ARBs
High-yield Verified · Oct 2026Block angiotensin II at the AT1 receptor whatever pathway made it, leave the AT2 receptor open, and — because ACE (kininase II) is untouched — do not change the response to bradykinin.
Nursing view → administration, monitoring and patient teaching
Compare: Antihypertensives compared — mechanism and drug choice →
Drugs
Mechanism
Selectively block the angiotensin II type-1 (AT₁) receptor, preventing angiotensin II from causing vasoconstriction and aldosterone release — lowering blood pressure and reducing sodium/water retention. Bradykinin metabolism is unaffected (hence cough is rare — about the placebo rate).
AT1 versus AT2: what an ARB blocks and what it leaves alone
Angiotensin II acts on two receptors. AT1 activation raises blood pressure: vascular smooth muscle contracts, systemic vascular resistance rises, sympathetic activity increases, the proximal tubule reabsorbs more sodium, and the adrenal cortex makes more aldosterone. AT1 receptors sit in many tissues, including vascular smooth muscle and the adrenal gland. Chronically high angiotensin II also drives smooth- and cardiac-muscle growth, endothelial dysfunction and inflammation. (How angiotensin II is made is covered by the RAAS cascade on the ACE-inhibitor page.)
AT2 activation points the other way — vasodilation through nitric oxide and bradykinin, renal sodium excretion, and antiproliferative effects — although the labels note that AT2 is not known to be associated with cardiovascular homeostasis. ARBs are highly selective for AT1: about 1,000-fold for losartan, over 10,000-fold for candesartan, over 12,500-fold for olmesartan and about 20,000-fold for valsartan.
Blocking AT1 removes more than vasoconstriction and aldosterone: losartan also inhibits angiotensin II–induced vasopressin release, adrenal catecholamine release, thirst and cellular hypertrophy. Losartan and its metabolite show no partial agonism at AT1 and do not bind other hormone receptors or ion channels important in cardiovascular regulation; heart rate essentially does not change.
Feedback: renin and angiotensin II rise, but blood pressure still falls
Angiotensin II normally suppresses renin secretion. Block AT1 and that negative feedback is lost: plasma renin activity rises two- to threefold with losartan and valsartan, and circulating angiotensin II rises with it. The extra angiotensin II does not overcome the blood-pressure effect, because the receptor — not the hormone supply — is the target.
For the same reason an ARB works whichever pathway made the angiotensin II. ACE is not the only route from angiotensin I to angiotensin II (non-ACE pathways exist), and the ARB’s action is independent of the pathways for angiotensin II synthesis. The higher angiotensin II level may also stimulate the unblocked AT2 receptor.
Aldosterone falls with losartan, but only minimally with valsartan and olmesartan, and with candesartan only at higher doses; in the labels serum potassium changed little or not at all. Losartan showed no apparent rebound after abrupt withdrawal.
No ACE inhibition, so no bradykinin effect
ACE is also kininase II, the enzyme that degrades bradykinin. ARBs do not inhibit ACE, so they do not affect the response to bradykinin, whereas ACE inhibitors increase it. That is why cough and angioedema are less common with ARBs than with ACE inhibitors — ARBs do not raise bradykinin levels — although rare cases of both have been reported. (The bradykinin mechanism itself is on the ACE-inhibitor page.)
With sacubitril/valsartan, valsartan supplies the AT1 blockade while sacubitril’s active metabolite inhibits neprilysin, raising natriuretic peptides and other peptides that neprilysin degrades. Because that combination is contraindicated with an ACE inhibitor, switching between them needs a 36-hour washout.
Binding, prodrugs and drug-specific effects
Losartan is a reversible, competitive AT1 inhibitor. About 14% of a dose is converted by CYP2C9 and CYP3A4 to a carboxylic acid metabolite (E-3174, also written EXP3174), which is 10 to 40 times more potent, behaves as a reversible non-competitive AT1 inhibitor and accounts for most of the receptor blockade; its exposure (AUC) is about 4 times that of losartan.
Candesartan cilexetil and olmesartan medoxomil are prodrugs: ester hydrolysis during absorption from the gut rapidly and completely releases the active drug. Neither active form undergoes much further metabolism.
Two drug-specific effects are high-yield. Losartan is uricosuric: it inhibits urate transporter 1 (URAT1) in the proximal tubule and lowers uric acid, whereas valsartan and candesartan had no notable effect on uric acid. Olmesartan can cause a sprue-like enteropathy — severe chronic diarrhea with substantial weight loss, months to years after starting, with villous atrophy on biopsy.
Comparing the drugs
Receptor pharmacology and distinguishing features
| Drug | AT1 : AT2 selectivity | Active form | Distinguishing point |
|---|---|---|---|
| Losartan | About 1,000-fold | Losartan plus active E-3174 (10–40× more potent; non-competitive) | Uricosuric (URAT1 inhibition) |
| Valsartan | About 20,000-fold | Valsartan itself (main metabolite has about 1/200 the AT1 affinity) | The ARB in sacubitril/valsartan; no notable effect on uric acid |
| Olmesartan | Over 12,500-fold | Prodrug: olmesartan medoxomil hydrolyzed to olmesartan in the gut | Sprue-like enteropathy |
| Candesartan | Over 10,000-fold | Prodrug: candesartan cilexetil hydrolyzed to candesartan in the gut | Not significantly metabolized by CYP450; no clinically significant effect on uric acid |
Selectivity figures are each label’s own estimate of AT1 versus AT2 affinity.
Pharmacokinetics at a glance
| Drug | Oral bioavailability | Metabolism | Elimination | Half-life |
|---|---|---|---|---|
| Losartan | About 33% (first pass) | CYP2C9 and CYP3A4 → E-3174 | Bile and urine (oral dose: about 35% urine, 60% feces) | About 2 h (E-3174 6–9 h) |
| Valsartan | About 25% | Minimal (about 9% to an inactive CYP2C9 metabolite) | Mostly feces (about 83%), mainly unchanged | About 6 h |
| Olmesartan | About 26% | Ester hydrolysis only; virtually no further metabolism | 35–50% urine; the rest in bile | About 13 h |
| Candesartan | About 15% | Ester hydrolysis; minor O-deethylation | Unchanged in urine and bile | About 9 h |
All four are highly protein-bound, and none accumulates appreciably with repeated once-daily dosing.
Pharmacokinetics
- Prodrug activation — candesartan, olmesartan, losartan
- Candesartan cilexetil and olmesartan medoxomil are rapidly and completely bioactivated by ester hydrolysis during absorption. Losartan is active itself, but its carboxylic acid metabolite is responsible for most of the receptor antagonism.
- CYP metabolism and interactions — losartan
- Losartan depends on CYP2C9 and CYP3A4 to form E-3174: fluconazole (a CYP2C9 inhibitor) lowered the active metabolite’s AUC, and rifampin lowered losartan and metabolite AUC by 30% and 40%. Candesartan is not significantly metabolized by CYP450, and valsartan’s low extent of metabolism makes CYP interactions unlikely.
- Protein binding and distribution
- Losartan (free fraction 1.3%), E-3174 (0.2%), valsartan (95% bound), olmesartan (99%) and candesartan (over 99%) are highly bound, mainly to albumin. Valsartan’s small volume of distribution (17 L) means little tissue distribution. In rats, losartan, olmesartan and candesartan crossed the blood–brain barrier poorly, if at all, and olmesartan and candesartan crossed the placenta.
- Routes of elimination
- Renal excretion accounts for about 60% of the clearance of carboxylosartan (E-3174), 40% for olmesartan and candesartan, 30% for valsartan and 10% for losartan; biliary excretion also contributes. Losartan and its metabolite, valsartan and candesartan are not removed by hemodialysis.
- Half-life and accumulation
- Half-lives range from about 2 hours (losartan, with 6–9 hours for E-3174) to about 13 hours (olmesartan). None accumulates appreciably with once-daily dosing.
- Food — valsartan, olmesartan, candesartan
- Food lowers valsartan exposure by about 40%, yet the label still allows it with or without food; food does not affect olmesartan or candesartan bioavailability.
- Hepatic impairment — losartan
- In mild-to-moderate hepatic impairment, plasma levels of losartan and its active metabolite were 5 times and 1.7 times those in healthy volunteers.
Uses & drug choice
- Hypertension
- Heart failure & post-MI (ACE-inhibitor alternative)
- Diabetic nephropathy / chronic kidney disease (renal protection)
Adverse effects
- Hyperkalemia
- Blocking AT1 lowers aldosterone, and aldosterone drives potassium secretion in the distal nephron. In trials the effect on serum potassium was small; it matters in renal disease or with other potassium-raising drugs.
- Dizziness and first-dose or orthostatic hypotension
- When the RAAS is already activated — high-dose diuretics, volume or salt depletion — blood pressure depends on angiotensin II, so removing its AT1 effect can cause symptomatic hypotension.
- Rising creatinine and acute kidney injury
- ARBs lower intraglomerular pressure. When renal function depends on the RAAS — bilateral renal artery stenosis, chronic kidney disease, severe heart failure or volume depletion — that can tip into acute renal failure.
- Angioedema (rare)
- ARBs do not inhibit ACE and do not raise bradykinin, so angioedema and cough are less common than with ACE inhibitors — but rare cases of both have been reported.
- Fetal toxicity
- Reduced fetal kidney perfusion causes renal dysgenesis and oliguric or anuric renal failure; the resulting oligohydramnios contributes to limb contractures, craniofacial deformities and lung hypoplasia, and reduced placental blood flow can impair growth and skull ossification.
Toxicity & antidote
Many ARB ingestions stay asymptomatic. When toxicity occurs, it is hypotension and vasodilatory (vasoplegic) shock — high cardiac index, low systemic vascular resistance, preserved cardiac function — often with a normal-anion-gap metabolic acidosis and a raised lactate; tachycardia is likely, though vagal bradycardia can occur. With long-acting olmesartan the hypotension may start late and last more than 16 hours.
In a reported case, catecholamines helped little — StatPearls attributes this to suppression of the sympathetic nervous system — and calcium, glucagon and high-dose insulin (the calcium-channel-blocker therapies) did not work. In that case, vasopressin raised blood pressure through V1a-receptor vasoconstriction; angiotensin II may also be useful as a vasopressor. Losartan, valsartan and candesartan are not removed by hemodialysis.
Interactions
Contraindications
- Pregnancy — Fetal renal toxicity, oligohydramnios, and death (the boxed warning). Stop immediately if pregnancy occurs.
- Concurrent aliskiren in diabetes, or an ACE inhibitor (dual RAS blockade) — Dual RAAS blockade sharply increases hyperkalemia, hypotension, and renal failure without added benefit.
- Bilateral renal artery stenosis — These kidneys depend on angiotensin II to maintain filtration pressure — blocking it precipitates acute kidney injury.
- History of angioedema; hyperkalemia use caution — Angioedema can recur, and ARBs raise potassium — starting one with an already-high level (potassium > 5.5 mEq/L is a relative contraindication) can worsen hyperkalemia, which can cause life-threatening arrhythmias.
High-yield
- C — candesartan cilexetil: ester hydrolysis during absorption releases candesartan
- O — olmesartan medoxomil: ester hydrolysis during absorption releases olmesartan
- L — losartan: hepatic CYP2C9/CYP3A4 make the more potent E-3174
- LOS — losartan inhibits URAT1 in the proximal tubule
- LOSE urate — uric acid falls (valsartan and candesartan had no notable effect)
Practice questions
Q1A 58-year-old woman with hypertension develops a persistent dry cough on lisinopril. She is switched to losartan, and the cough resolves over the next month.
Which property of losartan best explains why the cough is unlikely to return?
- A.It stimulates AT2 receptors that degrade bradykinin
- B.It lowers angiotensin II synthesis
- C.It inhibits neprilysin
- D.It blocks the AT1 receptor without inhibiting ACE, so bradykinin does not accumulate
- E.It blocks bradykinin B2 receptors in the airway
Show answer
D. It blocks the AT1 receptor without inhibiting ACE, so bradykinin does not accumulate — ACE is also kininase II, the enzyme that degrades bradykinin. Losartan does not inhibit ACE and does not affect the response to bradykinin, whereas ACE inhibitors increase it — so cough and angioedema are less common with ARBs. Angiotensin II synthesis is not reduced: renin and angiotensin II actually rise on an ARB. Neprilysin inhibition belongs to sacubitril, AT2 activation produces vasodilation partly through bradykinin rather than degrading it, and blocking bradykinin receptors is not losartan’s action — the labels say it does not affect the response to bradykinin.
Q2A 50-year-old man with hypertension starts valsartan. Two weeks later his blood pressure is lower, and a research blood sample shows plasma renin activity two to three times his baseline, with a higher angiotensin II level.
Which best explains the laboratory change?
- A.Direct stimulation of juxtaglomerular cells by valsartan
- B.Loss of angiotensin II negative feedback on renin secretion because AT1 is blocked
- C.Partial agonist activity of valsartan at the AT1 receptor
- D.Volume overload from aldosterone excess
- E.Inhibition of angiotensin II breakdown by valsartan
Show answer
B. Loss of angiotensin II negative feedback on renin secretion because AT1 is blocked — Blocking AT1 removes angiotensin II’s negative feedback on renin, so plasma renin rises two- to threefold and angiotensin II rises with it. The extra angiotensin II does not overcome the blockade, so blood pressure still falls, and it may stimulate the unblocked AT2 receptor. ARBs show no partial agonism at AT1, and aldosterone falls rather than rises.
Q3A 67-year-old man has had severe watery diarrhea and a 9-kg weight loss over 4 months. Duodenal biopsy shows villous atrophy. His medications have been unchanged for 3 years, and no infectious or other cause is found.
Which of his antihypertensives is the most likely cause?
- A.Losartan
- B.Hydrochlorothiazide
- C.Amlodipine
- D.Metoprolol
- E.Olmesartan
Show answer
E. Olmesartan — Olmesartan is associated with sprue-like enteropathy: severe chronic diarrhea with substantial weight loss, starting months to years after initiation, with villous atrophy on biopsy. Once other causes are excluded, the label advises considering an alternative antihypertensive.
Q4A 55-year-old man with hypertension and recurrent gout needs a renin–angiotensin blocker. His physician wants the agent that will also lower his serum urate.
Which drug fits, and by what mechanism?
- A.Valsartan — inhibits xanthine oxidase
- B.Candesartan — inhibits URAT1 in the proximal tubule
- C.Losartan — inhibits URAT1 in the proximal tubule
- D.Losartan — inhibits xanthine oxidase
- E.Valsartan — inhibits URAT1 in the proximal tubule
Show answer
C. Losartan — inhibits URAT1 in the proximal tubule — Among ARBs, losartan has uric acid–lowering properties: it acts as a uricosuric agent by inhibiting urate transporter 1 (URAT1) in the proximal tubule. Valsartan and candesartan had no notable effect on uric acid in their label studies.
Q5A 45-year-old woman is admitted after intentionally ingesting her amlodipine and olmesartan. Despite IV fluids, calcium, glucagon, high-dose insulin and norepinephrine, she remains hypotensive 16 hours later; echocardiography shows preserved cardiac function with a high cardiac index.
In a published case like hers, which drug finally raised her blood pressure, and through what mechanism?
- A.Vasopressin — V1a-receptor vasoconstriction
- B.Isoproterenol — β1 stimulation raises cardiac output
- C.Dobutamine — improves contractility
- D.Milrinone — raises cAMP to improve contractility
- E.More glucagon — raises cAMP in myocytes
Show answer
A. Vasopressin — V1a-receptor vasoconstriction — ARB overdose causes vasodilatory (vasoplegic) shock with a high cardiac index, low vascular resistance and preserved cardiac function, and olmesartan’s long half-life can keep it going beyond 16 hours. In a reported case like this, catecholamines helped little (StatPearls attributes this to suppression of the sympathetic nervous system) and calcium-channel-blocker therapies failed, while vasopressin raised mean arterial pressure through V1a-receptor vasoconstriction. Drugs aimed at contractility do not target the low vascular resistance.
Sources
- COZAAR (losartan) — boxed warning (fetal toxicity), hyperkalemia, contraindications (FDA label) — FDA / DailyMed
- Angiotensin II Receptor Blockers — mechanism, adverse effects, no-cough advantage — StatPearls (NCBI)
- DIOVAN (valsartan) — prescribing information — DailyMed (NLM)
- BENICAR (olmesartan) — prescribing information — DailyMed (NLM)
- ATACAND (candesartan) — prescribing information — DailyMed (NLM)
- Antihypertensives — ARBs / losartan (Ch. 6.10) — Open RN — Nursing Pharmacology
- The use of stems in the selection of INN (stem -sartan) — World Health Organization
- Antihypertensive Medications — ACE inhibitor/ARB monitoring, expected creatinine rise, contraindications, cough rates — StatPearls (NCBI)
- Hyperkalemia — RAAS inhibitors as a cause; life-threatening arrhythmias — StatPearls (NCBI)
- Lithium Toxicity — ARBs reduce lithium clearance — StatPearls (NCBI)
- Losartan — AT1 selectivity, effects blocked beyond vasoconstriction, E-3174, Marfan syndrome — StatPearls (NCBI)
- Entresto (sacubitril/valsartan) — neprilysin inhibition plus AT1 blockade (FDA label) — FDA / DailyMed
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.