Drugs for Heart Failure

Southern Africa Nazarene University

Diploma in Pharmacy
DPS 103 Lecture 5
 Heart Failure

Heart failure (CHF) is a

complex, progressive
disorder in which the heart
is unable to pump
sufficient blood to meet the
needs of the body.
 Heart Failure
The cardinal symptoms of CHF are;
• Dyspnea
• Fatigue, and
• Fluid retention
CHF is due to an impaired ability of the
heart to adequately fill with and/or eject
blood.
 Heart Failure

• CHF is often accompanied by abnormal increases in

blood volume and interstitial fluid.
• Underlying causes of CHF include, but are not limited to,
atherosclerotic heart disease, hypertensive heart
disease, valvular heart disease, and congenital heart
disease.
 Role of physiologic compensatory mechanisms in the
progression of CHF

• Chronic activation of the sympathetic nervous system and the

renin–angiotensin–aldosterone system (RAAS) is associated with
remodeling of cardiac tissue, loss of myocytes, hypertrophy, and
fibrosis.
• This prompts additional neurohormonal activation, creating a
vicious cycle that, if left untreated, leads to death.
Goals of pharmacologic intervention in CHF

Goals of treatment are;

• To alleviate symptoms
• slow disease progression, and
• improve survival.
 Classes of drugs used in CHF
The following have been shown to be effective:
1) Angiotensin-converting enzyme (ACE) inhibitors
2) Angiotensin receptor blockers
3) Aldosterone antagonists
4) β-blockers
5) Diuretics
 Classes of drugs used in CHF
The following have been shown to be effective:
6) Direct vaso- and venodilators
7) Hyperpolarization-activated cyclic nucleotide-gated
channel blockers
8) Inotropic agents
9) Combination of a neprilysin inhibitor with an angiotensin
Note: Depending on the severity of CHF and
receptor blocker individual patient factors, one or more of these
classes of drugs are administered
 Benefits of Pharmacologic
Intervention in CHF
• Reduced myocardial work load
• Decreased extracellular fluid volume
• Improved cardiac contractility, and
• Reduced rate of cardiac remodeling
 Physiology of Muscle Contraction
The myocardium, like smooth and skeletal muscle,
responds to stimulation by depolarization of the membrane,
which is followed by shortening of the contractile proteins
and ends with relaxation and return to the resting state
(repolarization).
 Physiology of Muscle Contraction
Action potential

• Cardiac myocytes are electrically excitable and have a

spontaneous, intrinsic rhythm generated by specialized
“pacemaker” cells located in the sinoatrial (SA) and
atrioventricular (AV) nodes.
• Cardiac myocytes also have an unusually long action
potential, which can be divided into five phases (0 to 4).
Action potential of a cardiac
myocyte
Action potential of a cardiac
myocyte. ATPase = adenosine
triphosphatase
 Physiology of Muscle Contraction
Cardiac contraction

• The force of contraction of the cardiac muscle is directly

related to the concentration of free (unbound) cytosolic
calcium.
• Therefore, agents that increase intracellular calcium
levels increase the force of contraction (inotropic effect).
 Compensatory physiological
responses in CHF
The failing heart evokes four major compensatory
mechanisms to enhance cardiac output
1. Increased sympathetic activity
2. Activation of the renin–angiotensin–aldosterone system
(RAAS)
3. Activation of natriuretic peptides
4. Myocardial hypertrophy
Cardiovascular consequences of CHF
 Acute (decompensated) CHF
• If the compensatory mechanisms adequately restore
cardiac output, CHF is said to be compensated.
• If the compensatory mechanisms fail to maintain cardiac
output, CHF is decompensated and the patient develops
worsening CHF signs and symptoms.
• Typical CHF signs and symptoms include dyspnea on
exertion, orthopnea, paroxysmal nocturnal dyspnea,
fatigue, and peripheral edema.
 Therapeutic strategies in CHF
• Chronic CHF is typically managed by fluid limitations
(less than 1.5 to 2 L daily)
• Low dietary intake of sodium (less than 2000 mg/d)
• Treatment of comorbid conditions; and
• Use of diuretics
• Inotropic agents are reserved for acute signs and
symptoms of CHF and are used mostly in the in-patient
setting.
 Therapeutic strategies in CHF
• Drugs that may precipitate or exacerbate CHF, such as
nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol,
non-dihydropyridine calcium channel blockers, and
some antiarrhythmic drugs, should be avoided if
possible.
 ACE inhibitors

Effects of ACE inhibitors. [Note: The reduced retention of sodium

and water results from two causes: decreased production of
angiotensin II and aldosterone.]
 ACE inhibitors
MoA
ACE inhibitors decrease vascular resistance (afterload) and
venous tone (preload), resulting in increased cardiac output.
ACE inhibitors improve clinical signs and symptoms of CHF
and have been shown to significantly improve patient survival
in CHF.
 ACE inhibitors
Therapeutic use
• ACE inhibitors may be considered for patients with
asymptomatic and symptomatic CHF.
• These agents should be started at low doses and titrated
to target or maximally tolerated doses in the management
of CHF.
• ACE inhibitors are also used in the treatment of
hypertension.
 ACE inhibitors
Pharmacokinetics
• ACE inhibitors are adequately absorbed following oral
administration.
• Food may decrease the absorption of captopril, so it
should be taken on an empty stomach.
• Except for captopril and injectable enalaprilat, ACE
inhibitors are prodrugs that require activation by hydrolysis
via hepatic enzymes.
 ACE inhibitors
Pharmacokinetics contd…
• Renal elimination of the active moiety is important for most
ACE inhibitors except fosinopril, which also undergoes
excretion in the feces.
• Plasma half-lives of active compounds vary from 2 to 12
hours.
 ACE inhibitors
Adverse effects
1) Because of the risk of hyperkalemia,
• Postural hypotension potassium levels must be monitored,

• Renal insufficiency particularly with concurrent use of

potassium supplements, potassium-
• Hyperkalemia
sparing diuretics, or aldosterone
• Persistent dry cough antagonists.

• Angioedema(rare) 2) Serum creatinine levels should also

be monitored, particularly in patients
with underlying renal disease.
 ACE inhibitors
Adverse effects contd…
• The potential for symptomatic hypotension with ACE
inhibitors is much more common if used concomitantly with
a diuretic.
• ACE inhibitors are teratogenic and should not be used in
pregnant women.
 Angiotensin receptor blockers
• ARBs competitively block angiotensin II type 1 receptor.
• Because ACE inhibitors inhibit only one enzyme responsible for the
production of angiotensin II, ARBs have the advantage of more
complete blockade of the actions of angiotensin II.
• ARBs have actions similar to those of ACE inhibitors, however,
they are not therapeutically identical.
• ARBs are a substitute for patients who cannot tolerate ACE
inhibitors due to cough or angioedema.
 Angiotensin receptor blockers
Pharmacokinetics
• ARBs are orally active and are dosed once daily, with the exception
of valsartan, which is dosed twice daily.
• They are highly plasma protein bound.
• Losartan differs in that it undergoes extensive first-pass hepatic
metabolism, including conversion to an active metabolite.
• Elimination of metabolites and parent compounds occurs in urine
and feces.
 Angiotensin receptor blockers
Adverse effects
• ARBs have an adverse effect and drug interaction profile
similar to that of ACE inhibitors.
• However, the ARBs have a lower incidence of cough and
angioedema.
• Like ACE inhibitors, ARBs are contraindicated in pregnancy
 Aldosterone receptor antagonists
• Patients with CHF have elevated levels of aldosterone due
to angiotensin II stimulation and reduced hepatic clearance
of the hormone.
• Spironolactone and eplerenone are antagonists of
aldosterone at the mineralocorticoid receptor, thereby
preventing salt retention, myocardial hypertrophy, and
hypokalemia.
 Aldosterone receptor antagonists
Adverse effects
• Gynecomastia
• Dysmenorrhea
 β-Blockers
• Bisoprolol, carvedilol, metoprolol succinate
• β-blockers act to prevent the changes that occur because of
chronic activation of the sympathetic nervous system.
• These agents decrease heart rate and inhibit release of
renin in the kidneys.
• β-blockers prevent the deleterious effects of norepinephrine
on the cardiac muscle fibers, decreasing remodeling,
hypertrophy, and cell death.
 β-Blockers
• β-Blockade is recommended for all patients with chronic,
stable CHF.
• Treatment should be started at low doses and gradually
titrated to target doses based on patient tolerance and vital
signs.
 β-Blockers
Pharmacokinetics
• Carvedilol and metoprolol are metabolized by the
cytochrome P450 2D6 isoenzyme
• Carvedilol is a substrate of P-glycoprotein (P-gp).
• Increased effects of carvedilol may occur if it is
coadministered with P-gp inhibitors.
 Diuretics
• Diuretics reduce signs and symptoms of volume overload,
such as dyspnea on exertion, orthopnea, and peripheral
edema.
• Diuretics decrease plasma volume and, subsequently,
decrease venous return to the heart (preload).
• This decreases cardiac workload and oxygen demand.
 Diuretics
• Diuretics may also decrease afterload by reducing plasma
volume, thereby decreasing blood pressure.
• Loop diuretics are the most commonly used diuretics in
CHF.
• Since diuretics have not been shown to improve survival in
CHF, they should only be used to treat signs and symptoms
of volume excess.
Diuretics has been discussed previously
 Vaso- and Venodilators
• Dilation of venous blood vessels leads to a decrease in
cardiac preload by increasing venous capacitance.
• Nitrates are commonly used venous dilators to reduce
preload for patients with chronic CHF.
• Arterial dilators, such as hydralazine, reduce systemic
arteriolar resistance and decrease afterload.
 Vaso- and Venodilators
If the patient is intolerant of ACE inhibitors or ARBs, or if
additional vasodilator response is required, a combination of
hydralazine and isosorbide dinitrate may be used.

Adverse effects

Headache, dizziness, and hypotension are common adverse

effects with this combination.
 Inotropic Drugs

• Positive inotropic agents enhance cardiac contractility and,

thus, increase cardiac output.
• The inotropic action is due to an increased cytoplasmic
calcium concentration that enhances the contractility of
cardiac muscle.
 Inotropic Drugs

• All positive inotropes that increase intracellular calcium

concentration have been associated with reduced survival,
especially in patients with CHF.
• For this reason, these agents, with the exception of digoxin,
are only used for a short period mainly in the in-patient
setting.
 Inotropic Drugs
Digitalis glycosides
Mechanism of action
1) Regulation of cytosolic calcium concentration
2) Increased contractility of the cardiac muscle
3) Neurohormonal inhibition
 Inotropic Drugs
Digitalis glycosides
Therapeutic use
• Digoxin therapy is indicated in patients with CHF who are
symptomatic.
• A low serum drug concentration of digoxin (0.5 to 0.8 ng/mL)
is beneficial in CHF.
 Inotropic Drugs
Pharmacokinetics
• Digoxin is available in oral and injectable formulations.
• It has a large volume of distribution, because it accumulates in
muscle.
• The dosage is based on lean body weight.
• Digoxin has a long half-life of 30 to 40 hours.
• It is mainly eliminated intact by the kidney, requiring dose adjustment
in renal dysfunction.
 Inotropic Drugs
Adverse effects
• At low serum drug concentrations, digoxin is well tolerated. However,
it has a very narrow therapeutic index.
• Anorexia, nausea, vomiting, blurred vision, or yellowish vision may
be initial indicators of toxicity.
• Increase the risk of arrhythmias
• Decreased levels of serum potassium (hypokalemia) predispose a
patient to digoxin toxicity, because digoxin normally competes with
potassium for the same binding site on the Na+/K+-ATPase pump.
 Inotropic Drugs
Drug interactions
• Digoxin is a substrate of P-gp, and inhibitors of P-gp, such as
clarithromycin, verapamil, and amiodarone, can significantly increase
digoxin levels, necessitating a reduced dose of digoxin.
• Digoxin should also be used with caution with other drugs that slow
AV conduction, such as β-blockers, verapamil, and diltiazem.
 β-Adrenergic agonists

• β-Adrenergic agonists, such as dobutamine and dopamine,

improve cardiac performance by causing positive inotropic effects
and vasodilation.
• β-Adrenergic agonists ultimately lead to increased entry of calcium
ions into myocardial cells and enhanced contraction.
• Both drugs must be given by intravenous infusion and are primarily
used in the short-term treatment of acute CHF in the hospital setting.
Order of Therapy in CHF