L8: Treatment of heart failure

What is heart failure a consequence of ?

Acute Myocardial Infarction

- HF develops after a period of weeks after a heart attack

State the characteristics of heart failure ?

1) Impaired cardiac output

2)Activation of renin-angiotensin system

3) Sodium retention

4) Reduced diuresis

5)High venous pressure

What are the adverse consequences of heart failure ?

- Impaired cardiac output =>inadequate reperfusion of the body which manifests in skeletal muscles causing MUSCLE FATIGUE

- Increase BV causes high venous pressure so messes up arteriovenous pressure gradient so water comes out of the tissue causing OEDEMA

What are the three different main underlying causes of heart failure ?

1) High resistance of cardiac output (afterload) i.e aortic stenosis/arterial hypertension => less blood ejected per heart beat

2) Heart valves not closing properly => less blood available to eject per heartbeat

3) Heart muscle disease i.e cardiomyopathy, myocardial infarction => less blood ejected per heartbeat

State the 5 principles of treatment ?

- Relieve underlying condition (replace valve)

-Relieve aggravating conditions (w.g anaemia)

-Reduce central venous pressure (preload) to reduce oedema

- Increase cardiac output (positive inotropes) to reduce skeletal muscle fatigue

- Reduce resistance to cardiac output (vasodilation) to reduce skeletal and cardiac muscle fatigue

What is the common feature of positive inotropes ?

- Increase the the intracellular calcium concentration in the ventricular myocytes => more Ca2+ available to bind to troponin C stimulating force of contraction

What are the three types of positive inotropes used to treat heart failure ?

- Cardioglycosides (digitalis)

- B1 sympathomimetics (i.v dobutamine & dopamine)

- Phosphodiesterase (PDE) inhibitors (milrinone)

What is the mechanism of action of cardioglycosides ?

1) Inhibition of Na-K ATPase

2) Intracellular Na+ increase

3) Inhibition of Na+-Ca2+ exchange

4) Conc of Ca2+ increases

What is the mechanism of action of B1 agonists (sympathomimetics) ?

1) Activate cardiac B1 adrenoceptors coupled via g protein to enz

2) Activates adenylyl cyclase

3) Increase synthesis of intracellular cAMP

4) cAMP inhibits inactivation of slow inward current (calcium current carried by L type calcium channel )

5) Increasing Ca2+ conc

What type of drugs are used as acute intervention ?

Positive Inotropes

(not taken regularly only when lives are at risk )

What is the molecular mechanism of phosphodiesterase inhibitors ?

1) Inhibition of PDE

2) Inhibits metabolism (degradation) of cAMP

3) cAMP inhibits inactivation of slow inward current

4) Concentration of Ca2+ increases

( More cAMP so its effects are sustained for longer )

What is on the x-axis of the Frank-Starling curve ?

Left ventricular diastolic pressure

- the amount of stretch of the ventricle at the end of diastole (rest period when heart is filling up with blood)

Why does the left ventricular end-diastolic pressure determine cardiac output ?

It is the muscle length and tension generated at each heartbeat

What is the length-tension relationship?

The more you stretch the muscle the stronger the contraction when stimulated electrically

What is the set point in the Frank-Starling curve ?

Where homeostasis regulates cardiac output

What types of drugs are used to reduce central venous pressure (preload) ?

- Venodilators

- Diuretics

How do venodilators work?

- Dilate the central veins so reduce venous pressure which in turn reduces oedema

Describe how venodilators cause a negative inotropic effect ?

- Decrease in venous pressure will reduced pressure of blood going to lungs

- It will reduce left ventricle pressure at the end of diastole as heart is filling up

- Negative inotropic effect through Starling mechanism

- So lower cardiac output

Name two venodilators ?

- Nitroprusside

- Glyceryl trinitrate (GTN)

What is oedema associated with ?

- High blood volume

- High venous pressure

How do diuretics help reduce the tendency of oedema ?

By reducing blood volume

Name two diuretics ?

- Furosemide (ferusemide)

- Spironolactone

What effects do drugs that reduce afterload have ?

Reduce muscle fatigue

What effects do drugs that reduce both afterload and preload have ?

Reduce oedema and muscle fatigue

What are the two types of drugs that reduce both afterload and preload ? Name the drugs

- A1 adrenoceptor antagonist (prazosin)

- Block angiotensin converting enz (captopril, ramipril and enalapril)

How does prazosin reduce afterload and preoload ?

Blocks vaso and venoconstrictor effects of noradrenaline and adrenaline

What is the benefit of blocking angiotensin converting enz (ACE) ?

- Less circulating angiotensin-II which is a vaso/venoconstrictor

State additional benefits of the block actions of angiotensin-II ?

Diuretic action reduces blood volume

What is the problem with ACE inhibitors ?

- ACE is involved in degradation of vasopressin

- High levels of vasopressin is responsible for ACE induced cough

Which types of drugs provide the same effects of ACE inhibitors but without ACE-induced cough ?

Angiotensin- II receptor (AT-1 type) blockers

- Losartan, valsartan & candesartan ("ARBs")

What drugs can be used for long term treatment of heart failure ?

Beta blockers (B1 antagonists)

- Carvedilol & metoprolol symptoms initially worsen

- Long-term use, symptoms lessen and risk of death lowered - due to inhibition of adverse adaptive changes in heart (remodelling)