RAAS Inhibitors: Types, Uses, and Potential Side Effects

RAAS inhibitors are a family of medications that block different steps of the renin-angiotensin-aldosterone system, a hormonal cascade your body uses to regulate blood pressure, fluid balance, and sodium levels. They include several distinct drug classes, each with its own mechanism, and collectively they rank among the most widely prescribed medications in cardiology and nephrology. While their benefits in treating high blood pressure, heart failure, and kidney disease are well established, they share a set of side effects tied to the very hormonal pathways they block.

What the RAAS Actually Does

Your kidneys, liver, and lungs collaborate on a chain reaction that raises blood pressure when the body senses it is too low. When blood volume drops, sodium levels fall, or the sympathetic nervous system fires, the kidneys release an enzyme called renin. Renin converts a liver-produced protein into angiotensin I, which travels to the lungs, where angiotensin-converting enzyme (ACE) clips it into angiotensin II. Angiotensin II is the main actor: it tightens blood vessels, tells the adrenal glands to release aldosterone (which makes the kidneys hold onto sodium and water), and drives blood pressure up.¹ Every class of RAAS inhibitor targets a different link in this chain.

Types of RAAS Inhibitors

Though all RAAS inhibitors share the goal of dampening this hormonal cascade, they do it in meaningfully different ways, and those differences shape which patients benefit most and which side effects to expect.

ACE Inhibitors

ACE inhibitors (names ending in “-pril,” like lisinopril, enalapril, and ramipril) block the enzyme that converts angiotensin I into angiotensin II. Less angiotensin II means less vasoconstriction and less aldosterone release, so blood pressure falls and the heart and kidneys face less strain. But ACE does more than make angiotensin II. It also breaks down bradykinin, a substance that dilates blood vessels. When ACE is blocked, bradykinin accumulates, which contributes to some of the blood-pressure-lowering benefit but also causes the most distinctive side effects of this class, particularly cough and angioedema.

Angiotensin Receptor Blockers

ARBs (names ending in “-sartan,” like losartan, valsartan, and telmisartan) take a different approach. Instead of preventing angiotensin II from being made, they block the receptor it binds to, the AT1 receptor, which belongs to a large family of cell-surface signaling proteins.² Because ARBs do not interfere with ACE or bradykinin breakdown, they produce far less cough and angioedema than ACE inhibitors, which is often why patients get switched from one class to the other.

Mineralocorticoid Receptor Antagonists

MRAs, including spironolactone, eplerenone, and the newer finerenone, work further downstream. They block the receptor that aldosterone binds to, preventing aldosterone from telling the kidneys to retain sodium and water.³ Beyond their effect on fluid balance, MRAs also counter the inflammatory and tissue-remodeling damage that excess aldosterone causes in blood vessels, the heart, and the kidneys.⁴ This makes them especially useful in heart failure and resistant hypertension, where aldosterone-driven organ damage is a major concern.⁵

Direct Renin Inhibitors and ARNIs

Aliskiren is the only widely available direct renin inhibitor. It blocks renin itself, the very first step of the cascade. In practice, aliskiren never gained the traction of ACE inhibitors or ARBs, partly because large trials did not show clear superiority and partly because combining it with other RAAS drugs raised safety concerns.

ARNIs combine an ARB (valsartan) with a neprilysin inhibitor (sacubitril), packaged together as sacubitril/valsartan. Neprilysin is an enzyme that breaks down several beneficial hormones, including natriuretic peptides that lower blood pressure and reduce fluid overload. By inhibiting neprilysin while simultaneously blocking the AT1 receptor, ARNIs attack the problem from two angles. This combination has become a mainstay in heart failure with reduced ejection fraction.

Clinical Uses

High Blood Pressure

ACE inhibitors and ARBs are first-line treatments for hypertension in most guidelines worldwide. A 2024 expert consensus recommended that ACE inhibitors be considered the first choice, ahead of ARBs, for reducing the risk of heart attack and for primary prevention of heart failure. For stroke prevention specifically, the two classes appear equally effective.⁶ MRAs, particularly spironolactone, fill a critical niche in resistant hypertension, the subset of patients whose blood pressure remains high despite three or more medications.

Heart Failure

In patients whose heart pumps weakly (reduced ejection fraction), RAAS inhibitors significantly improve outcomes, even when kidney function worsens during treatment.⁷ That last point matters because doctors sometimes hesitate to continue these drugs when creatinine rises, but the evidence suggests the benefit persists. In heart failure with preserved ejection fraction, the picture is less clear: RAAS inhibitors have not been definitively shown to improve outcomes in that population, even though they are still frequently prescribed.

Kidney Protection in Diabetes

Diabetic kidney disease is one of the strongest indications for RAAS blockade. ACE inhibitors and ARBs are standard therapy for protecting the kidneys and slowing disease progression in people with both type 1 and type 2 diabetes.⁸ They reduce the pressure inside the tiny filtering units of the kidney (glomeruli) by relaxing the outflow vessel, which lowers the protein leak into urine and slows scarring. Finerenone, the newer MRA, adds another layer of protection on top of standard RAAS blockade in diabetic kidney disease by reducing inflammation and fibrosis.

The Cough That Gives ACE Inhibitors Away

A dry, persistent, tickly cough is the most common reason patients stop taking ACE inhibitors. It stems from the buildup of bradykinin and a related molecule called substance P in the airways. These substances sensitize nerve fibers in the throat and lungs, triggering a reflex that constricts airway smooth muscle and provokes cough.⁹ The cough can start weeks or months after beginning the drug and sometimes gets mistaken for allergies or a lingering cold. It resolves within days to weeks of stopping the medication.

A Cochrane review comparing ACE inhibitors head-to-head with ARBs for primary hypertension found that ARBs had a slightly lower rate of side effects leading patients to discontinue treatment, and that difference was mainly driven by the higher rate of cough with ACE inhibitors.¹⁰ Switching from an ACE inhibitor to an ARB is the standard fix when cough becomes intolerable.

Angioedema

Far less common but far more dangerous, angioedema involves sudden swelling of the deeper tissue layers, usually in the face, lips, tongue, or throat. It is also bradykinin-mediated, making it a nonallergic reaction that does not respond well to the epinephrine and antihistamines used for typical allergic swelling.¹¹ One study reviewing 84 patients with RAAS-inhibitor-induced angioedema found that roughly 80% were on ACE inhibitors, the oral cavity was the most commonly affected site, and nearly 60% of cases appeared after more than a year of uneventful treatment.¹² That delayed onset catches both patients and clinicians off guard, since the drug has been tolerated for months or years before the first episode. Though angioedema is more common with ACE inhibitors, it can occur with ARBs as well, so anyone who has experienced it typically needs to avoid the entire class.

Hyperkalemia

Because RAAS inhibitors reduce aldosterone activity, and aldosterone is what tells the kidneys to excrete potassium, these drugs raise the risk of high potassium levels in the blood. Hyperkalemia can cause muscle weakness, heart rhythm disturbances, and in severe cases cardiac arrest.¹³ The risk is highest when multiple RAAS inhibitors are combined, when kidney function is already impaired, or when patients also take potassium supplements or potassium-sparing diuretics. Routine blood tests to monitor potassium are standard practice when these drugs are prescribed, especially early in treatment or after dose increases.

The Expected Kidney Function Dip

Patients starting RAAS inhibitors often see a small drop in their estimated kidney filtration rate (eGFR) on blood work. This alarms some patients and even some clinicians, but the dip is generally a sign the drug is doing its job. By relaxing the outflow blood vessel of the kidney’s filtering units, RAAS inhibitors reduce the abnormally high pressure inside those units. The eGFR falls because the kidney is no longer being pushed to over-filter, and that reduction in stress is precisely what protects against further damage over time.¹⁴ A modest initial dip that stabilizes is generally tolerated without stopping the drug, though a large or progressive decline warrants closer evaluation.

Who Should Not Take RAAS Inhibitors

Pregnancy

All RAAS inhibitors are contraindicated in pregnancy, particularly during the second and third trimesters. The RAAS is critical for normal development of the fetal kidney, and blocking it pharmacologically can cause a severe developmental problem called renal tubular dysgenesis, where the kidneys fail to form properly. This leads to reduced fetal urine output and dangerously low amniotic fluid.¹⁵ Women of childbearing age who need blood pressure medication should discuss alternatives with their physician, and any woman who becomes pregnant while on a RAAS inhibitor should contact her provider immediately.

Bilateral Renal Artery Stenosis

When both arteries supplying the kidneys are narrowed, the kidneys depend heavily on angiotensin II to maintain filtration pressure. Blocking angiotensin II in this setting can cause a dramatic and dangerous drop in kidney function.¹⁶ Single-kidney patients with renal artery stenosis face the same risk. Once the narrowing has been corrected with a stent, RAAS inhibitors may become safe again, but the decision requires specialist judgment.

Why Combining Two RAAS Inhibitors Usually Backfires

The idea of blocking the RAAS at multiple points simultaneously has an intuitive appeal: if one drug is good, two should be better. Clinical trials have largely disproven this. In diabetic kidney disease, dual RAAS blockade has been shown to increase the risk of acute kidney injury and hyperkalemia without providing additional benefit for mortality, cardiovascular events, or kidney disease progression compared to using a single agent.¹⁷

The landmark ONTARGET trial, which combined an ACE inhibitor with an ARB, found that combination therapy significantly worsened kidney outcomes, including a higher rate of serum creatinine doubling and more episodes of acute kidney injury requiring dialysis, despite the combination actually reducing protein in the urine, which on the surface looked promising.¹⁸ That disconnect between the encouraging lab marker (less proteinuria) and the worse clinical outcomes was a cautionary lesson about trusting surrogate endpoints.

A more recent long-term follow-up of dual RAAS blockade in autosomal dominant polycystic kidney disease found no definitive benefit, though the data suggested a higher likelihood of benefit than harm and less signal for potential harm than the earlier diabetic trials.¹⁹ Even so, combining an ACE inhibitor with an ARB remains generally discouraged in practice. The exception is adding an MRA on top of an ACE inhibitor or ARB, which is well supported in heart failure and resistant hypertension, though potassium monitoring becomes even more important.

Does It Matter When You Take Them

Blood pressure naturally dips during sleep and surges in the early morning. The idea that taking RAAS inhibitors at bedtime might better control nighttime pressure and reduce cardiovascular risk has generated considerable debate. Some studies have reported that evening dosing of ARBs like irbesartan, olmesartan, telmisartan, and valsartan lowers nighttime blood pressure more effectively and shifts patients toward a healthier sleep-to-wake blood pressure pattern.²⁰ However, a rigorous trial specifically testing evening versus morning dosing of valsartan found no benefit to bedtime dosing for nighttime blood pressure, early morning blood pressure, or morning blood pressure surge.²¹ The practical takeaway is that consistency matters more than clock time. If you reliably remember your pill at breakfast, take it at breakfast. If you forget morning doses, bedtime works fine.

RAAS Inhibitors and Liver Disease

The RAAS is not only active in the kidneys and blood vessels. As liver fibrosis progresses, levels of angiotensin II and its receptor increase within the liver itself, driving inflammation, scarring, and the formation of new blood vessels that contribute to portal hypertension.²² This has prompted researchers to investigate whether ACE inhibitors and ARBs could slow liver fibrosis or help in nonalcoholic fatty liver disease (NAFLD). Animal studies have shown promising results, suggesting that blocking the RAAS may reduce liver fat accumulation and fibrosis.²³ Human data remain limited, and no RAAS inhibitor is currently approved for treating liver disease. Still, this is an area worth watching, especially given the growing prevalence of fatty liver disease worldwide and the scarcity of effective treatments for it.

Spironolactone and Hormonal Side Effects

Spironolactone deserves special mention because, unlike most RAAS inhibitors, it has off-target hormonal effects that are entirely unrelated to the RAAS. The drug also blocks androgen receptors and weakly activates progesterone receptors. In men, this can cause breast tenderness and breast tissue growth (gynecomastia). In women, it can disrupt menstrual cycles. These effects are dose-dependent and reversible once the drug is stopped, but they are a frequent reason for discontinuation, particularly at the higher doses used for resistant hypertension or heart failure. Eplerenone was developed specifically to avoid these hormonal effects. It is much more selective for the mineralocorticoid receptor, so gynecomastia and menstrual irregularities are far less common, though eplerenone is generally less potent and more expensive. Finerenone, the newest MRA, is also highly selective and is primarily being studied in kidney and heart disease rather than as a blood pressure drug.

ACE Inhibitors, Snake Venom, and Drug Discovery

The story behind ACE inhibitors is one of the more unusual chapters in pharmaceutical history. The initial discovery that led to the entire class came from studying the venom of a Brazilian pit viper, Bothrops jararaca. Researchers in the 1960s noticed that the venom contained peptides that amplified the effects of bradykinin and inhibited ACE, causing a dramatic drop in blood pressure in bitten animals. That observation was refined over the next decade into captopril, the first oral ACE inhibitor, which was approved in 1981.²⁴ The progression from lethal snake toxin to one of the world’s most prescribed drug classes has become a textbook case for why studying animal venoms can pay off in drug development.