Angiotensin-converting enzyme inhibitors (ACEI) is a commonly used group of drugs used to treat high blood pressure. They efficiently treat some of the more common conditions affecting the population as a whole. Overall, they have an excellent safety profile and are associated with relatively few side effects.
ACE-inhibitors are frequently used for a number of common and potentially deadly medical conditions:
- High blood pressure
- Left ventricular dysfunction (a type of heart failure)
- Myocardial infarction (heart attack), especially within the first 24 hours
- Treatment and prevention of kidney disease associated with diabetes and hypertension
Unfortunately, as is the case for most medications, ACE-inhibitor use is associated with side effects, which in some cases may make the patient’s life miserable. Most of the side effects are not serious, but they may be difficult for the patients to cope with in their daily lives.
Dry, chronic cough tends to affect 5-35%(1) of individuals taking ACE-inhibitors. The cough is usually more pronounced at night, but exceptions are not that uncommon. This means that if you simply have a dry cough that tends to be of the same intensity night and day, and you happen to be taking an ACE-inhibitor, then you should still be considering ACEI as the cause of your chronic cough.
- Dry cough tends to develop within hours to months of starting an ACE-inhibitor
- Women appear to be affected slightly more often than men
- Once an ACEI is discontinued, the cough usually goes away within 2 weeks, but in some cases may take a few months to completely disappear
There is no effective treatment for the cough. The only way to get rid of it is to discontinue an ACE-inhibitor.
This association between ACE-inhibitors and cough is so characteristic, that I dare to say that 100% of 2nd-year medical students will immediately think “cough” when you mention the term “ACE-inhibitor”.
Why do ACE-inhibitors cause cough?
Scientists and clinicians have been trying to determine the exact mechanism of cough caused by ACE-inhibitors since the 1990’s. Unfortunately to this day, the mechanism of cough is still unclear.
One of the most common theories involves bradykinin and substance P (2).
Bradykinin is a peptide involved with inflammation. One of its actions is to dilate the blood vessels.
Substance P is another peptide mainly involved with inflammation and nociception. Nociception is a term for the body’s defense against dangerous stimuli, such as pain, high temperature, etc.(3). When you stick your hand in fire, it is substance P along with other body’s messengers that tell your brain to pull your hand back immediately!
Bradykinin and substance P are naturally inhibited by the angiotensin converting enzyme (ACE). ACE-inhibitors turn this enzyme “off”, leading to a buildup of bradykinin and substance P. It is thought that this increased accumulation of bradykinin and substance P is responsible for the development of dry cough associated with ACE-inhibitor use.
ACE-inhibitor Cough and Iron
In 2001, there was a very small study done that suggested that iron supplementation may suppress the cough associated with ACEI (4). The results of this study are promising, however the study involved only 19 subjects, which is not enough to be regarded as hard evidence of effectiveness. Without clear evidence, iron supplementation is not recommended because it is associated with serious side effects.
Alternatives to ACEI
Fortunately for those suffering from severe ACEI-associated cough, there are a few alternatives. They include the following classes of medications:
- Angiotensin receptor blockers (ARBs)
- Calcium channel blockers
Your doctor will decide which specific medication you should be switched to. The specific choice of drug will depend on factors such as: severity of your hypertension, other drugs you are taking, other medical conditions you are suffering from.
I should note, that for reasons that are not entirely clear, ACE-inihibitors are not recommended as first-line therapy for hypertension in African-Americans. They tend to respond better to another group of antihypertensive drugs called calcium channel blockers.
Other Side Effects
- High potassium levels (hyperkalemia) – this is a relatively common finding in patients taking ACEI. Usually the increase is not significant to warrant a change in therapy regimen. Individuals taking ACEI should have their potassium levels checked on a regular basis because very high levels of potassium may be fatal.
- Low blood pressure
- Skin rash that may itch
- Sun sensitivity
- Metallic taste
- Angioedema – this is a rare, but serious side effect of ACEI. It involves sudden swelling of your face, tongue and throat. If severe and untreated, it may be fatal.
- Pregnancy – ACE-inhibitors are strongly contraindicated for use in pregnant women, because they have been found to cause birth defects in the offspring
- Renal artery stenosis (especially bilateral) – individuals with this condition should not be taking ACEI due to an increased risk of severe kidney disease
- Anaphylaxis (or allergy) to other ACEI-class drugs is also a strong contraindication for its use
List of ACE inhibitors available in the US:
- benazepril (Lotensin, Lotensin HCT)
- captopril (Capoten)
- enalapril (Vasotec)
- fosinopril (Monopril)
- lisinopril (Prinivil, Zestril)
- moexipril (Univasc)
- perindopril (Aceon)
- quinapril (Accupril)
- ramipril (Altace)
- trandolapril (Mavik)
Captopril was the first ACE-inhibitor ever produced. It was developed in 1975 by a group of scientists at Squibb, an American company now part of Bristol-Myers Squibb. It was patented in 1976 and four years later, in 1980 the FDA formally approved Captopril for medicinal use in humans.
Captopril is derived from the venom of a pit viper (5), a venomous viper species found in Central and South America. Pit vipers kill their prey by injecting venom into their prey. The venom causes a sudden and relatively significant drop in blood pressure in the animal. This drop in blood pressure leads to loss of consciousness making the animal vulnerable to the attacker. This same mechanism of lowering blood pressure works in humans taking ACE inhibitors.
One of the most common and obvious side effects of ACE inhibitors is hypotension (or low blood pressure). Similarly to animals, people who take too much of an ACE inhibitor will experience low blood pressure pressure, headache, dizziness and other symptoms associated with it.
Currently, captopril is rarely used for a prolonged period of time. It’s most common use is to manage a sudden spike in blood pressure. In this scenario, the patient takes one captopril tablet and puts it in his or her mouth under the tongue. This allows for the fastest distribution within the body. A blood pressure-lowering effect that takes place within 15 to 30 minutes of ingestion.
Lisinopril is a lab-derived form of captopril. It was developed by the researchers at Merck. In 1987, it was approved by the FDA for the treatment of hypertension. Six years later, in 1993, a further approval for the treatment of congestive heart failure was granted for the drug.
Lisinopril is one of the best-selling drugs to ever hit the market. Between 2012 and 2015, it ranked as #1 best-selling drug in the US (based on the number of prescriptions). In 2016, over 110 million prescriptions for lisinopril were issued (6).
Despite the commonly discussed, but benign side effect of a dry cough, or the more serious, but rare angioedema, ACE inhibitors continue to be commonly prescribed medications for the treatment of a wide range of conditions, including hypertension, heart attack or kidney disease associated with diabetes.
Considering the adverse effect profile of other medications, ACE inhibitors are associated with relatively benign side effects that are few and far between. It is for this reason, as well as for the relatively good therapeutic effect, that ACE inhibitors remain being some of the most commonly used prescription medications.
When evaluating potential candidates for the treatment with ACE inhibitors, the physician will take into consideration the patient’s current medical conditions, race, past medical history and other factors.