RAAS Inhibitors

Drug interaction

Inhibitors of the renin-angiotensin-aldosterone system

  1. Direct renin inhibitors: Aliskiren
  2. Angiotensin-converting enzyme (ACE) inhibitors: Benazepril, Captopril, Enalapril, Lisinopril, Peridopril, Quinapril, Ramipril, Trandolapril
  3. Angiotensin receptor blockers: Candesartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan
  4. Mineralocorticoid receptor antagonists: Eplerenone, Spironolactone
  5. Sacubitril/Valsartan

Aliskiren

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions

- ACEIs
- ARBs
- Eplerenone
- K+ salts and supplements
- K+-sparing diuretics
- Spironolactone
Increased risk of hypotension, renal dysfunction and hyperkalemiaThe coadministration is contraindicated in patients with DM, HF or renal impairment (GFR <60 ml/min/1.73 m2)
CiclosporinIncreases the plasma levels of aliskirenAvoid the combination
Drugs that raise serum K+ levels:
- ACEIs
- ARBs
- Heparin
- Mineralocorticoid receptor antagonists: Eplerenone, Spironolactone
Increased risk of hyperkalemiaMonitor serum potassium levels
Dual blockade of the renin-angiotensin-aldosterone systemHigher frequency of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure)Monitor the patient
FurosemideReduces furosemide serum concentrations.Increase the dose of furosemide. Monitor the clinical response
ItraconazoleIncreases the plasma levels of aliskirenAvoid the combination
NSAIDsMay reduce effect of aliskiren and increase risk of renal impairmentWith caution
Potent P-gp inhibitors:
- Amiodarone
- Atorvastatin
- Ciclosporin
- Clarithromycin
- Erythromycin
- Itraconazole
- Ketoconazole
- Quinidine
Avoid the combination

Aliskiren shows no clinically relevant interactions with atenolol, celecoxib, cimetidine, digoxin, lovastatin, warfarin.

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Angiotensin-converting enzyme inhibitors (ACEIs)

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AlcoholIncreases the risk of hypotensionAvoid alcohol intake, monitor BP
Antidiabetics:
- Insulins
- Oral hypoglycemic agents
May increase the blood-glucose-lowering effect with risk of hypoglycemiaMonitor glucose plasma levels
Antihypertensives Increase the risk of hypotensionMonitor BP
CiclosporinInhibit the antihypertensive effects of ACEIsMonitor BP
DiureticsACEIs attenuate the hypokalemia produced by thiazides and loop diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with an ACEI The risk of hypotension can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of ACEIs
Drugs that produce hyperkalemia:
- ARBs
- Beta-blockers
- Eplerenone
- K+ salts and supplements
- K+-sparing diuretics
- NSAIDs
- Spironolactone
- Trimethoprim-sulfamethoxazole
- Unfractioned heparin
Increased risk of hyperkalemiaMonitor serum potassium levels
Drugs that reduce their antihypertensive effect:
- Ciclosporin
- Sympathomimetics
Inhibit the antihypertensive effects of ACEIs and increase the risk of hyperkalemiaMonitor BP and serum potassium levels
Dual blockade of the RAASThe concomitant use of ACEIs with ARBs or aliskiren increases the risk hypotension, hyperkalemia and decreased renal function (including acute renal failure)Dual blockade it not recommended.
The combination is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²)
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and close monitoring of renal function, electrolytes and BP
ErythropoietinHigher doses of erythropoietin are needed in dyalized patients treated with ACEIs
GoldNitritoid reactions (facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients treated with injectable gold (sodium aurothiomalate) and an ACEI
Immunosuppressants:
- Everolimus
- Sirolimus
- Temsirolimus
Increases the risk for angioedemaWith caution
LithiumIncreases the risk of lithium toxicity The combination is generally not recommended. Monitor lithium plasma levels
NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs)Reduce the antihypertensive effects of ACEIs, increase serum potassium levels and may result in a deterioration of renal functionMonitor BP, serum potassium level and renal function. With caution in patients with compromised renal function
Vasodilators:
- Alcohol
- Amifostine
- Antipsychotics
- Baclofen
- Nitrates
- Tricyclic antidepressants
Increases the risk of hypotension

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Angiotensin II (AT1) receptor blockers (ARBs)

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
ACEIs decrease the renal excretion of:
- Atenolol
- Disopyramide
- Flecainide
- Nadolol
- Procainamide
- Sotalol
AntihypertensivesIncreases the risk of hypotensionMonitor BP
CYP inducers May reduce drug plasma levelsMonitor the clinical response
Diuretics:
- Loop diuretics
- Thiazides
Additive effects. Prior treatment with high dose diuretics may result in volume depletion and hypotension when initiating therapy with an ARB
ARBs attenuate diuretic-induced potassium loss
Monitor BP
Drugs that produce hyperkalemia:
- ACEIs
- Beta-blockers
- Eplerenone
- K+ salts and supplements
- K+-sparing diuretics
- NSAIDs
- Spironolactone
- Trimethoprim-sulfamethoxazole
- Unfractiones heparin
Increased risk of hyperkalemiaMonitor serum potassium levels
Dual blockade of the RAASDual blockade of the RAAS (combined use of ACEIs, ARBs or aliskiren) increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure)Avoid the combination. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and close monitoring of renal function, electrolytes and BP
Immunossupressants:
- Temsirolimus
- Sirolimus,
- Everolimus
Increased risk for angioedemaMonitor the patient
LithiumIncreases the risk of lithium toxicity Decrease the renal excretion of lithiumUse with caution.
Monitor lithium plasma levels
NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs)Attenuate the antihypertensive effects of ARBs and increase the risk of hyperkalemia and worsening of renal function, including possible acute renal failureMonitor BP, serum potassium level and renal function. With caution in patients with compromised renal function
Sodium aurothiomalateNitritoid reactions (flushing, nausea, dizziness and hypotension)Avoid the combination
Vasodilators:
- Alcohol
- Antipsychotics
- Baclofen
- Nitrates
- Tricyclic antidepressants
Increases the risk of hypotensionMonitor BP

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Selective mineralocorticoid receptor antagonists

Eplerenone

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AntihypertensivesIncreases the risk of hypotensionMonitor BP

- ACTH
- Glucocorticoids
- Tetracosactide
Reduce the antihypertensive effect of eplerenone and increase the risk of hypokalemiaIncrease the dose of eplerenone, monitor BP and serum K+ levels

- Cyclosporin
- Tacrolimus
The combination impairs renal function and increases the risk of hyperkalaemiaAvoid the combination
Drugs that produce hyperkalemia:
- ACEIs
- Aliskiren
- ARBs
- β-blockers
- Ciclosporin
- Drosperidone
- Eplerenone
- I.V. penicillin G potassium
- K+ salts and supplements
- K+-sparing diuretics
- Mitotane
- NSAIDs
- Pentamidine
- Spironolactone
- Tacrolimus
- Tolvaptan
- Trimethoprim-sulfamethoxazole
- Unfractioned heparin
Produces hyperkalemia, particularly in the elderly and in patients with renal impairmentMonitor serum K+ levels. Restrict dietary K+ and reduce/avoid K+ supplements without consulting the prescribing physician
Dual RAAS blockadeThe risk of hyperkalaemia increases when eplerenone is combined with an ACEIs and/or ARBsClose monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function. The triple combination of an ACE inhibitor and an ARB with eplerenone should not be used
LithiumIncreases the risk of lithium toxicityEplerenone reduces the renal clearance and increases the plasma levels of lithiumReadjust the dose of lithium and monitor its plasma levels
Mild to moderate CYP3A4 inhibitors Eplerenone should not be used at doses above 25 mg
NSAIDsReduce the antihypertensive effects of eplerenone and increase the risk of acute renal failureMonitor BP and monitor creatinine plasma levels
Potent CYP3A4 inducers Decrease eplerenone efficacyAvoid the combination
Potent CYP3A4 inhibitorsAvoid the combination
Vasodilators:
- Alcohol
- Antipsychotics
- Baclofen
- Neuroleptics
- Nitrates
- Tricyclic antidepressants
Increases the risk of hypotensionMonitor BP

There are no pharmacokinetic interactions when eplerenone is administered with antiacids, cisapride, cyclosporine, digoxin, , glyburide midazolam, simvastatin, or oral contraceptives (norethindrone/ethinyl estradiol), warfarin.

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Spironolactone

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
ACE inhibitors Both drugs produce hyperpotassemiaMonitor the plasma levels of potassium
Ammonium chloride Risk of acidosisAttention to acidosis
AnticoagulantsSpironolactone reduces the effect of anticoagulantsWith caution
AntihypertensivesIncreases the risk of hypotensionMonitor BP in these patients
CarbenoxoloneInhibits the gastroprotective activity Use triamterene
Cholestyramine Risk of hyperchloremic metabolic acidosis, frequently associated with hyperkalemiaWith caution
DigoxinDecrease the renal excretion of digoxin and increases digoxin plasma levelsReduce the dose of digoxin and monitor digoxin plasma levels
Drugs that produce hyperkalemia:
- ACEIs
- Aliskiren
- ARBs
- β-blockers
- Ciclosporin
- Drosperidone
- Eplerenone
- I.V. penicillin G potassium
- K+ salts and supplements
- K+ -sparing diuretics
- NSAIDs
- Pentamidine
- Spironolactone
- Tacrolimus
- Tolvaptan
- Trimethoprim-sulfamethoxazole
- Unfractioned heparin
Produces hyperkalemia, particularly in the elderly and in patients with renal impairmentMonitor serum K+ levels. Restrict dietary K+ and reduce/avoid K+ supplements without consulting the prescribing physician
LithiumIncreases the risk of lithium toxicity Spironolactone decreases the renal excretion of lithium and incresaes its exposureReadjust the dose of lithium and monitor its plasma levels to avoid the risk of toxicity. Amiloride does not present this interaction
Loop and thiazide diureticsIncrease diuresis and reduce renal K+ and Mg2+ excretionMonitor BP and serum potassium levels
NoradrenalineSpironolactone reduces the vasoconstrictive effects of noradrenalineWith caution
NSAIDs Antagonize the diuretic and antihypertensive effects of spironolactone. Risk of renal insufficiency. Indomethacin combined with spironolactone may precipitate acute renal failureMonitor BP and the plasma levels of creatinine. Avoid the combination
Sodium lactate solutionBecause of its potassium content, this solution should be administered with cautionMonitor serum potassium levels
MitotaneSpironolactone can decrease the effects of mitotaneWith caution
Potassium supplements Hyperkalemia may resultIncrease the bioavailability of spironolactone Administer spironolactone with meals
Vasodilators:
- Alcohol,
- Nitrates
- Neuroleptics
- Tricyclic antidepressants
Increases the risk of hypotensionMonitor BP in these patients

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Sacubitril/Valsartan

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
ACE inhibitorsIncreases the risk of angioedema, hypotension, renal dysfunction and hyperkalemiaThe concomitant use of sacubitril/valsartan with ACEIs is contraindicated. Sacubitril/valsartan must not be started until 36 h after discontinuing ACEI therapy
AliskirenIncreases the risk of hypotension, hyperkalemia and decreased renal functionThis concomitant is contraindicated in patients with DM or with renal impairment (eGFR < 60 mL/min/1.73 m²)
ARBsAvoid use of sacubitril/valsartan with any other ARB, because it contains valsartan
Drugs that increase serum potassium levels:
- Heparin
- K+ salts and supplements
- K+ -sparing diuretics
- Drospirenone
- Eplereone
- Spironolactone
Increase the risk of hyperkalemiaWith caution. Monitor serum potassium levels
LithiumValsartan increases serum lithium levels and lithium toxicity Monitor serum lithium levels
MetforminReduces the exposure to metformin by 25%Unclear clinical relevance. Monitor the response to metformin
MRP2 inhibitors:
- Ritonavir
Valsartan is a MRP2 substrateMay increase the systemic exposure of LBQ657 or valsartanWith caution
NSAIDs (including selective cyclooxygenase-2 (COX-2) inhibitors)In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, this combination may increase the risk of worsening of renal function.Monitor renal function when initiating or modifying treatment with sacubitril/valsartan in patients treated with NSAIDs
OAT1 inhibitors:
- Cidofovir
- Tenofovir
LBQ657 and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substratesMay increase the systemic exposure of LBQ657 or valsartanWith caution
OATP1B1, OATP1B3, OAT3 inhibitors:
- Ciclosporin
- Rifampicin
LBQ657 and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substratesMay increase the systemic exposure of LBQ657 or valsartanWith caution
PDE inhibitors:
- Sildenafil
A greater reduction in BPMonitor BP

No drug interactions with amlodipine, atorvastatin, carvedilol, digoxin, furosemide, hydrochlorothiazide, levonorgestrel/ethinyl estradiol, omeprazole or warfarin.

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Abbreviations

ACEIs: angiotensin-converting enzyme inhibitors.
ACTH: adrenocorticotropic hormone.
ARBs: angiotensin receptor blockers.
AT1: AT1 angiotensin II receptor.
BP: blood pressure.
COX-2: cyclooxygenase-2. 
CYP: cytochrome P450 superfamily.
eGFR: estimated glomerular filtration rate.
I.V.: intravenous.
MRP2: multidrug resistance-associated protein 2.
NSAIDs: non-steroidal anti-inflammatory drugs.
OATP: organic-anion-transporting polypeptide.
PDE: phosphodiesterase.
P-gp: P glycoprotein.
RAAS: renin-angiotensin-aldosterone system.