ACE inhibitors.
ACE inhibitors are the cleanest example in pharmacology of one enzyme with two jobs. Block it and you get the therapeutic effect from the first job and the two most famous side effects from the second, which means the whole class can be reasoned out from a single sentence.
The mechanism in one sentence
ACE inhibitors block angiotensin converting enzyme, which both reduces angiotensin II production and prevents bradykinin breakdown.
Angiotensin converting enzyme sits at a junction of two systems. In the renin-angiotensin pathway it converts angiotensin I to angiotensin II, a potent vasoconstrictor that also drives aldosterone release. Separately, the same enzyme degrades bradykinin, an inflammatory peptide that dilates vessels and irritates airways. Inhibiting the enzyme therefore does two things at once: less angiotensin II, which lowers blood pressure and reduces aldosterone-driven sodium retention, and more bradykinin, which is responsible for the cough and the angioedema. Angiotensin receptor blockers act further downstream at the receptor, leave bradykinin breakdown untouched, and so avoid those two effects.
Members of the class
| Drug | What sets it apart |
|---|---|
| Ramipril | Widely used with strong outcome evidence in cardiovascular risk reduction. |
| Lisinopril | Long-acting and not a prodrug, unlike most of the class. |
| Enalapril | A prodrug converted to enalaprilat. |
| Perindopril | Long-acting, commonly used in hypertension and stable coronary disease. |
What the class is used for
- Hypertension, particularly where diabetes or renal disease coexists
- Heart failure with reduced ejection fraction
- After myocardial infarction, to limit adverse remodelling
- Diabetic nephropathy and proteinuric kidney disease, for their effect on intraglomerular pressure
Side effects, derived from the mechanism
Each entry below follows from the mechanism above rather than being a separate fact. Read the middle column as the answer to the question, why would that happen.
| Effect | Why it follows |
|---|---|
| Dry persistent cough | Bradykinin accumulates in the airways because the enzyme that clears it is blocked. It affects a substantial minority, is not dose-related in any useful way, and resolves on switching to an ARB. |
| Angioedema | The same bradykinin accumulation, acting on vascular permeability. It is rare but can be life-threatening, may appear months into treatment, and is an absolute contraindication to rechallenge. |
| Hyperkalaemia | Less angiotensin II means less aldosterone, and aldosterone is what drives potassium excretion. Remove it and potassium is retained. |
| First-dose hypotension | Removing angiotensin II vasoconstriction abruptly matters most in patients who are volume-depleted or already on a diuretic. |
| Rise in creatinine | Angiotensin II constricts the efferent arteriole to maintain filtration pressure. Blocking it drops that pressure, so a small creatinine rise is expected; a large one suggests the kidney was depending on it, as in bilateral renal artery stenosis. |
Contraindications and cautions
- Pregnancy, in any trimester, because of fetal renal damage
- Previous angioedema on an ACE inhibitor
- Bilateral renal artery stenosis
- Caution with potassium-sparing diuretics, potassium supplements and NSAIDs
The part you cannot derive
The combination of an ACE inhibitor, a diuretic and an NSAID is sometimes called the triple whammy, because each one impairs a different compensatory mechanism the kidney uses to protect filtration. Any two are tolerable in most patients; all three together is a recognised cause of acute kidney injury.
Exam traps
Cough means switch to an ARB, not stop the class
The therapeutic mechanism is shared; only the bradykinin effect is not. Angioedema is the exception, where caution extends to ARBs as well.
A small creatinine rise is expected
Stopping the drug for a modest rise removes a treatment that protects the kidney long-term. The threshold that matters is a large or progressive rise.
Hyperkalaemia is the interaction to watch
Add spironolactone, a potassium supplement or trimethoprim and the risk compounds rather than adds.
Test yourself on this
Reading a mechanism and being able to retrieve it under time are different skills, and only the second one is examined. These are free and need no account.
- Cardiovascular pharmacology practice questions — 10 questions with explanations
- ACE inhibitors versus ARBs
- CYP450 inducers and inhibitors
- Creatinine clearance calculator (Cockcroft-Gault) — free calculator with a worked example
Common questions
Why do ACE inhibitors cause a dry cough?
ACE also breaks down bradykinin, so inhibiting it lets bradykinin accumulate in the airways and provoke cough. ARBs act at the angiotensin receptor instead and leave bradykinin clearance intact, which is why they do not cause it.
What is the difference between an ACE inhibitor and an ARB?
An ACE inhibitor blocks the enzyme that makes angiotensin II; an ARB blocks the receptor angiotensin II acts on. The blood pressure effect is similar, but only the ACE inhibitor raises bradykinin, so cough and angioedema are largely confined to that class.
Why do ACE inhibitors raise potassium?
They reduce angiotensin II, which reduces aldosterone, and aldosterone is the hormone that makes the kidney excrete potassium. Less aldosterone means potassium is retained.
Other drug classes
Beta blockers · Statins · Anticoagulants · Diuretics · Opioids · Benzodiazepines · All drug classes
Study aid only. This page is written for learning and examination practice. It is not medical advice, not clinical decision support, and must never be used to make a decision about a real patient. Always verify against your local formulary, the product literature and a qualified pharmacist. See our medical disclaimer.
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