HSC Section 8_April 2017

Crowson et al

Table 7. Mechanisms of Action for Selected Diuretic Agents. a

Agent

Mechanism of Action

Acetazolamide

Reversible inhibition of the enzyme carbonic anhydrase resulting in reduction of hydrogen ion secretion at renal tubule and an increased renal excretion of sodium, potassium, bicarbonate, and water. Decreases production of aqueous humor and inhibits carbonic anhydrase in the central nervous system to retard abnormal and excessive discharge from its neurons. Sulfonamide-derived diuretic that inhibits sodium and chloride reabsorption in the cortical-diluting segment of the ascending loop of Henle. Inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions. Nimodipine is a dihydropyridine calcium channel blocker that has the general properties of nifedipine, which includes vasodilatation, with reduced peripheral resistance, blood pressure, and afterload; increased coronary blood flow; and a reflex increase in heart rate. Additional evidence suggests a diuretic action of calcium channel blockers through interference with renal and extrarenal systems involved in the regulation of physiologic fluid and electrolyte balance. 35 Blocks epithelial sodium channels in the late distal convoluted tubule and collecting duct, which inhibits sodium reabsorption from the lumen. This effectively reduces intracellular sodium, decreasing the function of Na 1 /K 1 ATPase, leading to potassium retention and decreased calcium, magnesium, and hydrogen excretion. Osmotic diuretic with properties similar to those of mannitol.

Chlorthalidone

Hydrochlorothiazide

Isosorbide Nimodipine

Triamterene

a Source: Lexicomp, 34 unless otherwise stated.

The natural history of MD is highly variable, which can make it difficult to discern differences between treatment and therapeutic effects. The natural history of an individual patient would be difficult to take into account when analyz- ing data from interventions, but this factor may explain the variation seen in the outcomes reported in the studies we reviewed. Moreover, we cannot ascertain the percentage of patients who experience spontaneous symptom improvement without the use of diuretic therapy. The natural history of MD lends itself to spontaneous recovery from symptoms without any intervention. Only 2 of our sources were RCTs in design with a placebo as control. 8,11 Patients in these pla- cebo groups did experience symptom improvement, although this was not significant in either RCT. Last, we suspect that publication bias may also explain the relative frequency of positive results reported by the compiled stud- ies in this review. It is probable that studies with negative results either have not been submitted or were not accepted for publication. Conclusion Multiple low-evidence-level studies report that oral diuretic therapy may be beneficial in the medical management of MD. If feasible, placebo-controlled studies will be required to fur- ther substantiate these claims. Improvement in vertigo episode frequency was often reported, with less convincing evidence for improvement in hearing outcomes. These conclusions are mitigated by multiple limitations, including the natural history of MD, study design, and the possibility of publication bias. Further investigation of the pathophysiology of MD will be essential for providing tailored direction for established and

new therapies. Attention will need to be paid to the natural his- tory of MD to determine true treatment effects. Acknowledgments We thank the Canadian Medical Association reference librarians for their assistance in constructing the MEDLINE literature review algorithm. Author Contributions Matthew G. Crowson , project design, data collection, data analy- sis, manuscript preparation, drafting, final approval, accountability for all aspects of the work; Aniruddha Patki , Project design, Data analysis, drafting, final approval, accountability for all aspects of the work; Debara L. Tucci , Project design, drafting, final approval, accountability for all aspects of the work Disclosures Competing interests: Debara L. Tucci, consult for Otonomy (chair, Data and Safety Monitoring Board). Sponsorships: None. Funding source: None. 1. Harris JP, Alexander TH. Current-day prevalence of Meniere’s syndrome. Audiol Neurootol . 2010;15:318-322. 2. American Academy of Otolaryngology—Head and Neck Foundation. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere’s dis- ease. Otolaryngol Head Neck Surg . 1995;113:181-185. 3. Gibson WP. Hypothetical mechanism for vertigo in Meniere’s disease. Otolaryngol Clin North Am . 2010;43:1019-1027. References

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