Endocrine hypertension
Philip E. Harris, Pierre-Marc G. Bouloux in Endocrinology in Clinical Practice, 2014
In patients with bilateral disease, or patients with APA and unsuitable for a surgical procedure, medical therapy with aldosterone antagonists is the cornerstone of therapy. Spironolactone is an effective MR antagonist, although is not specific and also acts as an antagonist for the androgen and progesterone receptors. These properties account for the side effects that can limit its use, particularly at high doses (gynecomastia, sexual dysfunction in males, and menstrual irregularity in women). Eplerenone is more specific for the MR but is less potent, requiring higher doses. Both should be started at low dose (25 mg once daily for spironolactone, twice daily eplerenone) and titrated slowly with monitoring of plasma potassium. Once aldosterone action is appropriately suppressed, plasma renin should rise, and this rise can be a useful way to monitor the titration regime. If adequate control of hypertension is not achieved with mineralocorticoid antagonists alone, amiloride is an appropriate and relatively effective antihypertensive. By blocking the epithelial sodium in the DCT, it is a rational second-line agent. Calcium channel blockers and diuretics are also reasonable to use in combination with MR antagonists; however, unless plasma renin (and angiotensin II) is released from the inhibitory effects of excessive action of aldosterone, angiotensin-converting enzyme (ACE) inhibitors, and ARB antagonists are unlikely to impact blood pressure control.
Resistant Hypertension: Medical Treatment
Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei in Manual of Hypertension of the European Society of Hypertension, 2019
The PATHWAY-2 study was followed by an optional 6–12 week open-label phase during which the potassium-sparing diuretic amiloride 10–20 mg once daily was given to the patients after the crossover study (45). Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20.4 mmHg (95% CI 18.3–22.5), a comparable BP decrease to that achieved with spironolactone 25 mg once daily (18.3 mmHg (16.2–20.5) (45). Finally, the ReHOT (Resistant Hypertension Optimal Treatment) randomized study (46), comparing 12-week treatment with spironolactone (12.5–50 mg QD) or clonidine (0.1–0.3 mg BID) in Brazilian patients, showed similar rates of combined office and 24-h ambulatory BP control (20.5% vs. 20.8%), similar office BP (33.3% vs. 29.3%) and 24-h ambulatory BP monitoring (44% vs. 46.2%) control for spironolactone and clonidine, respectively (46). However, spironolactone was more efficient on some ambulatory BP endpoints. The rate of side effects reported for both spironolactone and clonidine was low. The patients randomized to clonidine had more frequent somnolence.
Sympathetic Neurotransmission
Kenneth J. Broadley in Autonomic Pharmacology, 2017
Amiloride (MidamorR) is a K+-sparing diuretic which is also an inhibitor of uptake1, but via a completely different mechanism. Amiloride is an inhibitor of Na+ transport in the late distal tubule of the kidney. It inhibits primarily the electrogenic entry of Na+ into the tubular epithelium but additionally inhibits Na+-H+ exchange and Na+,K+-ATPase at higher concentrations. At the noradrenaline uptake carrier, amiloride and ethylisopropyl-amiloride (EIPA) compete with Na+ for the Na+ binding site (Figure 2.22). This prevents the Na+-dependent uptake of noradrenaline. EIPA has high lipid solubility and readily diffuses into the neurone where the low Na+ concentration permits more ready competition for Na+ binding sites. This results in an uncompetitive inhibition characterized by a decrease in both Vmax and Km for the uptake process (Trendelenburg 1991).
The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease
Published in Expert Opinion on Therapeutic Targets, 2018
Patrick J. Moore, Robert Tarran
Amiloride is a first-generation ENaC antagonist that was developed in the 1960s as a potassium-sparing compound by Cragoe and colleagues at Merck Pharmaceuticals [107]. ENaC is highly expressed in the distal convoluted tubule of the kidney and while this portion of the nephron is only responsible for handling 10% of reabsorbed Na+, it plays an important role in fine-tuning Na+ and fluid levels in the body [108,109]. Amiloride was initially used to prevent Na+ absorption in the kidney and to induce natriuresis/diuresis[110]. However, inhibition of ENaC leads to potassium-sparing excretion of Na+ and hyperkalemia [111,112]. Thus, whilst amiloride is an effective diuretic, it has now been superseded by so called ‘loop diuretics’ such as thiazide that target the Na+/K+/2 Cl− cotransporter (NKCC2) in the loop of Henle to block both Na+ and K+ reabsorption which does not cause hyperkalemia [113].
The effect of amiloride in decreasing albuminuria in patients with diabetic kidney diseases: a prospective, crossover, open-label study
Published in Renal Failure, 2021
Ruizhao Li, Zhiyong Xie, Li Zhang, Ying Huang, Jianchao Ma, Wei Dong, Zhilian Li, Yuanhan Chen, Huaban Liang, Yanhua Wu, Xingchen Zhao, Wenjian Wang, Zhiming Ye, Shuangxin Liu, Wei Shi, Xinling Liang
As Na channel blocker, amiloride would inhibit the exchange of Na+–K+ and Na+–H+ in distal tubules and collecting ducts of the kidney, thus increasing the excretion of Na+ and water and reducing the excretion of K+ and H+. Therefore, hyperkalemia and hyponatremia were the most common side effect of amiloride. In this study, significant hyperkalemia occurred in two patients and no patients experienced hyponatremia. And the serum potassium in both patients could return to normal after hypokalemia treatment. Additionally, there was no significant influence in fasting glucose, cholesterol, triglyceride, unic acid with amiloride/HCTZ when compared with HCTZ. Furthermore, amiloride would substantially reduce the SBP and volume status by blocking both ENaC and urokinase [31,32]. However, we had not found significant reductions in weight or SBP with amiloride/HCTZ compared with HCTZ. Our inability to detect significant effects on blood pressure and weight may be associated with the small sample size in this study. Unruh [33] et al. had also demonstrated the safety of amiloride in patients with type 2 diabetes, normal renal function, and proteinuria, which provided important research evidence for amiloride’s application in decreasing albuminuria in DKD.
Liddle syndrome misdiagnosed as primary aldosteronism is caused by inaccurate aldosterone-rennin detection while a novel SCNN1G mutation is discovered
Published in Blood Pressure, 2022
Yaling Yang, Chenwei Wu, Duoduo Qu, Xinyue Xu, Lili Chen, Quanya Sun, Xiaolong Zhao
This 21-year-old female presented with repeated hypokalaemia and latent hypertension, poor response to spironolactone, gene mutation located in SCNN1G, c.1729 C > T, leading to the diagnosis of Liddle syndrome instead of primary aldosteronism. Treatment was switched to amiloride accordingly. Since pure amiloride tablets are not available in the domestic market [5]. compound amiloride hydrochloride one tablet daily was prescribed which contains amiloride hydrochloride 2.5 mg and hydrochlorothiazide 25 mg. Her BP decrease was noticed in 3 days, regularly measured 6 times daily, and her plasma potassium climbed to normal with 3.8 mmol/L. After 3 weeks’ treatment, the plasma potassium was 4.3 mmol/L without potassium supplement; BP decreased gradually and stabilised at 110–120/70–80mmHg.
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