1. Pharmacology of Heart failure
By Rutendo Ganyani and Sarah Folkerts

2. What are the signs & symptoms of heart failure?

3. Signs and Symptoms of heart failure
Dyspnoea
Orthopnoea
Paroxysmal nocturnal dyspnoea
Fatigue
Cough (pink, frothy sputum)
Nocturia
Signs:
Resting tachycardia
JVP elevation
Lung crackles
Wheezing
3rd heart sound
Peripheral oedema
Ascites

4. What are the NICE guidelines for treatment of LV heart failure?

5. NICE Guidelines Diuretic for symptom relief…..then
ACEi + Beta blockers
Consider ARB if patient can’t tolerate ACEi
Consider adding an Aldosterone antagonist or an ARB or hydralazine + nitrate
Consider hydralazine + nitrate if patient can’t tolerate ACEi and ARBs
Digoxin
ACEi, beta-blockers, ARB & Spironolactone have mortality benefit in addition to relieving symptoms;
Diuretics and digoxin -> symptomatic relief;
Hydralazines & Nitrates beneficial to Afro-Caribbean patients
Implantable devices
When other heart pathologies or risk factors are present, consider treatment for these. e.g. aspirin, Ca-channel blockers
Transplantation

7. Describe the mechanism of action of ACE inhibitors!
Side effects?
Example?

8. ACEi pharmacology
stop the conversion of angiotensin I to angiotensin II thus stopping all the downstream effects. (vasodilation)
Side effects:
Dry cough
Hyperkalaemia
Other side effects include:
Teratogenic
Hypotension
Renal impairment (do not use w/ renal artery stenosis!)
Examples:
Ramipril
Dry cough due to the fact that ACE also converts bradykinin to inactive metabolites -> ACEi cause increased concentration of bradykinin and bradykinin causes cough (prob through bronchoconstriction)

9. Describe the mechanism of action of ARBs!
Side effects?
Example?

10. Angiotensin receptor blocker (ARB) pharmacology
Inhibit action of Angiotensin II
Reduce vascular resistance
Restore tissue perfusion
Reduce afterload
Reduce aldosterone production
Reduced sodium reabsorption
Water loss
Side effects:
Hypotension
Renal impairment
Hyperkalaemia
Examples: Losartan

11. Control of renin release and formation and action of angiotensin II (RAAS system)
Angiotensinogen is produced by the liver.
ACE is produced by cells of the pulmonary and renal endothelium.

12. Describe the mechanism of action of beta blockers!
Side effects?
Example?

13. Beta blocker pharmacology
block beta-1 adrenergic receptors (Gs coupled receptors which cause an increase in cAMP -> increase in PK-A -> increase of intracellular Ca in cardiac myocytes) in the heart.
Reduced heart rate
Decrease cardiac contractility
Reduce arterial pressure
Attenuate ventricular remodelling: fibrosis, apoptosis and arrythmogenesis
Side effects:
Bronchoconstriction
Cardiac depression
Bradycardia
Hypoglycaemia
Fatigue
Cold extremities
Examples: Bisoprolol, metoprolol
Blood pressure lowering effect of beta-blockers: patients with hypertension (although not normotensive subjects) show a gradual fall in arterial pressure that takes several days to develop fully. The mechanism is complex and involves the following:
Reduction in cardiac output
Reduction of renin release from the juxtaglomerular cells in the kidney
a central action, reducing sympathetic activity

14. Describe the mechanism of action of Aldosterone antagonists!
Side effects?
Example?

15. Aldosterone receptor blocker pharmacology
Blocks action of aldosterone at DCT (block mineralocorticoid receptors)
Reduced expression of ENac
Reduced Na+ reabsorption
Increased water excretion
K+-sparing
Side effects:
Hyperkalaemia,
Hypotension
Mainly w/ spironolactone
Gynaecomastia,
Impotence
Examples: Eplerenone, spironolactone
Gynaecomastia -> spironolactone also acts as an antagonists on androgen receptors and inhibits androgen production;
Epleronone is more selective to the mineralocorticoid receptors and thus has less side effects related to the androgenic receptors

16. Describe the mechanism of action of Nitrates!
Side effects?
Example?

17. Pharmacology of nitrates
Metabolised to NO  activate guanylate cyclase  increase in cGMP  activates protein kinase G  vascular relaxation
Side effect
Headache (due to dilatation of intracranial arteries)
Postural hypotension
Dizziness
Also problem with quickly developing tolerance that can lead to abnormal constriction of coronary arteries following withdrawal

18. ………….and the others Digoxin
Digoxin (in particular for heart failure w/ established atrial fibrillation or if symptomatic despite diuretics and ACEi) -> increases inotropy (=pos. inotrope)
Hydralazine - Unknown mechanism of action, however it dilates arteries & arterioles -> reducing the afterload. (= vasodilator)
Side effects:
Tachycardia
Headache
We will not be looking at transplantation or implantable devices….. Don’t worry about this at this stage. Just know the options exist.
Digoxin = cardiac glycoside -> works by inhibiting the Na+/K+ pump in cardiac myocytes; -> more Na+ inside the cell -> Na+/Ca+ exchanger pumps Na+ out of cell in exchange for Ca+ -> Ca+ inside cell accumulates -> force of contraction increases (main effect); additional effects: increase in ectopic pacemaker activity, impairment of AV conduction, increased vagal activity -> bradycardia (Don’t worry about this too much at this stage.)

19. Summary of site of action of different drugs used to treat heart failure

20. Any Questions?