Drugs for Heart Failure

what is Heart Failure described as?

Heart Failure is an abnormality of cardiac structure or function leading to the failure of the heart to deliver oxygen at a rate that fulfills the requirements of the tissues in the body

what are physical char heart failure patients usually have? (3)

• have hypertension

• have enlarged heart muscles and chamber

• have low ejection fraction meaning the heart does not provide adequate perfusion to the body

how many ppl are affected by heart failure

Heart Failure is a complex clinical disorder, affects
600,000 people in Canada

• 50,000 new patients each year

what is Systolic heart failure

Problem: The heart cannot CONTRACT properly.

• The heart muscle becomes weak and often dilated (enlarged).

• The ventricles can fill with blood, but they cannot pump enough of it out.

• This decreases the amount of blood delivered to the body.

• The ejection fraction (EF) is reduced.

Example: The left ventricle fills with 100 mL of blood but only pumps out 30 mL.

what is Diastolic heart failure (HFpEF)

Problem: The heart cannot RELAX properly.

• The ventricular walls become stiff, often due to thickening (hypertrophy).

• The ventricles cannot relax and fill properly during diastole.

• Less blood enters the ventricles.

• The heart muscle can still contract normally.

• The ejection fraction is usually preserved.

Example: The left ventricle fills with only 60 mL of blood and pumps out 36 mL.

what happens in Left-sided heart failure

Most common form of heart failure
Fluid may build up in the lungs and cause dyspnea and
pulmonary edema.

what happens in Right-sided heart failure

Often occurs along with left-sided heart failure
Fluid builds up in the abdomen, legs, and feet, resulting in
peripheral edema

What is echocardiography?

– Send soundwaves into the body which are reflected at the interfaces between tissue
– Return time tells us the depth of the reflecting surface

what is normal range EF and reduced range?

EF = 55% = normal

• Ejection Fraction ≤50% is reduced

What are cardiomyocytes?

Cardiomyocytes are simply heart muscle cells responsible for making the heart contract.

how do cardiomyocytes contract

• Cardiomyocytes respond to action potential by depolarization of the membrane

• Starts by shortening of contractile proteins and ends with relaxation and return to resting state

• Cardiomyocytes are interconnected in intercalated discs that respond to stimuli as a unit

• Force of muscle contraction is related to the amount of cytosolic Ca2+

• Ca2+ comes from outside the cell first which triggers release from SR and mitochondria stores

• Muscle relaxation is achieved through removal of free Ca2+ by the Na+/Ca2+ exchangers and reuptake into SR and mitochondria

which factors increase risk of HF

1. age

2. smoking

3. obesity

4. hypertension

5. coronary artery disease

6. diabetes

7. dyslipidemia

how does the body prevent heart failure

what does the Progression of Chronic Heart Failure look like

in HF Slight decreases in blood pressure corrected by

what are the effects of those changes

explain how those effects are caused in early heart failure

Late in heart failure (decompensated) these things worsen the condition. explain how those conditions worsen

what are the Physiological Consequences of Heart Failure

what does Decreased Renal Blood Flow lead too

Main Symptoms of HF

Shortness of Breath
Shortness of Breath at Night
Need to sit or stand to breath easily
Reduced exercise tolerance
Fatigue
Ankle swelling
Peripheral Edema
Pulmonary Edema

Main Signs of HF (6)

Sweating
Increased heart rate
Elevated jugular venous pressure
Hepato-jugular reflux
Rapid Breathing
Cardiac murmur

what are the stages of hf

1. A - at risk

2. B - pre-hf

3. C - symptomatic

4. D - advanced

what happens in Stage A

The patient does not have heart failure yet, but has risk factors that increase their likelihood of developing it.

Examples:

• Hypertension (high blood pressure)

• Diabetes

• Obesity

• Cardiovascular disease

• Family history of cardiomyopathy

• Exposure to cardiotoxic drugs

Key point: No symptoms AND no structural or functional heart abnormalities.

what happens in stage B

The patient still has no current or previous symptoms of heart failure, but there is already evidence of heart abnormalities or injury.

For example:

• Structural changes, such as an enlarged left ventricle

• Increased filling pressures

• Elevated BNP/NT-proBNP or cardiac troponin in an appropriate at-risk patient, without another explanation

Difference from Stage A: The heart is already showing evidence of damage or dysfunction, but the patient has no symptoms.

what happens in stage C

The patient has current or previous symptoms of heart failure.

Common symptoms include:

• Shortness of breath (dyspnea)

• Fatigue

• Swelling of the legs (peripheral edema)

• Difficulty breathing when lying flat (orthopnea)

Importantly, someone remains Stage C even if their symptoms improve with medication.

Your slide also shows four possible courses for Stage C:

what are the four plausible courses for stage C

1. New-onset (de novo) heart failure

2. Resolution of symptoms

3. Persistent heart failure

4. Worsening heart failure

what is Stage D: Advanced heart failure

Marked HF symptoms that
interfere with daily life and
with recurrent
hospitalizations despite
therap

HEart failure is a _____ with high _____

Heart Failure is a Progressive Condition with High Mortality

if frequency increases in acute events what happens?

• Increasing frequency of acute events with disease progression leads to high rates of hospitalization and increased risk of mortality
• With each acute event, myocardial injury may contribute to progressive LV dysfunction

Summary of HF

Drug Classes for Heart Failure (5)

1. inhibitors of renin angiotensin system

2. ARNIs

3. b-adrenergic receptor blockers

4. inotropes

5. diuretics

ex of inhibitors of renin angiotensin system

- ACEI, enalapril
- ARB, losartan, valsartan

ex of ARNIs

Entresto (sacubitril/valsartan)

ex b-adrenergic receptor blockers

metoprolol, carvedilol, propanolol

ex of inotropes

digoxin, dobutamine

ex of diuretics

- furosemide, metolazone, dapagliflozin
- aldosterone antagonist
- spironolactone

Why decrease formation of angiotensin II?

decreased constriction in arteries and veins
- decreased preload and afterload (heart works less)
decreased aldosterone by decreased angiotensin II
- decreased blood volume (and decreased venous return)
decreased remodeling
- decreased thickening of heart tissue

renin pathway to make angiotensin 2

what does acei do to bradykinin

ACE (angiotensin-converting enzyme) is responsible for breaking down and inactivating bradykinin (a vasodilator peptide). When an ACE inhibitor blocks the ACE enzyme, it prevents this breakdown, leading to an increase (accumulation) of bradykinin levels in the body

when should you start ACE Inhibitors? what are its initial effects?

started soon after diagnosis
- excellent single therapy
- improve clinical signs and symptoms
- significantly decrease morbidity and
mortality

ace inhibs reduces death caused by: (4)

- progressive heart failure
- cardiac arrhythmia
- myocardial infarction
- stroke

what is an ace inhib that is a first line drug for heart failure, how should it be used?

Enalapril

• After edema has been taken care of (if present).
  - generally used in combination with furosemide

what are the benefits of Enalapril

- survival
- symptoms/quality of life/exercise tolerance
- hospitalizations/ER visits
- ejection fraction and hemodynamics
Effective in slowing the course of heart failure

ACE Inhibitors side effects (4)

• should not be used in pregnancy(causes birth defect)

• may cause hyperkalemia (due to aldosterone decrease) - leading to abnormal heart rate and cardiac arrest

• commonly cause dry cough

• metabolically neutral – good
  – no effect on lipids or blood glucose

why should caution be taken when using ace inhibs with other meds?

caution taken with other medications mostly related to potential hyperkalemia

• Spironolactone- dose adjustments are necessary to avoid hyperkalemia

what medications should caution be taken when using ACE inhib?

– Ibuprofen/Indomethacin: Chronic use of Non-steroidal anti-inflammatory drugs
– Valsartan (ARBs)
– Sacubitril/Valsartan
– Alka-Seltzer (antacid)
– Trimethoprim (antibiotic)

why should caution be taken with those meds?

Caution must be taken with the following medications because they can increase potassium levels and in combination with enalapril could cause hyperkalemia

examples of Angiotensin Receptor Blockers (ARBs)

Losartan
Valsartan

what is Angiotensin Receptor Blockers (ARBs) main function

Ultimate action is similar to ACEi but without the effects of increasing bradykinin
Originally marketed as ACEi without the cough

what are consequences of ARBs

Similar complications and drug-drug interactions to those seen with ACEi
- combination with enalapril or spironolactone increase
the risk of hyperkalemia

what reduces the efficacy of ARBS?

Notably the efficacy of ARBs are reduced by grapefruit juice

what is Neprilysin

is an endopeptidase that degrades vasoactive peptides including atrial natiuretic peptide(ANP) and brain natiuretic peptide(BNP)

The net effect of neprilysin activity is?

- increased constriction in arteries and veins
- increased preload and afterload (heart works more)
- increased aldosterone
- increased blood volume (and decreased venous return)

what does Neprilysin inhibition (eg. sacubitril) do

- decreased constriction in arteries and veins
- decreased preload and afterload (heart works less)

Natiuretic Peptide System

What is an ARNI?

ARNI stands for Angiotensin Receptor–Neprilysin Inhibitor.

• Combines an ARB with a neprilysin inhibitor

contains two main drugs valsartan and sacubitril

what does Valsartan do

Blocks the RAAS pathway

• valsartan helps decrease both preload and afterload and reduces harmful cardiac remodeling.

what does Sacubitril do?

Inhibits neprilysin - Neprilysin is an enzyme that breaks down natriuretic peptides.

when are ARB/Neprilysin Inhibitors (ARNI) used

Recommended for use as a replacement for ACEi or ARB in individuals with heart failure with reduced ejection fraction

what line of drugs are ARNI?

Currently used as a second line drug in heart failure
- recommended to switch patients after ACEi or ARB
- can be used in patients with heart failure stage B, C or D.
- can be used in patients with high BP or reduced kidney function

Side effects of ARNIs (Sacubitril/Valsartan)

Benefits of b-adrenergic receptor blockade?

-decrease adverse effects of high catecholamine levels on the heart
- decreased cardiomyocyte apoptosis (cell death)
- decreased cardiac remodeling (decreased mitogenic activity)
- so mechanism not completely understood but clinical benefits are clear

benefits of beta blockers

what two important beta blockers

1. Carvedilol

2. Metoprolol

what does Carvedilol do?

- blocks b- AND a-adrenergic receptors
- a-adrenergic receptor blockade helps to relax (dilate) arteries
- the heart does not have to work as hard to eject blood
- decreases afterload
- b-adrenergic receptor blockade slows the heart and
decreases force of contraction

function of Metoprolol

- similar benefits to carvedilol
- selectively blocks b1-adrenergic receptors

when should you avoid using beta blockers

avoid in (or at least use with caution):
- asthma, COPD, peripheral vascular disease, insulin
dependent diabetes, physically active

when is it considered good?

good if certain other diseases present (treats both):
- hypertension
- glaucoma,
- certain arrhythmia,
- myocardial infarction,
- angina

for carvedilol and metoprolol what are harmful drug interactions you should be aware of?

• Carvedilol- interaction with ventolin worsens breathing problems due to narrowing of airways
• Carvedilol/Metoprolol- interaction with verapamil (anti-
hypertensive) may cause irregular heartbeat

what are two other things that dont interact well with beta blockers

Antiretroviral medications (e.g. saquinavir) could cause arrhythmia
• Alcohol dangerous since it has additive effects of lowering blood pressure

What are inotropes?

agents which alter the force of contraction of the heart
There are two types:

• Positive inotropes: Increase the force of contraction.

• Negative inotropes: Decrease the force of contraction.

what are two ex of positive inotropes

digoxin, dobutamine

• - increase contractility of the heart
• - symptomatic relief
• - chronic use associated with increased mortality

char of Dobutamine (6)

char of Digoxin

Digoxin mechanism of action

mechanism of action - increases calcium release for each beat

why must you monitor potassium lvls in digoxin

- hyperkalemia diminishes effectiveness of digoxin
- hypokalemia increases digoxin toxicity.
- both inhibit the Na/K ATPase

what can increase digoxin toxicity.

diuretic (loop) use may produce hypokalemia

what negative effects do harmful interations with other drugs with digoxin do?

Interactions with some medications can dangerously increase blood levels of digoxin resulting in cardiac arrhythmias
- common antibiotics such as amoxicillin and erythromycin,
- the anti-arrhythmic agent amiodarone

what do diuretics prevent in hf?

In heart failure, the heart may not pump blood effectively.

This can activate compensatory mechanisms such as RAAS, causing the kidneys to retain sodium and water.

As a result, excess fluid accumulates in the body.

This can cause:

• Peripheral edema (swelling in the legs and feet)

• Pulmonary edema (fluid accumulation in the lungs)

• Shortness of breath

what do diuretics do?

Diuretics help the kidneys eliminate excess sodium and water through urine.

• This decreases fluid overload and relieves symptoms.

strategies to help prevent Chronic Heart Failure

what is Diuretic Resistance

- Common problem in Heart Failure
- Defined as persistence of edema despite salt restriction and
adequate diuretic therapy (usually loop diuretic)

why does Diuretic Resistance happen

Consequence of RAAS-induced adaptive responses by the kidney

how do you fix diuretic resistance

Increasing the dose or more frequent dosing of loop diuretics is used
- Combination therapy of loop and thiazide diuretics also used
- Both approaches have associated risks of excessive depletion of water or electrolytes

where in kidney diuretic actions takes place

Site in nephron	Drug example	Main action
Proximal tubule	Dapagliflozin	Blocks SGLT2 → ↑ glucose and Na⁺ excretion
Proximal tubule	Acetazolamide	↑ Bicarbonate excretion
Loop of Henle (thick ascending limb)	Furosemide	Blocks Na⁺/K⁺/2Cl⁻ transporter
Distal convoluted tubule	Hydrochlorothiazide	Blocks Na⁺/Cl⁻ transporter
Late distal tubule/collecting duct	Spironolactone	Blocks aldosterone receptors
Collecting duct	Tolvaptan	Blocks ADH (V₂) receptors → ↑ free water excretion

Loop Diuretics function

preferred in heart failure with:
• Pulmonary edema
• renal insufficiency (glomerular filtration rate < 30 ml/min)

Problems? (in addition to electrolyte imbalances) with loop diuretics

- interaction with the anti-arrhythmic agent amiodarone can lead to a more irregular heartbeat

if refractory (not responding) to a loop diuretic what do you need to do?

- add a thiazide diuretic (proximal effect important here)
- metolazone often used for this

ex of Thiazide Diuretics and what it does

metolazone

• distal tubule (primary site of action)

• - inhibit Na+/Cl- transporter
  - ̄ Na/Cl reabsorption ( Na+ excretion )
  - Ca2+ reabsorption ( ̄ Ca2+ excretion )

what are Potassium Sparing Diuretics (4)

- these are weak diuretics
- give with other diuretics to decrease potassium loss
- may cause hyperkalemia
- never combine with K+ supplements

what is an ex of potassium sparing diuretics

spironolactone

function of spironolactone

what is Dapagliflozin

Diabetes medication
- Blocks the sodium glucose transporter (SGLT2) in the
proximal tubule of the kidney
- Reduces glucose reabsorption into the bloodstream and
causes glucose removal in the urine

Dapagliflozin how does it help with heart failure

reduces hospitalization, cardiovascular
events and death
- Reduces blood volume and the amount of work the heart
has to do to pump blood

what are adverse effects of dapagliflozin?

Adverse effects are primarily related to risk of hypoglycemia
or ketoacidosis

Symptomatic severity of heart
failure

general Treatment for HF

what is the Sequence for a “typical” patient

1. Loop diuretics

2. ACEis

3. beta blockers

4. Inotropes

explanation for that order