Acronyms
- DBP - Diastolic blood pressure
- ENaC - Epithelial sodium channel
- GFR - Glomerular filtration rate
- HCTZ - Hydrochlorothiazide
- OBS - Observational study
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- ULN - Upper Limits of Normal
DRUGS IN CLASS
- Epithelial sodium channel (ENaC) inhibitors
- Amiloride (Midamor®)
- Triamterene (Dyrenium®)
- Combination products with HCTZ
- Dyazide® (triamterene + HCTZ)
- Maxzide® (triamterene + HCTZ)
- Amiloride + HCTZ
FDA-APPROVED INDICATIONS
- Amiloride
- Amiloride HCl is indicated as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents in congestive heart failure or hypertension to:
- a. help restore normal serum potassium levels in patients who develop hypokalemia on the kaliuretic diuretic
- b. prevent development of hypokalemia in patients who would be exposed to particular risk if hypokalemia were to develop, e.g., digitalized patients or patients with significant cardiac arrhythmias.
- Triamterene
- Triamterene capsules are indicated in the treatment of edema associated with congestive heart failure, cirrhosis of the liver and the nephrotic syndrome; steroid-induced edema, idiopathic edema and edema due to secondary hyperaldosteronism.
- Triamterene capsules may be used alone or with other diuretics, either for its added diuretic effect or its potassium-sparing potential. It also promotes increased diuresis when patients prove resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism.
MECHANISM OF ACTION
- Epithelial sodium channels (ENaC) are located in the renal collecting duct, where they allow sodium to move from the tubular lumen into luminal epithelial cells in exchange for potassium. ENaC inhibitors block these channels, inhibiting sodium reabsorption and, in turn, reducing potassium excretion.
- ENaC inhibitors do not cause significant diuresis and, therefore, only have a minimal-to-null effect on blood pressure
- Nephron and diuretics illustration - illustration of the nephron and how diuretics work
HYPERTENSION
- ENaC inhibitors are typically added to thiazide diuretics to help prevent potassium loss. A Cochrane meta-analysis evaluating the effects of ENaC inhibitors on blood pressure is detailed below, and a randomized controlled trial comparing HCTZ to HCTZ + Amiloride with blood pressure as a coprimary outcome is detailed here - amiloride study. While the aforementioned studies did not find that ENaC inhibitors have a significant effect on blood pressure when combined with HCTZ, a small study comparing amiloride to spironolactone in patients with resistant hypertension found that amiloride was noninferior to spironolactone for reducing blood pressure. That study is also reviewed below.
- OBSBlood pressure lowering efficacy of ENaC inhibitors for primary hypertension, Cochrane meta-analysis (2010) [PubMed abstract]
- Six studies where ENaC inhibitors were added to HCTZ (4 with amiloride, 2 with triamterene) were included in the analysis. No studies were found where ENaC inhibitors were used as monotherapy to treat hypertension.
- Results:
- ENaC inhibitors had no significant effect on blood pressure when added to HCTZ. The highest doses in the studies were amiloride 5 mg and triamterene 50 mg. [1]
- Findings:
- ENaC blockers do not have a statistically or clinically significant BP lowering effect at low doses but trials at higher doses are not available. The review did not provide a good estimate of the incidence of harms associated with ENaC blockers.
- RCTAmiloride vs Spironolactone for Resistant Hypertension, JAMA (2025) [PubMed abstract]
- Design: Randomized, open-label trial (N=118 | length = 12 weeks) in patients with home SBP of 130 mmHg or greater after a 4-week run-in period with a fixed-dose triple medication combination (angiotensin receptor blocker, calcium channel blocker, and thiazide)
- Treatment: 12.5 mg/d of spironolactone vs 5 mg/d of Amiloride. If home SBP remained ≥130 mmHg and serum potassium was <5.0 mmol/L after 4 weeks, dosages were increased to 25 mg/d and 10 mg/d, respectively.
- Primary outcome: The between-group difference in home SBP change at week 12, with a noninferiority margin of -4.4 mm Hg for the lower bound of the confidence interval.
- Results:
- Primary outcome (BP reduction) Amiloride - 13.6 mmHg, Spironolactone - 14.7 mmHg (between-group difference in change, -0.68 mm Hg; 90% CI, -3.50 to 2.14 mmHg)
- Findings: Amiloride was noninferior to spironolactone in lowering home SBP, suggesting that it could be an effective alternative for treatment of resistant hypertension.
- Summary
- The effects of ENaC inhibitors on blood pressure have not been studied extensively. Trials where they have been added to HCTZ have not found that they enhance blood pressure lowering. However, amiloride lowered SBP by 13.6 mmHg and was noninferior to spironolactone in a small, open-label trial enrolling patients with resistant hypertension. These results are surprising given that even the amiloride prescribing information states that "amilrodie has weak (compared with thiazides) diuretic and antihypertensive effects." Larger, placebo-controlled studies are needed to confirm these findings.
POTASSIUM SPARING
- Two trials evaluating the potassium-sparing effects of ENaC inhibitors are detailed below
RCT
Amiloride + HCTZ vs HCTZ for Potassium and BP Effects in Hypertension, Can Med Assoc J, (1985) [PubMed abstract]
- The study enrolled 266 patients with hypertension
Main inclusion criteria
- Diagnosis of essential hypertension and DBP 95 - 109 mmHg after 2 weeks off meds
- Potassium ≥ 3.5 mmol/L
Main exclusion criteria
- History of hyperkalemia
- BUN > 30 mg/dl
- Serum creatinine > 20% above ULN
- Myocardial infarction within 6 months
- History of arrhythmia requiring therapy
Baseline characteristics
- Average age 53 years
- Average weight - 170 lbs
Randomized treatment groups
- Group 1 (133 patients) - HCTZ 50 mg + Amiloride 5 mg once daily for 8 weeks
- Group 2 (133 patients) - HCTZ 50 mg once daily for 8 weeks
- There was a 2 - 4 week washout period where all blood pressure medications were stopped
- If DBP did not decrease to < 90 after 2 weeks, dose of study drug could be doubled
Primary outcomes
- 1. Change in blood pressure
- 2. Change in potassium
Results
| Duration: 8 weeks | |||
| Outcome | Amiloride/HCTZ | HCTZ | Comparisons |
|---|---|---|---|
| Average baseline blood pressure | 156/99 | 157/99 | N/A |
| Average baseline potassium level | 4.23 mmol/L | 4.16 mmol/L | N/A |
| Primary outcome (change in potassium) | 3.91 mmol/L | 3.69 mmol/L | p<0.05 |
| Primary outcome (change in blood pressure) | 138/88 | 138/87 | p>0.05 |
| Percent of patients with potassium < 3.5 mmol/L | 14% | 29% | p=0.0026 |
|
|||
Findings: In light of growing concerns about the cardiovascular complications of hypokalemia, hydrochlorothiazide-amiloride appears preferable to hydrochlorothiazide alone for the treatment of some patients with hypertension
RCT
Triamterene vs Potassium Supplements for Potassium Restoration in Patients Receiving HCTZ, Arch Intern Med, (1989) [PubMed abstract]
- The study enrolled 252 patients with hypertension who were hypokalemic while being treated with HCTZ 50 mg/day for up to 4 weeks
Main inclusion criteria
- DBP < 100 mmHg
- Serum potassium < 3.5 mmol/L
Main exclusion criteria
- Taking BP med other than thiazide diuretic
- Renal insufficiency
- History of myocardial infarction
- Heart failure
- Fasting blood glucose > 140 mg/dl
- Using insulin
Baseline characteristics
- Average age 51 years
- Average magnesium level - 1.63 mmol/L
Randomized treatment groups
- Group 1 (86 patients) - HCTZ 50 mg + KCL 20 mmol/day for 4 weeks
- Group 2 (82 patients) - HCTZ 50 mg + KCL 40 mmol/day for 4 weeks
- Group 3 (79 patients) - HCTZ 50 mg + Triamterene 75 mg for 4 weeks
- Study treatment was open-label
Primary outcome: Change in potassium
Results
| Duration: 4 weeks | ||||
| Outcome | HCTZ + KCL 20 | HCTZ + KCL 40 | HCTZ + Triamterene | Comparisons |
|---|---|---|---|---|
| Average baseline potassium level (mmol/L) | 3.31 | 3.27 | 3.25 | N/A |
| Primary outcome (increase in potassium, mmol/L) | 0.31 | 0.48 | 0.48 | 2 or 3 vs 1 p<0.05 |
| Change in magnesium levels (mmol/L) | -0.01 | -0.01 | +0.09 | p<0.0001 for 3 |
|
||||
Findings: In conclusion, the combination of hydrochlorothiazide with triamterene is effective in correcting the hypokalemia seen in some
patients treated with hydrochlorothiazide alone and has the additional advantage of obviating the magnesium wasting that may result from diuretic therapy.
- Summary
- In the studies above, the addition of amiloride to HCTZ 50 mg/day reduced potassium loss by about 0.22 mmol/L over 8 weeks, and triamterene was equivalent to KCL 40 mmol/day over four weeks for restoring potassium in hypokalemic patients receiving HCTZ 50 mg/day.
SIDE EFFECTS
- Increased urination
- ENaC inhibitors have a weak diuretic effect, which does not typically cause a pronounced increase in urination. The triamterene package insert states that triamterene may promote increased diuresis when patients prove resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism.
- Elevated potassium (hyperkalemia)
- ENaC inhibitors reduce renal potassium excretion, which may increase the risk of hyperkalemia. They are typically combined with other diuretics like HCTZ to help prevent potassium loss.
- Factors that may increase the risk of hyperkalemia include the following:
- Kidney disease (GFR < 60 ml/min) or serum creatinine > 1.6 mg/dl
- Diabetes
- Dehydration (from diuretics, diarrhea, etc.)
- Advanced age
- Medications - see drug interactions below
- High Dietary potassium - salt substitutes, nuts, dried fruit, etc.
- Potassium supplements [2,4]
- Sodium loss
- ENaC inhibitors may enhance sodium loss from thiazide and loop diuretics. The magnitude of this effect appears to be small and is typically insignificant. [6,12,14]
- Kidney stones (triamterene)
- Triamterene and its metabolites have been found in kidney stones, raising concerns that it may promote stone formation. Studies evaluating kidney stone risk with triamterene have not found a link, but confounding is possible since triamterene is typically prescribed with thiazide diuretics, which lower the risk of kidney stones. Based on available information, it's unknown if triamterene increases the risk of kidney stones. Patients at high risk for stones may want to use amiloride instead of triamterene. [11,12]
- Uric acid effects
- Triamterene may raise uric acid levels, and it should be used with caution in patients with gout. Amiloride does not appear to have a significant effect on uric acid levels. [8,9,10]
- Magnesium retention
- ENaC inhibitors promote renal magnesium retention, while loop and thiazide diuretics promote its loss
- In one study (see triamterene study), the addition of triamterene 75 mg/day to HCTZ increased magnesium levels by 0.22 mg/dl over 4 weeks.
- Because of their magnesium-sparing effect, ENaC inhibitors are sometimes given with loop or thiazide diuretics to counteract the magnesium loss caused by these drugs [3,10,14]
CONTRAINDICATIONS
- Amiloride
- Elevated potassium (> 5.5 mEq/L)
- Concomitant spironolactone or triamterene
- Significant kidney disease (serum creatinine > 1.5 mg/dl)
- Known hypersensitivity
- Triamterene
- Elevated potassium - (> 5.5 mEq/L)
- Concomitant spironolactone or amiloride
- Significant kidney disease (serum creatinine > 1.5 mg/dl)
- Severe liver disease
- Known hypersensitivity
PRECAUTIONS
- Kidney disease
- ENaC inhibitors can raise potassium levels and should be used with caution in patients with significant kidney disease
- Liver disease
- Amiloride
- Amiloride does not undergo hepatic metabolism, and liver disease is not expected to affect its clearance
- Triamterene
- Triamterene is contraindicated in patients with severe liver disease
- Kidney stone disease (triamterene)
- Triamterene and its metabolites have been found in kidney stones. See kidney stones for more.
- Folic acid deficiency (triamterene)
- Triamterene is a weak folic acid antagonist and may worsen megaloblastic anemia caused by folic acid deficiency. [12]
DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Amiloride and triamterene
- Lithium - ENaC inhibitors may reduce lithium clearance, and coadministration is not recommended. If concomitant use cannot be avoided, monitor lithium levels closely.
- Medications that raise potassium - ENaC inhibitors may raise potassium levels and increase the risk of hyperkalemia when used with other potassium-raising medications. While it may be appropriate to prescribe ENaC inhibitors with these medications, patients and providers should be aware of the potential risks. See RAAS inhibitor-induced hyperkalemia for recommendations on addressing hyperkalemia induced by these medications.
- Medications that raise potassium levels include:
- Aldosterone antagonists (spironolactone and eplerenone)
- ARBs (valsartan, olmesartan, etc.)
- ACE inhibitors
- Aliskiren (Tekturna®)
- Cyclosporine (Neoral®)
- Finerenone (Kerendia®)
- Heparin - heparin raises potassium secondarily by inhibiting aldosterone synthesis. LMWH does not appear to have this effect. [13]
- Penicillin G potassium injection (1 million units contains 1.68mEq of potassium)
- Potassium supplements (K-Dur®, etc)
- Tacrolimus (Prograf®)
- Trimethoprim (part of Bactrim® and Septra®)
- Voclosporin (Lupkynis®)
- NSAIDS (Advil®, ibuprofen, naprosyn, etc.) - NSAIDS can block the effect of ENaC inhibitors. Monitor for decreased effectiveness when combining.
- Salt substitutes (No-Salt®, etc.) - Salt substitutes contain a high amount of potassium (16.4 mEq per 1/4 teaspoon) and may increase the risk of hyperkalemia when used with ENaC inhibitors
- Triamterene
- Nondepolarizing skeletal muscle relaxants - triamterene may potentiate the effect of muscle relaxants used during anesthesia
- Metabolism and clearance
DOSING
BIBLIOGRAPHY
- 1 - PMID 20091662 - Blood pressure lowering efficacy of potassium-sparing diuretics (that block the epithelial sodium channel) for primary hypertension, Cochrane review (2010)
- 2 - Eplerenone PI
- 3 - PMID 8373706 - Do diuretics cause magnesium deficiency? Br J Clin Pharmacol (1993)
- 4 - PMID 16342656 - Aldosterone receptor antagonists in the medical management of chronic heart failure, Mayo Clin Proc (2005)
- 5 - Aldactone PI
- 6 - PMID 8290411 - A study of plasma sodium levels in elderly people taking amiloride or triamterene in combination with hydrochlorothiazide, BMJ (1993)
- 7 - PMID 6409208 - Comparison of thiazides and amiloride in treatment of moderate hypertension, BMJ (1983)
- 8 - PMID 18855259 - Blood pressure-lowering efficacy of amiloride versus enalapril as add-on drugs in patients with uncontrolled blood pressure receiving hydrochlorothiazide Clin Exp Hypertens (2008)
- 9 - PMID 3904654 - Effectiveness of potassium chloride or triamterene in thiazide hypokalemia, JAMA Internal Medicine (1985)
- 10 - PMID 2596940 - Potassium restoration in hypertensive patients made hypokalemic by hydrochlorothiazide, JAMA Internal Medicine (1989)
- 11 - PMID 4031113 - Excretion of triamterene and its metabolite in triamterene stone patients, J Clin Pharmacol (1985)
- 12 - Triamterene PI
- 13 - PMID 22560830 - Use and safety of unfractionated heparin for anticoagulation during maintenance hemodialysis, Am J Kidney Dis (2012)
- 14 - Amiloride PI