HEART FAILURE (pharm)

1. Discuss the four determinants of cardiac performance

I. Preload: forward stroke volume ejected by the LV (CO) depends on the degree of LV filling during diastole (preload). This fundamental relationship
between preload and stroke volume is the Frank–Starling law  relationship between muscle length and degree of muscle shortening  ↑ diastolic
volume increases myocardial fiber length  higher fraction of the actin filament length is exposed in each sarcomere and is thereby available for
myosin cross-bridge formation when the cardiomyocyte is depolarized.
II. Afterload: Impedance to LV ejection (afterload); as afterload ↑ CO↓; ↑resistance against which cardiac muscle must contract  ↓ in the extent
of shortening (i.e., to reduced stroke volume); sensitivity of stroke volume to outflow resistance is accentuated in the failing ventricle  agents that
decrease afterload are able to increase LV stroke volume in patients with systolic HF.
III. Contractibility: The contractile state of the LV is described by the end-systolic pressure-volume relationship (ESPVR)  describes the relationship
between preload and LV tension development during isovolumetric contraction (variant of the Frank-Starling law)
 ↑contractile state of the LV  reflected by an upward shift of the ESPVR  results in a ↑ degree of tension development for any given
end-diastolic volume.
 In the presence of a fixed afterload  ↑contractility results in a greater degree of muscle shortening and an ↑ in LV stroke volume.
IV. Heart Rate: If LV contractile performance is preserved  abN HR causes abN CO only at extreme rates (outside physiologic range); can be important
determinant of CO in patients with systolic contractile dysfunction.

FIGURE 25-10. Determinants of cardiac output.

Changes in preload, afterload, and myocardial contractility alter the pressure-volume relationship of the cardiac cycle. A. Increases in preload (lines 1,2,3) result in
greater stretch of ventricular myocytes, development of greater ventricular end-diastolic pressure, and ejection
of greater stroke volume (the Frank-Starling mechanism). Note that the end-systolic volume (ESV) is the same in
each case, because the contractility of the heart has not changed. B. Increases in afterload (points 1, 2,3) create
greater impedance to left ventricular output and result in proportionately decreased stroke volume (the
difference between end-diastolic volume [EDV] and ESV). The end-systolic pressure is linearly related to ESV; this
linear relationship is called the end-systolic pressure-volume relationship (ESPVR). C. Increases in myocardial
contractility (lines 1,2), as occurs after administration of a positive inotrope, shift the ESPVR up and to the left,
resulting in increased stroke volume.
2. Define heart failure and discuss three mechanisms for functional compensation in heart failure
Heart failure: inability of the myocardium to maintain normal forward output resulting in insufficient perfusion of
tissues and organs.
3 compensation mechanisms:
I. Frank Starling Mechanisms: hemodynamic stress  ↑preload (recruitment of preload reserve is first
response)  ↑stroke volume (CO)
II. Remodeling: myocardial structural changes at cellular level initiated by signaling systems when
hemodynamic stress cannot be fully compensated by Frank Starling mechanisms; specific pattern of
remodeling determined by nature of applied stress
III. Neurohormonal Systems: activated when the other 2 mechanisms are unable to reestablish adequate
forward CO; modulate intravascular volume & vasomotor tone to maintain O2 delivery to critical organs
***these mechanisms contribute to maintenance of circulatory function, but can also contribute to development &
progression of pump dysfunction & circulatory failure.
3. Draw and describe the central aim of the current pharmacologic management of heart failure according to three physiological goals
3 physiological goals of pharmacologic management of heart failure:
I. Preload reduction
II. Afterload reduction
III. Contractility enhancement (↑inotropy)

Many therapeutic agents used in the management of heart failure modulate the neurohumoral
systems that are activated by compromised cardiac function.
 The renin-angiotensin–aldosterone system can be inhibited by
I. β adrenergic antagonists  inhibit renin release by juxtaglomerular cells of the
kidney
II. ACE inhibitors  prevent the conversion of angiotensin I to the active hormone
angiotensin II
III. Spironolactone  competitively antagonizes aldosterone binding to the
mineralocorticoid receptor
 Diuretics  promote Na+ excretion  counteract the Na+ retention stimulated by activation of
the renin-angiotensin–aldosterone system.
 Venodilators  counteract the effect of intravascular volume expansion by increasing
peripheral venous capacitance and thereby decreasing preload.
 Direct arterial vasodilators  alleviate the α-adrenergic receptor-mediated and angiotensin II
receptor-mediated vasoconstriction induced by increased sympathetic outflow.
 Cardiac glycosides, β-adrenergic agonists, and cardiac phosphodiesterase inhibitors  also
used in HF to increase myocardial contractility (not shown).
4. Differentiate the class, mechanism of action, and site of action of furosemide and hydrochlorothiazide
Furosemide Hydrochlorothiazide
Class: natriuretic loop diuretic Class: natriuretic thiazide diuretic
MOA: inhibit Na+-K+-2Cl- co-transporter (NKCC2)  ↑excretion of Na+, K+, & H2O MOA: inhibit Na+ & Cl- resorption via Na+-Cl- co-transporter (NCC)
Site of Action: thick ascending limb of Henle Site of Action: distal convoluted tubule
*less efficacious than loop diuretics
5. Describe the mechanism of action of conivaptan and tolvaptan (addendum i)
*pts w/ heart failure have ↑circulating vasopressin  extent of vasopressin elevation correlates w/ severity of heart failure
Selective antagonism of vasopressin V2 receptor  ↑solute-free urine output & ↑serum Na+ levels in pts w/ heart failure
Vasopressin receptor antagonist:
Conivaptan: mixed V1a & V2 receptor antagonist
 Disadvantage: also antagonizes V1a
 IV infusion for treatment of hypervolemic hyponatremia (SIADH)
Tolvaptan: specific V2 receptor antagonist
 Oral; in pts w/ decompensated heart failure  addition to standard therapy regimen  ↑weight loss & ↓edema
*In contrast to what is given in the textbook, conivaptan and tolvaptan are currently NOT FDA-approved for the treatment of heart failure. Instead, these agents are
used off-label as adjuncts to improve volume loss in patients with heart failure.
6. Compare and contrast the class, mechanism of action, and sites of action of spironolactone, eplerenone, and
amiloride
Spironolactone Eplerenone Amiloride
Class: K+-sparing diuretic  ↑nephron reabsorption Class: K+-sparing diuretic  ↑nephron reabsorption Class: K+-sparing diuretic  ↑nephron reabsorption
of K+ of K+ of K+
MOA: inhibit biosynthesis of new Na+ channels in MOA: inhibit biosynthesis of new Na+ channels in MOA: competitive inhibitor of principle cell luminal
principle cells principle cells membrane Na+ channels
Site of Action: collecting duct of principle cells Site of Action: collecting duct of principle cells Site of Action: collecting duct of principle cells

7. Describe situations where electrolyte imbalance must be monitored with the use of potassium-sparing diuretics
 K+-sparing drugs are used primarily in combination w/ other diuretics to ↓ or correct drug-induced kaliuresis (K + excretion) & resultant hypokalemia.
 Should not be used in combination w/ ACE inhibitors (ACEI) or K+ supplements  b/c life-threatening hyperkalemia can occur
o ACEI: ↓aldosterone activity  ↓K+ excretion
8. Describe why aldosterone antagonists, but not epithelial sodium channel blockers, reduce all-cause mortality in patients with heart failure (addendum ii)
 One functional compensation mechanism in heart failure is remodeling and concentric hypertrophy of the heart  partly mediated through actions of
aldosterone on cardiac myocytes.
 Based on the law of Laplace  concentric hypertrophy leads to ↓ left ventricular compliance  ↓left ventricular ejection fraction and worsening of heart
failure.
 By blocking actions of aldosterone through receptor antagonism  remodeling and hypertrophy of the heart is attenuated  functional improvement of the
heart  thus why aldosterone antagonists reduce all-cause mortality in patients with heart failure.
9. Describe the mechanism of action of organic nitrates
Organic Nitrates: chemically reduced to release NO (gas that dissolves in biological fluids & in cellular membranes)
 reacts directly w/ guanylyl cyclase
 dilate peripheral veins  ↓preload  ↓myocardial O2 demand
 also have anti-aggregatory effect on platelets
10. Compare and contrast the nomenclature, mechanism of action, and side effects of angiotensin converting
enzyme inhibitors (ACEI) and angiotensin receptor type 1 blockers (ARB)
Angiotensin Converting Enzyme Inhibitors (ACEI) Angiotensin Receptor Type 1 Blockers (ARB)
Nomenclature: “-pril” Nomenclature: “-sartan”
MOA: prevents ACE-mediated conversion of angiotensin I to angiotensin II  MOA: competitively antagonizes binding of angiotensin II to AT1 receptor 
↓angiotensin II  ↓systemic vascular resistance  ↓inpedance to LV ejection vasodilation
 ↓aldosterone  natriuresis (↑secretion of Na+ & H2O)  ↓reactive arteriolar intimal proliferation
↓intravascular volume Side Effects: nothing significant; useful in replacing ACEI in ACEI-induced cough
↓bradykinin degradation  ↑bradykinin  vasodilation
Side Effects: hypotension, hyperkalemia, angioedema, cough
*contraindicated in pts w/ intravascular volume depletion  ↓renal perfusion at
baseline  compensatory ↑renin & angiotensin II  physiologic mechanism by
which GFR is maintained  ACE inhibitors can disrupt this mechanisms  lead to
renal insufficiency; same mechanism in pts w/ bilat renal artery stenosis.
11. Describe three mechanisms of β-blockers that make them beneficial for the treatment of heart failure
 Although the use of β-antagonists might seem counterintuitive  clinical trials have established that these agents increase survival in heart failure patients
 The benefits of β-antagonists in patients with heart failure:
o Inhibition of renin release  inhibits RAAS activation  ↓ vasomotor tone  ↓ TPR  ↓ BP
o Attenuation of the cytotoxic and signaling effects of elevated circulating catecholamines
o Prevention of myocardial ischemia due to their negative inotropic and chronotropic effects.
 Thus, β-antagonists, like ACE inhibitors, may attenuate the adverse effects of neurohumoral regulators in patients with heart failure.
 Because β-antagonists and ACE inhibitors act through distinct mechanisms and have non-overlapping toxicities  reasonable to co-administer these drugs to HF
patients.
12. Describe the mechanism of action of hydralazine and discuss the limitations for the use of this agent
MOA: inhibits IP3-induced Ca2+ release from sarcoplasmic reticulum in vascular smooth muscle cells  arterial vasodilator  ↓vascular resistance  ↓afterload
 Can be co-administered w/ nitrates in pts intolerant to ACEIs
Limitations: use restricted to pts w/ severe hypertension that is refractory to other pharmacologic therapies (b/c Ca 2+ channel blockers have more favorable safety
profile)
 Can cause compensatory retention of Na2+ & H2O  reflex tachycardia
 Can develop tachyphylaxis (↓response to drug after repeated administration)
 Can get drug-induced lupus syndrome in chronic administration
13. Describe the physiology of natriuretic peptides in the vasculature and kidney
 Natriuretic peptides are hormones released by atria, ventricles, and vascular endothelium in response to volume overload. The classical natriuretic peptides are
A-type, B-type, and C-type natriuretic peptides.
o A-type natriuretic peptide (ANP)  released primarily by the atria
o B-type natriuretic peptide (BNP)  released mainly by the ventricles
o C-type natriuretic peptide (CNP)  released by vascular endothelial cells
o The natriuretic peptide uroguanylin (UGN)  released by enterocytes in response to dietary ingestion of salt
 Vascular natriuretic peptides are released in response to increased intravascular volume, an effect that may be signaled by increased stretch of natriuretic
peptide-secreting cells.
 Circulating natriuretic peptides bind to one of three receptors, termed NPR-A, NPR-B, and NPR-C.
o NPR-A and NPR-B are transmembrane proteins with cytoplasmic guanylyl cyclase domains  activation of these receptors ↑ intracellular cGMP
o NPR-C lacks an intracellular guanylyl cyclase domain and may serve as a “decoy” or “buffer” receptor to ↓ the level of circulating natriuretic peptides
available to bind to the two signaling receptors.
o Both ANP and BNP bind with high affinity to NPR-A, while only CNP binds to NPR-B. All three natriuretic peptides bind to NPR-C. UGN binds to and
activates transmembrane guanylyl cyclase C in both renal proximal tubule cells and enterocytes, and binds to an undefined receptor in the renal
collecting duct.
 Natriuretic peptides affect the cardiovascular system, the kidney, and the CNS. Integration of natriuretic peptide-derived signals serves to ↓ volume overload
and its sequelae.
o ANP relaxes vascular smooth muscle by ↑ intracellular cGMP  causes dephosphorylation of myosin light chain  vasorelaxation.
o ANP also ↑ capillary endothelial permeability  fluid filtration from the plasma into the interstitium  ↓BP
 In the kidney, natriuretic peptides promote both ↑ glomerular filtration rate (GFR) and natriuresis.
o GFR is increased because of constriction of the efferent arteriole and dilation of the afferent arteriole, resulting in higher intraglomerular pressure
and therefore increased plasma filtration.
o The natriuretic effects on the kidney result from antagonism of ADH action in the collecting ducts and antagonism of Na + reabsorption in multiple
nephron segments.
 The central effects of natriuretic peptides:
o ↓ perception of thirst (and therefore ↓ fluid intake)
o ↓ release of ADH
o ↓ sympathetic tone
*The signaling mechanisms mediating these actions are uncertain, but may be via CNP, as this natriuretic peptide is expressed at high levels in the brain.
 These hormones appear to play an important role in regulating the pathophysiology of volume excess.

A. A-type and B-type natriuretic peptides (ANP and BNP) are hormones
secreted in response to volume overload. These peptides bind to
natriuretic peptide receptor-A (NPR-A) and natriuretic peptide receptor-
C (NPR-C). NPR-A is a transmembrane receptor with intrinsic guanylyl
 cyclase activity associated with its cytoplasmic domain. Increased
intracellular cGMP levels mediate the effects of natriuretic peptides,
including increased natriuresis. NPR-C is believed to be a “decoy
receptor,” because the protein lacks the intracellular catalytic domain.
Binding of natriuretic peptide to NPR-C may result in receptor
internalization and in degradation of the internalized receptor together
with the bound natriuretic peptide. A third natriuretic peptide, CNP, is
expressed by vascular endothelial cells and binds to NPR-B (not shown).
B. Antidiuretic hormone (ADH), also known as vasopressin, is secreted
by the hypothalamus in response to increased osmolality and volume
depletion. ADH mediates renal collecting-duct water reabsorption by
activating the Gs-coupled V2 vasopressin receptor. Activation of Gs leads
to increased adenylyl cyclase activity and increased cAMP levels. cAMP
increases collecting-duct water reabsorption by promoting the
translocation and insertion of aquaporin 2 water channel (AQP2)-
containing vesicles into the collecting duct apical membrane. The
increased apical membrane AQP2 results in increased water flux across
the collecting duct, and therefore greater reabsorption of filtered water.
Hydrolysis of cAMP by phosphodiesterase leads to removal of AQP2
from the luminal membrane by endocytosis of AQP2-containing vesicles
(not shown).
14. Describe the mechanism of action and side effects of nesiritide
MOA: recombinant human-sequence B-type natriuretic peptide (BNP); ↓pulmonary capillary wedge press (measure of hydrostatic press in pulm system), ↓systemic
vascular resistance, improves cardiac hemodynamic parameters (i.e. stroke volume); at low doses  ↑ water excretion>Na+ excretion
Side Effects: hypotension; ↑risk of renal dysfunction
*used for short-term management of decompensated heart failure
15. Describe the mechanism of action and side effects of sacubitril/valsartan combination (addendum iii)
Approved in July 2015, sacubitril is currently approved for use in combination with valsartan for the treatment of chronic heart failure.
Sacubitril is a new class of agent classified as neprilysin inhibitor.
 The function of neprilysin in physiology is the degradation of natriuretic peptides (ANP, BNP) and angiotensin II (Ang II) into inactive fragments.
 Sacubitril, by inhibiting neprilysin, increases the half-life of ANP and BNP, resulting in vasodilation and natriuresis.
o However, sacubitril also inhibits the degradation of Ang II, leading to increased plasma Ang II and activation of AT1 receptors, resulting in
vasoconstriction and water retention.
o This is the rationale for the combination therapy of sacubitril and valsartan:
 sacubitril increases levels of natriuretic peptides
 valsartan inhibits the actions of Ang II
*Due to effects on natriuresis and vasodilation, sacubitril/valsartan combination reduces both preload and afterload in the treatment of heart failure.
Side Effects: mostly related to the effects of valsartan  hypotension, hyperkalemia, renal failure, and rarely, angioedema

16. Briefly discuss the regulation of contractility

Three major control mechanisms regulate calcium cycling and myocardial contractility in cardiac myocytes.
o At the sarcolemma  calcium flux is mediated by interactions between the sodium pump and sodium-calcium exchanger.
o At the sarcoplasmic reticulum  calcium channels and pumps regulate the extent of calcium release and reuptake.
o Neurohumoral influences, especially the β-adrenergic signaling pathway, further modulate calcium cycling through these channels and transporters.
17. Identify at the cellular level, the pathophysiologic mechanisms associated with heart failure, and list three classes of inotropic agents that may be used to
improve cardiac contractility
Also see objective #2
Heart failure:
LV contractile dysfunction (systolic heart failure) is the primary cause of heart failure. Although multiple disease states can result in contractile dysfunction, the
majority of cases of left HF (-70%) are attributed to CAD. Additional causes of systolic HF include chronic abnormalities of the loading conditions imposed on the heart,
such as systemic arterial hypertension (pressure loading) and valvular heart disease (volume loading from mitral regurgitation or aortic insufficiency; pressure loading
from aortic stenosis). The contractile performance of the myocardium is initially preserved in disease states associated with abnormal loading conditions, but
cardiomyocyte injury and whole-organ contractile dysfunction supervene if the abnormal loading conditions are not corrected. The latter phase of cardiac pump
dysfunction has been referred to as cardiomyopathy of chronic overload. Systolic dysfunction can also result from diverse conditions in which the proximate pathologic
abnormality is cardiomyocyte injury or dysfunction. These conditions are referred to as dilated cardiomyopathies, because the heart characteristically remodels to
produce LV chamber dilation (with or without wall thinning) in states of primary myocyte dysfunction.
Symptomatic HF can also occur in patients with normal or near-normal LV systolic function (i.e., preserved LV ejection fraction). In such cases, the symptoms of left HF
are caused by abnormalities of LV relaxation and/or filling (diastolic heart failure). Impaired relaxation results in an elevation of LV diastolic pressure at any given filling
volume. This elevation of LV diastolic pressure causes elevation of left atrial and pulmonary capillary pressures, leading to transudation of fluid into the pulmonary
interstitium (as well as secondary, or passive, elevation of pulmonary artery and right heart pressures). The most common acute cause of isolated diastolic HF is acute
myocardial ischemia. In the setting of acute reversible ischemia (i.e., ischemia not associated with MI), LV diastolic pressures increase as a consequence of incomplete
LV relaxation. (Recall that both contraction and relaxation of cardiomyocytes depend on adequate levels of intracellular ATP.)

3 classes of inotropic agents:

 Cardiac glycosides (inhibits sarcolemmal Na+/K+-ATPase pump  ↑ intracellular [Ca2+])
o Digitalis glycosides inhibit the sarcolemmal Na+-K+ ATPase in cardiac myocytes  ↑ intracellular Na+, activates the Na+-Ca2+ exchanger, and ↑
intracellular Ca2+ (incl the Ca2+ stores in the sarcoplasmic reticulum)  ↑ calcium release upon myocyte stimulation  ↑ myocardial contractility
(i.e., upward/leftward shift of the ESPVR). Although patients with HF often experience relief of congestive symptoms during treatment with the
cardiac glycosides, these drugs have not been shown to decrease mortality.
 Sympathomimetic amines (↑intracellular cAMP)
o Dobutamine is the parenteral sympathomimetic amine used most commonly in the treatment of decompensated systolic HF (pulmonary congestion
accompanied by reduced forward cardiac output). This agent is a synthetic congener of epinephrine that stimulates β 1-receptors and, to a lesser
extent, β2-receptors and α1-receptors. The stimulation of β1-receptors predominates at therapeutic infusion rates, leading ultimately to an increase in
the contractility of cardiac myocytes. Stimulation of vascular β2-receptors causes arterial vasodilation and a reduction in afterload. The combined
effects of increased contractility and decreased afterload lead to improvement in overall cardiac performance. Dobutamine is typically used in the
acute setting (i.e., intensive care unit).
 Phosphodiesterase inhibitors (↑intracellular cAMP)
o Phosphodiesterase inhibitors (such as inamrinone and milrinone) inhibit the degradation of cAMP in cardiac myocytes and thereby increase
intracellular calcium and enhance contractility (inotropy). In the systemic vasculature, these agents cause dilation of both arteriolar resistance vessels
and venous capacitance vessels, thereby decreasing afterload and preload. As a result of these aggregate effects, phosphodiesterase inhibitors have
been referred to as “inodilators.” Despite these positive actions, both phosphodiesterase inhibitors and sympathomimetic amines are reserved for
short-term treatment of patients with acute decompensation of heart failure. Indeed, long-term treatment with oral phosphodiesterase inhibitors has
been shown to increase mortality.
18. Describe the actions of digoxin, include the mechanisms if applicable, on the following: myocardial contractility, autonomics, automaticity, conduction
velocity
Digoxin: cardiac glycoside; selective inhibitor of plasma membrane sodium pump
 Extrude ↓ sodium  ↑ intracellular [Na+]  alters equilibrium of the Na+-Ca2+ exchanger  ↓calcium efflux because the gradient for sodium entry is ↓,
while calcium influx is ↑ because the gradient for sodium efflux is ↑  net result is a rise in the intracellular [Ca2+]  SR sequesters more Ca2+  more
Ca2+ available to bind troponin C when depolarizes in response to an action potential  tension development during contraction is facilitated
 also exerts autonomic effects by binding to sodium pumps in the plasma membranes of neurons in the CNS & PNS  inhibition of sympathetic nervous
outflow, sensitization of baroreceptors, and increased parasympathetic (vagal) tone.
o also alters electrophysiologic properties of the heart by a direct action on the cardiac conduction system.
o At therapeutic doses  decreases automaticity at the atrioventricular (AV) node  prolonging the effective refractory period of AV nodal tissue
and slowing conduction velocity through the node.
o These combined vagotonic and electrophysiologic properties underlie the use of digoxin in the treatment of patients with atrial fibrillation and
rapid ventricular response rates; both the decreased automaticity of AV nodal tissue and the decreased conduction velocity through the node
increase the degree of AV block  decrease the ventricular response rate.
 In contrast to its effects at the AV node, enhances automaticity of the infranodal (His-Purkinje) conduction system.
o These divergent effects at the AV node and His-Purkinje system explain the characteristic electrophysiologic disturbance of complete heart block
with accelerated junctional or accelerated idioventricular escape rhythm (referred to as “regularized” atrial fibrillation) in patients with atrial
fibrillation and digoxin toxicity.
 Digoxin has a narrow therapeutic window, and prevention of digoxin toxicity depends on a complete understanding of the pharmacokinetics of this agent.
o Orally administered digoxin has a bioavailability of approximately 75%.
o A minority of patients harbor gut flora that metabolize digoxin to the inactive metabolite dihydrodigoxin  sometimes necessary to co-
administer antibiotics in order to decontaminate the gut and thereby facilitate oral absorption of digoxin.
o Digoxin has a large volume of distribution; the primary binding reservoir consists of Na+/K+-ATPase molecules in skeletal muscle.
o Approximately 70% of the drug is excreted unchanged by the kidney; the rest is excreted in the gut or via hepatic metabolism.
 Pharmacokinetics: Chronic kidney disease reduces both the volume of distribution and the clearance of digoxin  obligating a reduction in both the loading
dose and the maintenance dose of the drug. The reduced volume of distribution appears to be related to reduced tissue binding of the drug.
o Hypokalemia increases the myocardial localization of digoxin. Reductions in extracellular K+ appear to result in increased phosphorylation of the
sodium pump or, potentially, its regulator phospholemman, and digoxin may have a higher binding affinity for the phosphorylated form of these
proteins than for the dephosphorylated forms. (Conversely, increasing plasma K+ can help to relieve symptoms of digoxin toxicity by promoting
dephosphorylation of these proteins.)

Digoxin selectively binds to and inhibits the Na+/K+-ATPase. Decreased Na+ extrusion (dashed arrows)
leads to an increased concentration of cytosolic Na+. 2. The Increased intracellular Na+ decreases the
driving force for the Na+/Ca2+exchanger (dashed arrows), leading to decreased extrusion of Ca2+ from the
cardiac myocyte into the extracellular space and to increased cytosolic Ca2+. 3. An increased amount of
Ca2+ is then pumped by the SERCA Ca2+-ATPase (large arrrow) into the sarcoplasmic reticulum, creating a
net Increase in Ca2+ that is available for release during subsequent contractions. 4. During each
contraction, the increased Ca2+ release from the sarcoplasmic reticulum leads to increased myofibril
contraction, and therefore increased cardiac inotropy.

19. Discuss side effects of digoxin based its actions

 Arrhythmias (especially conduction disturbances with or without AV block, premature ventricular contractions (PVCs), and supraventricular tachycardias)
 Agitation, fatigue, muscle weakness, blurred vision, yellow-green halo around visual images, anorexia, nausea, vomiting
20. Discuss two pharmacodynamics interactions and two pharmacokinetic interactions with digoxin
Digoxin also interacts with many drugs. These interactions can be divided into pharmacodynamic and pharmacokinetic interactions:
 Pharmacodynamic interactions: include those with β-adrenergic antagonists, Ca2+ channel blockers, and K+-wasting diuretics.
o β-Adrenergic antagonists decrease AV nodal conduction, and the combined use of β-antagonists and digoxin can increase the risk of developing high-
grade AV block.
o Both β-antagonists and Ca2+ channel blockers can decrease cardiac contractility and potentially attenuate the inotropic effects of digoxin.
o K+-wasting diuretics (e.g., furosemide) can decrease plasma potassium concentration, which can increase the affinity of digoxin for the Na +/K+-ATPase
and thereby predispose to digoxin toxicity (see above).
 Pharmacokinetic interactions: can result from changes in the absorption, volume of distribution, or renal clearance of digoxin.
o Many antibiotics, such as erythromycin, can increase digoxin absorption by killing the enteric bacteria that would ordinarily metabolize a fraction of
orally administered digoxin before its absorption.
o Co-administration of digoxin with verapamil (a calcium channel blocker), quinidine (a class IA antiarrhythmic), or amiodarone (a class III
antiarrhythmic) can increase digoxin levels because of the impact of these drugs on the volume of distribution and/or renal clearance of digoxin.
21. Identify two treatment strategies for digoxin toxicity
 Treatment of digoxin toxicity relies on: normalizing plasma K+ levels & minimizing the potential for ventricular arrhythmias
 In addition, life-threatening digoxin toxicity can be treated with antidigoxin antibodies. These polyclonal antibodies form 1:1 complexes with digoxin that are
rapidly cleared from the body. Fab fragments of these antibodies (i.e., the portion of the antibody that interacts with antigen) have been shown to be less
immunogenic than antidigoxin IgG and to have a larger volume of distribution, more rapid onset of action, and higher clearance than the intact IgG.

22. Describe the limitations of sympathomimetic agents in the treatment of heart failure
 Clinical use of the sympathomimetic inotropes is generally reserved for short-term support of the failing circulation  due to adverse effect profile of these
agents and to their pharmacodynamic and pharmacokinetic properties
 sympathomimetic agents that stimulate myocardial β-adrenergic receptors share the adverse effect profile of tachycardia, arrhythmia, and increased myocardial
oxygen consumption
 These agents also induce tolerance via rapid down-regulation of adrenergic receptors at the surface of cells in target organs
 sympathomimetic amines have low oral bioavailability and are typically administered by continuous intravenous infusion
23. Apply the indication and mechanism of action of dobutamine to a clinical scenario
Dobutamine: synthetic sympathomimetic amine; to optimize the overall hemodynamic benefits of β-adrenergic receptor activation for patients with acute cardiogenic
circulatory failure.
 approximates the desirable hemodynamic profile of a “pure” β1 agonist  not the result of selective activation of β1-receptors, but rather derives from the fact
that the clinically available formulation is a racemic mixture of enantiomers that have differential effects on adrenergic receptor subtypes.
o Both the (+) and (−) enantiomers stimulate β1receptors and, to a lesser degree, β2-receptors, but the (+) enantiomer acts as an α1 antagonist, whereas
the (−) enantiomer is an α1 agonist.
o Because the clinical formulation includes both enantiomers, the opposing hemodynamic responses produced by these enantiomers at the α 1-receptor
effectively negate one another.
o The predominant overall effect is that of an agonist at cardiac β1-receptors, with modest peripheral vasodilation via agonist action at peripheral β2-
receptors.
 administered by continuous intravenous infusion and titrated to achieve the desired clinical effect
o Catechol-O-methyl transferase rapidly metabolizes dobutamine, so that the circulating half-life is only about 2.5 minutes.
o As with all sympathomimetic amines with β-agonist effects, dobutamine has the potential to induce cardiac arrhythmias. In clinical practice,
supraventricular tachycardia and high-grade ventricular arrhythmia occur less frequently with dobutamine than with dopamine.
o On the basis of this constellation of clinical effects, dobutamine has become the sympathomimetic inotrope of choice for patients with acute
cardiogenic circulatory failure.
24. Describe the mechanism of action of inamrinone and milrinone and identify a reason that limits the use of this class of agents (addendum iv)
Phosphodiesterase (PDE) inhibitors increase cardiac contractility by ↑ intracellular cAMP levels (similar to β-adrenergic receptor agonists).
 inhibit the enzyme that hydrolyzes cAMP  ↑ intracellular cAMP  indirectly ↑ intracellular [Ca2+]
 Although cardiac muscle expresses multiple PDE isoenzymes, selective inhibition of PDE3 has been shown to have beneficial cardiovascular effects
o Inamrinone (aka amrinone) and Milrinone: relatively selective PDE3 inhibitors  ↑ contractility and enhance the rate and extent of diastolic
relaxation.
o PDE3 inhibitors also have important vasoactive effects in the peripheral circulation  occur through cAMβ-mediated effects on intracellular
calcium handling in vascular smooth muscle and result in decreased arterial and venous tone in the systemic arterial circulation, vasodilation
leads to a decrease in systemic vascular resistance (decreased afterload); in the systemic venous circulation, an increase in venous capacitance
results in a decrease in venous return to the heart (decreased preload).
 The combination of positive inotropy and mixed arterial and venous dilation has led to the designation of PDE inhibitors as “inodilators.”
 Similar to β-agonists, PDE inhibitors have found clinical utility in short-term support of the severely failing circulation.
o Widespread application of inamrinone has been limited by the adverse effect of clinically significant THROMBOCYTOPENIA in about 10% of
patients.
 Oral formulations of PDE3 inhibitors have been developed  Unfortunately, long-term use of these agents has been limited by data
demonstrating increased mortality.
*In contrast to what is given in the textbook (p436), oral formulation of milrinone is NOT available. The development of oral formulation of milrinone was
discontinued worldwide as a result of a large multicenter trial that indicates oral formulation results in excessive increase in mortality rate (27%).
25. Discuss the physiological goal(s) of heart failure treatment that can be achieved by the agents listed in LO4-LO24
Goals: Preload reduction, afterload reduction, and contractility enhancement (increased inotropy)