Flashcards in L28. Drugs Affecting Cardiac Function Deck (22):
Describe the steps of the cardiac cycle: at a cellular level (in terms of calcium flux)
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)
What are the mechanisms of heart failure?
Insufficient CO as a result of:
Loss of myocardial muscle (poor contractility)
What are the 3 main aims of heart failure treatment?
1. Decrease the work of the cardiac system and improve function
2. Reduce signs and symptoms
3. Increase survival
What are the 5 main mechanisms for improving cardiac function?
2. Beta adrenoreceptor agonists
3. PDE inhibitors
4. Preload reduction
5. Afterload reduction
What is the mechanism of action of the Glycosides?
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.
What are the side effects of glycosides?
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
What is an example of a glycoside used in cardiac failure?
How does sympathetic activity affect the heart?
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
What are the actions of the beta adrenoreceptor antagonists? Give examples
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
Why are B agonists not used in chronic heart failure?
Because chronic B-receptor activation leads to reduced expression and impaired coupling (ie. reduced sensitivity) especially to partial agonists (dobutamine)
What is the mechanism of action of phosphodiesterase PDE inhibitors?
Give an Example
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.
What are the three main methods of reducing preload?
3.Aldosterone Receptor Antagonists
How do the venodilators work to reduce preload?
They allow a higher capacity for the blood volume and thus decrease the venous return
How do the diruetics act to reduce preload? Give examples
Increase water retention to increase blood volume
How do the aldosterone receptor antagonists work?
Inhibit the action of aldosterone on the cortical and distal tubule and improves survival combination therapy
What are the four main methods of reducing afterload?
1. Arterial vasodilators
2. ACE inhibitors
3. AT1 antagonists
4. B adrenoreceptor antagonists
How to ACE inhibitors work?
Inhibit the conversion of AngI to Ang II and thus inhibit hypertrophy, volume retention, vasoconstriction
What are some advantages of ACE inhibitors in heart failure?
Decreases morbidity and mortality (better outcome when combined with glycosides)
Improve symptoms and delays progression
What are some adverse effects of ACE inhibitors?
First dose hypotension
Loss of Taste
Acute renal failure
Itching, rash, angiooedema
[Contraindicated in pregnancy, bilateral renal failure and oedema]
Why would Beta adrenoreceptor antagonists be considered in heart failure? When is it used?
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
What are the mechanisms of action of b blockers?
Reduces tachycardia and cardiac work
Inhibits renin release
Protects against B receptor down regulation