Lecture 7 - treatment of heart failure

Question 1

what are the 3 main underlying causes of heart failure

Answer 1

1. High resistance to cardiac output
2. heart valves not closing properly
3. heart muscle disease

Question 2

what are the characteristics of heart failure

Answer 2

condition often caused by IHD, sudden lack of O2 leads to myocardial cell malfunction

Question 3

what are the principles of treatment

Answer 3

1. Relieve underlying condition (i.e. replace valve)
2. Relieve aggravating conditions (i.e. anaemia, lack of RBCs)
3. Reduce Central Venous Pressure (preload) to reduce Oedema
4. Increase CO (positive inotropy) to lower skeletal muscle fatigue
5. Reduce resistance to CO (vasodilation) to reduce skeletal & cardiac muscle fatigue

Question 4

positive inotropes

Answer 4

Increase work of the heart, i.e. HR or SV
a) 3 Main Types:
i. Cardioglycosides, i.e. Digitalis
ii. Beta1 Sympathomimetics, i.e. Dobutamine
iii. Phosphodiesterase (PDE) Inhibitors, i.e. Milrinone

b) Common Function of Positive Inotropes: To raise Intracellular [Ca2+] and make heart more likely to contract
i. Ca2+ binds to troponin C and stimulates heart contractions

Question 5

positive inotropes: Cardioglycosides

Answer 5

Cardioglycosides: Digitalis
a) Site of Action: Binds to Na+/K+-ATPase of Cardiac Sarcolemma

b) Mechanism of Action:
1. Inhibits Na+/K+-ATPase that pumps 3 Na+ out from intracellular space & 2 K+ in
2. Causes for increase of Intracellular Na+
3. Reduced function of Na+/Ca2+ Exchanger that pumps 3 Na+ In & 1 Ca2+ Out
4. Intracellular [Ca2+] increases & heart more likely to contracts

Question 6

positive inotropes: beta 1 sympathomimetics

Answer 6

Dobutamine
a) Site of Action: Beta1 Adrenoreceptors on Heart

b) Mechanism of Action:
1. Activation of Beta1 Adrenoreceptors, causing for activation of GPCRs
2. Leads to increased activation of Adenylyl Cyclase, converting more ATP to cAMP
3. cAMP inhibits the inactivation of Isi (slow inward current)
4. With increased inward current, there is increased flow of Ca2+ into myocardial cells –> Heart more likely to contract

Question 7

positive inotropes: PDE inhibitors

Answer 7

PDE Inhibitors: Milrinone
a) Site of Action: PDE Enzymes

b) Mechanism of Action:
1. Inhibit PDE –> PDE responsible for cAMP metabolism
2. Increased cAMP levels allows for increased inhibition of inactivation of slow inward calcium current
3. Raised intracellular [Ca2+] –> Heart more likely to contract

Question 8

Drugs lowering preload

Answer 8

work to lower central venous pressure
1. Venodilators: Glycerl Trinitrate (GTN)
a) Bind to venous blood vessels and cause for vasodilation –> May reduce CVP and reduce Oedema
c) However, this lowers CO, so Venous Dilators always used alongside Positive Inotropes

*Frank-Starling Mechanism: if venous dilation occurs, central venous pressure will decrease. This is due to the lowered blood pressure from the arterial circulation to the right atria (via vena cava), leading to reduce pressure of blood from the right ventricle and through the pulmonary circulation to the left atria & ventricle. This lowers the ventricular filling pressure and causes for less work done by the heart to pump the lowered blood volume.

2. Diuretics: Furosemide
   a) Lower total blood volume by lowering kidney function & water reabsorption

Question 9

drugs lowering afterload

Answer 9

work to lower the resistance of vessels heart has to pump against
1. Arteriolar Dilators: Hydralazine
a) Act as ‘direct’ (receptor-independent) arteriolar dilation
i. Cause for reduced cAMP levels –> Reduced inactivation of inhibition of slow current, so less Ca2+
b) Bind to arteries and cause vasodilation to reduce skeletal muscle fatigue and prolongs life

*Risk of Cardiac remodelling lowered as cardiac hypertrophy prevented!

Question 10

Drugs Lowering Pre & Afterload

Answer 10

main effect to reduce oedema and muscle fatigue
a) Prazosin: Alpha1-Antagonist for Alpha1-Adrenoceptors
i. Inhibits NA & Adrenaline activation & vasoconstriction –> Inhibition leads to vasodilation of veins and arteries

b) Captopril: Block ACE
i. Less AT2, reduced binding to AT1 receptors & lowered effects of vasoconstriction
ii. Less AT2 also lowers Renin secretion –> Renin stimulates Na+ reabsorption and water retention, so blood volume lowers and may reduce oedema
*Side effect of dry cough –> Due to ACE function to metabolise Bradykinin, where raised Bradykinin levels leads to cough

c) ARBs (AT1-Type): Losartan
i. Inhibit binding of AT2 and vasoconstrictive effects without side effects of dry cough

Question 11

Beta1 Antagonists

Answer 11

Beta-Blockers: Carvedilol
a) For long-term use, as initial use lowers heart function and further lowers CO
*However, after prolonged use, symptoms lessen and risk of Cardiac remodelling lowered as cardiac hypertrophy prevented
*Ultimate Effect: Lowered risk of death