9-16 & 9-21 Anti CHF Drugs Flashcards Preview

Cardiovascular II Exam 3 > 9-16 & 9-21 Anti CHF Drugs > Flashcards

Flashcards in 9-16 & 9-21 Anti CHF Drugs Deck (105):

What are the major types of positive inotropic agents for heart failure?

cardiac glycosides


beta-adrenergic receptor agonists


What are some important classes of drugs in the treatment of HF that have NO positive inotropic effects?


ACE inhibitors

Angiotensin receptor blockers


beta-adrenergic receptor blockers

natriuretic peptide



When does HF occur?

HF occurs when cardiac output is inadequate to provide the oxygen needed by the body, usually due to a decrease in contractility of the myocardium, which can be caused by diminished coronary blood flow (i.e., coronary artery disease)


Reduction in myocardium contractility is a frequent problem associated with HF. What can this reduction in contractility be caused by?

caused by damaged heart valves

external pressure around the heart

vitamin B deficiency

 primary cardiac muscle disease,

or any abnormality that makes the heart an ineffective pump


What is the primary defect in early HF?

deficits in the excitation-contraction coupling machinery of the heart. 

As HF develops, additional organs and systems become involved and pathological events occur within the baroreceptor reflex, sympathetic nervous system, kidneys, angiotensin II, aldosterone, and cardiac cells (apoptosis).


What improves relief of symptoms of HF? (not survival)

diuretics --> address volume overload

positive inportopic agents --> address myocardial dysfxn/contractility


What improves survival in HF?

agents that act directly on organs and systems other than the heart are more valuable in the long-term treatment of heart failure

(e.g., angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers, and aldosterone receptor antagonists have been shown to reduce mortality).


HF results in a decreased CO. What are 2 direct consequence of this?

decreased carotid sinus firing

decreased renal blood flow


HF-associated decrease in CO is associated with a drop in carotid sinus firing, which will increase what type of nerve signalling? How will this lead to compensatory cardiac measures?

drop in carotid sinus firing = increased sympathetic discharge


results in increased force, rate and preload

 - increases CO ultimately. for awhile at least


HF-associated decreased CO will also lead to a decrease in renal blood flow. What are the humoral and cardiac responses to this that?

decreased renal blood flow = increased renin release

increased renin = increased Ang II

increased Ang II = increased preload, afterload, remodeling


Increased Ang II released associated with HF will also increase what step before compensation?

increased renin = increased NE released, sympathetic discharge

increased sympathetic discharge = more renin released


What 2 signs or changes would you associated with systolic failure in HF? What kind of HF are these signs typical for, and what drugs do they respond to?

  1. Reduced cardiac output and contractility
  2. Reduced ejection fraction (≤40%, although definitions vary; normal > 60%)
  3. Typical of acute failure (e.g., resulting from myocardial infarction)
  4. Responds to positive inotropic agents


HF is also associated with diastolic failure. What changes would you expect, and what drugs do they tend NOT to respond to?

  1. Occurs as a result of hypertrophy and stiffening of the myocardium
  2. Although cardiac output is reduced, ejection fraction may be normal
  3. Does not typically respond optimally to positive inotropic agents


What are the signs and Sx's of all forms of HF?

Signs and symptoms of all forms of heart failure include:


decreased exercise tolerance,

shortness of breath,

peripheral and pulmonary edema,



decreased exercise tolerance is the major direct consequence of diminished cardiac output while other manifestations result from compensatory adaptations


What is the prototype for cardiac glycosides?



What is digoxin used for?

HF and A-fib


How is digoxin distributed in tissues? How is it cleared from the body?

Widely distributed to tissues, including the CNS


For patients with normal renal function, the half life is 36-48 hours, permitting once-a-day dosing (66% is eliminated unchanged by the kidney)


Since digoxin is cleared by the kidney, what kinds of changes in clearance should you watch out for?

  1. In patients with renal insufficiency (or elderly patients), the half life increases to 3.5-5 days and requires dosing adjustments


  1. 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


What is the MOA for digoxin?

  1. MOA: 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


What are the 2 desired effects of digoxin?

(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)


Describe the mechanism for the positive inotropic effect. (More of an FYI slide)

  1. nhibition 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
  2. 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)
  3. With reduced Ca2+ efflux and repeated entry of Ca2+ with each action potential, Ca2+ accumulates in the myocyte
  4. 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
  5. Therefore, cardiac glycosides increase myocardial contractility by ultimately increasing the releasable Ca2+ from the SR (see lecture slides for more information)
  6. The magnitude of the positive inotropic effect correlates with the degree of Na+/K+ ATPase inhibition


Summarize the mechanism of digoxin's positive inotropic effect.

Na/K ATPase pump is inhibited

intracellular Na+ increases

Na+ importer/Ca++ exporter gradient stops

Intracellular Ca++ increased

more Ca++ taken up then released from SR

more Ca++ released from SR = more contractility


The magnitude of digoxin's positive inotropic effect is actually dependent on what?

correllates with degree of Na+/K+ ATPase inhibition


Digoxin causes what electrical changes in the action potential?

early, brief prolongation of the action potential,

followed by action potential shortening (especially the plateau phase)


What causes the decrease in AP duration with digoxin?


The decrease in action potential duration may be the result of increased potassium conductance that is caused by increased intracellular calcium


Digoxin-induced elevated intracellular Ca2+ increases the activity of Ca2+-dependent K+ channels


Increased Ca2+-dependent K+ channel activity promotes K+ efflux and a more rapid repolarization (i.e., shortened cardiac action potential)


Digoxin will also increase PNS tone and reduce SNS tone. How does it accomplish this? What inhibits the PNS effect?

Something something rib raising?


Actually, it's this:

Parasympathomimetic effects predominate on cardiac tissue at therapeutic levels of digoxin 

Parasympathomimetic effects are inhibited by atropine


What are the PSNS effects that digoxin potentiates?

Parasympathomimetic effects involve:


sensitization of the baroreceptors,

central vagal stimulation, and

facilitation of muscarinic transmission at the cardiac muscle cell (unknown mechanism)


Where is cholinergic stimulation at the heart concentrated, and what does that mean for digoxin's effect on the heart?

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


What are the rhythm changes associated with toxic levels of digoxin?

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)


If digoxin toxicity is persistent, what arrhythmia can develop? What exacerbates digoxin toxicity?

If allowed to progress, the tachycardia may deteriorate into fibrillation that could be fatal unless corrected

At toxic levels, sympathetic outflow is increased by digoxin, which exaggerates toxic effects of the drug


What toxic effects can digoxin have outside of the heart?

Cardiac glycosides affect all excitable tissues due to their MOA and can cause adverse effects throughout the body (primarily GI and CNS)


Gastrointestinal system (most common site of digoxin toxicity outside the heart)

Anorexia, nausea, vomiting, and diarrhea


CNS: vagal and chemoreceptor trigger zone stimulation can cause GI symptoms; disorientation, hallucinations, and visual disturbances and/or changes

Gynecomastia is a rare effect that can occur in men



What drug can be administered in case of digoxin overdose?

Antidigoxin immunotherapy (antidigoxin fab antibody) can be utilized in cases of digoxin overdose


What is the effect of potassium levels on digoxin?

Digoxin and potassium bind to competing sites on the Na+/K+ ATPase


Hyperkalemia can reduce the effects of digoxin (especially the toxic effects)

Hypokalemia can potentiate the toxic effects of digoxin


Hyperkalemia inhibits abnormal cardiac automaticity (i.e., hyperkalemia decreases pacemaker arrhythmogenesis)


What is the effect of digoxin on a healthy heart? On a chronically failing heart?

Digoxin has little effect on 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%


What are 2 examples of bipyridines?




What are bipyridines meant to treat?

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


How are bypridines excreted? Half life? Route of administration?

10-40% is excreted in the kidney

Elimination half-lives are 3-6 hours in patients with severe heart failure (approximately half that in healthy patients)

parenteral administration only


What is the MOA for bipyridines?

selective inhibition of phosphodiesterase isozyme 3 (PDE3),

which increases cyclic adenosine monophosphate (cAMP) concentrations

(phosphodiesterase enzymes degrade cellular cAMP and cGMP)


What effect of bipyridines provides most of the benefit to HF patients?

Although they are positive inotropes,

most of their benefit in HF is due to their vasodilatory action


Bipyridines increase levels of cAMP in the heart. What does this cause? How?

Increased concentrations of cAMP in the heart result in direct stimulation of myocardial contractility and acceleration of myocardial relaxation


cAMP-dependent protein kinases (PKA) in the heart phosphorylate and activate voltage-gated Ca2+ channels, increasing the amount of Ca2+ entering the cell during an action potential

Increased concentrations of Ca2+ increase the force of contraction of the heart


PKA also phosphorylates other targets resulting in a faster rate of relaxation


Do bipyridines and digoxin increase contractility though the same mechanism?


Even though both increase intracellular Ca++, it's done via different mechanisms


What effect do bipyridines have on the vasculature?

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


cAMP-dependent protein kinases in smooth muscle phosphorylate and inactivate myosin-light chain kinase


Inactivation of myosin-light chain kinase causes smooth muscle relaxation (vasodilation)


What do PDE3 inhibitors do to CO? How?

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’)


What toxic side effects are associated with inamrinone?




thrombocytopenia, and

liver enzyme changes


What toxic side effects are associated with milrinone?


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


What would you use bipyridines long-term for?

 these agents are only used for short-term therapy;


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


What are the prototypical beta-adrenergic and dopaminergic agonists for HF? (positive inotropic effects)

dobutamine - beta agonist



What kind of HF are dopamine and dobutamine approved for?

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


What is the MOA for dopamine and dobutamine?

MOA: act via stimulation of the cardiac myocyte β1-adrenergic receptor

Receptor activation leads to stimulation of the GS-adenylyl cyclase-cAMP-protein kinase A (PKA) pathway

PKA phosphorylates a number of substrates that enhance Ca2+-dependent contraction and speed relaxation


What receptors does dobutamine stimulate?

Stimulates β1-receptors with little effect on β2- or α-receptors

1 selective)


What is the beta agonist of choice for HF and systolic dysfxn?



What is the principle hemodynamic effect of dobutamine?

increase in stroke volume due to its positive inotropic action and an increase in cardiac output


What are the major side effects of dobutamine?

excessive tachycardia and arrhythmias


How is dobutamine administered?



When is dopamine useful in HF?

Endogenous catecholamine with limited utility in the treatment of most patients with HF

May be useful in patients if there is a need to raise blood pressure


What is the effect of dopamine at low doses?


by stimulating dopaminergic (D1) receptors on smooth muscle (causing cAMP-dependent relaxation)

stimulating presynaptic D2 receptors on sympathetic nerves in the peripheral circulation (inhibiting norepinephrine release and reducing α-adrenergic stimulation of vascular smooth muscle)


What is the effect of intermediate doses of dopamine?

dopamine directly stimulates β receptors on the heart and vascular sympathetic neurons (enhancing cardiac contractility and neural norepinephrine release)


What is the effect of high doses of dopamine?

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)


What is a side effect and contraindication of dopamine?

Tachycardia is more pronounced with dopamine than with dobutamine and may provoke ischemia in patients with coronary artery disease


How is dopamine adminstered?



What classes of agents are used that don't have positive inotropic effects in HF?




Vasodilators - veno- and arteriolar dilatorors

beta blockers


What role do diuretics play in HF? Kidneys?

Play a key role in the pharmacological management of ‘congestive’ symptoms in patients with HF

Major mechanism of action in HF is to reduce extracellular fluid volume, venous pressure, and ventricular preload

(highlights the central role of the kidney in the hemodynamic, hormonal, and autonomic responses to myocardial failure)

Use of diuretics, with the exception of aldosterone antagonists, does not reduce mortality in heart failure

The use of ADH antagonists in patients with heart failure is somewhat controversial and not universally recommended by major society guidelines


What cardiac effects do diuretics have in HF?

reduce ventricular preload

reduction of edema and its symptoms, and reduction of cardiac size, which leads to improved pump efficiency

Reduces preload with no significant effect on afterload


Which loop diuretics are used for HF?





How are thiazide diuretics useful in HF?

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

combination with loop diuretics is often effective in those refractory to loop diuretics alone


Are potassium-sparing diuretics useful for HF?

Potassium-sparing diuretics are relatively weak diuretics and therefore are not effective for volume reduction


Are aldosterone antagonists useful in HF? How?

aldosterone antagonists have been shown to improve survival in patients with advanced heart failure via a mechanism that is independent of diuresis

Aldosterone antagonists

Decreases high RAS/aldosterone levels seen in HF

aldosterone can cause fibrosis in myocardium and vasculature, and baroreceptor dysfn

block aldosterone = block this pathology


What are the prototypical aldosterone antagonists?




Why are ADH antagonists useful in HF?

ADH excess causing water retention resulting in hyponatremia


What are 2 prototypical ADH antagonists and what is their MOA?

Conivaptan is an ADH receptor antagonist (V1a and V2) in the cortical collecting tubule


Tolvaptan is a selective antagonist of V2 ADH receptors that is given PO


What are some adverse effects of conivaptan and tolvaptan?

hypernatremia, nephrogenic diabetes insipidus


How is angiotensin problematic in HF?

Angiotensin II is a potent arterial vasoconstrictor, increases retention of sodium and water through its effects on glomerular filtration pressure and aldosterone secretion, potentiates neural catecholamine release, is a secretagogue for catecholamine release from the adrenal medulla, is arrhythmogenic, promotes vascular hyperplasia and pathologic myocardial hypertrophy, and stimulates myocyte death


What are the cardiac effects of inhibiting ang II?

Inhibition of the actions of angiotensin II will reduce both preload (intravascular volume is reduced by blocking aldosterone secretion) and afterload (via vasodilation)


What neural effects of ACE inhibitors are helpful in HF treatment?

ACE inhibitors decrease sympathetic nervous system activity, most likely through attenuation of presynaptic angiotensin effects on norepinephrine release


What mechanism has been proposed to account for the beneficial effects of ACE inhibitors on remodeling?

ACE inhibitors reduce the long-term remodeling of the heart and vessels

ACE is the same enzyme as kininase II, which degrades bradykinin and other kinins

Kinins stimulate the production of nitric oxide (NO), cyclic GMP, and vasoactive eicosanoids, substances which seem to oppose the effects of angiotensin II on the growth of vascular smooth muscle and cardiac fibroblasts and on production of extracellular matrix

Increased levels of bradykinin that result from ACE inhibition may play a role in the hemodynamic and anti-remodeling effects of ACE inhibitors


What other beneficial medication do ACE inhibitors potentiate?

potentiate the effects of diuretics in heart failure


What are the adverse effects of ACE inhibitors?





Which ACE inhibitors are approved for use in HF?










What receptor mediates the deleterious effects of ang II in HF?

mediated through the angiotensin II receptor AT1 (a second angiotensin II receptor, AT2, mediates responses that counterbalance the biological effects of AT­1 stimulation)


How are ARBs helpful in HF? (hint: what receptors do they work at?)

ARBs selectively block AT1 receptors, resulting in beneficial effects of AngII action at AT2 receptors

ARBs do not alter bradykinin metabolism, which ACE inhibitors reduce


When are ARBs indicated?

Should be considered in patients intolerant to ACE inhibitors (e.g., because of the ACE inhibitor cough, angioedema)


What are the prototypical ARBs?




How are vasodilators effective in acute HF?

they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both


How do vasodilators work/MOA?

Vasodilators relax vascular smooth muscle by supplying nitric oxide (NO) and thereby activating soluble guanylyl cyclase, which increases cGMP concentrations and ultimately results in relaxation


What are some examples of vasodilators?

nitrovasodilators (isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, sodium nitroprusside),

hydralazine, and



What are some important venodilators in HF? What is the MOA?

Nitrates: e.g., nitroglycerin, isosorbide dinitrate

MOA: NO released when drug is metabolized; NO activates guanylyl cyclase


What are the cardiac effects of venodilators?

Causes venodilation and reduces preload and ventricular stretch


When are nitrates used? What limits their effectiveness?

Used in acute and chronic HF as well as angina and hypertensive emergencies

Long-term effectiveness limited by nitrate tolerance


What are the adverse effects of venodilators?

postural hypotension, headache, flushing, reflex tachycardia


What is the effect of arteriolar dilators?

Stimulates release of NO from endothelium

Causes direct vasodilation of arterioles with little effect on veins

Reduces blood pressure and afterload; results in increased cardiac output


What drug is an example of an arteriolar dilator?



What are the toxicites associated with hydralazine?

Toxicities include reflex tachycardia, fluid retention, lupus-like syndrome


What is a combined arteriolar and venodilator?



What is the MOA for nitroprusside?

MOA: spontaneously converted to NO, which activates guanylyl cyclase


What are the pharmacodynamics of nitroprusside?

marked vasodilation

profound reduction in preload and afterload


What is nitroprusside used for?

Used for acute cardiac decompensation and hypertensive emergencies


What is Nesiritide? What does it treat?

  1. Recombinant form of human brain natriuretic peptide (BNP) that has been approved for treatment of acutely decompensated HF with dyspnea at rest or with minimal activity


What is the MOA for Nesiritide?

MOA: binds to natriuretic peptide receptor (NPR) on vascular smooth muscle and endothelial cells, increasing intracellular cyclic GMP, resulting in smooth muscle cell relaxation and reduced endothelin production

The vasodilation, natriuresis, and diuresis produced by nesiritide counteract the effects of angiotensin and norepinephrine


How is Neisiritide administered? What are the common adverse effects?

Most common adverse effects include excessive hypotension; IV administration of nitroglycerin or nitroprusside is usually preferred vasodilator therapy in acute decompensated heart failure


What neural effect in HF are beta blockers effective at counter-acting?

HF is characterized by sympathetic hyperactivation, a response to reduced cardiac output that is both compensatory and maladaptive 

Sympathetic activation supports circulatory function by enhancing contractility, augmenting ventricular relaxation and filling, and increasing heart rate


What beta blockers are shown to reduce mortality in HF, and why?

Agents shown to reduce mortality are: 

bisoprolol1-selective antagonist; off-label use for HF in USA),

carvedilol (nonselective α and β receptor antagonist with vasodilating activity; mild-to-severe heart failure), and

metoprolol1-selective antagonist; mild-to-moderate heart failure)


What 5 mechanisms are beta blockers throught to do to reduce mortality in HF?

Exact mechanisms in treating heart failure unknown

Improve contractile function (inotropic and chronotropic) by upregulating beta receptors

Attenuation or prevention of the maladaptive catecholamine-induced cardiomyocyte toxicity (including apoptosis)

Favorable effects on remodeling (improving LV geometry to increase ejection fraction)

Reduce myocardial oxygen consumption

Decrease the frequency of unstable tachyarrhythmias


What dose do you start beta blockers in HF at?

Therapy is initiated at low doses because β-blockers can acutely antagonize the supportive effects of catecholamines and may worsen heart failure, especially during the first few weeks of treatment


How long until beta blockers cause an improvement in HF?

Several months of therapy may be required before improvement is noted, usually by a slight rise in ejection fraction, slower heart rate, improved exercise tolerance, and reduction in symptoms