Dr Sharon Rees @reesprescribe
Day 1: In the early 1950s, after aldosterone was extracted and purified, there followed an investigation re the action and development of antagonists. An oral agent #spironolactone was approved by the FDA in 1960 and by the UK in the early 60s.
Dr Sharon Rees @reesprescribe
(cont) It took until 1987 to clone the mineralocorticoid receptor (MR), via which aldosterone/spironolactone act. By this time, the dose-dependent limitations for use in oedema were known, as poor MR selectivity leads to many sexual adverse drug reactions (ADRs), such as voice pitch change, breast pain and gynaecomastia.
Dr Sharon Rees @reesprescribe
Day 2: Indications for #spironolactone include moderate-severe heart failure (main UK use), oedema associated with ascites, nephrotic syndrome and CHF. Unlicensed uses include resistant hypertension (adjunct). Antiandrogen properties make it suitable for acne and hirsutism.
Dr Sharon Rees @reesprescribe
(cont) #spironolactone was revived after the RALES study (1999) showed a 30% reduction in heart failure in any type of mortality and this drug is now key to the management pathway for heart failure.
Dr Sharon Rees @reesprescribe
Day 3: MOA – #spironolactone blocks the mineralocorticoid receptor (MR) inhibiting actions of aldosterone; blood pressure and oedema are reduced and potassium is ‘spared’ in the tubule.
Dr Sharon Rees @reesprescribe
(cont) The MR receptor is expressed in multiple tissues and adaptive changes in myocardium from heart failure are partly driven by blocking aldosterone; blocking activity reduces fibrosis, hypertrophy and inflammation, thereby producing cardio-protective effects.
Dr Sharon Rees @reesprescribe
Day 4: Key kinetics – #spironolactone has good oral absorption. It is a prodrug with several active metabolites, released by liver metabolism. It also undergoes enterohepatic recycling. The metabolite canrenone has the longest half-life at 15-17 hrs. Metabolites excreted through urine and faeces.
Dr Sharon Rees @reesprescribe
(cont) Dose range is 25-50 mg for heart failure; 25-200 mg for oedema associated with liver, kidney, heart disease.
Dr Sharon Rees @reesprescribe
Day 5: Hyperkalaemia (routine monitoring important and care with anything affecting K+ levels, including food), GI disturbance, ataxia, gynaecomastia, menstrual disturbance, leg cramps. Serious; AKI, agranulocytosis, DRESS, SJS.
Dr Sharon Rees @reesprescribe
(cont) Sexual ADRs mostly reversible on stopping #spironolactone. Eplenerone is an alternative, as more selective to the mineralocorticoid receptor.
Dr Sharon Rees @reesprescribe
Day 6: Caution with any drug increasing K+ levels, such as ACE inhibitors, ARBs, aliskiren, ciclosporin. Care with NSAIDs re renal impairment and increased K+. #spironolactone can increase lithium and digoxin levels and affect INR. Corticosteroids can oppose K+ sparing effects (not exhaustive).
Dr Sharon Rees @reesprescribe
Day 7: #spironolactone resembles progesterone and can act as an agonist at the progesterone receptor. The testosterone-suppressing effects have led to a role in gender transition (male to female), such as 100-400 mg/day can be used in combination with other drugs (unlicensed use).