L28. Drugs Affecting Cardiac Function

Question 1

Describe the steps of the cardiac cycle: at a cellular level (in terms of calcium flux)

Answer 1

1. Action Potential
2. Opening of voltage gated Ca channels (increases Ca)
3. Leads to opening of the Ca channels in the SR (high increase in Ca)
4. Ca binding to troponin = myosin binding to allow contraction
5. Ca unbinds = relaxation
6. Ca pumped back into the SR or out of the cell in exchange for Na (under a gradient formed by the Na-K-ATPase)

Question 2

What are the mechanisms of heart failure?

Answer 2

Insufficient CO as a result of:
Loss of myocardial muscle (poor contractility)
Pressure Overload
Volume overload

Question 3

What are the 3 main aims of heart failure treatment?

Answer 3

1. Decrease the work of the cardiac system and improve function
2. Reduce signs and symptoms
3. Increase survival

Question 4

What are the 5 main mechanisms for improving cardiac function?

Answer 4

1. Glycosides
2. Beta adrenoreceptor agonists
3. PDE inhibitors
4. Preload reduction
5. Afterload reduction

Question 5

What is the mechanism of action of the Glycosides?

Answer 5

Inhibition of the Na-K-ATPase which increases the Na concentration in the cell and this reduces the drive for Ca to leave the cell.

Once SR capacity for Ca storage has been reached then he Ca concentration in the cytoplasm rises such that forces of contraction are stronger.

Question 6

What are the side effects of glycosides?

Answer 6

Very low therapeutic index 
Affects all excitable tissues that have the Na-K-ATPase pump 
Gut: anorexia, nausea, diarrhoea
CNS: drowsiness, confusion, psychosis
Cardiac: ventricular dysrhythmia

Has a long half life: problem with toxicity

Question 7

What is an example of a glycoside used in cardiac failure?

Answer 7

Digitoxin

Question 8

How does sympathetic activity affect the heart?

Answer 8

Adrenaline binding to B1 receptors in the cardiac myocyte leads to activation (GPCR stimulatory) which increases cAMP levels which activates protein Kinase A (PKA) and this phosphorylates the calcium channel to be activated and allow more calcium into the cell = increases force of contraction

Question 9

What are the actions of the beta adrenoreceptor antagonists? Give examples

Answer 9

they mimic noradrenaline and adrenaline to allow increases in intracellular calcium and increase in contraction.
Eg. Exogenous adrenaline (non-selective for adrenoreceptors)
Dobutamine: b1 selective, partial agonist

Question 10

Why are B agonists not used in chronic heart failure?

Answer 10

Because chronic B-receptor activation leads to reduced expression and impaired coupling (ie. reduced sensitivity) especially to partial agonists (dobutamine)

Question 11

What is the mechanism of action of phosphodiesterase PDE inhibitors?
Give an Example

Answer 11

PDE normally breaks down cAMP into AMP and thus inhibition of this keeps cAMP levels up so that the influx of calcium and thus contractility remains high.

Question 12

What are the three main methods of reducing preload?

Answer 12

1. Venodilators
2. Diuretics
3. Aldosterone Receptor Antagonists

Question 13

How do the venodilators work to reduce preload?

Give examples

Answer 13

They allow a higher capacity for the blood volume and thus decrease the venous return
Eg. Nitrates

Question 14

How do the diruetics act to reduce preload? Give examples

Answer 14

Increase water retention to increase blood volume

Question 15

How do the aldosterone receptor antagonists work?

Answer 15

Inhibit the action of aldosterone on the cortical and distal tubule and improves survival combination therapy
Eg. Spironolactone

Question 16

What are the four main methods of reducing afterload?

Answer 16

1. Arterial vasodilators
2. ACE inhibitors
3. AT1 antagonists
4. B adrenoreceptor antagonists

Question 17

How to ACE inhibitors work?

Answer 17

Inhibit the conversion of AngI to Ang II and thus inhibit hypertrophy, volume retention, vasoconstriction

Question 18

What are some advantages of ACE inhibitors in heart failure?

Answer 18

Decreases morbidity and mortality (better outcome when combined with glycosides)
Improve symptoms and delays progression

Question 19

What are some adverse effects of ACE inhibitors?

Answer 19

First dose hypotension
Dry cough
Loss of Taste
Hyperkalaemia
Acute renal failure
Itching, rash, angiooedema
Foetal Malformation
[Contraindicated in pregnancy, bilateral renal failure and oedema]

Question 20

Why would Beta adrenoreceptor antagonists be considered in heart failure? When is it used?

Answer 20

Because the heart is already pumping as hard as it can, slowing the heart down may make pumping more efficient
These are used to inhibit the disease process in EARLY stages

Question 21

What are the mechanisms of action of b blockers?

Answer 21

Reduces tachycardia and cardiac work
Inhibits renin release
Protects against B receptor down regulation
Vasodilation

Question 22

What are the side effects of beta blockers?

Answer 22

Hypotension
Fatigue
Bronchoconstriction
Cold extremities
May cause and/or mask signs of hypoglycaemia