Discuss the pharmacology and place in the management of severe chronic heart failure of:

(a) enapapril 
(b) spironolactone 
(c) digoxin

[Click here to toggle visibility of the answers]

College Answer

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.

Discussion

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
Renally excreted
Minimal metabolism

Orally available
Hepatic metabolism

Orally available
Renally excreted
Minimal metabolism

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.
Also increases the  availability of intracellular calcium, and thus acts as a positive inotrope).

Advantages in  severe chronic heart failure

Decreased afterload
Improved cardiac remodeling and thus decreased morbidity and mortality

Decreased preload
Improved cardiac remodeling and thus decreased morbidity and mortality

Increased contractility
Rate control in arrhythmia

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
Risk of toxicity

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.

References