Heart Failure II

Question 1

MOA of Ivabradine (Corlanor)

Answer 1

-inhibition of “Funny” Na HCN channels on the SA node
-controls the heart rate –> slows the heart, “giving the heart a break”

-Heart failure drug for pts who don’t tolerate ß-blockers

Question 2

What is the consequence of HFrEF?

Answer 2

-Cardiomegaly - the heart is getting bigger (to pump more blood)
-also after MI (compensation of tissue loss)
-Law of LaPlace
-harder to squeeze due to increased wall tension

Question 3

Which enzyme is mainly responsible for vascular smooth muscle CONTRACTION?

Answer 3

-MLCK
-activated by Ca2+
-deactivated by Protein Kinase G - cGMP
-deactivated by Protein Kinase A - cAMP

Question 4

How does cGMP/cAMP get activated?

Answer 4

-GTP is converted to cGMP by the Guanylate cyclase (GC) -> drug target

-ATP is converted to cAMP by the Adenylate cyclase

Question 5

Which drug targets the soluble Guanylate cyclase?

Answer 5

-Guanylate cyclase activator
-Riociguat
-Vericiguat

-Nitrates activate Nitric oxide (gaseous NT)
-> ADE: flushing due to VASODILATION

Question 6

What is the indication of Guanylate cyclase activators?

Answer 6

-Pulmonary hypertension

-Riociguat
-Vericiguat
-Hydralazine

Question 7

MOA of PDE5 inhibitor

Answer 7

-PDE5 breaks down cGMP
-inhibition of PDE5 -> higher level of cGMP and PKG -> VASODILATION

Question 8

Which effect does Vasodilation of vascular smooth muscles in blood vessels have on the heart’s work rate?

Answer 8

it reduces the work the heart has to overcome to achieve appropriate ejection fraction (pump blood)

-Afterload reduction

Question 9

Nitrate drug

Answer 9

-Nitroglycerin
-rapid onset, short-acting
-treats angina, to some extent for HF
-causes VENODILATION -> reduces Preload

-Nitroprusside (IV)
-> decompensated HF

Question 10

Nitrate drug used for decompensated HF

Answer 10

Nitroprusside (IV)
-short half-life

Question 11

The enzyme that converts Nitrate to nitric oxide

Answer 11

mitochondrial aldehyde dehydrogenase
nitric oxide (NO) stimulates the soluble guanylate cyclase

Question 12

MOA of Hydrazaline

Answer 12

-used in combination with Isosorbide Dinitrate (ISDN)
-activation of the soluble guanylate cyclase (like NO)
-causes VASODILATION of the veins
-approved for use in African-American
-Nitrates show rapid tolerance -> prevented by hydralazine

Question 13

How might SGLT2 reduce the risk of HF?

Answer 13

-indicated for diabetes -> blocking the SGLT2 transporter -> more Glucose in the urine (ADE: UTI)

-Glucose attracts water molecules and thereby has a small osmotic and diuretic effect - pulling water into the urine

-diabetic is a risk factor for HF, so lowering blood glucose might help in reducing the risk of HF

Question 14

SGLT2 blocker drug

Answer 14

-Sotagliflozin (Inpefa)
-blocks SGLT1 and SGLT2
-recommended as the first-line drug for HFrEF

-others like Dapagliflozin are more specific to SGLT2 but still useful in HF

Question 15

Which curve illustrates the contractility in heart failure?

Answer 15

-Frank-Starling curve

-Ventricular performance (how well the blood pumps blood)
-Ventricular end-diastolic volume

Question 16

Acute decompensated heart failure

Answer 16

-sudden or gradual onset of symptoms of HF requiring hospitalization of the patient

Question 17

What is the best way to increase Cardiac output?

Answer 17

Heart failure: the heart doesn’t pump enough blood
-> need to increase CO

-increasing CO by increasing stroke volume -> requires less O2 as if CO was increased solely by increasing HR

Question 18

Which drugs increase cardiac output by increasing stroke volume?

Answer 18

-increase SV = increase in ionotropy (strength in contraction)

-Milrinone (Primacor) -> increases contractility without increasing HR
-PDE3 inhibitor
-also has effects on blood vessels causing Vasodilation

Question 19

How is this drug different from Vericiguat or Riociguat???

Answer 19

-Vericiguat block PDE5
-They work on vascular smooth muscles causing Vasodilation

-Milrinone (Primacor) worse directly on the heart and blocks PDE3 and increasing levels of cAMP -> more Ca2+ -> stronger contraction of the heart

Question 20

ß1-Agonists

Answer 20

-bind to ß1-receptors attached to the heart

-Dobutamine (also has ß2 agonist activity -> vasodilation, which also lowers the work the heart has to do)

-Dopamine:
binds to ß1-cardiac receptors -> heart beats harder and faster
binds to D2 receptors -> increases renal blood flow

-Epinephrine: agonist at all sympathetic receptors

-Norepinephrine: like EPI but with more alpha1 effects -> dangerous (too much vasoconstriction???)

Question 21

Ionotropic agents

Answer 21

-Cardiac glycoside (ATPase inhibitor): narrow therapeutic window, long halflife

-Digoxin: long half-life (1-5d) depending on renal function, narrow therapeutic window, overdose is often a concern

Question 22

MOA of Digoxin

Answer 22

-works on the heart muscle cells
-ATPase blocker that increases intracellular Ca2+

-after depolarization (Na+ influx) -> Ca2+ enters the cell -> followed by repolarization (K+ leaving)

-ATPase uses K+(outside) to exchange Na+
-Na+ (outside) is used to get Ca2+ out of the cell (Na+ gets in)

-Digoxin blocks the ATPase so Na+ levels outside stays low -> enables Antitransport with Ca2+ -> Ca2+ levels insight stays high -> greater heart muscle contraction

Question 23

ADE of Digoxin

Answer 23

-Atrial fibrillation
-AV conduction block, other electrical abnormalities
-Bradycardia
-nausea
-altered color perception and visual halos

Question 24

What is the Antidote of Digoxin?

Answer 24

-Digoxin immune antigen-binding fragments (Fab, antibody)
-binds Digoxin and takes it out of circulation