Flashcards in Clinical pharmacology of heart failure Deck (55):
What is chronic heart failure characterised by (symptoms)?
- By progressive cardiac dysfunction
- Neurohormonal disturbances
- Sudden death
What are the 2 types of heart failure
- Systolic heart failure (HFrEF)
- Diastolic (or relaxation) heart failure (HFpEF)
Know systolic, not diastolic!!
Features of Systolic heart failure (HFrEF)
Decreased pumping function of the heart, which results in fluid back up in the lungs and heart failure
Features of Diastolic heart failure (HFpEF)
- Involves a thickened and stiff heart muscle
- As a result, the heart does not fill with blood properly
- This results in fluid backup in the lungs and heart failure
What is the Ejection fraction?
Volume of blood ejected from the ventricle with each beat
Chronic heart failure facts
- Affects 2-10% of the population
- Incidence rises with increasing age
- Has a poor prognosis with a 5 year mortality of 50% rising to 80% in a year for some patients
- Patients are often very symptomatic
Risk factors for heart failure
- Coronary artery disease
- Hyperension (LVH)
- Valvular heart disease
- Infection (viral)
- Congenital heart defects
- Other: obesity, age, smoking, high or low haematocrit level, obstructive sleep apnoea
What is the no.1 risk factor for Heart failure?
What is the Frank-Starling Law?
If the muscle of a healthy heart is stretched it will contract with greater force and pump out more blood.
Features of Systolic Dysfunction
- Frank-Starling law
- In the failing or damaged heart this relationship is lost
- As circulatory volume increases the heart dilates, the force of contraction weakens and cardiac output drops further
- Cardiac output then activates the RAAS further
What is the result of systolic dysfunction?
- The result is a vicious cycle in which the RAAS is activated, circulatory volume increases and cardiac performance deteriorates further.
- As the heart starts to dilate the cardiac myocytes undergo hypertrophy and then fibrosis and thus the heart is further weakened.
What is activated fir salt and water retention and vasoconstriction?
What does the activation of the sympathetic system cause the release of?
Noradrenaline and Adrenaline
- Stimulate renin release
- Myocyte hypertrophy
What is used for salt and water excretion and vasodilatation?
- Natriuretic peptide system ANP/BNP
Features of atrial and brain natriuretic peptides
- Potent vasodilators and natriuretic peptides
- Short half-life
What are the 2 main aims of heart failure treatment?
To improve symptoms and improve survival
Treatment used to improve symptoms
- Diuretics (loop diuretics)
Treatment used to improve symptoms and survival
- ACE inhibitors/ARBs
Treatment used to improve survival
What is used for blocking detrimental hormonal changes?
- Carvedilol, Bisoprolol and Metoprolol are beta blockers which are of proven benefit in the treatment of CHF.
RAAS activation: inhibition of Angiotensin II
- Two groups of drugs available to block the effects of angiotensin II
- ACE inhibitors (Ramipril)
- Angiotensin antagonists (Valsartan, Losartan_ but these are not as effective (ELITE II)
RAAS activation: Aldosterone inhibition
- Effects blocked by Spironolactone
- Produces a significant reduction in morbidity (RALES)
What treatments are used for enhancing beneficial hormonal changes?
- Natriuretic peptide system
- ANP/BNP: atrial natriuretic and brain peptides are potent natriuretic agents and vasodilators
- Metabolised by neutral endopeptidase
- Neprolysin prevents metabolism and enhances ANP/BNP actions
What treatments are used for enhancement of cardiac function?
- Positive Inotropes
Features of positive inotropes
- These drugs improve the ability of the heart to pump and so improve cardiac status
- Digoxin is the only drug in common use
Features of Vasodilators
- The nitrovasodilators by reducing preload and afterload improve cardiac function (Isosorbide mono or Dinitrate)
- Hydralazine an arterial dilator has also been shown to improve cardiac function
By how much do ACEi and beta blockers reduce mortality and hospitalisation?
ACEi - relative risk reduction 35%
Beta Blockers - relative risk reduction 38%
Features of Loop Diuretics (Furosemide)
- The main stay of treatment
- Removes excess salt and water
- The loop diuretics induce profound diuresis
- Inhibit the Na-K-Cl transporter in the Loop of Henle
- Work at very low glomerular filtration rates
- Prevent the reabsorption of 20% of filtered sodium and water
Adverse drug reactions of diuretics
- Hypokalaemia, Hyponatraemia
- Impaired glucose tolerance, diabetes
Drug-Drugs interactions: Frusemide and aminoglycosides
Aural and renal toxicity
Drug-Drugs interactions: Frusemide and Lithium
Drug-Drugs interactions: Frusemide and NSAIDs
Drug-Drugs interactions: Frusemide and antihypertensives
Drug-Drugs interactions: Frusemide and Vancomycin
Mechanism to reducing mortality
- Angiotensin blockade
- Beta receptor blockade
- Aldosterone blockade
- ANP/BNP enhancement
Does local angiotensin II synthesis require ACE inhibitors?
No it is independent of ACE
Examples of Angiotensin converting enzyme inhibitors
Features of Angiotensin converting enzyme inhibitors
- Completely block angiotensin converting enzyme
- Prevent the conversion of angiotensin I to angiotensin II
- Reduce preload and afterload on the heart
Features of ACE inhibitors
- In CHF patients significantly reduce: morbidity, mortality
- Post MI patients to reduce: morbidity, mortality, onset of heart failure
- Main studies CONSENSUS, SOLVD, SAVE, AIRE, ISSIS-4
Adverse drug reactions of ACE inhibitors
- First dose hypotension
- Renal impairment
- Renal failure
ACE inhibitor drug-drug interactions
NSAIDs - acute renal failure
Potassium supplements - hyperkalaemia
Potassium sparing diuretics - hyperkalaemia
Features of Angiotensin receptor blockers
- ARBs selectively block the angiotensin II, AT1 receptor
- They are effective, but not as effective as ACEi's
- At present recommended for use in ACEi intolerant patients
What are the roles of AT1 receptors?
- Vascular proliferation
- Aldosterone secretion
- Cardiac myocyte proliferation
- Increased sympathetic tone
What are the roles of AT2 receptors?
According to studies, is ACEi therapy good?
No, greatest benefits in patients not on ACE inhibitor therapy
Features of Valsartan-Sacubitril (ARNI)
- Combined valsartan and ARB and Neprilysin
- ARB blocks AT1 receptor
- Neprilysin stops break down of ANP and BNP by neutral endopeptidases
Features of Aldosterone Antangonists (Spirolactone)
- Potassium sparing diuretic
- Inhibits the actions of aldosterone
- Acts in the distal tubule
- Used in combination with loop diuretics
- Particularly useful in resistant oedema
Proven to reduce mortality when used in combinations with ACEi's
Examples of Beta-Blockers in treatment of CHF
Features of Beta-blockers in treatment of CHF
- Use of beta-blockers in this treatment of CHF is potentially hazardous and patients must be selected carefully
- Block the actions of the sympathetic system
- May precipitate severe deterioration in CHF
- Have been demonstrated to reduce morbidity and mortality in mild/moderate and severe heart failure by 30%
- Should be used only when a patient has been stabilised and not during an acute presentation
- Specialist use only
Features of Ivabradine
- Ivabradine is a specific inhibitor of the If current in the sinoatrial node.
- No action on other channels in the heart or vascular system.
- Does not modify myocardial contractility and intracardiac conduction, even in patients with impaired systolic function.
When is Ivabradine recommended?
It can be beneficial to reduce HF hospitalisation for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF <35%) who are receiving standard therapy, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70bpm or greater at rest.
Features of Positive Inotropes (Digoxin)
Digoxin (the DIG study)
- Increases availability of calcium in the myocyte
- Shown to reduce number of hospitalisations
- No effect on mortality
- Narrow therapeutic index
Features of Anticoagulants (Warfarin)
- Dilated ventricle gives rise to thrombus formation and thrombo-embolic events
- Warfarin has proven to prevent these events
- Anticoagulant use if high risk of thromboembolic disease
What is the therapeutic regime for heart failure?
- Furosemide +- thiazide, appropriate dose
- Furosemide + pulsed metolazone
- ACE inhibitor, appropriate dose
- Angiotensin receptor blocker
- Beta-blocker +- Ivabradine
- MRA-spironolactone, 25mg
- Digoxin, TDM
- Warfarin, TDM