Spironolactone

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Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Pharmacokinetics 6 Monitor 7 Adverse-effects 8 Drug-interactions 9 Mechanism-of-action 10 More General Terms 11 Additional Terms 12 Internet Database 13 References

Introduction

• Tradename: Aldactone.

Indications

• treatment of hypertension
• treatment of edema
• treatment of ascites & edema associated with alcoholic liver disease
• short-term preoperative treatment of hyperaldosteronism
• long-term maintenance therapy in patients with aldosterone- producing adrenal adenomas
• treatment of hypokalemia when other treatment is inappropriate or indadequate
• used in combination with testosterone in the management of certain forms of gonadotropin-releasing hormone- independent precocious puberty
• congestive heart failure
• treatment of polycystic ovary syndrome [9]
• chronic renal disease due to diabetic nephropathy [12]

Contraindications

• renal insufficiency:

• serum creatinine > 2.5 mg/dL (men) or > 2.0 mg/dL (women) [7,13]
• estimated GFR < 30 mL/min [14]

• hypersensitivity to spironolactone
• hyperkalemia ( serum K+ > 5 meq/L)
• concurrent use of other K+ sparing diuretics
• concurrent use of K+ supplements
  

• pregnancy category = d
• safety in lactation = ?

Dosage

• edema:

• 25-200 mg/day divided BID- QID
• adjust dose after 5 days if response is inadequate

• hypertension

• start 12.5-50 mg/day [8]
• adjust after 2 weeks if necessary
• divide dose BID if > 25 mg/day
• usual dose: 50-100 mg/day

• ascites:

• start 100 mg/day
• increase to 200-400 mg/day in 2-4 divided doses

• congestive heart failure:

• start 12.5-25 mg PO QD
• max 50 mg PO QD

• diagnosis of primary hyperaldosteronism:

• 100 to 400 mg/day in 1-2 divided doses

• Tabs: 25, 50, 100 mg.

Pharmacokinetics

• oral bioavailability is about 90%
• onset of action (gradual)
• extensive hepatic metabolism to active metabolites that are eliminated in the urine
• duration of action: 2-3 days (multiple doses)
• elimination 1/2life

• 1.4 hours for spironolactone
• 13.8 & 16.5 hours for active metabolites [4]
  

• elimination via liver
• elimination via kidney

Monitor

• serum K+ [7,13]

• baseline, then 3 & 7 days after initiation [13]
• every 4 weeks for 12 weeks, then
• every 3 months for 1 year
• every 6 months
• check 1 week after dose increase

• reinitiate serum K+ monitoring cycle if ACE inhibitor or ARB added or their dose increased [13]
• serum creatinine levels may be increased by spironolactone by 20%; discontinue spironlactone when estimated GFR < 30 mL/min [14]
  
• monitor with potassium-sparing diuretics

Adverse-effects

• not common (1-10%)

• constipation, dizziness, nausea, hypotension, headache, hyperkalemia*, edema, CHF, fatigue, dyspnea, bradycardia, rash

• uncommon (< 1%)

• flushing, dehydration, hyponatremia, gynecomastia, hyperchloremia, metabolic acidosis, postmenopausal bleeding, sexual dysfunction

• * hyperkalemia:

• 50 hospitalizations per 1000 new prescriptions [10]
• 11 hospitalizations per 1000 new prescriptions [11]
• mortality associated with hospitalization NOT insignificant

Drug-interactions

• NSAIDs in combination potentiate hyperkalemia & antagonize diuretic effect
• ACE inhibitors in combination potentiate hyperkalemia
• digoxin in combination increases incidence of gynecomastia
• other K+ sparing diuretics in combination potentiate hyperkalemia
  
• drug interaction(s) of antiarrhythmic agents in combination with diuretics
• drug interaction(s) of renin-angiotensin inhibitors with trimethoprim-sulfamethoxazole
• drug interaction(s) of spironolactone with trimethoprim
• drug interaction(s) of spironolactone with potassium-sparing diuretics
• drug interaction(s) of spironolactone with ACE inhibitors
• drug interaction(s) of diuretics with angiotensin II receptor antagonists
• drug interaction(s) of diuretics with ACE inhibitors
• drug interaction(s) of spironolactone with beta blockers
• drug interaction(s) of NSAIDs, diuretics & angiotensin II receptor antagonists
• drug interaction(s) of NSAIDs, diuretics & ACE inhibitors

Mechanism-of-action

• an aldosterone antagonist & an androgen antagonist
• K+ sparing diuretic

• inhibits action of aldosterone at the distal tubule & collecting duct
• causes excretion of Na+, Cl- & H2O ) decreases excretion of K+, NH4+, titratable acid & phosphate

• since most Na+ is eliminated in the proximal tubule, spironolactone has minimal effects when used alone; combination with a thiazide or loop diuretic is necessary for maximum effect

More General Terms

• K+ sparing diuretic
• aldosterone receptor antagonist (aldosterone antagonist)
• steroid

Additional Terms

• Randomized ALdactone Evaluation Study (RALES)

Internet Database

PubChem: 5833
PubChem: 5267
PubChem: 452291
PubChem: 162324

References

1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 620
3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 473-74
4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
5. a: Journal Watch, Mass Med Soc 20(1):7 (Jan 1) 2000 b: N Engl J Med 341:709, 1999
6. Kaiser Permanente Northern California Regional Drug Formulary, 1998
7. Prescriber's Letter 10(3):15 2003
8. Prescriber's Letter 11(1):1 2004 Detail-Document#: [1] (subscription needed) [2]
9. Journal Watch 24(14):115, 2004 Ganie MA, Khurana ML, Eunice M, Gulati M, Dwivedi SN, Ammini AC. Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. J Clin Endocrinol Metab. 2004 Jun;89(6):2756-62. PMID: [3]
10. Prescriber's Letter 11(9): 2004 Detail-Document#: [4] (subscription needed) [5]
11. Journal Watch 24(17):133, 2004 Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004 Aug 5;351(6):543-51. PMID: [6]
12. Rossing K et al. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy. A randomized, double-masked, cross-over study. Diabetes Care 2005 Sep; 28:2106-12. PMID: [7]
13. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: [8] (subscription needed) [9]
14. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010

spironolactone (Aldactone)