ACE Inhibitors: Uses, Side Effects, and How They Work

ACE inhibitors are a class of blood pressure medications that work by blocking the angiotensin-converting enzyme, a protein involved in constricting blood vessels and retaining sodium. They rank among the most widely prescribed drugs in the world, used not just for high blood pressure but also for heart failure, kidney protection, and recovery after a heart attack. The science behind them is more layered than a simple “they lower blood pressure” explanation, and so are the side effects, contraindications, and ongoing debates about when they are the right choice versus a closely related alternative.

How ACE Inhibitors Lower Blood Pressure

Your body has a built-in system for regulating blood pressure called the renin-angiotensin-aldosterone system. When blood pressure drops or your kidneys detect low sodium, the enzyme renin kicks off a cascade that eventually produces a molecule called angiotensin II. Angiotensin II is a potent vasoconstrictor, meaning it squeezes blood vessels tighter, and it also signals the adrenal glands to release aldosterone, a hormone that tells the kidneys to hold onto sodium and water. The net result is higher blood pressure.

ACE inhibitors interrupt this chain by blocking the enzyme that converts angiotensin I into angiotensin II. With less angiotensin II circulating, blood vessels relax, aldosterone drops, and the kidneys let go of more sodium and water. A Cochrane systematic review estimated that ACE inhibitors as a class lower systolic blood pressure by about 8 points and diastolic by about 5 points at trough, measured right before the next dose when the drug is at its weakest. Measured closer to peak effect, the reduction was roughly 11 systolic and 6 diastolic.¹

But blocking ACE does more than just reduce angiotensin II. The same enzyme also breaks down bradykinin, a small peptide that dilates blood vessels, promotes the release of nitric oxide, and plays a role in inflammation. When ACE is inhibited, bradykinin accumulates, and that buildup contributes to the blood-pressure-lowering effect.² Research in humans has confirmed that ACE inhibitors enhance the ability of blood vessels to dilate in response to increased blood flow, and that this dilation depends on bradykinin.³ This dual mechanism, reducing a constrictor while boosting a dilator, is part of what distinguishes ACE inhibitors from drugs that only target one side of the equation.

What ACE Inhibitors Are Prescribed For

High blood pressure is the most common reason doctors reach for an ACE inhibitor, but it is far from the only one. The major indications fall into a few categories.

Hypertension. For straightforward high blood pressure, ACE inhibitors are considered a first-line option. In diabetic patients with hypertension, early trials showed that ACE inhibitor therapy brought blood pressure from roughly 155/100 down to about 125-128/82-84 over 16 weeks.⁴ Whether ACE inhibitors offer cardiovascular protection beyond what can be explained by the blood pressure drop alone has been debated for years. A review in Progress in Cardiovascular Diseases concluded that, under closer scrutiny, there is little evidence their benefits in hypertension extend meaningfully beyond what blood pressure reduction accounts for.⁵ In practical terms, this means the key benefit for most people with high blood pressure is the drop in numbers, not some secret extra protective effect.

Heart failure. This is where ACE inhibitors have some of their strongest evidence. In patients with reduced heart pumping ability, ACE inhibitors have significantly decreased cardiovascular deaths, heart attacks, and hospitalizations for heart failure.⁶ The extended follow-up of the landmark SOLVD trials, tracked over 12 years, showed that patients on an ACE inhibitor had a lower cumulative rate of death from any cause compared with placebo. A systematic review and meta-analysis of five trials covering more than 9,000 heart failure patients estimated that you would need to treat about 50 patients with an ACE inhibitor for six months to prevent one death.⁷

After a heart attack. When the heart muscle is damaged by a heart attack, the heart can gradually enlarge and weaken, a process called remodeling. ACE inhibitors slow this remodeling. Animal studies have confirmed that ACE inhibitor administration significantly reduces progressive enlargement of the heart’s main pumping chamber after an infarction.⁸ This is one of the more broadly accepted benefits and is why post-heart-attack patients are routinely started on one.

Kidney Protection, With Caveats

ACE inhibitors are widely used to protect the kidneys in people with diabetes, particularly when protein is spilling into the urine, an early sign of kidney damage. The logic is solid: by dilating the tiny blood vessels leaving the kidney’s filtering units, ACE inhibitors reduce the pressure inside those filters and slow damage to them. But the strength of evidence is not as robust as the widespread use might suggest. A review noted that evidence for ACE inhibitors slowing kidney disease progression in type 2 diabetes has been drawn primarily from small trials using surrogate endpoints like protein in the urine, rather than large trials tracking hard outcomes like progression to end-stage kidney disease.⁹ This does not mean the drugs are unhelpful for the kidneys; it means the evidence is less airtight than the way they are sometimes described.

There is also an important safety boundary. In people with narrowing of the arteries that supply both kidneys, ACE inhibitors are contraindicated because blocking angiotensin II removes the mechanism that maintains filtering pressure in those kidneys. The result can be a sharp decline in kidney function.¹⁰ Doctors typically check kidney function and potassium levels shortly after starting an ACE inhibitor for exactly this reason.

Side Effects You Are Likely to Hear About

The most notorious side effect is a dry, persistent cough. It is not dangerous but can be annoying enough to make people stop the medication. The cough is thought to result from the same bradykinin buildup that helps lower blood pressure: excess bradykinin and related substances like substance P and prostaglandins irritate airway nerve endings.¹¹ In some studies, the cough shows up in up to one in five users, though the actual rate varies depending on the population. The cough typically resolves within a week or two of stopping the drug.

A much rarer but more serious side effect is angioedema, a rapid swelling of tissue, often around the face, lips, tongue, or throat. This can be life-threatening if it compromises breathing. The mechanism is not fully understood, but it is believed to involve the same bradykinin pathway, with genetic and metabolic factors influencing who is vulnerable.¹² Anyone who has ever experienced angioedema from an ACE inhibitor should not take one again.

Elevated potassium is another concern. Because ACE inhibitors reduce aldosterone, which normally signals the kidneys to excrete potassium, potassium levels can creep up. This is especially relevant for people with kidney disease or those taking potassium-sparing diuretics. Routine blood work after starting the drug catches most cases before they become dangerous.

Pregnancy and ACE Inhibitors

ACE inhibitors are firmly contraindicated in pregnancy. The fetal effects can be severe and include kidney failure, underdeveloped lungs, skull bone abnormalities, growth restriction, low amniotic fluid, and neonatal death.¹³ The greatest danger appears in the second and third trimesters, though a high incidence of fetal complications has been reported across all trimesters.¹⁴ Women of childbearing age who are prescribed an ACE inhibitor should have a clear plan with their doctor for switching to a safer alternative before becoming pregnant.

ACE Inhibitors Versus ARBs

Angiotensin receptor blockers, or ARBs, are the closest alternative. Rather than blocking the enzyme that makes angiotensin II, ARBs block the receptor that angiotensin II binds to. The clinical result is similar. A systematic review found that ACE inhibitors and ARBs had similar long-term effects on blood pressure.¹⁵ A Cochrane review comparing the two classes head-to-head found no meaningful difference in total mortality, cardiovascular events, or cardiovascular deaths. The one consistent difference was that ARBs caused fewer side effects leading to drug discontinuation, mainly because the dry cough is substantially less common with ARBs.¹⁶

The practical upshot: if you develop that characteristic cough on an ACE inhibitor, switching to an ARB usually solves the problem without sacrificing blood pressure control or cardiovascular protection. From a cost perspective, ACE inhibitors tend to be slightly cheaper. A cost-effectiveness analysis in heart failure management found ACE inhibitors had a mean cost of about $15,000 compared with $16,500 for ARBs, with ARBs yielding only marginally higher quality-adjusted life years.¹⁷ For most patients, the choice between the two comes down to tolerability and cost rather than a clear clinical superiority of one over the other.

Differences Among Individual ACE Inhibitors

There are over a dozen ACE inhibitors on the market, and while they share the same core mechanism, they are not identical. Most ACE inhibitors are prodrugs, meaning the pill you swallow is inactive and must be converted to its active form by the liver. Two exceptions are captopril and lisinopril, which are already active when absorbed.¹⁸ This matters for patients with significant liver disease, where prodrug activation may be unreliable.

The drugs also differ in how fat-soluble they are. Fosinopril is the most lipophilic, while lisinopril is the least. Lipophilicity influences how readily a drug penetrates into tissues. ACE is found not just in the blood but throughout the body, including the heart, kidneys, and brain. There is growing evidence that ACE inhibitors differ in how effectively they inhibit tissue-bound ACE, which could have clinical implications beyond simple blood pressure control.

Why the Drug Can Stop Working Over Time

One of the more frustrating realities of long-term ACE inhibitor therapy is a phenomenon called aldosterone escape. When you first start an ACE inhibitor, aldosterone levels drop as expected. But over weeks to months, aldosterone can creep back up even while you continue taking the drug. In chronic heart failure, long-term ACE inhibition is associated with aldosterone suppression that is weak, variable, and unsustained.¹⁹ This reactivation of aldosterone is not just a lab curiosity; it may herald clinical deterioration in heart failure patients.²⁰

The escape phenomenon is one reason heart failure patients often end up on additional drugs like spironolactone or eplerenone, which directly block aldosterone’s effects at the receptor level. It also affects people with milder hypertension: an increase in aldosterone has been observed within just 12 weeks of starting either a diuretic or an ACE inhibitor-based combination.²¹ This is not a reason to stop the medication, but it does explain why some patients need dose adjustments or additional drugs over time.

Combination Therapy

Most people with hard-to-control blood pressure end up on more than one drug, and ACE inhibitors combine well with certain other classes. Pairing an ACE inhibitor with a calcium channel blocker is a particularly well-supported combination. The two classes work through complementary mechanisms: ACE inhibitors suppress the renin-angiotensin system and reduce sympathetic nervous system activity, while calcium channel blockers relax large arteries.²² Evidence suggests this combination is well tolerated and also reduces the risk of cardiovascular and kidney complications.²³

One combination to avoid: ACE inhibitors together with ARBs. Although it seems logical that blocking both the enzyme and the receptor would provide extra benefit, trials have shown that dual blockade increases the risk of kidney problems and high potassium without meaningfully improving outcomes. The same goes for combining an ACE inhibitor with a direct renin inhibitor. Current guidelines generally recommend against doubling up on drugs that target the same hormone pathway.

The COVID-19 Scare

Early in the pandemic, alarm spread because the virus that causes COVID-19 enters cells through a receptor called ACE2, which is related to (but distinct from) the ACE that ACE inhibitors target. There was speculation that ACE inhibitors might upregulate ACE2 expression and thereby make people more susceptible to infection, or alternatively, that the drugs might be protective by boosting a beneficial arm of the system. A large study from Denmark found no significant association between ACE inhibitor or ARB use and the likelihood of being diagnosed with COVID-19.²⁴

Among patients already hospitalized with COVID-19 and coexisting hypertension, inpatient use of ACE inhibitors or ARBs was actually associated with lower all-cause mortality compared with non-users, though the researchers cautioned about residual confounding.²⁵ The consensus that emerged was that patients already taking these drugs should not stop them because of COVID-19 concerns.²⁶ The whole episode is a useful reminder of how a plausible-sounding biological hypothesis can generate panic that the actual data does not support.

ACE Inhibitors and the Brain

An intriguing line of research looks at whether ACE inhibitors can slow cognitive decline. ACE is present in brain tissue, and angiotensin II appears to play a role in neuroinflammation and reduced cerebral blood flow. A review of the published literature found that studies have shown reduced rates of cognitive decline in elderly patients treated with centrally active ACE inhibitors, meaning ACE inhibitors that can cross the blood-brain barrier.²⁷ This distinction matters: not all ACE inhibitors penetrate into the brain equally. Lipophilic ones like perindopril, ramipril, and captopril cross the barrier more effectively than hydrophilic ones like lisinopril and enalapril.

The evidence is still preliminary enough that no one is prescribing ACE inhibitors specifically for dementia prevention. But if a patient with high blood pressure also has early cognitive concerns, the choice of a brain-penetrating ACE inhibitor over a non-penetrating one could be a reasonable conversation to have with a doctor, given that the blood-pressure benefit would be similar either way.

The Snake Venom Connection

The entire class of ACE inhibitors traces its origin to a decidedly non-pharmaceutical source: snake venom. In the 1960s, Brazilian scientist Sérgio Ferreira discovered that venom from a pit viper contained peptides that inhibited ACE. That discovery led to the development of captopril, the first ACE inhibitor, which reached the market in the early 1980s. Researchers continue to mine snake venoms for novel ACE-inhibiting peptides. A study using advanced screening techniques identified two new bioactive peptides, one from prairie rattlesnake venom and another from a horned viper species, both of which inhibited ACE at low concentrations.²⁸ The search for better or more selective ACE-inhibiting compounds from natural sources continues, though modern drugs on pharmacy shelves are all fully synthetic.