Heart Failure Drugs (details)

Question 1

What is the MOA of sacubitril?

Answer 1

It inhibits neprilysin (breaks down BNP) –> prolongs BNP effects (ie: vasodilation, natriuresis and diuresis) –> beneficial for heart failure

Question 2

Why does sacubitril need to be combined with valsartan?

Answer 2

Because neprilysin also breaks down ANGII, so when sacubitril inhibits neprilysin, more ANGII would be broken down too –> bad for heart failure because more sodium and water retention occurs

Question 3

What is the MOA of valsartan?

Answer 3

Valsartan is a angiotensin ii receptor blocker, thus, when combined with sacubitril, it helps to mitigate the negative effects of ANGII

Question 4

What are the pharmacological features of sacubitril-valsartan?

Answer 4

• Can be used to replace ARB/ACE inhibitors and therefore can be combined with other drugs normally combined with ARB or ACE inhibitors

Because neprilysin also breaks down bradykinin, so sacubitril-valsartan will inhibit neprilysin and the break down of bradykinin will be inhibited

Question 5

What are the adverse effects of sacubitril-valsartan?

Answer 5

1) Hypotension
2) Hyperkalemia
3) Renal failure (rare)
4) Cough (because bradykinin is not broken down)
5) Angioedema (because bradykinin is not broken down)

Question 6

Which part of the loop of Henle does loop diuretics work on?

Answer 6

The thick ascending limb of the loop of Henle.

This is where NaCl is actively reabsorbed

Question 7

What is the MOA of loop diuretics?

Answer 7

1) Selective inhibition of the luminal Na+/K+/2Cl- transporter in the thick ascending limb of the loop of Henle, and increases Mg+ and Ca2+ excretion
2) Furosemide increases renal blood flow

Question 8

What drug class should be taken together with loop diuretics and why?

Answer 8

NSAIDs

Loop diuretics induce renal PG synthesis, so NSAIDs should be taken to offset this effect.

Question 9

What are the PK properties of loop diuretics?

Answer 9

1) They are rapidly absorbed, and thus have short onset of action.
2) The duration of effect for furosemide is usually 2-3 hours.
3) They are eliminated by tubular secretion as well as by glomerular filtration

Question 10

What are the clinical uses of loop diuretics?

Answer 10

1) Acute pulmonary edema and other edema (can be used for acute PE because of its rapid onset of action)
2) Acute hyperkalemia
3) Acute renal failure
4) Anion overdose - toxic ingestions of bromide, fluoride and iodide (since loop diuretics inhibit the luminal Na+/K+/2Cl- transporter and Cl- is affected, the other halogen ions would be affected as well since they all belong to the same valence group)

Question 11

What are the adverse effects of loop diuretics?

Answer 11

1) hypokalemic metabolic alkalosis
2) ototoxicity
3) hyperuricemia
4) hypomagnesemia
5) hypocalcemia

Question 12

What class of drugs should you avoid taking together with loop diuretics?

Answer 12

Aminoglycosides

because both aminoglycosides and loop diuretics cause ototoxicity

Question 13

Which part of the nephron will potassium-sparing diuretics exert their influence on?

Answer 13

The collecting tubule

Question 14

What is the MOA of potassium-sparing diuretics?

Answer 14

They block either the aldosterone receptor or the sodium channel.

Question 14

Which of the potassium-sparing diuretics block the aldosterone receptor?

Answer 14

Spironolactone and eplerenone

Question 15

Which of the potassium-sparing diuretics block the sodium channel?

Answer 15

Triamterene and amiloride

Question 16

If you want to use 2 diuretics, what can you use?

Answer 16

1 potassium-sparing diuretic + 1 loop diuretic OR 1 thiazide

no point using spironolactone together with triamterene even though they block different receptors because they’re still in the same pathway.

Pharmaco principle: if you want to use combo therapy, NEVER use 2 drugs that work on the same pathway!

Question 17

What is the effect of potassium-sparing diuretics on potassium?

Answer 17

Potassium secretion will be decreased since sodium reabsorption is decreased

Question 18

Discuss the PK properties of spironolactone, triamterene and amiloride

Answer 18

Spironolactone: slow onset of action, requires several days before full therapeutic effect is achieved

Triamterene: metabolised in the liver, shorter half-life and must be given more frequently than amiloride

Amiloride: excreted unchanged in the urine

Question 19

What are the clinical uses of potassium-sparing diuretics?

Answer 19

1) Diuretic
2) Hyperaldosteronism (ie: over-retention of sodium)

Question 20

What are the adverse effects of potassium-sparing diuretics?

Answer 20

1) Hyperkalemia
2) Metabolic acidosis
3) Gynecomastia (only for spironolactone)
4) Acute renal failure (when triamterene is taken together with indomethacin)
5) Kidney stones (with triamterene)

Question 21

What are the MOAs of hydralazine?

Answer 21

Direct arteriole vasodilator –> reduces peripheral resistance –> compensatory release of epinephrine/ norepinephrine –> increase venous return and cardiac output + reduces afterload (directly via arteriole vasodilation + indirectly through release of epinephrine and norepinephrine)

Question 22

What are the clinical indications of hydralazine?

Answer 22

1) HFrEF (given PO in combination with ISDN)
2) Essential hypertension (ie: primary hypertension). Given PO
3) Acute onset, severe peripartum or post-partum hypertension (>15min). Given IV

Question 23

What are the adverse effects of hydralazine?

Answer 23

1) Symptoms associated with baroreflex associated sympathetic activation (ie: flushing, hypotension, tachycardia)

2) Hydralazine-induced lupus syndrome (HILS): athralgia, myalgia, serositis, fever
- Dose dependent & higher chance with long-term use
- Can be resolved with hydralazine discontinuation

3) Contraindicated in coronary artery disease
- Hydralazine stimulates the sympathetic nervous system –> increased cardiac output/ oxygen demand –> myocardial ischemia

Question 24

(popular exam question!) Compare the PK properties of digoxin and digitoxin

Answer 24

SIMILARITIES
- both administered PO
- both have large volume of distribution

DIFFERENCES
- digitoxin is extensively metabolised by the liver, digoxin is not extensively metabolised (almost 2/3 is excreted unchanged)
- digitoxin is excreted in the feces, digoxin is excreted by the kidney
- digoxin has a faster onset of action than digitoxin
- digoxin has a shorter half life than digitoxin
- digoxin binds to proteins less than digitoxin

Question 25

What is the MOA of the cardiac glycosides?

Answer 25

Inhibition of sodium potassium ATPase –> increase in intracellular [Na+] –> impairs functioning of sodium-calcium exchanger –> decrease in calcium efflux –> CICR induced –> cardiac myocytes activated –> stronger systolic contraction

Question 26

What are the clinical uses of cardiac glycosides?

Answer 26

1) systolic dysfunction
2) atrial fibrillation

Question 27

What are the adverse effects of cardiac glycosides?

Answer 27

1) Progressively more severe dysrhythmia: AV block, AF, VF
2) GI effects: anorexia, nausea, and vomiting
3) CNS effects: headache, fatigue, confusion, blurred vision