Heart Failure drugs

Question 1

How to choose between drugs that reduce workload of heart vs drugs that increase workload?

Answer 1

• Drugs that reduced workload = compensatory stage of HF
• Drugs that increase workload = chronic HF

As the pump becomes less effective, more blood remains in the ventricles at the end of each cycle. Gradually, end-diastolic volume (preload) increases. Initially, increase in preload may promote increased force of contraction (Frank-Starling Curve)
But as preload increases, further, the heart is overstretched and contracts less forcefully (chronic HF)

Question 2

Drugs used in HF

Answer 2

1. Beta blockers
2. Sacubitril-Valsartan
3. Diuretics (Loop, K+ sparing)
4. Hydralazine
5. Isosorbide mononitrate/dinitrate
6. Ivabradine
7. Cardiac Glycosides

Question 3

Examples of beta blockers

Answer 3

Non-selective: carvedilol
(Cardvedilol also blocks a1 receptors → reducing peripheral vascular resistance)

Beta-1 selective: bisoprolol, metoprolol XL

Dose-dependent: Nebivolol (b1 selective in low doses, non selective in high doses)

Question 4

MOA of beta blockers

Answer 4

Beta-adrenoreceptor antagonists decreases the HR → more time for ventricular filling during diastole → increase CO

Question 5

What classes of drugs ends with -lol?

Answer 5

beta blockers

Question 6

Beta blockers contraindicated in?

Answer 6

1. Contraindicated in asthmatic patients as they can cause bronchoconstriction (b1 selective only)
2. Contraindicated in diabetics as they can mask the effects of hypoglycaemia (palpitations, tremors etc.) preventing them from getting appropriate intervention

Question 7

Clinical uses of beta blockers

Answer 7

1.Hypertension
2.HF (slower HR → increase time for ventricular filling → increase CO)
3.Abnormal heart rhythms
4.Following myocardial infarction
5.Anxiety disorders

Question 8

MOA of Sacubitril

Answer 8

BNP antagonise the RAAS and has favourable effects on HF

BNP are broken down by neprilysin

Sacubitril inhibits neprilysin → prolongs BNP effects (antagonise RAAS which is activated under HF)

Question 9

Why is Valsartan added

Answer 9

Neprilysin also breaks down angiotensin II (Sacubitril inhibiting neprilysin prevents the breakdown of angiotensinII)

Therefore add Valsartan (a AT1 receptor blocker)

Valsartan avoids the negative effects of angiotensin II that is prolonged by Sacubitril

Question 10

Clinical uses of Sacubitril- Valsartan

Answer 10

HFrEF (decreases workload of the heart → preserves the heart’s function and prevent further damage)

Question 11

Adverse effects of Sacubitril- Valsartan

Answer 11

1. dry cough and angioedema (Neprilysin is also involved in the breakdown of Bradykinin, which is inhibited by Sacubitril)
2. Hypotension
3. Hyperkalaemia
4. Renal failure

Question 12

Examples of Loop diuretics

Answer 12

Furosemide, Bumetanide, Ethacrynic acid, Sulfonamide derivatives

Question 13

Which channels of the nephron do loop diuretics act on

Answer 13

Na/K/2Cl cotransporter at the thick ascending limb

Question 14

Which ions are affected by loop diuretics

Answer 14

Reduce absorption of Na+, K+, Cl-, Mg2+ and Ca2+

Question 15

Adverse effects of Loop diuretics

Answer 15

1. Hypokalemic metabolic alkalosis
2. Ototoxicity (avoid use with aminoglycosides)
3. Hyperuricemia
4. Hypomagnesemia

Question 16

Clinical uses of Furosemide

Answer 16

1. Acute pulmonary oedema
2. Acute hyperkalaemia (reduces K+ absorption from lumen)
3. Anion overdose
4. Acute renal failure

Question 17

Do the Nitrates reduce the workload of the heart directly or indirectly

Answer 17

Indirectly.
Donates NO which activates guanylyl cyclase, increasing cGMP and causing inactivation of myosin-LC

a. Vasodilation → venodilation (decrease preload)
b. Vasodilation → arteriolar dilation (decrease afterload)
Overall decreases workload of the heart

Question 18

Potassium sparing diuretics and which part of the nephron they work on

Answer 18

Spironolactone, Epierenone: blocks aldosterone receptor –> no activation of Na+ channel –> no reabsorption of Na+ at the collecting duct –> no water retention

Triamterene, Amiloride: blocks Na+ channels at the collecting duct directly

Question 19

Do they K+ sparing diuretics have a slower onset of action than loop diuretics?

Answer 19

YES

Question 20

Clinical uses of K+ sparing diuretics

Answer 20

1. diuretics
2. hyperaldosteronism

Question 21

Side effects of Spironolactone and Triamterene

Answer 21

1. Hyperkalaemia (decreasing Na+ reabsorption decreases K+ secretion by the Na+/K+/Atpase pump)
2. Gynecomastia (only spironolactone which may block the testosterone receptor)
3. Acute renal failure (triamterene + indomethacin)
4. Kidney stones (triamterene)

Question 22

Clinical use of Hydralazine

Answer 22

Second line hypertensive, first line for HF

1. Essential hypertension (2nd line)
2. HFrEF (in combination with isosorbide dinitrate, orally)
3. Acute-onset, severe peripartum or postpartum hypertension (IV)

Question 23

Adverse effects of Hydralazine

Answer 23

1. Baroreflex associated sympathetic activation: flushing, tachycardia
2. Hypotension
3. HILS – arthralgia, myalgia, serositis, fever
4. Contraindicated in coronary disease due to stimulation of SNS → increase CO output → increase myocardial oxygen demand

Question 24

MOA of hydralazine

Answer 24

Direct vasodilator → decreasing total peripheral resistance → decrease afterload

1. Vasodilator by inhibiting IP3-induced Ca2+ release from the smooth muscle cell sarcoplasmic reticulum
2. Can trigger compensatory release of NE/adrenaline → increase CO

Question 25

MOA of Isosorbide dinitrate/ Mononitrate

Answer 25

Donates NO which activates guanylyl cyclase, increasing cGMP and causing inactivation of myosin-LC a. Vasodilation → venodilation (decrease preload) b. Vasodilation → arteriolar dilation (decrease afterload) Overall decreases workload of the heart

Question 26

Comment on the duration of action and onsent of action of ISDN and ISMN

Answer 26

- long duration of action and long onset of action - ISMN has a faster onset of action (30-45 min) compared to ISDN (60 min)

Question 27

Clinical uses of ISMN/ISDN

Answer 27

1. Angina pectoris prophylaxis (decreasing workload of heart reduce oxygen consumption + decrease end diastolic pressure for better blood flow to coronary arteries) 2. HF

Question 28

Side effects of ISMN/ISDN

Answer 28

1. Reflex tachycardia (due to baroreceptors picking up lower BP) 2. Hypotension 3. Headache (meningeal artery vasodiation)

Question 29

MOA of Ivabradine

Answer 29

A heart rate lowering agent Does not reduce preload, afterload or contractility, just reduces heart rate Inhibits cardiac pacemaker I(f) current that controls the spontaneous diastolic depolarisation in the SA node → slows down/regulates heart rate

Question 30

Clinical uses of Ivabradine

Answer 30

Useful in HFrEF, in patients in sinus rhythm whose heart rate > 75 bpm (increase time for ventricular filling, improving overall cardiac function )

Question 31

Does Ivabradine reduce preload, afterload or contractility?

Answer 31

No. just reduces heart rate

Question 32

Adverse effects of ivabradine

Answer 32

1. Visual problems: Luminous phenomena, transient enhanced brightness in a limited area of the visual field 2. Dizziness (bradycardia) 3. Hypotension, fatigue, malaise (all related to bradycardia)

Question 33

Examples of Cardiac glycosides

Answer 33

Faster onset, shorter half life: Digoxin Slower onset, longer half life: Digitoxin

Question 34

MOA of Digoxin

Answer 34

Inhibits the Na+/K+/Atpase pump in cardiac muscle cells Prevents efflux of Na+ → increase Na+ intracellularly → decrease efflux of Ca2+ (through the Ca2+ Na+ channel) → increased CICR from sarcoplasmic reticulum → increased myocyte contraction → increase CO

Question 35

Clinical uses of DIGOXIN

Answer 35

1. Late stage HF 2. Systolic dysfunction 3. Atrial fibrillation

Question 36

Adverse effect of cardiac glycosides

Answer 36

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

Question 37

How to treat Digitalis toxicity

Answer 37

- Discontinue cardiac glycoside therapy - Correction of K+ or Mg+ deficiency - Antiarrhythmic drugs (as it can increase automaticity leading to AF or VF) - if automaticity is predominant: lidocaine, propranolol Digoxin antibody (FAB fragments, digibind)

Question 38

Do ACE inhibitors, sacubitril and valsartan cause dry cough?

Answer 38

Only ACE inhibitors (e.g. Lisinopril) and Sacubitril