Drugs for Heart Failure - Kruse

Question 1

Cardiac glycosides

Answer 1

Inotropic agents

Digoxin
Digoxin immune fab (digoxin antibody)

Question 2

Bipyridines

Answer 2

Inotropic agents

Inamrinone (no longer available)
Milrinone

Question 3

Beta-adrenergic receptor agonists

Answer 3

Inotropic agents

Dobutamine
Dopamine

Question 4

Agents without positive inotropic effects

Answer 4

Diuretics
ACEI
ARBs
Vasodilators
Beta-adrenergic receptor blockers
Natriuretic peptide

Question 5

Diuretics used in HF

Answer 5

Loop diuretics:
Bumetanide
Furosemide
Torsemide

Thiazide diuretics:
hydrochlorothiazide

Aldosterone antagonists:
Eplerenone
Spironolactone

Vasopressin (ADH) antagonists:
Conivaptan
Tolvaptan

Question 6

ACEI used in HF

Answer 6

Captopril
enalapril
fosinopril
lisinopril
quinapril
ramipril

Question 7

ARBs used in HF

Answer 7

Candesartan
Losartan
valsartan

Question 8

Vasodilators

Answer 8

Venodilators: Isosorbide denigrate

Arteriolar dilators: hydrazine

Combined arteriolar and venodilator: Nitroprusside

Question 9

Beta-adrenergic receptor blockers

Answer 9

bisoprolol
carvedilol
metoprolol
nebivolol

Question 10

Natriuretic peptide

Answer 10

Nesiritide

Question 11

Pharmacokinetics of digoxin (cardiac glycosides)

Answer 11

1) 65-80% absorbed after oral administration
(2) Widely distributed to tissues, including the CNS
(3) For patients with normal renal function, the half life is 36-48 hours, permitting once-a-day dosing (66% Digoxin
is eliminated unchanged by the kidney)
(4) In patients with renal insufficiency (or elderly patients), the half life increases to 3.5-5
days and requires dosing adjustments
(5) In patients with HF who are taking vasodilators or sympathomimetic agents, cardiac output and renal blood flow are increased, which may increase renal digoxin clearance

Question 12

MOA of digoxin

Answer 12

at the molecular level, digoxin causes inhibition of the membrane-bound (sarcolemma) Na+/K+ ATPase, ultimately causing an increase in the contraction of the cardiac sarcomere

The two desired effects of digoxin are (1) to improve contractility of the failing heart and (2) to prolong the refractory period of the atrioventricular node in patients with supraventricular arrhythmias (no effect on preload or afterload)

Question 13

Mechanism of positive inotropic effect

Answer 13

(a) Inhibition of the Na+/K+ ATPase stops the cellular Na+ pump activity and reduces the
rate of active Na+ extrusion out of the cell, which results in a rise in intracellular Na+
concentrations
(b) Rising intracellular Na+ concentrations reduce the transmembrane Na+ gradient that
drives the extrusion of intracellular Ca2+ during myocyte repolarization by the
Na+/Ca2+ exchanger (NCX)
(c) With reduced Ca2+ efflux and repeated entry of Ca2+ with each action potential, Ca2+
accumulates in the myocyte
(d) Ca2+ uptake into the sarcoplasmic reticulum (SR) is increased and more Ca2+ becomes available for release from the SR during the next action potential, which
enhances myocardial contractility
(e) Therefore, cardiac glycosides increase myocardial contractility by ultimately increasing the releasable Ca2+ from the SR (see lecture slides for more information)
(f) The magnitude of the positive inotropic effect correlates with the degree of Na+/K+ ATPase inhibition

Question 14

Electrical cardiac effects at therapeutic levels - digoxin

Answer 14

(a) Direct actions on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential, followed by action potential shortening (especially the plateau phase)
(b) The decrease in action potential duration may be the result of increased potassium conductance that is caused by increased intracellular calcium
(i) Digoxin-induced elevated intracellular Ca2+ increases the activity of Ca2+- dependent K+ channels
(ii) Increased Ca2+-dependent K+ channel activity promotes K+ efflux and a more rapid repolarization (i.e., shortened cardiac action potential)
(c) Parasympathomimetic effects predominate on cardiac tissue at therapeutic levels of digoxin (see table below)
(i) Parasympathomimetic effects are inhibited by atropine
(ii) Parasympathomimetic effects involve sensitization of the baroreceptors, central
vagal stimulation, and facilitation of muscarinic transmission at the cardiac
muscle cell (unknown mechanism)
(iii) Cholinergic innervation is more concentrated in the atria, resulting in increased
actions of digoxin on atrial and atrioventricular nodes compared to Purkinje or
ventricular function

Question 15

Electrical cardiac effects at toxic levels of digoxin

Answer 15

(a) Toxic levels are associated with depolarization of the resting potential (less negative), a marked shortening of the action potential, and the appearance of oscillatory depolarizing afterpotentials (delayed after depolarizations, DADs) following normally evoked action potentials (Figure 13-5, panel B on p. 215)
(i) Delayed after depolarizations are associated with overloading of the intracellular
Ca2+ stores and oscillations in free intracellular Ca2+ concentrations
(ii) When afterpotentials reach threshold, they elicit action potentials (premature
depolarizations, ectopic beats)
(b) Most common cardiac manifestations of digoxin toxicity include changes to
atrioventricular junctional rhythm, premature ventricular depolarization, bigeminal rhythm, and second-degree atrioventricular blockade (it is claimed that digoxin can cause virtually any arrhythmia)
(c) If allowed to progress, the tachycardia may deteriorate into fibrillation that could be fatal unless corrected

Question 16

Digoxin toxicity

Answer 16

(1) Cardiac glycosides affect all excitable tissues due to its MOA and can cause adverse effects throughout the body (primarily GI and CNS)
(2) Heart: arrhythmias (see above)
(3) Gastrointestinal system (most common site of digoxin toxicity outside the heart)
(a) Anorexia, nausea, vomiting, and diarrhea
(b) Due to direct effects on the GI tract and CNS actions
(4) CNS: vagal and chemoreceptor trigger zone stimulation can cause GI symptoms; disorientation, hallucinations, and visual disturbances and/or changes
(5) Gynecomastia is a rare effect that can occur in men
(6) Antidigoxin immunotherapy (antidigoxin fab antibody) can be utilized in cases of digoxin
overdose

Question 17

Interactions of digoxin with K, Ca, Mg

Answer 17

(1) Digoxin and potassium bind to competing sites on the Na+/K+ ATPase
(a) Hyperkalemia can reduce the effects of digoxin (especially the toxic effects) (b) Hypokalemia can potentiate the toxic effects of digoxin
(2) Hyperkalemia inhibits abnormal cardiac automaticity (i.e., hyperkalemia decreases pacemaker arrhythmogenesis)
(3) Hypercalcemia and hypomagnesemia increase the risk of a digoxin-induced arrhythmia

Question 18

Digoxin in healthy heart vs chronically failing heart

Answer 18

little effect on individuals with a healthy heart, however, when administered to
individuals with a chronically failing heart, digoxin can increase the strength of contraction as much as 50-100%

Question 19

Pharmacokinetics of bipyridines (inamrinone, milrinone)

Answer 19

(1) Elimination half-lives are 3-6 hours in patients with severe heart failure (approximately half that in healthy patients)
(2) 10-40% is excreted in the kidney
(3) Only available for parenteral administration

Question 20

MOA for bipyridines

Answer 20

cause selective inhibition of phosphodiesterase isozyme 3 (PDE3), which increases cyclic adenosine monophosphate (cAMP) concentrations (phosphodiesterase enzymes degrade cellular cAMP and cGMP)

Question 21

Pharmacodynamics of bipuridines

Answer 21

Increased concentrations of cAMP in the heart result in direct stimulation of myocardial contractility and acceleration of myocardial relaxation
(a) cAMP-dependent protein kinases in the heart phosphorylate and activate voltage-
gated Ca2+ channels, increasing the amount of Ca2+ entering the cell during an
action potential
(b) Increased concentrations of Ca2+ increase the force of contraction of the heart

Increased concentrations of cAMP in the vasculature cause balanced arterial and venous dilation with a consequent fall in systemic and pulmonary vascular resistances and left and right heart filling pressure
(a) cAMP-dependent protein kinases in smooth muscle phosphorylate and inactivate
myosin-light chain kinase
(b) Inactivation of myosin-light chain kinase causes smooth muscle relaxation
(vasodilation)

PDE3 inhibitors increase cardiac output due to the stimulation of myocardial contractility
and the decrease in left ventricular afterload (they are sometimes called ‘ino-dilators’)

Caffeine and theophylline are nonspecific PDE inhibitors and their use in HF is limited
by their lack of specificity and concomitant side effects

Question 22

Toxicity of inamrinone

Answer 22

nausea, vomiting, arrhythmias, thrombocytopenia, and liver enzyme
changes

Question 23

Toxicity of Milrinone

Answer 23

arrhythmias (bone-marrow suppression and liver toxicity is less likely
compared to inamrinone)

Question 24

Bipyridines

Answer 24

Approved for the short-term support of the circulation in advanced heart failure

chronic parenteral
therapy does not show any signs of improving the quality or length of life and, in fact, may actually increase mortality

Question 25

B-adrenergic and dopaminergic agonists

Answer 25

dobutamine (β-agonist) and dopamine (dopaminergic agonist)

Question 26

MOA of B-adrenergic and dopaminergic agonists

Answer 26

act via stimulation of the cardiac myocyte dopamine D1 receptor (dopamine) and β1-adrenergic receptor (dobutamine)
(1) Receptor activation leads to stimulation of the GS-adenylyl cyclase-cAMP-protein kinase
A (PKA) pathway
(2) PKA phosphorylates a number of substrates that enhance Ca2+-dependent contraction and speed relaxation

Question 27

Dobutamine

Answer 27

(1) Stimulates β1-receptors with little effect on β2- or α-receptors (β1 selective)
(2) The β agonist of choice for the management of patients with systolic dysfunction and HF
(3) Principal hemodynamic effect is an increase in stroke volume due to its positive
inotropic action and an increase in cardiac output
(4) The major side effects are excessive tachycardia and arrhythmias
(5) Parenteral administration

Question 28

Dopamine

Answer 28

(1) Endogenous catecholamine with limited utility in the treatment of most patients with HF
(2) May be useful in patients if there is a need to raise blood pressure
(3) At low doses, dopamine causes vasodilation by stimulating dopaminergic receptors on
smooth muscle (causing cAMP-dependent relaxation) and by stimulating presynaptic D2 receptors on sympathetic nerves in the peripheral circulation (inhibiting norepinephrine release and reducing α-adrenergic stimulation of vascular smooth muscle)
(4) At intermediate doses, dopamine directly stimulates β receptors on the heart and vascular sympathetic neurons (enhancing cardiac contractility and neural norepinephrine release)
(5) At high doses, dopamine causes peripheral arterial and venous constriction via α- adrenergic receptor stimulation, which may be desirable in patients where circulatory failure is the result of vasodilation (e.g., sepsis, anaphylaxis)
(6) Tachycardia is more pronounced with dopamine than with dobutamine and may provoke ischemia in patients with coronary artery disease
(7) Parenteral administration

Question 29

Loop diuretics

Answer 29

widely used in the treatment of heart failure (furosemide, bumetanide,
and torsemide are most commonly used)

Question 30

Thiazide diuretics

Answer 30

most frequently used in the treatment of systemic hypertension and
have a more restricted role in the treatment of HF

Question 31

Potassium-sparing diuretics

Answer 31

relatively weak diuretics and therefore are not effective
for volume reduction; however, aldosterone antagonists have been shown to improve survival in patients with advanced heart failure via a mechanism that is independent of diuresis

Question 32

Aldosterone antagonists

Answer 32

(1) One of the principle features of HF is marked activation of the renin-angiotensin-
aldosterone system (some patients with HF have plasma aldosterone concentrations as
high as 20 times the normal level)
(2) Aldosterone not only is involved in increased sodium and water retention but may also
cause myocardial and vascular fibrosis (remodeling) and baroreceptor dysfunction
(3) Antagonism of the effects of aldosterone has been shown to improve survival in patients
with advanced HF
(4) Prototypes: spironolactone and eplerenone

Question 33

Vasopressin (ADH) Antagonists

Answer 33

A variety of medical conditions (e.g., heart failure and syndrome of inappropriate ADH
(SIADH)) cause water retention as the result of ADH excess, which can result in
hyponatremia

Question 34

Conivaptan

Answer 34

an ADH receptor antagonist and has been approved for use in the
above-mentioned cases

Conivaptan is administered parenterally with a half-life of 5-10 hours

Question 35

MOA of vasopressin antagonists

Answer 35

antagonist at ADH receptors (V1a and V2) in the CCT

Question 36

Vasopressin antagonist toxicity

Answer 36

conivaptan can cause hypernatremia, nephrogenic diabetes insipidus

Question 37

Tolvaptan

Answer 37

selective antagonist of V2 ADH receptors that is given PO (use and
toxicity is similar to conivaptan)