerapamilVerapamil [ ↑ risk of AV block] [ ↑ risk of AV block]

DiureticsDiuretics [ ↑ risk of hypokalemia [ ↑ risk of hypokalemia ↑ risk of toxicity] ↑ risk of toxicity]

spironolactonespironolactoneDigoxinDigoxin [ spironolactone [ spironolactone interfers with the measurements interfers with the measurements of plasma levels of digoxinof plasma levels of digoxin inaccurate interpretation]inaccurate interpretation]

9696

THANK THANK YOUYOU