ACE inhibitor cough and the switch to an ARB
ACE inhibitors block angiotensin-converting enzyme, so bradykinin (a small signalling molecule) builds up and can cause a dry cough; if troublesome, an ARB (angiotensin receptor blocker) is the usual alternative.
Remember
Blocking ACE stops bradykinin being broken down, so a new persistent dry cough after starting an ACE inhibitor points to the drug, and the usual switch is an ARB such as losartan, which leaves bradykinin alone.
Memory aid
picture ACE as a bin that clears away bradykinin. Block the bin and the rubbish piles up in the airways as a cough.
Use the picture to recall why blocking ACE leaves bradykinin to pile up in the airways and cause the cough.
ACE (angiotensin-converting enzyme) has two jobs. It converts angiotensin I into angiotensin II, a hormone that tightens blood vessels. It also breaks down bradykinin, a small signalling molecule that widens blood vessels and makes them leakier.
An ACE inhibitor (the -pril drugs, such as ramipril, lisinopril, perindopril and enalapril) blocks that enzyme. Less angiotensin II is made, which lowers blood pressure. Blocking the enzyme lets bradykinin accumulate in the circulation and the airways. This build-up is the accepted explanation of the persistent dry cough, the most distinctive side effect of the class. It affects around 10% of patients and is more common in women.
The cough comes from the drug class and not from infection, so cough medicines do not usually help. It does not depend on the dose, and it can begin from one day to 12 months after starting, so a new cough two weeks into treatment fits well. A normal chest examination and no history of asthma point towards a drug effect rather than lung disease.
An ARB (angiotensin II receptor blocker, such as losartan, candesartan, valsartan or irbesartan) blocks angiotensin II at the AT1 receptor, the docking site through which it acts. It leaves ACE alone, so bradykinin is still broken down and cough is much less common, although it can still occur. That is why an ARB is the usual switch when the cough is troublesome. Swapping one ACE inhibitor for another would be expected to cause the same cough, because the cough comes from blocking ACE itself.
Key facts
- Mechanism
- ACE also breaks down bradykinin, so blocking the enzyme raises bradykinin levels.
- How common
- Around 10% of patients taking an ACE inhibitor have the dry cough, and it is more common in women.
- Timing
- The cough does not depend on the dose and can begin from one day to 12 months after starting.
- Cough medicines
- They do not usually help, because the cough comes from the drug class and not from infection.
- The usual switch
- An ARB leaves bradykinin breakdown alone, so cough is much less common, although it can still occur.
- Shared effects
- Hyperkalaemia (a raised blood potassium) and first-dose hypotension occur with both classes, so they do not separate an ACE inhibitor from an ARB.
Exam traps
- Blocking the angiotensin II type 1 receptor is how ARBs such as losartan work, so it does not explain the cough of an ACE inhibitor, which acts earlier by blocking the enzyme.
- Hyperkalaemia (a raised blood potassium) tempts because it is a well-known problem with ACE inhibitors, but ARBs share it, so it does not separate the two classes.
- Lisinopril is another ACE inhibitor, so swapping to it would be expected to cause the same cough, because the cough comes from blocking ACE itself.
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