ENaC INHIBITORS
- NOTE: ENaC inhibitors are sometimes
referred to as "potassium-sparing diuretics"
- ENaC inhibitors
- Amiloride (Midamor®)
- Triamterene (Dyrenium®)
- Combination products with HCTZ
- Dyazide® (triamterene + HCTZ)
- Maxzide® (triamterene + HCTZ)
- Amiloride + HCTZ
- General
- Diuretics cause the kidneys to produce more urine and therefore more
fluid is removed from the body
- Fluid loss causes blood pressure to decrease and it reduces the workload
on the heart
- Diuretics are used to treat a number of conditions where excess body
fluid is a problem - heart failure, kidney failure, liver failure, etc.
- Specific
- "ENaC" is short for "Epithelial sodium channel"
- The nephron is the fundamental working unit of the kidney
- The "collecting duct" is part of the nephron
- In the collecting duct, there are channels called "Epithelial sodium
channels"
- Epithelial sodium channels cause sodium to be reabsorbed (saved) in
exchange for potassium (lost in urine)
- ENaC inhibitors block these channels
- High blood pressure (hypertension)
- ENaC inhibitors do not have a significant effect on blood pressure
- They are primarily used with thiazide diuretics to help prevent potassium loss
- Cochrane meta-analysis
- 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 [7]
- StraightHealthcare analysis:
- ENaC inhibitors have a weak diuretic effect, and therefore do not have a
significant effect on blood pressure
- They are used primarily to counteract potassium loss from thiazide and
loop diuretics
- Prevention of potassium loss from other diuretics
- ENaC inhibitors are primarily used to prevent potassium loss caused by loop and thiazide diuretics
- A handful of older, small trials have evaluated the effects of ENaC inhibitors on potassium levels in patients taking thiazide diuretics
Amiloride
- Amiloride + HCTZ vs HCTZ, Can Med Assoc J, (1985) [PubMed abstract]
- 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
- Patients were randomized to 1 of 2 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 OUTCOME: 1. Change in blood pressure 2. Change in potassium
- After 8 weeks of treatment, the following was seen:
- Average baseline blood pressure: Group 1 - 156/99, Group 2 - 157/99
- Average baseline potassium level: Group 1 - 4.23 mmol/L, Group 2 - 4.16 mmol/L
- Primary outcome (change in potassium): Group 1 - 3.91, Group 2 - 3.69 (diff 0.22 mmol/L, p<0.05)
- Primary outcome (change in blood pressure): Group 1 - 138/88, Group 2 - 138/87 (p>0.05)
- Percent of patients with potassium < 3.5 mmol/L: Group 1 - 14%, Group 2 - 29% (p=0.0026)
- The study originally enrolled 338 patients, but a number of patients were excluded or dropped out and were not counted in the final analysis so the study was not intention-to-treat [69]
Triamterene
- Triamterene vs Potassium Supplements in Patients Receiving HCTZ, Arch Intern Med, (1989) [PubMed abstract]
- 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
- Main inclusion criteria: DBP < 100 mmHg; serum potassium < 3.5 mmol/L after receiving HCTZ 50 mg daily for a maximum of 4 weeks
- 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
- Patients were randomized to 1 of 3 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
- After 4 weeks of treatment, the following was seen:
- Average baseline potassium level (mmol/L): Group 1 - 3.31, Group 2 - 3.27, Group 3 - 3.25
- Primary outcome (increase in potassium, mmol/L): Group 1 - 0.31, Group 2 - 0.48, Group 3 - 0.48 (2 vs 1, p<0.05; 3 vs 1, p<0.05)
- There was no significant difference between the groups in blood pressure response
- The incidence of adverse events was similar between the groups [108]
- StraightHealthcare analysis:
- 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 (diuretic dose, kidney function, diet, other medications, etc.)
- In general, when ENaC inhibitors are combined with thiazide diuretics, potassium increases in the range of 0.20 - 0.50 mEq/L can be expected
- Increased urination
- Because diuretics promote fluid loss by the kidneys, they all
can cause increased urination
- This effect is greatest with loop diuretics and less with
thiazides, potassium-sparing diuretics, and aldosterone antagonists
- Elevated potassium (hyperkalemia)
- ENaC inhibitors promote potassium retention by the kidneys,
therefore they may lead to elevated potassium levels
- When they are prescribed with thiazide or loop diuretics, this
is not typically a problem since thiazide and loop diuretics promote
potassium loss and the effects offset each other
- 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 [11,59,60]
- StraightHealthcare analysis:
- ENaC inhibitors are typically used with thiazide or loop diuretics to
counteract potassium loss induced by these diuretics
- Patients at high-risk for hyperkalemia who are taking ENaC inhibitors
should have their potassium levels monitored appropriately
- Low sodium (hyponatremia)
- ENaC inhibitors may cause a slight increase in the sodium loss
induced by loop or thiazide diuretics
- The additional effect of ENaC inhibitors appears to be small and
typically insignificant [70, 107]
- 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
- Studies evaluating the association of triamterene and kidney stones
were performed in the 1980s
- These studies did not find an increased risk of kidney stones among
triamterene users
- Confounding the issue is the fact that triamterene is typically
prescribed with thiazide diuretics which are known to 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 avoid
triamterene [109]
- Uric acid/gout risk
- Amiloride does not appear to have a significant effect on uric acid
levels [71, 106]
- The triamterene PI states that it may elevate uric acid levels [110]
- Magnesium retention
- ENaC inhibitors appear to promote magnesium retention by the kidneys
(loop and thiazide diuretics promote magnesium loss)
- The magnitude of this effect is not well-defined [22,70,108]
- 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
- Kidney disease
- ENaC inhibitors can raise potassium levels and should be used with
caution in patients with kidney disease
- See elevated potassium above
- If used in patients with suspected kidney disease, frequent lab
monitoring of potassium is recommended
- 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 under
side effects 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 [110]
- 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.
- HIGH ALERT 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 taking ENaC inhibitors..
- Medications that can raise potassium levels -
see below
- Salt substitutes (No-Salt®, etc.) - Salt
substitutes typically contain a high amount of potassium. Since ENaC
inhibitors can raise potassium levels, caution should be used when consuming
salt substitutes.
- MEDICATIONS THAT RAISE POTASSIUM LEVELS
- ENaC inhibitors have the potential to raise potassium levels
- When taken with other medications that raise potassium, the risk may be
compounded
- While it is often appropriate to prescribe ENaC inhibitors with these
medications, patients and providers should be aware of the potential risks
(see
elevated potassium above)
- Common medications that may raise
potassium levels include:
- METABOLISM AND ELIMINATION
- NOTE: Drugs
can be metabolized by more than one enzyme. Drugs may be metabolized by an
enzyme and inhibit/induce the enzyme at the same time. Drug transporters
(ex. p-glycoprotein) can play a role in drug metabolism. Not all drug
interactions are clinically significant. Consult your physician or
pharmacist if you are taking medications together and are concerned about a
possible interaction.
- Amiloride (Midamor®)
- No significant liver metabolism
- OCT2 - substrate
- Triamterene (Dyrenium®)
- OTHER
- 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.
- Preanesthetic and anesthetic agents, skeletal muscle relaxants (nondepolarizing) - triamterene may potentiate the
effect of muscle relaxants used during anesthesia
- ENaC inhibitors have been used for more than 30 years
- They have been shown to be safe in long-term use
- DIFFERENCES BETWEEN DRUGS IN CLASS
- Triamterene may contribute to kidney stone disease where amiloride does
not (see kidney stones above)
- ENaC inhibitors vary in their metabolism and potential
drug interactions
- What is PMID?
- PI = Manufacturer's Package Insert
- # PMID
- 1 - 19940300
- 2 - 16145005
- 3 - 12759325
- 4 - 8446138
- 5 - 20821851
- 6 - 19821314
- 7 - 20091662
- 8 - 20687095
- 9 - 20448074
- 10 - 17309946
- 11 - Eplerenone PI
- 12 - 15073471
- 13 - 12842242
- 14 - 19821398
- 15 - 21073363
- 16 - 12668699
- 17 - 10471456
- 18 - 12106936
- 19 - 16160202
- 20 - 21029871
- 21 - 20010338
- 22 - 8373706
- 23 - 2046107
- 24 - 18550938
- 25 - European Association of Urology. Guidelines on Urolithiasis. 2011
- 26 - 20818905
- 27 - 11015164
- 28 - 13679324
- 29 - 2271853
- 30- 2344503
- 31 - 10653441
- 32 - 9554680
- 33 - 17904464
- 34 - 6137813
- 35 - 7388366
- 36 - Demadex PI
- 37 - 8432162
- 38 - 21095025
- 39 - 21285714
- 40 - 16291814
- 41 - 18946066
- 42 - 11733620
- 43 - 18413556
- 44 - 16355285
- 45 - 15656876
- 46 - 19368583
- 47 - 12639869
- 48 - 10672134
- 49 - 9665357
- 50 - 9702848
- 51 - 1486908
- 52 - 5920655
- 53 - 7752176
- 54 - 4102452
- 55 - 1486906
- 56 - Bumetanide PI
- 57 - Furosemide PI
- 58 - 15295047
- 59 - 16342656
- 60 - Aldactone PI
- 61 - 19843067
- 62 - 2050832
- 63 - 3661395
- 64 - 6338681
- 65 - 3189169
- 66 - 19865106
- 67 - 10199763
- 68 - 7104176
- 69 - 3884122
- 70 - 8290411
- 71 - 6409208
- 72 - 6389077
- 73 - 6619267
- 74 - 7282751
- 75 - 3521452
- 76 - 1747638
- 77 - 7431573
- 78 - 19074530
- 79 - 16035375
- 80 - 15601807
- 81 - 12011477
- 82 - 20216123
- 83 - 21193625
- 84 - 14573734
- 85 - 12020173
- 86 - 14638621
- 87 - 20010338
- 88 - 21272751
- 89 - removed
- 90 - National Kidney Foundation Guidelines on Hypertension and
Antihypertensive Agents in Chronic Kidney Disease
- 91 - 20633946
- 92 - 19475696
- 93 - 19940300
- 94 - 16801488
- 95 - 19160242
- 96 - 21975748
- 97 - 12479763
- 98 - 2318517
- 99 - 22017784
- 100 - 17101936
- 101 - 19171809
- 102 - 21382989
- 103 - 19858405
- 104 - 18574054
- 105 - 16740618
- 106 - 18855259
- 107 - 3904654
- 108 - 2596940
- 109 - 4031113
- 110 - Triamterene PI
- 111 - Amiloride PI
- 112 - 22560830
