Introduction

ACE inhibitors (angiotensin converting enzyme inhibitors) e.g. ramipril, perindopril, enalapril, lisinopril, captopril are commonly used medications to treat hypertension and heart failure – they are considered first line agents in both of these important conditions. Through multiple mechanisms they act to both reduce the blood volume, and cause vasodilation, therefore decreasing peripheral vascular resistance.

About 10% of patients will get a dry cough as a result of an accumulation of bradykinin in the lungs. These patients should be switch to an angiotensin-II receptor blocker instead. They also carry a small risk of renal failure and hyperkalaemia.

They are also commonly referred to as ‘reno-protective’ – meaning that in the early stages of renal failure – particularly that associated with proteinuria (especially in T2DM) they can prevent the advancement of renal disease.

Mechanism

ACE inhibitors competitively inhibit the angiotensin converting enzyme (ACE), and thus reduce the generation of angiotensin-II, and also consequently aldosterone. This reduces sodium and water retention.
  • Reduced tissue concentration of angiotensin-II also leads to arterial and venous dilation
  • There is no reflex tachycardia – probably due to stimulation of the vagus nerve and a reduction in sympathetic activation caused by reduced angiotensin-II
  • These drugs also inhibit bradykinin breakdown by ACE – bradykinin is a vasodilator.
  • Angiotensin-II is associated with arterial, and left ventricular hypertrophy in hypertension. However, the role of ACE inhibitors in this system is not fully understood – there may be some extra benefit on top of the hypotensive benefits of the drug
Renin-angiotension-aldosterone system indicating the mechanism of action of ACE inhibitors

Renin-angiotension-aldosterone system indicating the mechanism of action of ACE inhibitors

Pharmakokinetics

  • Usually given as pro-drugs, as the active forms are water soluble, and thus poorly absorbed from the gut. They are converted in the liver to the active agent, e.g. ramipril becomes ramiprilat.
  • For most forms, the active drug is excreted, unchanged, by the kidney
  • Half-lives are generally short, but the half-life of enalapril is long.

Indications

  • Hypertension
  • Heart failure
  • Early renal failure with proteinuria
  • Secondary prevention after MI

Cautions

  • Be careful when used in combination with other drugs that can increase potassium, as there is an increased risk of hyperkalaemia – e.g. thiazide-like diuretics, potassium sparing diuretics
  • The triple whammy!
    • A famous cause of renal failure, when drugs from three particular classes are used together. Thankfully, electronic prescribing methods are reducing the likelihood of these three medications being prescribed together. They are:
      • ACE inhibitors (or ARB) PLUS
      • Thiazide diuretic PLUS
      • NSAID
    • DO NOT prescribe these three drug classes together in the same patient – use alternatives
    • It is not as uncommon as it may seem – many hypertensive patients will already be on an ACE and thiazide diuretic, and you have better be careful when they come and see you because of their lower back pain / renal colic / headaches / other MSK injury!

Unwanted effects

  • Persistent dry cough – this is non-dose related, and may be caused by accumulation of kinins. It is more common in women, and occurs in approximately 10-30% of those who take the drug
  • Postural hypotensionthis is rare unless there is salt and water depletion, e.g. in people who are also taking diuretics. In people where it does occur there can be very profound hypotension, particularly after the first dose. This is rarely a problem when treating hypertension, but can occur when treating heart failure. Risks such as this can be minimised by taking a once-a-day preparation, when lying down, just before going to sleep at night
  • Renal impairment – particularly in those with severe bilateral renal artery stenosis, who are relying on angiotensin mediated efferent glomerular arterial vasoconstriction to maintain a good filtration pressure. Can be serious and result in renal failure (rare).
  • Disturbance of taste, nausea, vomiting, dyspepsia, bowel disturbance
  • Rashes
  • Angioedema – this is the rapid swelling of the dermis and subcutaneous tissues. It is very similar to urticaria (hives), except that hives occurs in the upper layers of the dermis and angioedema occurs in lower layers. Angioedema is most commonly seen with anaphylaxis, but it is well recognised that an ACE inhibitor induced angioedema can occur, and is may be mistaken for anaphylaxis.
    • Can occur anywhere on the body, but most commonly affects the airway
    • Occurs in <0.5% of patients
    • Can occur after years of use, but most commonly in the first year of use
    • May be a medical airway emergency 

References

  • Ramipril - AMH
  • Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
  • Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
  • Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy
  • Waller, DG., Renwick AG., Hillier K. (2005). Medical Pharmacology and Therapeutics. 2nd ed. Elsevier Saunders

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