Heart Failure Drugs

Question 1

other than Na+ retention, what role does aldosterone play in the development of heart failure?

Answer 1

aldosterone stimulates remodeling of heart muscle —> fibrosis

Question 2

when considered alone, how do each of the following drug types influence the Frank-Starling LV curve of SV x LVP?
a. diuretics
b. vasodilator
c. inotropics

Answer 2

a. diuretics: decrease volume/congestion —> shift left (along same ventricular function curve)

b. vasodilator: decrease afterload —> shift curve up and left (higher ventricular function curve)

c. inotropics: increase stroke volume —> shift curve up (higher ventricular function curve)

Question 3

______ agents result in greater cardiac work for a given level of ventricular filling pressure

Answer 3

positive inotropic agents result in greater cardiac work for a given level of ventricular filling pressure

Question 4

what kind of drugs are furosemide and spironolactone?

Answer 4

diuretics: decrease ECF volume/preload (furosemide) and curtail heart remodeling/fibrosis (spironolactone - aldosterone antagonist)

Question 5

what is the goal of short term inotropes for acute heart failure?

Answer 5

increase cardiac output!

Question 6

what are the stages of congestive heart failure (CHF)?

Answer 6

Stage A (pre-heart failure): high risk of HF but no structural heart disease or symptoms

Stage B (pre-heart failure): structural heart disease but no symptoms
for Stages A/B - control progression o things that will lead to heart damage (diabetes, HTN, etc)

Stage C: structural heart disease and symptoms of HF

Stage D: refractory HF requiring specialized interventions

Question 7

what is the mechanism of cardiac glycosides? name at least 1 drug in this group

Answer 7

cardiac glycosides: digitalis, digoxin, digitoxin, ouabain - inotropic agents

block Na+/K+ pump —> increased [Na+] reduces drive for NCX (Na+/Ca2+ exchanger) —> increased [Ca2+] increases force of contraction

Question 8

describe the limits of digoxin use

Answer 8

digoxin: cardiac glycosides inotrope —> blocks Na+/K+ pump to reduce drive for NCX exchanger —> increased Ca2+ increases force of contraction

limits: K+ antagonizes action —> hyperkalemia makes drug less effective, hypokalemia increases sensitivity = narrow therapeutic window

for this reason, reduction in mortality is balanced with more from sudden death due to narrow therapeutic index = reduces morbidity but not overall mortality

mostly used in seriously compromised patients who are monitored closely

Question 9

how does toxicity develop following high levels of cardiac glycosides, such as digitalis, digoxin, digitoxin, or ouabain?

Answer 9

cardiac glycosides are positive inotropes via increased [Ca2+] —> enhanced vagal tone/reduced SNS tone —> slows conduction velocity in AV node

at toxic levels, AP shorten and additional depolarization/contractions are induced

—> AV block
—> arrhythmia
—> reflex SNS increase, sensitizing the myocardium

—> nausea, vomiting, visual disturbances
—> digitalis/digoxin-induced tachyarrhythmias if hypokalemic

Question 10

which of these (multiple) are effects of cardiac glycosides?
a. increase CO
b. increase heart size
c. decrease venous pressure
d. increase EDV
e. diuresis
f. decrease blood/ECF volume
g. decreased SNS and increased vagal activity

Answer 10

cardiac glycosides increase [Ca2+] - positive inotropes (digoxin, digitoxin, ouabain)

a. increase CO (increased contractibility)
c. decrease venous pressure
e. diuresis (Na+/K+ ATPase inhibition + improved renal perfusion)
f. decrease blood/ECF volume
g. decreased SNS (direct and reflex) and increased vagal activity (decrease in HR, vasodilation)

b. DECREASE heart size
d. DECREASE EDV

Question 11

what are 2 ways (direct and indirect) by which cardiac glycosides (digoxin, digitoxin, ouabain) promote diuresis

Answer 11

direct: inhibit renal Na+/K+ ATPase, promoting Na+ excretion (water follows)

indirect: improved renal perfusion (via high CO) leads to reduced renin output —> less plasma volume is retained

Question 12

which cardiac glycoside has a very long half life

Answer 12

cardiac glycosides: increase [Ca2+] to increase force of contraction

digoxin t1/2 = 36-40 hours, used almost exclusively in seriously compromised patients due to narrow therapeutic window (antagonized by K+)

Question 13

when are beta1 agonists and bipyridines used in the progression of heart failure, and what are their respective mechanisms of action?

Answer 13

short term inotropes, used for acute HF

effects in heart:

beta1 agonists —> Gs —> adenylate cyclase —> cAMP —> Ca2+ influx —> positive inotropy/chronotropy

bipyridines block PDE3 (phosphodiesterase 3), which breaks down cAMP —> increased cAMP —> Ca2+ influx —> positive inotropy

Question 14

what kind of drugs are milrinone and enoximone, and when are they used?

Answer 14

bipyridines: PDE3 (phosphodiesterase) inhibitors in cardiac and smooth muscle
[recall PDE3 breaks down cAMP]

in heart, cAMP raises activity of L-type Ca2+ channels and contractibility (cardiac)

in smooth muscle, cAMP deactivates MLCK —> vasodilation

safe for short-term support of acute HF or exacerbation of chronic HF, when other treatments are failing

Question 15

in what clinical scenarios are the following adrenergic agonists typically used?
a. dobutamine
b. dopamine
c. norepinephrine
d. epinephrine

Answer 15

a. dobutamine: HF not accompanied by hypotension (via beta1, beta2/alpha1 cancel each other out)

b. dopamine: AVOIDED bc it is more likely to cause persistent elevation of vascular resistance/ LVP/ edema

c. norepinephrine: “warm” septic shock with drop in BP (via beta1, alpha1)

d. epinephrine: cardiac arrest - drop in contraction and HR (via beta1, beta2>alpha1 at low doses, alpha1>beta2 at high doses)

Question 16

an increase in which of the following induces cardiac remodeling, as seen in heart failure?
a. myocardium stretch
b. adrenergic tone
c. angiotensin II
d. endothelin
e. ADH
f. aldosterone

Answer 16

ALL of them

therefore ACE inhibitors and ARBs (angiotensin receptor blockers) decrease cardiac remodeling

recall that angiotensin increases adrenergic tone (via SNS - NE release), ADH, and aldosterone

therefore by blocking angiotensin, these other components are decreased, as well

Question 17

what kind of drugs are named with “-opril” endings?

Answer 17

ACE inhibitors

Question 18

which of these is NOT an effect of ACE inhibitors (captopril, enalopril, lisinopril)?
a. decreased conversion of Angiotensin I to II
b. increased K+ secretion
c. increased bradykinin
d. decreased NE release
e. decreased heart/vessel remodeling

Answer 18

a. decreased conversion of Angiotensin I to II
c. increased bradykinin (via decreased degradation)
d. decreased NE release (—> decreased SNS tone)
e. decreased heart/vessel remodeling

b. DECREASED K+ secretion via decreased synthesis of aldosterone - risk of hyperkalemia, be careful with combining with digoxin!

Question 19

what kind of drugs are captopril, enalopril, and lisinopril?

Answer 19

ACE inhibitors (end in “-opril”)

—> decreased Ang I to Ang II
—> decreased aldosterone (—> increased K+ retention, possible hyperkalemia)
—> decreased NE release/SNS tone
—> decreased heart remodeling
—> decreased degradation of bradykinin - stimulates prostaglandin formation and NO output (—> cough side effect)

Question 20

why would giving a patient a combination therapy of captopril and digoxin be potentially ineffective?

Answer 20

captopril (ACE inhibitor): decreases synthesis of aldosterone (which causes K+ secretion) —> risk of hyperkalemia

digoxin (cardiac glycoside, positive inotrope): inhibited by K+ —> doesn’t work under hyperkalemia

Question 21

what are 2 key adverse effects of ACE inhibitors? name at least 1 drug in this class

Answer 21

ACE inhibitors: captopril, enalopril, lisinopril

adverse effects: cough and angioneurotic edema (swelling of nose/throat/tongue) - associated with high bradykinin levels

recall that ACE inhibitors decrease degradation of bradykinin, and that bradykinin stimulates prostaglandin formation and NO output —> helps reduce BP

Question 22

when are ACE inhibitors typically used in the progression of heart failure, and in combination with what other class of drugs?

Answer 22

used for grades II-IV (grade C, D) CHF

most frequently used with diuretics and digitalis

when in combination, prolonged treatment reduces symptoms of CHF and mortality

Question 23

what are the adverse effects of ACE inhibitors? can you explain why these occur?

bonus if you can name 2 contraindications

Answer 23

—> cough and angioedema (swelling of nose/throat/tongue) - due to high levels of bradykinin

—> hypotension - due to decreased peripheral resistance
—> renal functional insufficiency - due to inhibition RAAS
—> hyperkalemia - due to inhibition of aldosterone (concern when used with K+ sparing diuretics like digoxin!)

*contraindicated in pregnancy (birth defects) and bilateral renal artery stenosis

Question 24

what class of drugs have names that end in “-sartan”?

Answer 24

ARBs: angiotensin II receptor blockers

ex: losartan, valsartan

Question 25

what kind of drugs are losartan and valsartan, and what effect do they have?

Answer 25

ARBs (angiotensin II receptor blockers): block AT1 receptors - same effects as ACE inhibitors, but no increase in bradykinin

therefore, not as good as ACE inhibitors, but useful in patients who can’t tolerate the cough and angioedema adverse effects of high levels of bradykinin

recall bradykinin stimulates prostaglandin formation and NO output

Question 26

this class of drugs decreases cardiac afterload by lowering peripheral resistance and reduce preload by reducing aldosterone secretion, however, they will NOT cause cough as an adverse effect

what are?

name 1 drug in this class

Answer 26

ARBs: angiotensin II receptor blockers

ex: losartan, valsartan

do NOT cause cough because unlike ACE inhibitors, ARBs do not lead to an increase in bradykinin, which at high levels causes cough and angioedema

therefore, they are only used in patients who cannot tolerate the cough, because you WANT increased bradykinin (increases prostaglandins and NO output)

Question 27

in what scenario would you give a patient with CHF losartan over captopril?

Answer 27

“-opril” = ACE inhibitor
“-sartan” = ARB

ACE inhibitors (captopril) are preferred because they increase levels of bradykinin (—> prostaglandins, NO increase)

however, high levels of bradykinin cause cough and angioedema which is sometimes intolerable for patients… in which case you can give an ARB (losartan)

*ARBs are also more selective for inhibition of effects of Ang. II because there are other enzymes (besides ACE) which can generate Ang. II

Question 28

which of these drugs is safe for use during pregnancy?
a. losartan
b. captopril
c. alpha-methyl dopa

Answer 28

c. alpha-methyl dopa: alpha2 adrengic agonist —> decreased SNS tone, ONLY used for HTN in pregnancy (safe for fetus)

losartan = ARB (Ang. II receptor blocker)
captopril = ACE inhibitor
these are both contradicted in pregnancy due to birth defects

Question 29

what is the clinical use of hydralazine plus isosorbide dinitrate (BiDil)?

Answer 29

BiDil (hydralazine + isosorbide dinitrate) is an alternative to ACE inhibitors and ARBs

not as effective, used as addition to standard treatment or in patients with persistence symptoms

Hydralazine is a vasodilator

Question 30

what kind of drug is aliskiren?

Answer 30

aliskiren: renin blocker, alternative to ACE inhibitors and ARBs

not as effective, as similar side effects as ACE inhibitors

taken orally, long t1/2 (20-45h)

Question 31

what kind of drug is nitroprusside?

Answer 31

nitroprusside = nitrodilator, dilates both arterial/venous vessels to increase CO

give by IV for acute HF, short t1/2 (2 mins)

Question 32

what kind of drug is nitroglycerin?

Answer 32

nitroglycerin: topical nitrate, decreases pulmonary/systemic venous pressures and LV filling pressure

Question 33

what kind of drug is spironolactone?

Answer 33

spironolactone: aldosterone antagonist, prescribed to counteract high [aldosterone] in heart failure patients (as stimulated by Ang. II)

can be added to therapy with ACE inhibitors to decrease mortality, helps reduce cardiac remodeling (effect of high aldosterone)

Question 34

what kind of drug is LCZ696 (Entresto), and what is it being used for?

Answer 34

Entresto/LCZ696: sacubitril (neprilysin inhibitor) + valsartan (ARB - Ang. II receptor blocker)

newer drug for HF, found to be more effective than ACE inhibitor alone to due to additional inhibition of neprilysin —> boosted ANP/BNP action

[recall that neprilysin breaks down natriuretic peptide]

adverse effects: hypotension, hyperkalemia (via aldosterone inhibition by ARB), renal failure

Question 35

what class of drugs has the following effects and uses?
- reduces cardiac remodeling in HF
- attenuated adverse effects of high concentrations of catecholamines
- decreased HR and arrhythmias
- recommended for patients with symptoms of HF or asymptomatic patients with decreased LVEF/history of MI
- adverse effects include fatigue, hypotension, bradycardia/heart block

name at least 1 drug in this class

Answer 35

beta adrenergic antagonists (beta blockers) - used to reduce arrhythmogenesis, cardiac remodeling, and SNS tone

ex: (end in “-lol”) bisoprolol, carvedilol, metoprolol-succinate (sustained-release)