Heart Failure Drugs Flashcards
other than Na+ retention, what role does aldosterone play in the development of heart failure?
aldosterone stimulates remodeling of heart muscle —> fibrosis
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
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)
______ agents result in greater cardiac work for a given level of ventricular filling pressure
positive inotropic agents result in greater cardiac work for a given level of ventricular filling pressure
what kind of drugs are furosemide and spironolactone?
diuretics: decrease ECF volume/preload (furosemide) and curtail heart remodeling/fibrosis (spironolactone - aldosterone antagonist)
what is the goal of short term inotropes for acute heart failure?
increase cardiac output!
what are the stages of congestive heart failure (CHF)?
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
what is the mechanism of cardiac glycosides? name at least 1 drug in this group
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
describe the limits of digoxin use
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
how does toxicity develop following high levels of cardiac glycosides, such as digitalis, digoxin, digitoxin, or ouabain?
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
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
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
what are 2 ways (direct and indirect) by which cardiac glycosides (digoxin, digitoxin, ouabain) promote diuresis
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
which cardiac glycoside has a very long half life
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+)
when are beta1 agonists and bipyridines used in the progression of heart failure, and what are their respective mechanisms of action?
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
what kind of drugs are milrinone and enoximone, and when are they used?
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
in what clinical scenarios are the following adrenergic agonists typically used?
a. dobutamine
b. dopamine
c. norepinephrine
d. epinephrine
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)
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
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
what kind of drugs are named with “-opril” endings?
ACE inhibitors
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
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!
what kind of drugs are captopril, enalopril, and lisinopril?
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)
why would giving a patient a combination therapy of captopril and digoxin be potentially ineffective?
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
what are 2 key adverse effects of ACE inhibitors? name at least 1 drug in this class
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
when are ACE inhibitors typically used in the progression of heart failure, and in combination with what other class of drugs?
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
what are the adverse effects of ACE inhibitors? can you explain why these occur?
bonus if you can name 2 contraindications
—> 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
what class of drugs have names that end in “-sartan”?
ARBs: angiotensin II receptor blockers
ex: losartan, valsartan
what kind of drugs are losartan and valsartan, and what effect do they have?
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
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
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)
in what scenario would you give a patient with CHF losartan over captopril?
“-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
which of these drugs is safe for use during pregnancy?
a. losartan
b. captopril
c. alpha-methyl dopa
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
what is the clinical use of hydralazine plus isosorbide dinitrate (BiDil)?
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
what kind of drug is aliskiren?
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)
what kind of drug is nitroprusside?
nitroprusside = nitrodilator, dilates both arterial/venous vessels to increase CO
give by IV for acute HF, short t1/2 (2 mins)
what kind of drug is nitroglycerin?
nitroglycerin: topical nitrate, decreases pulmonary/systemic venous pressures and LV filling pressure
what kind of drug is spironolactone?
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)
what kind of drug is LCZ696 (Entresto), and what is it being used for?
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
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
beta adrenergic antagonists (beta blockers) - used to reduce arrhythmogenesis, cardiac remodeling, and SNS tone
ex: (end in “-lol”) bisoprolol, carvedilol, metoprolol-succinate (sustained-release)
