Pharmacology of Heart Failure

-Neurohumoral modulation

-preload and afterload reduction

-increasing cardiac contractility

-heart rate reduction

What is the goal in tx of chronic HF?

-diuretics

-vasodilators

-postitive iontropic drugs

What drug classes can be used for tx of acute decompensated HF?

1) decreased barorecptor input to vasomotor center

2) decrease blood flow causes renin release

What is the compensatory mechanism in heart failure?

neurohormonal modulation

-ACE/ ARBs

-Aldosterone antagonists

-Angiotensin receptor and Neprilysn inhibitors

-SGLT2 inhibitors

-BB

preload and afterload reduction

-diuretics

-vericiguat

-hydralazine-isosorobide dinitrate

increasing cardiac contractility (iontropic agents)

-cardiac glycosides: digoxin

heart rate reduction

ivabradine

SNS and RAAS

What does the decrease in CO activate?

ACEis

increase bradykinin

ACEis AE

-cough

-angioedema

ARBs

-Losartan (Cozaar®)

-Valsartan (Diovan®)

-Candesartan (Atacand®)

-Eprosartan

-Irbesartan

-Telmisartan

-Azilsartan

-Olmesartan (Benicar®)

ACEi

-Captopril

-Enalapril (Vasotec®)

-Lisinopril (Prinivil®)

-Benazepril

-Fosinopril

-Moexipril

-Perindopril

-Quinapril

-Ramipril (Altace®)

-Trandolapril (Mavik®)

RAAS

ACE/ARBs are _____ inhibitors.

mineralocorticoid receptor antagonists (MRAS)

antagonists of nuclear receptors of aldosterone (K sparing diuretics)

all

MRAs inhibit ____ the effects of aldosterone.

Spironolactone (Aldactone)

-Competitive aldosterone antagonist (synthetic steroid)

-also targets and antagonizes progesterone and androgen receptors

-slow onset and offset of action

Spironolactone AEs

-hyperkalemia

-worsening SrCr

-menstrual abnormalities

-dysmenorrhea

-gynecomastia

-ED

Eplerenone (Inspra)

-spironolactone analog

-more selective anti-aldosterone activity

-CYP3A4 substrate

Epleronone AEs

-hyperkalemia

-worsening SrCr

Angiotensin receptor and neprilysn inhibitors (ARNI)

Entresto (Sacubitril + Valsartan)

Sacubitril

prodrug that inhibits neprilysin

Neprilysin

peptidase that degrades and inactivates natriuretic peptides (ANP,BNP, CNP), bradykinin, and substance P

Entresto (Sacubitril/Valsartan) MOA

Inhibition of the RAAS (valsartan) + preservation of natriuretic peptides (beneficialaxis of neurohormonal activation; sacubitril)

diuretic effects

What effect does Entresto have on the kidney?

vasodilation

What effect does Entresto have on vasculature?

-antihypertrophic

-antifibrotic

-compliance increasing effects

What effect does Entresto have on the heart?

To minimize dry cough risk

When developing the ARNI combination, why did they

choose valsartan to inhibit RAAS instead of an ACEi?

a. They were not thinking straight, ACEIs are superior

b. ARBs are superior in HF

c. To minimize hypokalemia risk

d. To minimize dry cough risk

e. To minimize angioedema risk

Beta-1 adrenergic receptors

-primarily in the heart

-Also, macula densa→ renin release

Beta-2 adrenergic receptors

in smooth muscle of the bronchioles, arterioles, and visceral organs

slow progression by decreasing cardiac work

What do beta blockers do in chronic HF?

-alpha 1

-beta 1

-beta 2

What receptors does Carvedilol act on?

beta 1

What receptor does Metoprolol succinate act on?

beta 1

What receptor does Bisoprolol act on?

beta 1 and NO production

What receptors do Nebivolol work on?

AEs of BB

-bradycardia

-ED

-vivid dreams

-sedation

-orthostasis

-broncospam

-hypoglycemia

-worsening of airways

-abrupt discontinuation can lead to withdrawal syndrome

Carvedilol (Coreg)

What is the non-selective beta blocker used in HF?

Carvedilol

-nonselective BB and alpha 1 receptor antagonist

-t 1/2 6-10 hrs

Metoprolol Succinate (Toprol XL)

-CYP2D6 metabolism (genetic variants)

-short T 1/2 3-7 hrs

-extended release formulation

Bisoprolol (Zebeta)

longer plasma t 1/2 10-12 hrs

Nebivolol (Bystolic)

additional vasodilatory actions (NO mediated)

-decrease HR, force and conduction and O2 demand

-lower renin release

-decrease AngII mediated effects

What are the effects of BBs?

yes, 35% prolongation of life expectancy

Do we really want to decrease HR & contractility in someone with problems maintaining a decent CO?

SGLT2 inhibitors

oral drugs approved for the tx of T2DM

SGLT2 inhibitor MOA

Inhibition of the sodium-glucose co-transporter 2 (SGLT2) in proximal convoluted tubule

SGLT2 inhibitor AEs

-genitourinary tract infections

-osmotic diuresis and natriuresis

-glycosuria

-lowers glucose levels

What are some of the effects of SGLT2 inhibitors?

SGLT2 inhibitor drugs

-Dapagliflozin (Farxiga)

-Empagliflozin (Jardiance)

-Sotagliflozin (Inpefa)

loop diuretics

reduce preload by decreasing fluid and sodium retention

vasodilators

reduce afterload/preload

diuretics

inhibit sodium and water retention (inhibit reabsorption/induce excretion)

loop diuretics

immediate relief of pulmonary congestion and severe edema

thiazide

metolazone drug class

Potassium sparing diuretics

aldosterone antagonists

Loop diuretic drugs

-Furosemide (Lasix)

-Bumetanide (Bumex)

-Torsemide (Demadex)

-Ethacrynic acid

Loop Diuretics MOA

Inhibit Na+-K+-2Cl- symporter in the ascending limb of the Loop of Henle→ No NaCl reabsorption through TAL → no medullary gradient→ no water reabsorption from TDL

short

Loop diuretics are ____ acting.

glomerulus

filters loop diuretics

tubular secretion (PCT)

How are loop diuretics actively secreted?

-NSAIDs

-Probenecid

What are the DDIs with loop diuretics?

Loop diuretic AEs

-hypokalemia

-hypomagnesemia

-hyponatremia

-hyperuricemia

-ototoxicity/tinnitus

-photosensitivity

-hypersensitivity: sulfonamide

Ethacrynic acid (Edecrin)

What loop diuretic can you take if you have a sulfa allergy?

Vericiguat

What is the only vasodilator drug that can be used in HF?

Vericiguat (Verquvo)

-Oral Soluble Guanylate Cyclase Stimulator (approved 2021).

-Directly stimulates sGC through a binding site independent of NO, and it sensitizes sGC to endogenous NO by stabilizing NO binding to the binding site.

-Increases cGMP pathway → protective cardiovascular, kidney,

and metabolic actions

AEs of vericiguat (Verquvo)

-hypotension

-syncope

-anemia

BiDil

isosorbide dinitrate/hydralazine

BiDil

-Direct vasodilators

-Decrease preload and afterload → reduce cardiac work

ISDN

venous pooling and reduction of diastolic filling pressure (preload)

hydralazine

direct vasodilator, prevents nitrate tolerance

BiDil AEs

-HA

-lightheadedness

-dizziness

-hypotension

PDE-5 inhibitors (Sildenafil)

What are the DDIs with BiDil?

ionotropes (Digoxin)

increase contractility and cardiac output

cardiac glycosides

slow the heart rate and increase the force of contraction

Digoxin

-cardiac glycosides

-has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences (very narrow TI!)

-undesirable effects on the CNS and gut

Digoxin primary MOA

Inhibition of the cardiomyocyte's Na+/K+-ATPase to increase the concentration of free intracellular calcium

foxglove

What is the flower that Digoxin is made from?

1) an increase of intracellular sodium concentration because of Na+/K+-ATPase inhibition

2) a relative reduction of calcium removed from the cell by the NCX (caused by the increase in intracellular sodium

Digoxin increases contraction of the sarcomere by increasing the free calcium concentration during systole through 2 steps. What are the 2 steps?

positive

Digoxin has a ______ inotropic effect in the heart.

CO and renal perfusion

What does Digoxin increase in the heart?

electrophysiological actions of Digoxin

-Early cardiac parasympathomimetic responses and later arrhythmogenic actions

-Increase parasympathetic outflow at sinoatrial and atrioventricular node → decreased HR and decreased AV node automaticity (sometimes digoxin is used to treat tachyarrhythmias)

-Higher concentrations (toxicity): fatal cardiac arrhythmias

anorexia, D/N/V

What are the GI effects of Digoxin?

-Vagal stimulation (most P-ANS activity)

-Disorientation and hallucinations

-Visual disturbances

-Blurred vision

-Yellow vision

What are the CNS effects of Digoxin?

toxicity (low TI)

What is the notable risk for Digoxin?

kidney and GI tract

What is the primary excretory route for Digoxin?

-hypokalemia

-hypomagnesemia

What are the electrolyte issues that are seen with Digoxin toxicity?

toxicity of Digoxin

-arrhythmias

-N/V/D

DigiFab

What is the Digoxin antibody that is used as a antidote for Digoxin toxicity?

Ivabradine (Corlanor) MOA

Selective inhibitor of cardiac pacemaker ion channels HCNs (hyperpolarization-activated cyclic nucleotide-gated channels) involved in the generation of automaticity in the SA node through the "funny" current

dose

The reduction of heart rate with Ivabradine is ____________ dependent.

Ivabradine (Corlanor) AEs

-bradycardia

-atrial fibrillation

-QT prolongation

-fetal tox

in pts in whom BB are not tolerated or insufficiently effective

When is Ivabradine (Corlanor) used in HF?

thiazides

If you have resistance with loop diuretics what can you add?

Nitroglycerin

-low dose: venodilator

-higher dose: arterial vasodilator

Nitroprusside

equal arterial and venous vasodilator

risk of diffuse cardiac myocyte death (they are already not being well perfused) and tachycardia

What is the caution with positive ionotropes?

arrhythmias

All positive ionotropes increase the risk of __________.

Dobutamine

Relative β1-selective adrenergic agonist

Dobutamine MOA

beta 1 agonist activity predominates → increased myocardial contractility(positive ionotropic effect)

AEs of Dobutamine

-HTN

-Arrhythmias

Dobutamine (+) enantiomer

is beta 1 and β2 agonist (and alpha 1 antagonist!) → positive inotropism and vasodilation

Dobutamine (-) enantiomer

is alpha 1 agonist → vasoconstriction