Heart Failure Flashcards
diuretics
Hydrochlorothiazide,
furosemide
Triamterene
Amiloride
ACE inhibitors
- captopril (Capoten™)
- enalapril (Vasotec™)
- lisinopril (Zestril™)
- Ramipril
- Quinapril
nitro vasodilators
nitroglycerin
isosorbide dinitrate (Isordil™)
isosorbide mononitrate (Ismo™)
hydralazine
digitalis glycosides
digoxin
digoxin immune fab (Digibind™)
Catecholamines
dopamine
dobutamine (Dobutrex™)
isoproterenol
PDE-III inhibitors
amrinone
milirinone
B adrenergic receptor blockers
carvedilol (Coreg™)
metoprolol CR/XL (Toprol-XL™)
Bisoprolol (Zebeta™)
aldosterone antagonists
sprionolactone
eplerenone
neprilysin inhibitors
valsartan
sacubitril
soluble GC activators
vericiguat
SGLT2 inhibitors
Dapagliflozin (JardianceTM)
other gliflozins
heart failure to usually associated with ____ ventricular dysfunction or _____ stroke volume
left; reduced
Patients with a ____ and symptoms of heart failure are considered to have heart failure with preserved ejection fraction (HFpEF).
left ventricular ejection fraction LVEF ≥50%
stroke volume
A most important measure of cardiac function is the stroke volume. , i.e. ml of blood that are pumped out of the left or right ventricles/beat.
cardiac output
= Stroke Volume x Heart Rate
factors that regulate stroke volume
- The length of the muscle at the onset of contraction (preload) [Starling’s law of the heart].
- The inotropic state of the muscle (i.e., the position of its force-velocity relation).
- Stroke volume is inversely proportional to the tension which the muscle is called upon to develop during contraction (i.e., afterload)
frank-starling relationship
stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (the end diastolic volume or preload). This occurs because stretching of the myofibrils results in more efficient creation of cross-bridges between the contractile proteins
preload (end-diastolic volume)
force distending the ventricles. It references the length of the muscle prior to contractility
moment in the cardiac contraction-relaxation cycle when the ventricle contains the greatest volume of blood, just before it contracts and ejects its volume
afterload
the resistance to ventricular ejection
wall tension during systolic ejection
sources of afterload resistance
- blood pressure (major)
- systemic vascular resistance (SVR)
- condition of the aortic valve
laplace law for afterload or tension
Tension = V.P. x Vent. radius / 2 x wall thickness
conditions that can reduce the force of cardiac contractions
Myocardial ischemia
Hypertension
Toxic injury (alcohol and smoking)
Infections
Congenital and genetic abnormalities
Other
etiology of HFrEF
- The heart
- vasculature
- kidney
- Neurohumoral regulatory circuits
treatment of heart failure
reduction of cardiac load
control of excessive fluid retention
ACEi and ARBS actions
- Prevent conversion of AI to AII and lower circulating AII.
- antagonize deleterious actions of AII on the heart, BV and Kidneys
- Cause veno and arterial dilation to decrease mean arterial BP.
- Reduce levels of aldosterone (act as an indirect diuretic)
- Increase stroke volume and cardiac output for a given preload
- reduce ventricular end-diastolic pressure and volume
- Increase bradykinin (ACEI)
- improve myocardial energy metabolism
net effect of ACEi and ARBs
direct effects on preload and afterload and improved survival
side effects of ACEI
- hypotension
- Cough ~15-20% of patients (bradykinin acting on stretch receptors in the throat).
- Hyperkalemia because they reduce aldosterone, which normally mediates Na+ absorption and K+ excretion
- Proteinuria and angioedema
side effects of ARBs
- Hypotension
- Recommended for patients with cough from ACEI.
- Less angioedema Than ACEI.
patients with heart failure and reduced ejection fraction should receive what
ACEI or ARB
what do ACEI and ARBs do for hospitalizations
decrease incidences and prolong survival
also improve symptoms
T/F: ACEI and ARB should be started at higher doses
FALSE - low doses and titrate to the highest tolerated dose targeting max daily
can you combine diuretics with ACEI and ARB
yes, if the patient has fluid retention
what type of diuretics are more effective in treatment of HF
loop of henle aka loop diuretics > thiazides
what is chronic HF associated with?
increased catecholamine neurotransmitter release, which increase HR and force and maintain CO
the heart reacts to ______ by a HF-specific gene program
chronic sympathetic stimulation
B blockers reverse the heart failure gene program by?
administration at very low doses initially then gradually increased over 8 week intervals
what happens when B blockers are administered?
lower HR, reduce O2 consumption, fibrosis, arrhythmias, cell death
_____ improve contractile function and improve cardiac perfusion by prolonging _____ thereby reducing ischemia
B blockers; diastole
carvedilol
- NON-selective B blocker with NO intrinsic sympathomimetic activity and alpha-1 adrenergic receptor blocker
- scavenger of O2 free radicals → role in myocardial necrosis
- metabolizes by CYP2D6, but half life of the drug is 7h, allowing twice a daily dosing
clinical effects of carvedilol
- with continuous use, Carvedilol increases S.V. decreases intracardiac and pulmonary vascular pressure
- decreases heart rate.
- prevents progressive enlargement of the left ventricle.
- Reduces incidence of diabetes mellitus.
metoprolol
- B blocker
- zero-order prolonged release formulation
why choose metoprolol over carvedilol
metoprolol once a day dosing, less hypotension because alpha 1 (orthostatic hypotension), more selective B1 blockade (reduce risk of bronchospasm)
disadvantages of metoprolol
- metabolism dependent on polymorphic CYP2D6
- CYP2D6 poor metabolizers
bisoprolol
long-half life and give once daily
side effects of beta blockers
- May aggravate heart failure
- they are administered at low doses that are built slowly. (START LOW AND GO SLOW).
- Like other β-blockers, may aggravate bronchospasm and precipitate asthma.
population that SHOULD be treated with B blocker
- All patients with symptomatic heart failure and
- all patients with left ventricular dysfunction (stage B, NYHA I)
- after myocardial infarction
when shouldn’t beta blockers be administered
in new-onset or acutely decompensated heart failure. If patients are hospitalized with acute decompensation
PEARL OF B blockers
Use of ß-blockers such as bisoprolol, carvedilol, or extended-release metoprolol succinate in addition to ACEI consistently leads to a 30-40% reduction in hospitalization and mortality
aldosterone receptor antagonists MOA
- Aldosterone, as the second major actor of the RAAS, promotes Na+ and fluid retention, loss of K+ and Mg2+ , and myocardial and vascular fibrosis and damage.
- MRAs are K+-sparing diuretics but gained more importance in the treatment of heart failure for their additional efficacy in suppressing the consequences of neurohumoral activation.
- Aldosterone plasma levels decrease under therapy with ACEIs or ARBs, but quickly increase again, a phenomenon called aldosterone escape.
what do mineralocorticoid receptor antagonists (MRA) do
MRAs act as antagonists of nuclear receptors of aldosterone.
side effects of MRA
hyperkalemia
what is the only MRA drug approved as an add on for HF
eplenorone
when can you not use MRAs in CHF
Do not use if the GFR is less than 30 mL/min (creatinine ~ 2 mg/dL).
why must you be more careful using MRAs in diabetic patients?
carry higher risk of hyperkalemia
____ are contraindicated in heart failure
NSAIDs
peptides related to ANP
- Atrial Natriuretic peptide (ANP)
- Brain Natriuretic peptide (BNP)
- C-Type Natriuretic peptide (CNP) (endothelial and renal origin)
- Urodilatin (found in urine, paracrine regulator of Na+ transport)
atrial natriuretic peptide
- an atrial peptide produced in response to stretch.
- It binds to NP receptor-A (NPR), activates GC and increases cGMP.
brain natriuretic peptide
- BNP is produced by the ventricle
- BNP also binds to NPR-A and acts like ANP
C-type natriuretic peptide
CNP binds to NPR-B in vascular smooth muscle cells and mediates relaxation.
urodilatin
what is an inhibitor of peptidase neprilysin
sacubitril
Neprilysin mediates enzymatic degradation and inactivation of natriuretic peptides (ANP, BNP, CNP), bradykinin, and substance P
Entresto
- recommended over an ACEI or ARB in patients with NYHA class II or III HF
- ARB-NI combination (ARNI)
- A combination of an ARB “Valsartan” and sacubitril (an inhibitor of the peptidase neprilysin
- Entresto combines inhibition of the RAAS with activation of a beneficial axis of neurohumoral activation, the natriuretic peptides
clinical effects of ARNI (ARB-NI)
- ARNI promote the beneficial effects natriuresis, diuresis, and vasodilation of arterial and venous blood vessels.
- ARNI also inhibit thrombosis, fibrosis, cardiac myocyte hypertrophy, and renin release.
- They augment ANP/BNP levels by inhibiting their degradation, which is a better pharmacological principle than giving the agonist BNP (neseritide).
adverse effects of ARNI
- Hypotension, renal insufficiency, and hyperkalemia can occur.
- BP and serum K+ should be monitored
who shouldn’t take ARNI?
Patients with a history of angioedema should not take an ARNI.
what are ARNI contraindicated with
- contraindicated for use with or within 36 hours after the last dose of an ACE inhibitor.
- Concurrent use of potassium-sparing diuretics is contraindicated.
- NSAIDs might worsen renal function when taken with EntrestoTM.
- Contraindicated in Pregnancy (ARB)
nitrovasodilators MOA
activate soluble guanylyl cyclase by mimicking the activity of nitric oxide (NO)
net effects of nitrovasodilators
- Increase concentration of cyclic GMP in vascular smooth muscles relaxes smooth muscles in peripheral veins
- increase venous capacitance
- Improve exercise capacity
- Reduce pulmonary and systemic vascular resistance
side effects of net effects of nitrovasodilators
nitrate tolerance and hypotension
vericiguat
- Potent soluble guanylate cyclase STIMULATOR.
- Reduces afterload by increasing cyclic GMP leading to smooth muscle relaxation and vasodilation of veins/arteries.
- Intended for use in adults with symptomatic chronic HF and EF <45% who are receiving standard therapy without further symptom improvement
- Contraindicated in pregnancy
- Should not be taken with PDE5 inhibitors (e.g. Viagra) Hypotension.
MOA of hydralazine
relaxes arteriolar smooth muscles
pharm effects of hydralazine
- Reduces systemic and vascular resistance
reduces R and L ventricular afterload - Increases stroke volume and reduces stress during ventricular systole.
- Has no effect on venous capacitance, used with a nitrovasodilator for HFrEF patients.
- A fixed combination of Hyd 37.5 mg and 20 mg of isosorbide dinitrate is sold as Bidil™ (it is the first race-based drug in the US, because it is marketed exclusively for CHF in African Americans).
clinical uses of hydralazine
used in a combination with a diuretic, isosorbide mono- or dinitrate and occasionally with a ACE inhibitor
MOA of digoxin and digitoxin
- Digoxin binds to and inhibits the -subunit of the sarcolemmal Na+-K+- ATPase.
- Inhibition of the ATPase leads to an increase in intracellular Na+ concentration which in turn activate Na+/Ca++ exchange leading to increased intracellular Ca++ concentration.
- Increased Ca++ ions are reabsorbed by the S.R. Therefore, the Conc. of Ca++ in the S.R. increases
- Consequently increased amounts of Ca++ are released by the S.R. after depolarization.
- Summary: Digitalis glycosides increase the release of calcium during systole and there by increase FORCE
positive inotropic effect
- Increase the velocity of cardiac muscle shortening.
- Increased stroke volume is generated for a given preload.
- These changes are caused by the increase availability of Ca++ ions during systole
regulation of sympathetic activity
- Direct: Inhibit Na-K-ATPase in neuronal cells. Stimulate parasympathetic and inhibit sympathetic discharges.
- Indirect: improve the pattern of fluctuating sympathetic discharges because digitalis sensitizes pressure sensitive baroreceptor cells.
electrophysiological effects
- Prolong the effective refractory period and decrease conduction velocity the AV node.
- increase in vagal tone impedes transmission through the AV node.
does Digitalis (Digoxin) prolong survival?
NO. decreases symptoms of heart failure, increases exercise tolerance, decreases the rate of hospitalization
half life 26-45 hours
what condition influences the pharmcokinetics of digoxin
impaired kidney function
factors that increase the toxicity of digitalis
- Narrow margin of safety (monitor digoxin serum levels).
- Hypokalemia – hypokalemia enhances digitalis toxicity by promoting glycoside binding to the Na+-K+-ATPase pump and by inhibiting the turnover of the Na+ pump.
- Hypokalemia decreases the margin of safety of digitalis glycosides.
side effects of digitalis
- Extracardiac
CNS: visual problems, fatigue,
G.I. Anorexia, nausea and vomiting - Cardiac
Electrophysiological, including suppression of AV conduction, ectopic beats in AV and ventricle. EKG reveals a prolonged PR interval
digoxin intoxication
- Administration of K+: potassium stimulates sodium pump activity, reduces glycoside binding to the Na+-K+-ATPase and alters membrane conductance to cations.
-
Anticardiac glycoside immunotherapy (Digibind™)
Digibind™ is a purified preparation of Fab fragments from sheep anti-digoxin antisera. 1 vial neutralizes 0.6 mg digoxin
dopamine MOA
- used short term
- activates cardiac ß1-adrenergic receptors (cardiotonic) and dopamine receptors in the kidney to produce renal vasodilatation.
dopamine is used in the _____
hospitals
preferentially dilates renal blood vessels, promoting renal blood flow and maintenance of GFR in patients with shock
dopamine clinical uses
maintenance of B.P. in cardiogenic, hemorrhagic or other types of shock
more ____ released from the SR during _____
Ca2+; systole
dobutamine MOA
It has a wider spectrum than dopamine and stimulates both β1- and β2-adrenergic receptors and also both alpha1- and alpha2-adrenergic receptors.
dobutamine pharm effects
- Positive inotropic effects due to activation of β1-AR
- Does not increase renal blood flow selectively like dopamine
- Dobutamine acts as a vasodilator and reduces vascular resistance
dobutamine uses
superior to Dopamine in patients with advanced heart failure who do not improve with oral vasodilators.
phosphodiesterase inhibitors
Cyclic AMP is degraded to AMP by “phosphodiesterases”. Therefore, by inhibiting the PDE, cAMP is preserved to produce its effects on contractility
milinone
- Inhibitors cyclic GMP-inhibited cyclic AMP PDE (type III).
- Milrinone is 10 times more potent, has a shorter half-life and is more selective for type III PDE than Amrinone.
- agent of choice among PDE inhibitors.
- Used for short-term only because long-term use of these drugs often causes intolerable side effects and increased death among heart failure patients.
MOA ivabradine
- inhibits cardiac pacemaker current (If), a mixed sodium-potassium inward current (funny current).
- slows firing in the SA node, and ultimately reduces heart rate.
- Its cardiac effects are specific to the SA node with no BP effects.
what line of drug is ivabradine
2nd line for symptomatic HF
side effects of ivabradine
mild and infrequent. but include luminous phenomena (phosphenes) or visual brightness because
ivabradine partially inhibits the retinal current (Ih), which has properties similar to that of cardiac
Empagliflozin
- inhibit the sodium-glucose co-transporter in the proximal convoluted tubule.
- used to lower blood glucose levels in patients with type II diabetes, by increasing the urinary excretion of glucose.
