Drugs used in congestive heart failure

A. Learning objective

A.1. Competency Standard from InaMc

Please refer to Competency Standard from Indonesian Medical Council / Konsil Kedokteran
Indonesia and Level of competency of

Heart failure 3B

A.2 You should be able to

Describe the strategies and lisl the major drag groups used in the treatment of congestive
heart failure.
Describe the probable mechanism of action of digitalis.
Describe the nature and mechanism of digitalis's toxic effects on the heart.
List some positive inotropic drugs that have been investigated as digitalis substitutes.
Describe the beneficial effects of diuretics, vasodilators. ACE inhibitors, and other drugs that
lack positive inotropic effects in congestive heart failure.

Learn the definitions that follow.

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CONCEPTS

PATHOPHYSIOLOGY OF CONGESTIVE HEART FAILURE & TREATMENT STRATEGIES

The drugs used in congestive heart failure are shown in Figure 13-1.

A. Pathophysiology:
The fundamental physiologic defect in congestive heart failure is a decrease in cardiac
contractility. The result of this defect is that cardiac output is inadequate for the needs of the
body. This is best shown by the ventricular function curve (Frank-Starling curve; Figure 13-
2). The ventricular function curve reflects some compensatory responses of the body and
may also be used to demonstrate the response to drugs. As ventricular ejection decreases,
the end-diastolic fiber length increases as shown by the shift from point A to point B in
Figure 13-2. Operation at point B is intrinsically less efficient than operation at shorter fiber
lengths because of the increase in myocardial oxygen requirement associated with
increased fiber stretch (see Figure 12-2).
The homeostatic responses of the body to depressed cardiac output are extremely
important and are mediated mainly by the sympathetic nervous system and the renin-
angiotensinaldosterone system. They are summarized in Figure 13-3. The major responses
include the following: (1) Tachycardia--an early manifestation of increased sympathetic
tone. (2) Increased peripheral vascular resistance--another early response, also mediated
by increased sympathetic tone. (3) Retention of salt and water by the kidney--an early
compensatory response, mediated by the renin-angiotensin-aldosterone system and
facilitated by increased sympathetic outflow.
Increased blood volume results in edema and pulmonary congestion and contributes to the
increased end-diastolic fiber length. (4) Cardiomegaly---enlargement of the heart is a slower
compensatory response, mediated at least in part by sympathetic discharge. Angiotensin II
also plays an important role. Recent evidence suggests that aldosterone may also play a
direct role in cardiac changes. While these compensatory responses may temporarily
improve cardiac output (and may be lifesaving), they also increase the load on the heart;
the increased load contributes to further long-term decline in cardiac function.

B. Therapeutic Strategies in Congestive Heart Failure:

Pharmacologic therapies for congestive heart failure include the removal of retained salt
and water with diuretics; direct treatment of the depressed hear! with positive inotropic
drugs such as digitalis glycosides: reduction of preload or aflerload with vasodilators; and
reduction of afterload and retained salt and water by angiotensin-converting enzyme
inhibitors. In addition, considerable evidence suggests that ACE inhibitors beneficially alter
the structural changes that often follow myocardial infarction and lead to congestive failure.
Recent clinical results show that beta-adrenoceptor blockers and spironolactone, an
aldosterone antagonist, also have long-term beneficial effects. The use of diuretics is
discussed in Chapter 15.
Current clinical evidence suggests that acute congestive failure should be treated with a
loop diuretic, a prompt-acting positive inotropic agent such as a beta agonist or
phosphodiesterase inhibitor, and vasodilators as required to optimize filling pressures and
blood pressure. Chronic failure is best treated with diuretics (often a loop agent plus

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spironolactone) plus an ACE inhibitor and, if tolerated, a beta blocker. Digitalis is used if
systolic dysfunction is prominent.

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CARDIAC GLYCOSIDE

A. Prototypes and Pharmacokinetics:

All cardiac glycosides include a steroid nucleus and a lactone ring; most also have one
or more sugar residues. The sugar residues constitute the glycoside portion of the
molecule, and the steroid nucleus plus lactone ring comprise the "'genin" portion. The
cardiac glycosides are often called "digitalis" because several come from the digitalis
(foxglove) plant. Digoxin is the prototype agent and the one most commonly used in the
USA. A very similar molecule, digitoxin, which also comes from the foxglove, is now
rarely used. Digitalis-like drugs come from many other plants, and a few come from
animals. Ouabain, a shorter-acting glycoside, is derived from a tropical plant, though
some evidence suggests that it is synthesized in mammals as well. The
pharmacokinetics of digoxin, digitoxin. and ouabain are summarized in Table 13-2.

B. Mechanism of Action:
Inhibition of Na+/K + ATPase of the cell membrane by digitalis is well-documented and is
considered to be the primary biochemical mechanism of action of digitalis (Figure 13-4).
Translation of this effect into an increase in cardiac contractility involves the Na+/Ca 2+
exchange mechanism. Inhibition of Na+/K + ATPase results in an increase in intracellular
sodium. The increased sodium alters the driving force for sodium-calcium exchange so
that less calcium is removed from the cell. The increased intracellular calcium is stored
in the sarcoplasmic reticulum and upon release increases contractile force. Other
mechanisms of action for digitalis have been proposed, but they are probably not as
important as the ATPase effect. The consequences of Na+/K + ATPase inhibition are
seen in both the mechanical and the electrical function of the heart. Digitalis also
modifies autonomic outflow, and this action has effects on the electrical properties of the
heart.

C. Cardiac Effects:

1. Mechanical effects: The increase in contractility evoked by digitalis results in increased

ventricular ejection, decreased end-systolic and end-diastolic size, increased cardiac output,
and increased renal perfusion. These beneficial effects permit a decrease in the compen-
satory sympathetic and renal responses previously described. The decrease in sympathetic
tone is especially beneficial: reduced heart rate, preload, and aftedoad permit the heart to
function more efficiently (point C in Figure 13-2).

2. Electrical effects: Electrical effects include early cardiac parasympathomimetic re-

sponses and later arrhythmogenic responses. They are summarized in Table 13-3.
a. Early responses: Increased PR interval, caused by the decrease in atrioventricular
conduction velocity, and flattening of the T wave are often seen. The effects on the atria
and AV node are largely parasympathetic in origin and can be partially blocked by atro-
pine. The increase in the atrioventricular nodal refractory period is particularly important
when atrial flutter or fibrillation is present because the refractoriness of the AV node de-
termines the ventricular rate in these arrhythmias. The effect of digitalis is to slow ven-
tricular rate. Shortened QT, inversion of the T, and ST depression may occur later.
b. Toxic responses: Increased automaticity, caused by intracellular calcium overload, is
the most important manifestation of toxicity. It results from delayed afterdepolariza-
tions, which may evoke extrasystoles, tachycardia, or fibrillation in any part of the

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heart. In the ventricles, the extrasystoles are recognized as premature ventricular beats
(PVBs). When PVBs are coupled to normal beats in a 1:1 fashion, the rhythm is called
bigeminy (Figure 13-5).

D. Clinical Uses:
1. Congestive heart failure: Digitalis is the traditional positive inotropic agent used in the
treatment of congestive heart failure. However, careful clinical studies indicate that while
digitalis improves functional status (reducing symptoms), it does not prolong life. Other
agents (diuretics, ACE inhibitors, vasodilators) may be equally effective and less toxic in
some patients, and some of these alternative therapies do prolong life (see below). Because
the half-lives of cardiac glycosides are long, the drugs accumulate significantly in the body,
and dosing regimens must be carefully designed and monitored.
2. Atrial fibrillation: In atrial flutter and fibrillation, it is desirable to reduce the conduction
velocity or increase the refractory period of the atrioventricular node so that ventricular rate
is decreased. The parasympathomimetic action of digitalis effectively accomplishes this
therapeutic objective.

E. Interactions: Quinidine causes a well-documented reduction in digoxin clearance and often

increases the serum digoxin level if digoxin dosage is not adjusted. Several other drugs have
been shown to have the same effect (amiodarone, verapamil, others), but the interactions with
these drugs are not clinically significant. Digitalis effects are inhibited by extracellular potas-
sium and magnesium and facilitated by extracellular calcium. Loop diuretics and thiazides, of-
ten used in treating heart failure, may significantly reduce serum potassium and thus precipitate
digitalis toxicity. Digitalis-induced vomiting may deplete serum magnesium and similarly facil-
itate toxicity. These ion interactions are important in treating digitalis toxicity (see below).

F. Digitalis Toxicity: The major signs of digitalis toxicity are arrhythmias, nausea, vomiting,
and diarrhea. Rarely, confusion or hallucinations and visual aberrations may occur. The treat-
ment of digitalis arrhythmias is important because this manifestation of digitalis toxicity is
common and dangerous. Chronic intoxication is an extension of the therapeutic effect of the
drug and is caused by excessive calcium accumulation in cardiac cells (calcium overload). This
overload triggers abnormal automaticity and the arrhythmias noted in Table 13-3. Digitalis ar-
rhythmia is more likely if serum potassium or magnesium is lower than normal or if serum cal-
cium is higher than normal.
Severe, acute intoxication is caused by suicidal or accidental extreme overdose and
results in cardiac depression leading to cardiac arrest rather than tachycardia or fibrillation.

Treatment of digitalis toxicity includes the following:

1. Correction of potassium or magnesium deficiency: Correction of potassium deficiency
(caused, for example, by diuretic use) is useful in chronic digitalis intoxication. Mild toxic-
ity may often be managed by omitting one or two doses of digitalis and giving oral or par-
enteral K + supplements. Potassium should not be raised above the normal level of 3.5-5
meq/L. Similarly, if hypomagnesemia is present, it should be treated by normalizing serum
magnesium. Severe acute intoxication (as in suicidal overdoses) usually causes marked hy-
perkalemia and should not be treated with supplemental potassium.
2. Antiarrhythmic drugs: Antiarrhythmic drugs may be useful if increased automaticity is
prominent and does not respond to normalization of serum potassium. Agents that do not
severely impair cardiac contractility (eg, lidocaine or phenytoin) are favored but drugs such as
propranolol have also been used successfully. Severe acute digitalis overdose usually causes
marked inhibition of all pacemaker cells. Antiarrhythmic drugs are dangerous in such patients.

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3. Digoxin antibodies: Digoxin antibodies (FAB fragments, Digibind) are extremely effec-
tive and should always be used if other therapies appear to be failing. They are effective for
poisoning with many cardiac glycosides in addition to digoxin and may save patients who
would otherwise die.

OTHER DRUGS USED IN CONGESTIVE HEART FAILURE

A Diuretics:

Diuretics are often used in congestive heart failure before digitalis and other drugs
are considered. Furosemide is a very useful agent for immediate reduction of the pulmonary
congestion and severe edema associated with acute congestive heart failure or severe chronic
failure. Thiazides such as hydrochlorothiazide are often used in the management of mild
chronic failure. Recent clinical studies suggest that spironolactone (an aldosterone antagonist
diuretic) has particularly significant long-term benefits in chronic failure. The pharmacology of
the diuretics is discussed in Chapter 15.

B Angiotensin-Converting Enzyme lnhibitors:

These agents have been shown to reduce mor-

bidity and mortality in chronic heart failure. Although they have no direct positive inotropic ac-
tion, ACE inhibitors reduce aldosterone secretion, salt and water retention, and vascular resis-
tance. They are now considered among the first line drugs for chronic heart failure, along with
diuretics. Angiotensin receptor antagonists (eg, losartan) probably have similar benefits al-
though long-term studies have not been completed with these newer drugs.

D. BetacSelective Adrenoceptor Agonists:

Dobutamine and dopamine are useful in many cases of acute failure, in which systolic function
is markedly depressed. However, they are not appropriate for chronic failure because of
tolerance, lack of oral efficacy, and significant arrhythmogenic effects.

E. Beta-Adrenoceptor Antagonists:

Several beta blockers (carvedilol, labetalol, metoprolol) have been shown in long-term studies to
reduce progression of chronic heart failure. This benefit of [-blockers had long been recognized
in patients with hypertrophic cardiomyopathy but has now been shown to also occur in patients
without cardiomyopathy. Beta-blockers are not of value in acute failure and may be detrimental
if systolic dysfunction is marked.

F. Phosphodiesterase Inhibitors:

Amrinone and milrinone are the major representatives of this infrequently used group,
although theophylline (in the form of its salt, aminophylline) was commonly used in the past.
These drugs increase cAMP by inhibiting its breakdown by phosphodiesterase and cause
an increase in cardiac intracellular calcium similar to that produced by beta adrenoceptor
agonists. Phosphodiesterase inhibitors also cause vasodilation, which may be responsible
for a major part of their beneficial effect. At sufficiently high concentrations, these agents
may increase the sensitivity of the contractile protein system to calcium (site 6 in Figure 13-

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 4). These agents should not be used in chronic failure: they have been shown to increase
morbidity and mortality.

G, Vasodilators:
Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe congestive
failure. The use of these vasodilator drugs is based on the reduction in cardiac size and
improved efficiency that can be realized with proper adjustment of venous return and reduction
of resistance to ventricular ejection. Vasodilator therapy can be dramatically effective, especially
in cases in which increased afterload is a major factor in causing the failure (eg, continuing
hypertension in an individual who has just had an infarct). Chronic congestive heart failure
sometimes responds favorably to oral vasodilators such as hydralazine or isosorbide dinitrate.

DRUGS LIST

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References
1. Katzung & Trevors Pharmacology, p.219 228, 2002
2. Basic & Clinical Pharmacology, BG Katzung, 2008
3. Goodman & Gilmans the Pharmacological Basis of Therapeuti,11th,2008

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Appendix

Assignment

Assignment 1

Please answer : poin A.2.

Assignment 2

Make notes in the form of a pocket book containing the Drugs used in astma,
including important notes about drug mechanism, specific pharmacokinetic, important
side effects, formulations of the medicine (written at home before skill lab activity).

An example of the pocket book/notes of drugs: (available in Indonesia)

Generic
Pharmaco Pharma Presentati
and Cost
Class & prototipe - co- on and
Brand / etc
dynamic kinetic Dosage
Name

Assignment 3

P-Drug Assignment:

Each class is divided into groups.

Each group formulates P-drug.
Each group divides itself into 8 subgroups (with a maximum of 4-5 people per subgroup).
Each subgroup chooses one P-drug case (the P drug is taken from the pocket book).

P-Treatment Assignment:

Each group works on one P-treatment case (make a P-treatment based on efficacy, safety,
suitability, and cost).
This assignment is done at home BEFORE skill lab activity (read the materials already
provided).

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Assignment 4

During the Skill Lab:

A short summary of Rational Drug Use
P-Drug practice and prescription writing practice: for normal adults, using various drug
forms.
P-treatment practice.

Assignment 5
Structured Assignment after Skill Lab:
a) Complete the pocket book of drug form and shapes.
b) Complete P drugs used in asthma

Assignment 6

This concept is applied during assistantship (Co As) in every clinic and also consists of
independent training during the internship. It is hoped that this 'habit' of knowledge application
would be carried on until the student is a physician working under the professional standard
(based on ethics, disciplined/ competent, and service standards consistent with the local means,
infrastructure and human resources).

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