Spironolactone

Brand Names: Aldactone

Clinical Names: Spironolactone

Summary

generic name: Spironolactone

trade names: Aldactone®; Aldactazide®

related drug: Spironolactone/Hydrochlorothiazide

type of drug: Aldosterone antagonist; aldosterone-inhibiting (potassium-sparing) diuretic.

used to treat: Congestive heart failure, edema associated with kidney and liver diseases; hypertension.

overview of interactions:
• nutrient affected by drug: Potassium

• nutrient affected by drug: Sodium

• diet affecting drug performance and toxicity: Food

• herb affecting drug performance: Glycyrrhiza glabra (Licorice)



Interactions

nutrient affected by drug: Potassium

• mechanism: Spironolactone intentionally reduces urinary excretion of potassium. As a result of its role as a potassium-sparing diuretic, spironolactone can produce a state of inappropriately elevated potassium levels. On the other hand, concern has been raised that this potassium-sparing diuretic may cause hypokalemia by blocking distal tubular sodium-potassium exchange.
(Herman E, Rado J. Arch Neurol 1966 Jul;15(1):74-77)

• nutritional concerns: Individuals using potassium-sparing such as spironolactone should limit their dietary intake of potassium to avoid excessive levels. Potassium supplements and potassium-containing salt substitutes, such as Lite Salt®, Morton's Salt Substitute and No Salt®, are designed for individuals suffering from potassium depletion due to other types of diuretics and should be avoided when taking potassium-sparing diuretics such as spironolactone. For some individuals, foods with high potassium content may need to be limited. Several pieces of fruit per day may provide adequate potassium to elevate serum levels. Individuals taking spironolactone should work with their prescribing physician to monitor potassium levels and modify their diet accordingly to avoid elevated potassium levels and associated problems.
(Herman E, Rado J. Arch Neurol 1966 Jul;15(1):74-77; Herman E, Rado J. Orv Hetil 1967 Jan 8;108(2):74-76; Stepan VM, et al. Eur J Gastroenterol Hepatol 1997 Oct;9(10):1001-1004.)

nutrient affected by drug: Sodium

• mechanism: The basic function of diuretics is to reduce the amount of water in the body. Therefore, by their very nature and intent diurectics, such as spironolactone, increase the amount of sodium excreted in the urine.

• nutritional concerns: Since the reduction of sodium levels in the body is purposeful, supplementation to reduce lost sodium would be counterproductive. However, if dietary changes undertaken to restrict sodium intake are successful the dosage of diuretic medications will need to be reevaluated and possibly modified. Thus, individuals with hypertension who are using a diuretic such as spironolactone while also strictly limiting their salt intake should work closely with their prescribing physician to monitor and revise their prescription based on changes in their blood pressure.
(Roe DA. Diet and Drug Interactions. New York, Van Nostrand Reinhold, 1989: 146.)

diet affecting drug performance and toxicity: Food

• mechanism: Eating food at the same time as taking spironolactone enhances the bioavailability of spironolactone, by increasing its absorption and decreasing the first-pass effect of spironolactone.
(Overdiek HW, Merkus FW. Clin Pharmacol Ther 1986 Nov;40(5):531-536; Overdiek HW, Merkus FW. Rev Drug Metab Drug Interact 1987;5(4):273-302.)

• nutritional concerns: For best therapeutic effect and safest use, spironolactone should be taken consistently with or apart from food, preferably at the same time each day. Individuals concerned about the timing of their meals should ask their prescribing doctor or pharmacist as to whether food and spironolactone should or should not be taken together.
(Threlkeld DS, ed. Jul 1993.)

herb affecting drug performance: Glycyrrhiza glabra (Licorice)

• mechanism: Licorice can offset the pharmacological effect of spironolactone. 11 beta-hydroxysteroid dehydrogenase (11 beta-DH) is the enzyme that oxidizes cortisol to inactive cortisone and prevents cortisol from acting like a mineralocorticoid at the aldosterone receptor site in the kidney. Some kinds of licorice contain glycyrrhetic acid which inhibits the action of 11 beta-DH (e.g. in the kidney) and causes cortisol to behave like aldosterone. Thus, licorice consumption can induce a mineralocorticoid excess state, most likely due to an acquired inhibition of this key enzyme, decreased transformation of cortisol into cortisone, and resultant increased cortisol levels at the mineralocorticoid receptor. In states of 11 beta-DH deficiency such as the syndrome of apparent mineralocorticoid excess (AME) and licorice ingestion, cortisol acts as a potent mineralocorticoid. Thus, by acting to enhance aldosterone effects licorice would oppose the therapeutic intent of spironolactone as an aldosterone antagonist or aldosterone-inhibiting agent. Furthermore, this increased mineralocorticoid action of cortisol can cause a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, and lead to water retention, weight gain, and increased risk of hypertension.
(Miller LG. Arch Intern Med 1998 Nov 9;158(20):2200-2211; Lee YS, et al. Clin Pharmacol Ther 1996 Jan;59(1):62-71; Pratesi C, et al. J Hypertens Suppl 1991 Dec;9(6):S274-275; Nanahoshi M. Nippon Naibunpi Gakkai Zasshi 1967 Mar 20;42(12):1312-1319.)

• herbal concerns: The research cited above has focussed on concentrated extracts and intravenous forms of licorice. Common "licorice" candy usually contains no actual Glycyrrhiza, other than perhaps a minute amount as flavoring. No solid conclusions can be drawn as to how much these findings relate to the use of licorice in the forms commonly used by practitioners of Western and Chinese herbal medicine. A substance known as DGL (Deglycyrrhizinated Licorice) is available which retains the anti-inflammatory actions of whole licorice root without pseudo-aldosterone side effects. Individuals using spironolactone should consult with their prescribing physician and/or a qualified practitioner of herbal medicine about the potential risks involved in using any form of licorice.

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References

Herman E, Rado J. Fatal hyperkalemic paralysis associated with spironalactone. Observation on a patient with severe renal disease and refractory edema. Arch Neurol 1966 Jul;15(1):74-77.

Herman E, Rado J. [Hyperkalemia with fatal paralysis in a diabetic patient treated with aldactone]. Orv Hetil 1967 Jan 8;108(2):74-76. [Article in Hungarian]

Lee YS, Lorenzo BJ, Koufis T, Reidenberg MM. Grapefruit juice and its flavonoids inhibit 11 beta-hydroxysteroid dehydrogenase. Clin Pharmacol Ther 1996 Jan;59(1):62-71.
Abstract: INTRODUCTION: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its congenital absence or inhibition by licorice increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. We tested the hypothesis that flavonoids found in grapefruit juice inhibit this enzyme in vitro and that grapefruit juice itself inhibits it in vivo. METHODS: Microsomes from guinea pig kidney cortex were incubated with cortisol and nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) and different flavonoids and the oxidation to cortisone measured with use of HPLC analysis. In addition, healthy human volunteers drank grapefruit juice, and the ratio of cortisone to cortisol in their urine was measured by HPLC and used as an index of endogenous enzyme activity. RESULTS: Both forms of 11 beta-OHSD requiring either NAD or NADP were inhibited in a concentration-dependent manner by the flavonoids in grapefruit juice. Normal men who drank grapefruit juice had a fall in their urinary cortisone/cortisol ratio, suggesting in vivo inhibition of the enzyme. CONCLUSION: Dietary flavonoids can inhibit this enzyme and, at high doses, may cause an apparent mineralocorticoid effect.

Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998 Nov 9;158(20):2200-2211. (Review)

Nanahoshi M. [Effect of glycyrrhizin on the action cortisone]. Nippon Naibunpi Gakkai Zasshi 1967 Mar 20;42(12):1312-1319. [Article in Japanese]

Overdiek HW, Merkus FW. Influence of food on the bioavailability of spironolactone. Clin Pharmacol Ther 1986 Nov;40(5):531-536.
Abstract: Nine healthy volunteers received a single oral dose of 200 mg spironolactone, once during fasting conditions and once immediately after a standardized breakfast. Serum concentrations of spironolactone and its metabolites 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and canrenone were determined by HPLC for 24 hours after dosing. By taking spironolactone with food, the mean (+/- SD) AUC (0 to 24 hours) of the parent drug increased from 288 +/- 138 (empty stomach) to 493 +/- 105 ng X ml-1 X hr (P less than 0.001). The AUC (0 to 24 hours) of the three metabolites together also increased significantly from 8511 +/- 2062 (empty stomach) to 11219 +/- 2471 ng X ml-1 X hr (P less than 0.01). The mean (+/- SD) percent increase in AUC (0 to 24 hours) of spironolactone when it was given with food, compared with the ingestion on an empty stomach (95.4% +/- 66.9%), was much more pronounced than the corresponding increase of 7 alpha-thiomethylspirolactone (45.4% +/- 33.7%), 6 beta-hydroxy-7 alpha-thiomethylspiro-lactone (21.8% +/- 21.5%), and canrenone (40.7% +/- 26.3%). These observations indicate that food promotes the absorption of spironolactone and possibly decreases its first-pass metabolism.

Overdiek HW, Merkus FW. The metabolism and biopharmaceutics of spironolactone in man. Rev Drug Metab Drug Interact 1987;5(4):273-302. (Review)
Abstract: Spironolactone, a competitive aldosterone antagonist, has been used for almost 30 years in those disorders associated with primary or secondary hyperaldosteronism. This review is confined to its metabolism and biopharmaceutics in man. Spironolactone undergoes extensive metabolism with no unchanged drug appearing in the urine. Its metabolites can be divided into two main categories: those in which the sulfur of the parent molecule is removed and those in which the sulfur is retained. The dethioacetylated metabolite canrenone, belonging to the former category, was long considered to be the major active metabolite of spironolactone. For this reason pharmacokinetic studies have focussed on its kinetic behaviour. However, pharmacodynamic studies indicated that canrenone could only partly explain spironolactone's action. Furthermore, with the advent of modern high-performance liquid chromatographic techniques to measure canrenone concentrations, it was shown that previously employed assay techniques were unspecific and consequently considerably overestimated true canrenone levels. Recently, it was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironolactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone. Both spironolactone and 7 alpha-thiomethylspirolactone are known to possess anti-mineralocorticoid activity, and they may be mainly responsible for the activity of spironolactone. It also appears likely that endocrine side effects of spironolactone, such as gynaecomastia, are mediated by these sulfur-containing compounds. The oral absorption of spironolactone is improved by using micronized drug or inclusion complexes of spironolactone with cyclodextrins. Concomitant food intake has also been shown to enhance the bioavailability, by increasing the absorption and decreasing the first-pass effect of spironolactone.

Pratesi C, Scali M, Zampollo V, Zennaro MC, De Lazzari P, Lewicka S, Vecsei P, Armanini D. Effects of licorice on urinary metabolites of cortisol and cortisone. J Hypertens Suppl 1991 Dec;9(6):S274-275.

Roe DA. Diet and Drug Interactions. New York, Van Nostrand Reinhold, 1989: 146.

Stepan VM, Hammer HF, Krejs GJ. Hyperkalaemia and diarrhoea in a patient with surreptitious ingestion of potassium sparing diuretics. Eur J Gastroenterol Hepatol 1997 Oct;9(10):1001-1004.
Abstract: We report a patient who presented with the unusual combination of chronic diarrhoea and hyperkalaemia. The patient was admitted to our hospital after repeated negative evaluations elsewhere including exploratory laparotomy. The patient had a long history of diarrhoea with hypokalaemia which was documented on several occasions in the past. Several months before admission to our hospital for evaluation of diarrhoea the patient developed hyperkalaemia. Her daily stool output reached 1200 g and her serum potassium was as high as 6.0 mmol/l. Extensive evaluation revealed surreptitious ingestion of the diuretics triamterene, hydrochlorothiazide and spironolactone as the cause of hyperkalaemia and diarrhoea. In addition, she had melanosis coli which was interpreted to be the consequence of surreptitious ingestion of anthraquinone-containing laxatives in the past although no current laxative intake could be proven. We postulate that diarrhoea in our patient was mainly due to the decreased sodium absorption in the small intestine and colon caused by diuretics. Serum aldosterone levels were more than eight times the upper limit of normal. Increased aldosterone levels presumably arose secondary to volume contraction and sodium chloride depletion, but presumably were not able to affect renal and colonic electrolyte transport because of blockage of mineralocorticoid receptors by spironolactone. Thus, the unusual combination of diarrhoea and hyperkalaemia resulted.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Potassium-Sparing Diuretics, Spironolactone. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jul 1993.