Treatment of heart failure Flashcards
NEP-I: neutral endopeptidase inhibitor –
enzyme that would normally break down the natriuretic peptides. This drug stops the breakdown of these peptides so they keep protecting the heart
Pharmacology of drugs used to treat heart failure- Diuretics
- Patients with left heart failure typically have a fluid build up in the lungs
- Therefore, they usually prefer sleeping propped up
- Patients with right heart failure typically have a fluid build up in the abdomen – ascites • One way to get rid of this fluid is to offer them a diuretic
- Diuretics remove from the body in the form of urine
- They can relieve the symptoms of heart failure
- They increase Na+ and H2O loss, which reduces preload which means the heart doesn’t have to work as heart
- However, there is no evidence that they reduce mortality of heart failure
- Long term use of these loop diuretics can cause resistance, and this may be overcome by adding a thiazide-like diuretic
- You may monitor dehydration by measuring weight
ACE-Inhibitors & beta-blockers
• At the same time as starting diuretics you would start the patient on an ACE-I and BB • BB: reduces frequency of beats, which allows the heart more time to fill
- less preload = less cardiac output
- less after load= more cardiac output
- improves mortality
- risk of :Hypotension,hyperkalaemia,dizzziness and coughs
ACE-I
- Decreasing preload (blood returning to the heart) and so, reduces cardiac output but decreasing afterload increases cardiac output (it is much easier to pump blood back out) – although less is coming back into the heart, the heart can compensate for that by pumping more out into the systemic circulation
- They counteract the remodeling that can occur if the heart is put under strain
- ACE-I can cause first dose hypotension
- Renal function needs to be monitored as well as blood potassium levels
Role of angiotensin receptor blockers (ARBs)
• Block the ability of angiotensin II to target AT1 receptor
(AT1 receptor has all the positive blood pressure increasing effects)
• Can be given if ACE-I are not tolerated
• Improves mortality (ELITE I and II / CHARM trials)
• Added into conventional therapy (ValHeft / CHARM added)
• Less s/es
Why add in an ARB?
- If you block ACE and you reduce the production of angiotension II, then the body notices and increases renin production, which produces more angiotensin I and eventually angiotension II
- ACE inhibitor therapy can lead to breakthrough due to increases in renin production and therefore Ang I
- Other enzymes that convert Ang I to Ang II (chymase)
BB
- BB reduce the frequency of heart beat and reduce the force of contraction
- They interrupt the compensatory mechanisms, things which damage the heart
- If you slow down the frequency of heart beat, then you give the ventricles more time to fill – so they can fill with a little bit more blood
- So even though the force of contraction will be reduced, because they have more blood in the ventricles, the amount of blood that is pumped forward will not change that much
- Usually given in very low doses
- Given in hospital so the patient can be observed in case cardiac output drops dramatically
- Only given to patients who’s heart failure is stable
- So, as well as reducing the effects of noradrenaline on the heart, they can also resensitize some of the beta receptors that are present in the heart – so the heart is more sensitive to adrenaline and noradrenaline so levels in the periphery don’t need to be as high to maintain cardiac output
- (Remember we said that high levels of noradrenaline can cause receptor desensitization) • Bisoprolol and carvedilol are the best BB to use here
- Revise the side effects of BB
Inverse agonists have negative efficacy
As you increase the dose of agonists, it increases receptor activation
• In the presence of a competitive antagonist, the dose response curve shifts to the right but still maintain the same maximum provided you increase the concentration of the natural ligand
• Inverse agonists reduce the level of receptor activation
• This requires that the receptors are active in the absence of any natural ligand – these receptors are constitutively active
• Receptor can be in 2 states: resting and active
• Receptor keeps moving between these 2 states, even in the absence of the agonist
• A lot of G protein coupled receptors are constitutively active
• Only when the receptor is in the active state can a response occur with agonist binding – the higher the conc. of agonist the more we shift to the activated receptor
• Inverse agonists predominantly bind to the resting state of the receptor
• Bisoprolol is an inverse agonist – will preferentially stabilize the beta 1 receptors in the resting state
Noradrenline/adrenaline are the agonists in the disease
These give a beneficial effect acutely but will desensitize the receptors in the long term
• Using agonists all the time is not good
• Inverse agonists can be dangerous acutely because more receptors are inactive (less are responding to the needs of the heart) HOWEVER the advantage of that is that you are going to sensitize and up regulate the receptors in the long term
• Recent trials have started to use sacubitril and valsartan
• Sacubitril is a neprilysin inhibitor which prevents the breakdown of natriuretic peptides
• Valsartan is an angiotension receptor blocker ARB
Vasodillators
• Vasodilators decrease preload
• Some can also decrease afterload
- can cause hypertension,headaches,tachycardia
Role of sprinolactone
- Improves mortality
- Added to conventional therapy
- only small doses needed, can cause hyperkalemia, gynaecomastia
• Also a useful drug and tends to be added in if ACE-I and BB cant control patients heart failure
• Not used alone
• Attenuates aldosterone effect – remember aldosterone can drive cardiovascular remodeling, which reduces the efficiency of the heart
• Blocking aldosterone can reduce hypertrophy of muscle fibres and fibrosis • Gynaecomastia: man boobs
Digoxin
- Used to be the drug of choice for the treatment of heart failure
- Increases myocardial contractility and therefore cardiac output is improved
- But because it was making the heart work harder, it wasn’t increasing mortality
- Its now added in much later in the therapy if all the previous therapies don’t help
- Can also be quite toxic (esp to kidneys) and has a narrow therapeutic window
- It inhibits the sodium potassium ATPase and as a consequence it reduces the amount of potassium that is brought back into the cell and reduces the amount of sodium ions that are removed from the cell – so sodium ion concentration builds up inside the cell
- Another protein called a sodium calcium exchanger usually uses the concentration gradient of sodium ions across the membrane to allow sodium ions to enter the cell and remove calcium against its concentration gradient
- However if we block the sodium potassium ATPase, sodium ion concentration will increase in the cell, this driving force will be reduced so the removal of calcium will be reduced
- As a consequence calcium levels will build up inside the cell and this will allow a much stronger contraction
- Digoxin can cause a range of arrhythmias (bradycardia)
- But if the levels of digoxin go too high then that increase in calcium inside the cell can cause late after depolarization which can lead to tachycardia
- If its used with calcium channel blockers or BBs, it can potentially cause heart block
Role of other treatments
- Ivabradine: used to treat adults who have chronic heart failure
- Biventricular pacing - severe CHF high cost • Transplantation - 85% survival @ 5yrs
New drug
dapagliflozin
Summary
- Heart failure is a serious condition which if not treated can lead to death.
- Current treatment designed to maintain heart function and reduce morbidity rather than markedly improving function.
- Main side effects of drugs hyperkalaemia (ACE-/sprionolactone); possible bradycardia decreased CO.
