Indications
Alone or with other agents in the management of hypertension.
Treatment of diabetic nephropathy in patients
with type 2 diabetes and hypertension (irbesartan and
losartan only). Management of HF (New York Heart Association
class II-IV) in patients who cannot tolerate
ACE inhibitors (candesartan and valsartan only) or in
combination with an ACE inhibitor and beta-blocker
(candesartan only). Prevention of stroke in patients
with hypertension and left ventricular hypertrophy (losartan
only). Reduction of risk of death from cardiovascular
causes in patients with left ventricular systolic dysfunction
after MI (valsartan only). Reduction of risk of
myocardial infarction, stroke, or cardiovascular death
in patients 55 yr who are at high risk for cardiovascular
events and are unable to take ACE inhibitors (telmisartan
only).
Action
Blocks vasoconstrictor and aldosterone-producing effects
of angiotensin II at receptor sites, including vascular
smooth muscle and the adrenal glands. Therapeutic
Effects: Lowering of BP. Slowed progression of diabetic
nephropathy (irbesartan and losartan only). Reduced
cardiovascular death and hospitalizations due to HF in
patients with HF (candesartan and valsartan only). Decreased risk of cardiovascular death in patients with left
ventricular systolic dysfunction who are post-MI (valsartan
only). Decreased risk of stroke in patients with hypertension
and left ventricular hypertrophy (effect may be
less in black patients) (losartan only).
Pharmacokinetics
Absorption: Azilsartan—Azilsartan medoxomil is
converted to azilsartan, the active component. 60% absorbed;
Candesartan—Candesartan cilexetil is converted
to candesartan, the active component; 15% bioavailability
of candesartan; Eprosartan—13%
absorbed after oral administration; Irbesartan—60–
80% absorbed after oral administration; Losartan—
well absorbed, with extensive first-pass hepatic metabolism,
resulting in 33% bioavailability; Olmesartan—
Olmesartan medoxomil is converted to olmesartan, the
active component; 26% bioavailability of olmesartan;
Telmisartan—42–58% absorbed following oral administration
(bioavailabilityqin patients with hepatic
impairment); Valsartan—10–35% absorbed following
oral administration.
Distribution: All angiotensin receptor blockers (ARBs)
cross the placenta; Candesartan—enters breast milk.
Protein Binding: All ARBs are 90% protein-bound.
Metabolism and Excretion: Azilsartan—50%
metabolized by the liver, primarily by the CYP2C9 enzyme
system. 55% eliminated in feces, 42% in urine
(15% as unchanged drug); Candesartan—Minor metabolism
by the liver; 33% excreted in urine, 67% in feces
(via bile); Eprosartan—Excreted primarily unchanged
in feces via biliary excretion; Irbesartan—
Some hepatic metabolism; 20% excreted in urine, 80%
in feces; Losartan—Undergoes extensive first-pass hepatic
metabolism; 14% is converted to an active metabolite.
4% excreted unchanged in urine; 6% excreted in
urine as active metabolite; some biliary elimination; Olmesartan—
30–50% excreted unchanged in urine,
remainder eliminated in feces via bile; Telmisartan—
Excreted mostly unchanged in feces via biliary excretion;
Valsartan—Minor metabolism by the liver; 13%
excreted in urine, 83% in feces.
Half-life: Azilsartan—11 hr; Candesartan—9 hr;
Eprosartan—20 hr; Irbesartan—11–15 hr; Losartan—
2 hr (6–9 hr for metabolite); Olmesartan—
13 hr; Telmisartan—24 hr; Valsartan—6 hr.
TIME/ACTION PROFILE (antihypertensive
effect with chronic dosing)
DRUG ONSET PEAK DURATION
Azilsartan within 2 hr 18 hr 24 hr
Candesartan 2–4 hr 4 wk 24 hr
Eprosartan 1–2 hr 2–3 wk 12–24 hr
Irbesartan within 2 hr 2 wk 24 hr
Losartan 6 hr 3–6 wk 24 hr
Olmesartan within 1 wk 2 wk 24 hr
Telmisartan within 3 hr 4 wk 24 hr
Valsartan within 2 hr 4 wk 24 hr
Contraindications/Precautions
Contraindicated in: Hypersensitivity; Concurrent
use with aliskiren in patients with diabetes or moderate-
to-severe renal impairment (CCr 60 mL/min); Severe
hepatic impairment (candesartan); OB: Can cause
injury or death of fetus—if pregnancy occurs, discontinue
immediately; Lactation: Discontinue drug or use
formula.
Use Cautiously in: HF (may result in azotemia, oliguria,
acute renal failure and/or death); Volume- or
salt-depleted patients or patients receiving high doses
of diuretics (correct deficits before initiating therapy or
initiate at lower doses); Black patients (may not be
effective); Impaired renal function due to primary renal
disease or HF (may worsen renal function); Obstructive
biliary disorders (telmisartan) or hepatic impairment
(losartan, or telmisartan); Women of childbearing potential;
Pedi: Safety not established in children 18 yr
(6 yr for losartan, olmesartan, and valsartan).
Adverse Reactions/Side Effects
CNS: dizziness, anxiety, depression, fatigue, headache,
insomnia, weakness. CV: hypotension, chest pain,
edema, tachycardia. Derm: rashes. EENT: nasal congestion,
pharyngitis, rhinitis, sinusitis. GI: abdominal
pain, diarrhea, drug-induced hepatitis, dyspepsia, nausea,
vomiting. GU: impaired renal function. F and E:
hyperkalemia. MS: arthralgia, back pain, myalgia.
Misc: ANGIOEDEMA.
Interactions
Drug-Drug: NSAIDs and selective COX-2 inhibitors
may blunt the antihypertensive effect andqthe
risk of renal dysfunction.qantihypertensive effects with
other antihypertensives and diuretics. Telmisartan
mayqserum digoxin levels. Concurrent use of potassium-
sparing diuretics, potassium-containing
salt substitutes, or potassium supplements mayq
risk of hyperkalemia.qrisk of hyperkalemia, renal dysfunction,
hypotension, and syncope with concurrent
use of ACE inhibitors or aliskiren; avoid concurrent
use with aliskiren in patients with diabetes or CCr 60
mL/min; avoid concurrent use with ACE inhibitors. Candesartan,
valsartan, and irbesartan mayqlithium levels.
Irbesartan and losartan mayqeffects of amiodarone,
fluoxetine, glimepiride, glipizide,
phenytoin, rosiglitazone, and warfarin. Rifampin
maypeffects of losartan.qrisk of renal dysfunction
when telmisartan used with ramipril (concurrent use
not recommended). Colesevelam maypolmesartan
levels; administer olmesartan 4 hr before colesevelam.
Route/Dosage
Azilsartan
PO (Adults): 80 mg once daily, initial dose may bep
to 40 mg once daily if high doses of diuretics are used
concurrently.
Candesartan A
PO (Adults): Hypertension—16 mg once daily; may
bequp to 32 mg/day in 1–2 divided doses (begin
therapy at a lower dose in patients who are receiving diuretics
or are volume depleted). HF—4 mg once daily
initially, dose may be doubled at 2 wk intervals up to
target dose of 32 mg once daily.
PO (Children 6–16 yr and 50 kg): 8–16 mg/day
(in 1–2 divided doses); may bequp to 32 mg/day (in
1–2 divided doses).
PO (Children 6–16 yr and 50 kg): 4–8 mg/day
(in 1–2 divided doses); may bequp to 16 mg/day (in
1–2 divided doses).
PO (Children 1–5 yr): 0.20 mg/kg/day (in 1–2 divided
doses); may bequp to 0.4 mg/kg/day (in 1–2
divided doses).
Hepatic Impairment
PO (Adults): Moderate hepatic impairment—Initiate
at 8 mg once daily.
Eprosartan
PO (Adults): 600 mg once daily; may beqto 800 mg/
day (in 1–2 divided doses) (usual range 400–800
mg/day).
Renal Impairment
PO (Adults): CCr 60 mL/min—Do not exceed 600
mg/day.
Irbesartan
PO (Adults): Hypertension—150 mg once daily;
may beqto 300 mg once daily. Initiate therapy at 75
mg once daily in patients who are receiving diuretics or
are volume depleted. Type 2 diabetic nephropathy—
300 mg once daily.
Losartan
PO (Adults): Hypertension—50 mg once daily initially
(range 25–100 mg/day as a single daily dose or 2
divided doses) (initiate therapy at 25 mg once daily in
patients who are receiving diuretics or are volume depleted).
Prevention of stroke in patients with hypertension
and left ventricular hypertrophy—50 mg
once daily initially; hydrochlorothiazide 12.5 mg once
daily should be added and/or dose of losartanqto 100
mg once daily followed by anqin hydrochlorothiazide
to 25 mg once daily based on BP response. Type 2 diabetic
nephropathy—50 mg once daily, mayqto 100
mg once daily depending on BP response.
Hepatic Impairment
PO (Adults): 25 mg once daily initially; may beqas
tolerated.
PO (Children 6 yr): Hypertension—0.7 mg/kg
once daily (up to 50 mg/day), may be titrated up to 1.4
mg/kg/day (or 100 mg/day).
Renal Impairment
PO (Children 6 yr): CCr 30 mL/min—Contraindicated.
Olmesartan
PO (Adults): 20 mg once daily; may bequp to 40 mg
once daily (patients who are receiving diuretics or are
volume-depleted should be started on lower doses).
PO (Children 6–16 yr): 35 kg—20 mg once
daily; may beqafter 2 wk up to 40 mg once daily; 20–
34.9 kg—10 mg once daily; may beqafter 2 wk up to
20 mg once daily.
Telmisartan
PO (Adults): Hypertension—40 mg once daily (volume-
depleted patients should start with 20 mg once
daily); may be titrated up to 80 mg/day; Cardiovascular
risk reduction—80 mg once daily.
Valsartan
PO (Adults): Hypertension—80 mg or 160 mg once
daily initially in patients who are not volume-depleted;
may beqto 320 mg once daily; HF—40 mg twice
daily, may be titrated up to target dose of 160 mg twice
daily as tolerated; Post-MI—20 mg twice daily (may be
initiated 12 hr after MI); dose may be titrated up to
target dose of 160 mg twice daily, as tolerated.
PO (Children 6–16 yr): Hypertension—1.3 mg/kg
once daily (maximum dose40 mg/day); may beq
up to 2.7 mg/kg once daily (maximum dose160 mg/
day).
Availability
Azilsartan
Tablets: 40 mg, 80 mg. Cost: All strengths $113.23/
30. In combination with: chlorthalidone (Edarbyclor);
see Appendix B.
Candesartan (generic available)
Tablets: 4 mg, 8 mg, 16 mg, 32 mg. Cost: Generic—
4 mg $99.16/30, 8 mg $99.16/30, 16 mg $285.56/30,
32 mg $386.60/30. In combination with: hydrochlorothiazide
(Atacand HCT); see Appendix B.
Eprosartan (generic available)
Tablets: 400 mg, 600 mg. Cost: Generic—600 mg
$102.78/30. In combination with: hydrochlorothiazide
(Teveten HCT); see Appendix B.
Irbesartan (generic available)
Tablets: 75 mg, 150 mg, 300 mg. Cost: Generic—75
mg $10.44/90, 150 mg $279.97/90, 300 mg $31.13/
90. In combination with: hydrochlorothiazide
(Avalide); see Appendix B.
Losartan (generic available)
Tablets: 25 mg, 50 mg, 100 mg. Cost: Generic—25
mg $151.43/90, 50 mg $67.88/30, 100 mg $277.36/90. In combination with: hydrochlorothiazide (Hyzaar);
see Appendix B.
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