Lecture 8/9 Heart Failure Flashcards
Can heart failure be cured?
No, it can only be managed through medication or by eventual transplant
Name the 6 major markers used in lab results to diagnose heart failure.
BNP
Troponin T
Troponin I
CK-MB
C-reactive protein
TNF Alpha
Describe the pathogenesis of heart failure in order.
- Initial trigger or insult results in cardiac dysfunction (various causes such as genetic or metabolic)
- Initial cardiac dysfunction exhibits as decrease in cardiac output
- Results in decreased perfusion of vessels and tissues, leading to oxygen deprivation and increased oxygen demand for heart muscle
- This turns on adaptive mechanisms to compensate (RAAS system) with aid of sympathetic nervous system
- After a period, the compensatory mechanisms fail accompanied by baroreceptor dysfunction
- Further contributes towards heart failure
- Increased RAAS activity results in edema, vascular dysfunction, and cardiac tissue damage
- Finally, cardiac output drops drastically
Heart failure is accompanied by:
increased resistance and decreased stroke volume, as the failing heart no longer abides by the Frank-Starling law
Name the two types of heart failure:
HFrEF: heart failure with reduced ejection fraction AKA systolic heart failure
HFpEF: heart failure with preserved ejection fraction AKA diastolic heart failure
Describe HFrEF:
Heart failure with reduced ejection fraction is presented with signs of impaired systolic function. the LVEF <40% (left ventricle ejection fraction)
Describe HFpEF:
Heart failure with preserved ejection fraction is presented with signs of PRESERVED systolic function, but the diastolic function is impaired, effecting cardiac relaxation. the LVEF >50%. HFpEF can be determined with both noninvasive and invasive measurements
Describe the major structural changes in the heart in HFrEF:
The LV is dilated and there is a weakened pump. Blood will back up and overload the heart. The ventricles are stretched and pump out less blood than normal.
Describe the major structural changes in HFpEF:
The walls of the LV are thickened or stiff (can be due to scarring), and there is abnormal relaxation which prevents the LV from filling up all the way before it squeezes. The thickened ventricles contract normally but have less blood to pump out.
What are the two types of drugs used for heart failure?
- Acute measures (short term) for acute events
- Maintenance measures (long term)
What are positive inotropic agents?
drugs that increase the force of contraction of the heart
name the inotropic agents
Digoxin (only one WITHOUT vascular effects)
Dopamine
Dobutamine
Phosphodiesterase (PDE) inhibitors
Inamrinone
Sildenafil
Digoxin is part of the _____ family
Cardiac glycosides
What is the mechanism of action for digoxin?
They inhibit the PHOSPHORYLATED ALPHA SUBUNIT (and ONLY this subunit) of the plasma membrane residing Na+K+ATPase channel
What is the result of taking digoxin?
Na+ EFFLUX via the NaKATPase is prevented, leading to an increase in cytosolic Na+ ions. This increase leads to Ca+ retention in cells, causing an increase in cytoslic Ca+ as well as Ca+ release from the sarcoplasmic reticulum by SERCA2. This all leads to increased contraction of the myocyte
What happens if digoxin is taken chronically?
This results in decreased drug action. The resultant increase in extracellular K+ levels promotes dephosphorylation of the Na+K+ATPase alpha subunit, minimizing the drugs potency
General notes on Digoxin:
T1/2 is 36-48 hours
steady state achieved following 7 days after maintenance dose
MOSTLY EXCRETED VIA RENAL ROUTE
affinity for skeletal muscle deposition, so dosing should be based on lean mass
Adverse affects/contraindications of digoxin:
Very narrow therapeutic window (<1ng/mL)
need to be careful in patients with ionic or acid base imbalances, and those with renal failure
co administration with Ca2+ can result in MALIGNANT ARRHYTHMIA
What is the mechanism of action for dopamine?
dopamine acts via the Dopamine receptors (D1 and D2)
How does the dosage of dopamine impact its effect?
extremely low dose (<2ug/kg lean body mass/min): induces cAMP and VASORELAXATION. acts on D2 receptors in sympathetic neurons inhibiting NE release
moderate dose (2-5ug/kg/min): direct stimulation of cardiac B1 receptors thus increasing contractility and sympathetic neuronal NE release
higher doses (>10ug/kg/min): stimulate alpha adrenergic receptor in both arteries and veins resulting in vasoconstriction, recommended during circulatory collapse
adverse effects of dopamine are:
tachycardia
causes ischemic attacks in patients with coronary artery disease
systemic nonspecific adverse effects
how are dobutamine infusions given?
started at a dose of 2-3ug/kg/min and slowly titrated up based on requirement
what is the mechanism of action for dobutamine?
it is a nonspecific BETA RECEPTOR AGONIST. they stimulate the B1 receptor in cardiac tissue resulting in increased contractility (major effect). They also act on beta 2 receptors in vascular smooth muscle resulting in vasodilation and decreasing resistance (minor effect)
What are the adverse effects of dobutamine?
tolerance may develop following 1 week of treatment due to increased PDE activity. If so, PDE3 inhibitor will yield better pharmacologic results
What is the mechanism of action for the PDE inhibitors inamrinone and sildenafil?
they inhibit PDE enzymes which raise or upregulate the cellular cAMP levels
What are the effects of PDE inhibitors?
there is a positive inotropic effect (increased contractility) in cardiac tissue as well as decreased resistance in both arteries and veins. this reduces both preload and afterload
Describe Inamrinone
inamrinone is a PDE 3 inhibitor and is approved for short term therapy in advanced CHF
What are the adverse effects of inamrinone?
around 10% of patients develop thrombocytopenia
describe sildenafil
Sildenafil is a PDE 5 inhibitor, which is mostly found in lung tissue. It is most effective for right ventricular systolic failure due to pulmonary artery hypertension
what is the major role of diuretics in treating heart failure?
decrease the preload and edema
how do diuretics work?
they decrease preload without a major change in cardiac output. they decrease ventricular filling pressure, and are preferred mostly to maintain a euvolemic state for patients suffering from hypervolemia
which are the loop diuretics used in treating heart failure?
Furosemide
Bumetamide
Torsemide
Describe the mechanism of action for loop diuretics
they inhibit the Na+K+2CL symporter on the apical membrane of the ascending limb of the loop of henle. This promotes Na+ and K+ excretion. They are suggested for hypervolemic patients with edema. They are known as high ceiling diuretics because of their ability to expel maximum Na+,Cl- and water
what are the thiazide and thiazide like diuretics?
chlorothiazide
hydrochlorothiazide
chlorthalidone
what is the mechanism of action for the thiazide and thiazide like diuretics?
they inhibit the Na+Cl- co-transporter in the apical membrane of the distal convoluted tubule. they are only recommended for combinatorial therapy
what are the K+ sparing diuretics?
amiloride and triamterene (direct ENaC inhibitors)
spironolactone and eplerenone (MR antagonists)
what is the mechanism of action for the direct ENaC inhibiting K+ sparing diuretics?
they are direct ENaC inhibitors. they target ENaC channels and prevent Na+ reabsorption in the collecting duct with minimal K+ and Mg2+ loss
what is the mechanism of action for the MR antagonist K+ sparing diuretics?
they downregulate ENaC expression on the luminal surface due to MR antagonism. heart failure patients have almost 20% more aldosterone in their circulation, so administration of aldosterone antagonists will provide benefits
what are the additional benefits exhibited by the MR antagonist k+ sparing diuretics?
protection against cardiac and renal fibrosis (beneficial for those with HFpEF)
prevents ischemia and inflammation
prevents endothelial and vascular smooth muscle constriction and damage
what are the adverse effects of the MR antagonist K+ sparing diuretics?
10% of men develop gynecomastia due to non specific effects (mostly with spironolactone. this can be substituted with eplerenone if it occurs
What is the major adverse effect from diuretics in general?
diuretic resistance. this occurs mostly because of a compensatory increase in Na+ reabsorption following Na+ loss from the body by RAAS activation (mostly seen with loop diuretics). some other factors that contribute are patient non-compliance and non adherence to sodium and fluid intake restrictions
what is the newer mechanism for diuretic resistance?
the enzymes plasmin and prostasin present in the tubular lumen cleaves the gamma subunit of the ENaC and activates the channel, resulting in enhanced reabsorption of sodium (mostly for k+ sparing diuretics)
how do NSAIDs contribute to diuretic resistance?
NSAIDs inhibit the prostaglandins which decreases renal perfusion and thus diuretic efficiency, as there will be a lesser amount of filtrate in the lumen
what are the SGLT2 inhibitors used for heart failure?
empagliflozin and dapagliflozin
What is the SGLT2?
the sodium glucose transporter 2 which is present in excess in the proximal tubule and is responsible for 90% of the filtered glucose and a considerable amount of Na+
what is the mechanism of action for the SGLT2 inhibitors?
they inhibit glucose and sodium uptake through SGLT2 transporters, reducing hyperglycemia, hypernatremia, and hypervolemia, leading to a decrease in preload
what are adverse effects of SGLT2 inhibitors?
UTI infections and could aggravate CKD
What is the vasodilating drug used for heart failure?
Bidil (brand name)
What is bidil?
bidil is a combination of both isosorbide dinitrate and hydralazine HCl. hydralazine is an arterial dilator and nitrate is a venous dilator, thus reducing both preload and afterload
Describe how the isosorbide dinitrate in bidil works
it gets converted to nitric oxide via the CYP450 system and promotes venous dilation
describe how the hydralazine HCl in bidil works
it causes a decrease in the release of calcium from intracellular pools by inhibiting inositol tri-phosphate 3 (IP3) decreasing vascular contraction
what are the systemic positive effects of nitrates
reduces preload by relaxing vascular smooth muscle and decreases incidences of MI and heart failure
known to increase cGMP levels inside platelets resulting in the prevention of platelet aggregation
what are the effects of Ang II in the RAAS system?
arterial vasoconstrictor, promotes Na+ and H2O retention
what are the drugs that target the RAAS system for heart failure?
Captopril, ramipril, lisinopril (ACE inhibitors)
candesartan, losartan (AT1R blockers)
what effects do drugs targeting the RAAS system have?
mortality reducing effect on heart failure patients with systolic dysfunction
prevent ventricular remodeling and LV dysfunction
AT1 receptor blockade provides both short and long term management of heart failure
AT1 receptors preferred due to less side effects
what is a combinatorial therapy used to target the RAAS system?
AT1R blockers with MR antagonists
for example: candesartan and spironolactone together improves quality of life and cardiac ejection fraction. this combo should be avoided in the elderly and can induce hypotension, renal dysfunction and hyperkalemia
what is entresto?
entresto is a combination drug made up of sacubitril and valsartan. it was approved by the FDA in 2015 for heart failure
sacubitril is a produg, converted to sacubitrilat which is a neprilysin inhibitor. neprilysin inhibits ANP and BNP and breaksdown ang2
what is the mechanism of action for entresto?
promotes the simultaneous inhibition of neprilysin and AT1R
what are the adverse effects of entresto?
hypotension, angioedema, hyperkalemia, reduced renal function
black box warning for fetal toxicity and should be avoided in pregnancy
should not be used with another ARB (angiotensin 2 receptor blocker)
which drugs reduce cardiac muscle stress resulting in proper diastolic filling and improving oxygen demand?
beta blockers and ivabradine
which drugs are beta blockers?
metoprolol (B1 selective)
carvedilol (nonselective b blocker)
beta blockers initiated at very lose dose and titrated upwards
what is the mechanism of action for ivabradine?
directly inhibits of Na+ entry (inward funny current) through HCN channels in the SA node, decreasing cardiac rate and reducing myocardial oxygen demand
who is recommended to use ivabradine?
patients with HFrEF with stable angina with a heart rate equal or greater than 70 as a combination therapy with ACE/ARB inhibitors or MR antagonists.
also especially useful for those intolerant to beta blockers
what are the adverse effects and contraindications of ivabradine?
bradycardia and atrial fibrillation
contraindicated in those with decompensated heart failure or a prior history of bradycardia or atrial fibrillation
