- ACRONYMS AND DEFINITIONS
- DBP - Diastolic blood pressure
- ENaC - Epithelial sodium channel
- GFR - Glomerular filtration rate
- HCTZ - Hydrochlorothiazide
- 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
- MECHANISM OF ACTION
- Epithelial sodium channels (ENaC) are channels in the renal collecting duct that allow sodium to move from the tubular lumen into the cells that line the lumen. ENaC inhibitors block these channels and inhibit the reabsorption of sodium. Blocking sodium reabsorption also prevents the exchange of potassium for sodium, and potassium excretion is reduced. This is why ENaC inhibitors are often referred to as "potassium-sparing diuretics."
- ENaC inhibitors do not exert a large diuretic effect, and they have a minimal to null effect on blood pressure
- Nephron and diuretics illustration - illustration of the nephron and how diuretics work
- HYPERTENSION
- Overview
- ENaC inhibitors do not have a significant effect on blood pressure
- They are primarily used with thiazide diuretics to help prevent potassium loss
- A Cochrane meta-analysis that looked at the effects of ENaC inhibitors on blood pressure is detailed below. A randomized controlled trial that compared HCTZ to HCTZ+Amiloride and had blood pressure as a coprimary outcome is detailed here - amiloride study.
- STUDY
- A Cochrane meta-analysis evaluated the use of ENaC inhibitors in the treatment of hypertension
- The analysis found no studies where ENaC inhibitors were used by themselves to treat hypertension
- Six studies were found (4 with amiloride, 2 with triamterene) where ENaC inhibitors were added to HCTZ
- The analysis found the following:
- ENaC inhibitors had no significant effect on blood pressure when added to HCTZ
- The highest doses in the studies were 5 mg for amiloride, and 50 mg for triamterene [1]
- Summary
- ENaC inhibitors have a weak diuretic effect, and therefore, they do not have a significant effect on blood pressure. They are primarily used to attenuate potassium loss from thiazide and loop diuretics.
- POTASSIUM SPARING
- Overview
- ENaC inhibitors are primarily used to prevent potassium loss caused by loop and thiazide diuretics
- Two small trials that looked at the effects
- A small study published in the Canadian Medical Assoc Journal 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 | 3.69 | 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
- A study published in the Archives of Internal Medicine 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 for 4 weeks
- Group 2 (82 patients) - HCTZ 50 mg + KCL 40 mmol 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
- ENaC inhibitors help to prevent potassium loss from thiazide and loop diuretics. The overall effect is difficult to predict and will depend on individual patient factors (e.g. diuretic dose, kidney function, diet). In general, when ENaC inhibitors are added to thiazide diuretics, serum potassium increases in the range of 0.20 - 0.50 mEq/L can be expected.
- SIDE EFFECTS
- Increased urination
- ENaC inhibitors have a weak diuretic effect, and they do 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 promote potassium retention by the kidneys, and therefore, they may cause hyperkalemia. When they are prescribed with thiazide or loop diuretics, the risk is lower because these drugs promote potassium excretion.
- 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]
- Summary
- ENaC inhibitors are typically used with thiazide and loop diuretics to counteract the potassium loss induced by these drugs
- Patients at high-risk for hyperkalemia who are taking ENaC inhibitors should have their potassium levels monitored appropriately
- Sodium loss
- ENaC inhibitors may enhance the sodium loss that occurs with thiazide and loop diuretics. The magnitude of this additional effect appears to be small and typically insignificant. [6,12,14]
- Kidney stones (triamterene)
- Deposits of triamterene and its metabolites have been found in kidney stones. This has raised concerns that triamterene may contribute to kidney stone formation. Older studies that evaluated the risk of kidney stones with triamterene did not find an association, but this issue may be confounded by the fact that triamterene is typically prescribed with thiazide diuretics which lower the risk of kidney stones.
- Based on the available information, it is difficult to know whether triamterene increases the risk of kidney stones. Patients at high-risk for kidney stones may want to use amiloride instead of triamterene. [11,12]
- Uric acid effects
- Amiloride does not appear to have a significant effect on uric acid levels [8,9]
- The triamterene package insert states that it may elevate uric acid levels. Patients with gout should use caution. [10]
- Magnesium retention
- ENaC inhibitors promote magnesium retention by the kidneys while loop and thiazide diuretics promote magnesium loss
- In a study detailed above (see triamterene study), triamterene 75 mg a day increased magnesium levels by an average of 0.22 mg/dl when added to HCTZ over a 4-week period
- Because of their effect on magnesium, ENaC inhibitors are sometimes prescribed with loop and 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 kidney disease
- See elevated potassium
- If used in patients with suspected kidney disease, frequent lab monitoring of potassium is recommended
- The manufacturer's package insert for both drugs lists significant kidney disease as a contraindication to use
- Liver disease
- Amiloride
- Amiloride is not metabolized by the liver
- Liver disease would not be 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 above for details.
- Folic acid deficiency (triamterene)
- Triamterene is a weak folic acid antagonist. It may contribute to the appearance of megaloblastosis in cases where folic acid stores have been depleted. [12]
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Amiloride and triamterene
- Lithium - ENaC inhibitors may reduce the clearance of lithium. ENaC inhibitors should not be taken with lithium if possible. Lithium levels should be monitored closely in patients receiving concurrent ENaC inhibitors.
- Medications that can raise potassium levels - ENaC inhibitors have the potential to raise potassium levels and cause hyperkalemia. When combined with other potassium-raising medications, the risk is increased. 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.
- Examples of medications that may 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 the same 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 therapeutic effect of ENaC inhibitors. Patients should monitor for decreased effectiveness of ENaC inhibitors when taking NSAIDS for extended periods.
- Salt substitutes (No-Salt®, etc.) - Salt substitutes typically contain a high amount of potassium (16.4 mEq per 1/4 teaspoon). Since ENaC inhibitors can raise potassium levels, caution should be used when consuming salt substitutes.
- Triamterene
- Nondepolarizing skeletal muscle relaxants - triamterene may potentiate the effect of muscle relaxants used during anesthesia
- Metabolism and clearance
- LONG-TERM SAFETY
- ENaC inhibitors have been used for more than 30 years
- They have been proven safe in long-term use
- 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