Discuss the pharmacology and place in the management of severe chronic heart failure of:
(a) enapapril
(b) spironolactone
(c) digoxin
A big question for ten minutes. Candidates were expected to only·cover the surface. Some kinetics and dynamics and' the role in CCF would be expected,eg:
(a) Enalapril
Phannacology: prodrug of angiotension II converting enzyme inhibitor enalaprilat. Long half·life,J 1 hours. Well absorbed orally. No IV preparation available. Offset of action due to renal excretion.
Indications·hypertension, CCF, EF<JS%
Ag II is now known to have numerous autocrine and paracrine effects. ACE inhibition produces far-reaching effects including-peripheral vasodilation, increased C.O.• myocardial remodeling etc.
Side effects include hypotension, renal failure in the setting of renovascular disease, hypotensive reaction to albumin infusion, hyperkalaemia, and cough.
Its role in severe chronic heart failure is well established in improving symptoms and exercise capacity, and improving survival due to myocardial and cerebral events.
(b) Spironolactone
Pharmacology: competitive aldosterone inhibitor. Orally well absorbed. No IV preparation.
Metabolised in the liver
Produces K-sparing diuresis via aldosterone blockade. Aldosterone most likely has other roles in blood vessels promoting fibroblast proliferation and dehydration. Side effects include hyperkalaemia, dehydration and gynaeoomastia. Has been shown to produce increased survival in severe CCF (NHYA IV) when added to
standard regimen of ACEI and loop diuretic. Recent placebo controlled trial stopped early because of marked benefit. Hyperkalaemia was not a problem.
(c) Digoxin
Non-sympathetic inotrope. Blocks Na-K ATPase and indirectly increases intracellular Ca.
Well absorbed orally. Renally excreted. Produces:
- increased contractility
- increased myocardial automaticity
- decreased A V conduction.
Plasma concentration increased by amiodarone, verapramil.
Side effects include nausea, vomiting, visual disturbance AV bradycardias, tachycardias
(flutter with block, VT, VF...).
Overdose or toxicity may be treated with K. Mg, and antibodies.
Its role in CCF is well established in patients with AF to control heart rate, improve mortality, exercise tolerance and symptoms. In patients with sinus rhythm and severe CCF unresponsive to other therapy, digoxin may produce improvement in symptoms but not mortality and hospital admission rate.
I will agree with the court of examiners. There is too much ground to cover for a few minutes. Again, perhaps it is better to tabulate this answer.
|
|
Enalapril |
Spironolactone |
Digoxin |
|
Class |
ACE-inhibitor |
mineralocorticoid receptor antagonist |
Cardiac glycoside |
|
Pharmacokinetics |
Orally available |
Orally available |
Orally available |
|
Mechanism of action |
Antihypertensive; modulates the activity of the renin-angiotensin-aldosterone system by inhibiting the conversion of antiotensinogen into angiotensin by ACE (angiotensin-converting enzyme) |
Diuretic; inhibits the effects of aldosterone in the cortical collecting duct, disabling the ENaC ion channel and thus increasing the excretion of sodium and water |
AV nodal blocker and weak positive inotrope. Inhibits the Na+/K+ ATPase, thereby lowering the intracellular membrane potential and decreasing the excitability of excitable tissues. |
|
Advantages in severe chronic heart failure |
Decreased afterload |
Decreased preload |
Increased contractility |
|
Precautions |
May cause disregulation of renal blood flow. May contribute to renal failure |
May cause type 4 renal tubular acidosis, hyponatremia, hyperkalemia. Gynacomastia in 10% |
Requires monitoring in renal failure |
The European statement I have referenced below is particularly helpful for this question.
In particular, section 7.2 (entitled "Treatments recommended in potentially all patients with systolic heart failure") lists the pharmacotherapy for heart failure, and provides evidence for it.
Enalapril must have been particularly exciting because of the CONSENSUS study (1988) which demonstrated an improvement in both mortality and NYHA grade. A smiliar high accolade is afforded to spironolactone by the RALES trial - fewer of those people died. Digoxin, on the other hand, does not seem to decrease mortality, but does seem to decrease the symptoms of people even while they are in sinus rhythm.
McMurray, John JV, et al. "ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC." European heart journal 33.14 (2012): 1787-1847.
CONSENSUS Trial Study Group. "Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)." N Engl j Med 316 (1987): 1429-1435.
Pitt, Bertram, et al. "The effect of spironolactone on morbidity and mortality in patients with severe heart failure." New England Journal of Medicine 341.10 (1999): 709-717.
Hood Jr, William B., et al. "Digitalis for treatment of congestive heart failure in patients in sinus rhythm: a systematic review and meta-analysis." Journal of cardiac failure 10.2 (2004): 155-164.