Everything You Need to Know About ACE inhibitors / ARBs for Step 1

ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are some of the most “USMLE-efficient” drugs in cardiovascular pharm: they show up everywhere—HTN, HF, diabetic nephropathy—and they come with a predictable set of side effects and lab changes that Step loves to test. If you can connect where they act in the RAAS pathway to what happens to arterioles, aldosterone, bradykinin, and GFR, you’ll answer a ton of questions quickly.

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Where ACE inhibitors / ARBs fit in: the RAAS in one mental model

RAAS quick pathway

• Kidney (JG cells) releases renin in response to:
  • ↓ renal perfusion pressure
  • ↓ NaCl delivery to macula densa
  • ↑ sympathetic tone ($\beta_1$)
• Renin converts angiotensinogen → angiotensin I
• ACE (mostly pulmonary endothelium) converts angiotensin I → angiotensin II
• Angiotensin II:
  • Constricts arterioles (especially efferent arteriole in kidney)
  • ↑ aldosterone (zona glomerulosa) → ↑ Na$^+$ reabsorption, ↑ K$^+$ and H$^+$ excretion
  • ↑ ADH, thirst, sympathetic activity
  • Promotes cardiac/vascular remodeling

Drug targets

First Aid cross-ref: Cardiovascular → Antihypertensives; Heart Failure drugs; Renal → RAAS & renal hemodynamics.

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Definition (Step-ready)

ACE inhibitors

• Competitive inhibitors of ACE → ↓ Ang II production and ↑ bradykinin
• Prototypical associations: cough, angioedema, hyperkalemia, teratogenicity

ARBs

• Block AT$_1$ receptor → blunt Ang II’s vasoconstriction + aldosterone effects
• Similar renal/hemodynamic effects as ACEi but less cough/angioedema (because no bradykinin accumulation)

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Pathophysiology: why these drugs do what they do

1) Blood pressure effects

• ↓ Ang II → vasodilation → ↓ SVR → ↓ BP
• ↓ aldosterone → modest diuresis/natriuresis → ↓ intravascular volume

2) Kidney hemodynamics (very high yield)

Ang II preferentially constricts the efferent arteriole to maintain glomerular pressure when renal perfusion is low.

• ACEi/ARBs dilate efferent arteriole
• This decreases intraglomerular pressure → can decrease GFR
• Clinically:
  • Small creatinine bump is expected after starting (often acceptable)
  • Big bump suggests renal artery stenosis or volume depletion

Testable concept: These drugs are “renal-protective” long-term in proteinuric disease (↓ intraglomerular pressure → ↓ proteinuria), yet can transiently lower GFR.

3) Bradykinin (ACE inhibitors only)

ACE breaks down bradykinin. Block ACE → ↑ bradykinin:

• Vasodilation (can help BP)
• Dry cough
• Angioedema (can be life-threatening)

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Clinical uses (when NBME wants you to pick ACEi/ARB)

Hypertension (especially with comorbidities)

Choose ACEi/ARB when HTN is accompanied by:

• Diabetes with albuminuria/proteinuria
• Chronic kidney disease with proteinuria
• Heart failure with reduced EF (HFrEF)
• Post-MI (especially with LV dysfunction)

First Aid cross-ref: HTN treatment classes; “Renal protective in diabetes.”

Heart failure (HFrEF)

ACEi/ARBs:

• ↓ preload and afterload
• ↓ remodeling (less Ang II-driven fibrosis/hypertrophy)
• Improve symptoms and outcomes

(For Step 2-style framing: ARB is used if ACEi causes cough/angioedema; sacubitril/valsartan is an ARNI—beyond Step 1 core but commonly referenced.)

Diabetic nephropathy & proteinuric CKD

• ↓ intraglomerular pressure → ↓ proteinuria
• Slows progression of nephropathy

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Clinical presentation: what you’ll “see” in vignettes

Expected/desired findings

• Lower BP
• In CKD/diabetes: decreasing albuminuria

Common adverse effects (HY)

ACE inhibitors

• Dry cough (bradykinin)
• Angioedema (bradykinin; swelling of lips/tongue/airway)
• Hyperkalemia (↓ aldosterone → ↓ K$^+$ excretion)
• Increase in creatinine (efferent dilation → ↓ GFR)
• Hypotension (especially first dose in volume depleted)
• Teratogenic (fetal renal damage → oligohydramnios)

ARBs

• Hyperkalemia
• Increase in creatinine
• Teratogenic
• Much less cough/angioedema than ACEi (still rare angioedema can occur)

Classic Step mnemonic (ACEi): Cough, Angioedema, Contraindicated in pregnancy, K+ (hyperkalemia)

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Diagnosis & monitoring (how questions test labs)

Before starting

• Baseline BMP: creatinine, potassium
• Assess pregnancy status if relevant

After starting (or increasing dose)

• Recheck creatinine and K$^+$ in ~1–2 weeks (clinical practice; Step may just ask what to monitor)
• Interpret creatinine rise:
  • Mild rise can be acceptable/expected
  • Large rise suggests:
    • Bilateral renal artery stenosis (or stenosis in solitary kidney)
    • Severe volume depletion (overdiuresis)
    • Advanced CKD

How renal artery stenosis shows up on Step

• Older patient with atherosclerosis or younger woman with fibromuscular dysplasia
• Abdominal bruit
• Sudden worsening renal function after ACEi/ARB

Mechanism tested: In renal artery stenosis, kidney relies on Ang II efferent constriction to maintain GFR. Remove Ang II → efferent dilation → GFR drops → creatinine rises.

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Treatment logic (choosing between ACEi vs ARB)

First-line choice

• ACE inhibitor is commonly first pick (classic board framing)

Switch to ARB when

• ACEi causes cough
• Mild non-life-threatening bradykinin-mediated issues

Avoid both (absolute/major contraindications)

• Pregnancy
• History of angioedema due to ACEi (ARB sometimes used cautiously in real life, but boards usually want “avoid ACEi”; choose alternative like CCB/thiazide depending on scenario)
• Bilateral renal artery stenosis (or stenosis to solitary kidney)
• Significant hyperkalemia at baseline

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High-yield associations & “NBME-style” traps

1) The “creatinine bump” question

• ACEi/ARB started → creatinine rises modestly:
  • Often expected
  • If large rise, think renal artery stenosis

2) Potassium changes

• Hyperkalemia is a big deal:
  • Higher risk with CKD, K-sparing diuretics (spironolactone/eplerenone/amiloride/triamterene), trimethoprim, NSAIDs

3) Cough vs no cough

• Dry cough points to ACE inhibitor
• If they want same benefits without cough → ARB

4) Angioedema emergency

• Airway symptoms after ACEi:
  • Stop drug
  • Treat as airway-threatening reaction
• Mechanism is bradykinin, not IgE (so it’s not “classic allergy”)

5) Pregnancy vignette

• Pregnant patient on lisinopril/losartan:
  • Stop immediately
  • Teratogenic: fetal renal dysgenesis → oligohydramnios, pulmonary hypoplasia, neonatal renal failure

First Aid cross-ref: Pregnancy contraindications for antihypertensives.

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Rapid review table (Step 1 memorization-friendly)

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Quick practice stems (what the test is really asking)

• “Diabetic patient with HTN and microalbuminuria” → ACEi (or ARB)
• “Started on lisinopril, now persistent dry cough” → switch to ARB
• “Creatinine jumped after ACEi; abdominal bruit; diffuse atherosclerosis” → renal artery stenosis physiology
• “Swollen lips/tongue after ACEi” → bradykinin-mediated angioedema; stop drug
• “Pregnant on losartan” → stop; teratogenic fetal renal effects

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Take-home high-yield checklist

• ACEi/ARBs reduce efferent arteriolar tone → ↓ intraglomerular pressure → ↓ proteinuria but can ↓ GFR.
• ACEi increase bradykinin → cough + angioedema.
• Both can cause hyperkalemia, ↑ creatinine, and are teratogens.
• Renal artery stenosis + ACEi/ARB = big creatinine rise (especially bilateral).