Cardiac therapy: Aldosterone inhibitors: Ettinger Flashcards
(16 cards)
Classically, aldosterone is a ……………… hormone produced by the zone …………………. of the adrenal cortex in response to hyper……………. and ……………… via angiotensin ……… The enzyme …………………. is the rate limiting step and is only present in that region of the ………………
Classically, aldosterone is a steroid hormone produced by the zona glomerulosa of the adrenal cortex in response to hyperkalemia and renin via angiotensin II. The enzyme aldosterone synthase is the rate limiting step and is only present in that region of the adrenal cortex.
Aldosterone acts on the ………………… and ………………………. in the kidney to conserve ………….., excrete …………….and hence increase ………….. retention and blood ……………
Aldosterone acts on the distal convoluted tubules and collecting ducts in the kidney to conserve sodium, excrete potassium and hence increase water retention and blood pressure.
However, in recent years the role of aldosterone has become more apparent in heart disease and levels of aldosterone correlate well with severity of heart failure and survival. As a result the use of an aldosterone antagonist has become part of the standard regime for treating heart disease.
FUNCTION
The role of aldosterone is to maintain ………….. and …………… homeostasis. The main stimuli are increases in ………. ……and serum ………….. and a decrease in serum ……….levels.
FUNCTION
The role of aldosterone is to maintain sodium and potassium homeostasis. The main stimuli are increases in angiotensin II and serum potassium and a decrease in serum sodium levels.
………..is responsible for maintenance of the integrity of the zona glomerulosa. Intracellular ……………… receptors form a complex with …………………. which binds with ………… leading to a delayed response via specific gene transcription, e.g., three subunits of the epithelial………. channel and the ……… pump. Receptors have also been detected in the ………., ……… and …………, suggesting paracrine and autocrine functions.
………. has a tenfold affinity for the receptor. However, the affinity for aldosterone is maintained by the action of the associated enzyme, ……………………., which converts ………. to the inactive ……………..
There is also a rapid response and this may be because of a membrane receptor that is not blocked by spironolactone.
ACTH is responsible for maintenance of the integrity of the zona glomerulosa. Intracellular mineralocorticoid receptors form a complex with aldosterone which binds with DNA leading to a delayed response via specific gene transcription, e.g., three subunits of the epithelial sodium channel and the Na/K pump. Receptors have also been detected in the heart, brain and vasculature, suggesting paracrine and autocrine functions. Cortisol has a tenfold affinity for the receptor. However, the affinity for aldosterone is maintained by the action of the associated enzyme, 11-β-hydroxysteroid dehydrogenase type 2, which converts cortisol to the inactive cortisone.
There is also a rapid response and this may be because of a membrane receptor that is not blocked by spironolactone.
Breed variations have been detected. Cavalier King Charles Spaniels have ………….. aldosterone and ………..renin levels than crossbreeds, Poodles have higher renin and Irish Wolfhounds have both lower renin and lower aldosterone levels.[4] The significance of these findings has not been established.
Breed variations have been detected. Cavalier King Charles Spaniels have lower aldosterone and higher renin levels than crossbreeds, Poodles have higher renin and Irish Wolfhounds have both lower renin and lower aldosterone levels.[4] The significance of these findings has not been established.
EFFECTS
The effects of increased aldosterone levels are detrimental to the cardiovascular system in the setting of congestive heart failure (Table 244-1). They include ……… conservation and blood volume …………
………………… and ……….. are lost in the urine and the resulting reductions in these ions predispose the patients to ventricular ……………..
Aldosterone potentiates the effects of ………………… by blocking their uptake, especially ………….. in tissues. …………………are known to be arrhythmogenic.
……………….and baroreceptor activity is reduced as shown by ………………….discharge from ………………… sinuses.
Heart rate response to changes in blood pressure is reduced. This results in decreased heart rate …………… which has a negative correlation with survival.
Myocardial fibrosis is produced by both ……………..and ………….. and this can be documented by assessing procollagen III amino terminal peptide, which is a useful marker of myocardial collagen turnover. This patchy myocardial fibrosis may lower the threshold for ventricular arrhythmias and affect diastolic ……………. QT dispersion is also recognized.
Hence, aldosterone has a malignant autonomic profile, increasing sympathetic tone while decreasing parasympathetic tone as well as predisposing the patient to ventricular arrhythmias via several mechanisms
(Figure 244-1).
EFFECTS
The effects of increased aldosterone levels are detrimental to the cardiovascular system in the setting of congestive heart failure (Table 244-1). They include sodium conservation and blood volume expansion. Magnesium and potassium are lost in the urine and the resulting reductions in these ions predispose the patients to ventricular arrhythmias.
Aldosterone potentiates the effects of catecholamines by blocking their uptake, especially norepinephrine in tissues. Catecholamines are known to be arrhythmogenic.
Parasympathetic and baroreceptor activity is reduced as shown by reduced discharge from carotid sinuses. Heart rate response to changes in blood pressure is reduced. This results in decreased heart rate variability which has a negative correlation with survival.
Myocardial fibrosis is produced by both angiotensin II and aldosterone and this can be documented by assessing procollagen III amino terminal peptide, which is a useful marker of myocardial collagen turnover.[7] This patchy myocardial fibrosis may lower the threshold for ventricular arrhythmias and affect diastolic dysfunction. QT dispersion is also recognized.
Hence, aldosterone has a malignant autonomic profile, increasing sympathetic tone while decreasing parasympathetic tone as well as predisposing the patient to ventricular arrhythmias via several mechanisms
(Figure 244-1).
Table • 244-1 – Detrimental Effects of Elevated Aldosterone in Congestive Heart Failure: Which ones?
- Sodium conservation: Blood volume expansion, hypertension
- Hypokalemia: Ventricular arrhythmias
- Hypomagnesemia: Ventricular arrhythmias
- Blocks uptake of norepinephrine: Potentiates effects of catecholamines, ventricular arrhythmias
- Reduces parasympathetic activity: Decreases heart rate variability
- Myocardial fibrosis : Decreases systolic and diastolic dysfunction, ventricular arrhythmias
- Increased QT dispersion: Ventricular arrhythmias
- Potentiates effects of vasoconstrictors: Endothelial dysfunction
- Oxygen free radical generator: Inflammatory mediator
- Increase in tissue plasminogen activator inhibitor: Hypercoagulability
- Increase ACE expression and AT1 receptor density
- Increased effects of angiotensin II
In the coronary ligation dog model, aldosterone was more arrhythmogenic than adrenaline. Aldosterone potentiates the effects of other vasoconstrictors via ………..–mediated pathways, suggesting a role in ……………. dysfunction.
A …………….. is seen in nitric oxide metabolites in dogs with acquired degenerative mitral valve disease before the clinical signs of heart failure are apparent. This decrease is related to the severity of heart disease. Aldosterone is an inflammatory mediator acting as a potent oxygen free radical generator and also causes an increase in plasminogen activator inhibitor, which may encourage coagulation.
It increases …………………………… expression in cardiac myocytes and increases ………… receptor density, a positive feedback mechanism.
In the coronary ligation dog model, aldosterone was more arrhythmogenic than adrenaline.[8] Aldosterone potentiates the effects of other vasoconstrictors via nitric oxide–mediated pathways, suggesting a role in endothelial dysfunction.
A decrease is seen in nitric oxide metabolites in dogs with acquired degenerative mitral valve disease before the clinical signs of heart failure are apparent.[9] This decrease is related to the severity of heart disease. Aldosterone is an inflammatory mediator acting as a potent oxygen free radical generator and also causes an increase in plasminogen activator inhibitor, which may encourage coagulation.
It increases angiotensin converting enzyme (ACE) expression in cardiac myocytes and increases AT1 receptor density, a positive feedback mechanism.
ALDOSTERONE ANTAGONISTS
Aldosterone levels rise in congestive heart failure in dogs and cats with deleterious effects and as a result, it is a target in the treatment of congestive heart failure. Using an ACE inhibitor…………………. aldosterone levels. However, “…………………” is well recognized where aldosterone levels rise again in up to 40% of people receiving ACE inhibitors after 6 weeks. The phenomenon has also been seen in dogs and cats. Two antagonists have been used in veterinary medicine, spironolactone and eplerenone. Sadly, there is little trial data available.
Aldosterone levels rise in congestive heart failure in dogs and cats with deleterious effects and as a result, it is a target in the treatment of congestive heart failure. Using an ACE inhibitor initially reduces aldosterone levels. However, “aldosterone escape” is well recognized where aldosterone levels rise again in up to 40% of people receiving ACE inhibitors after 6 weeks. The phenomenon has also been seen in dogs and cats. Two antagonists have been used in veterinary medicine, spironolactone and eplerenone. Sadly, there is little trial data available.
SPIRONOLACTONE
In 1999, the seminal randomized Aldactone evaluation study (RALES) was published.[11] This trial involved 1663 patients with severe heart failure, 95% receiving an ACE inhibitor, randomized to receive a placebo or spironolactone (mean dose 26 mg/day). The trail was terminated early as interim analysis showed a 30% reduction in risk of death and a 35% reduction in risk of hospitalization.
In 1999, the seminal randomized Aldactone evaluation study (RALES) was published.[11] This trial involved 1663 patients with severe heart failure, 95% receiving an ACE inhibitor, randomized to receive a placebo or spironolactone (mean dose 26 mg/day). The trail was terminated early as interim analysis showed a 30% reduction in risk of death and a 35% reduction in risk of hospitalization.
Spironolactone is a nonspecific ……………. also binding to ………………, ………………., and ………….. receptors as well as inducing ……………………….enzymes which may affect drug interactions.
As a result, up to 10% of people suffer gynecomastia, breast pain, or sexual dysfunction. It is metabolized by the …………and the metabolites, e.g., canrenone, are also active and are responsible for the long half-life.
Spironolactone is a nonspecific antagonist, also binding to androgen, glucocorticoid, and progesterone receptors as well as inducing cytochrome P450 enzymes which may affect drug interactions.[2] As a result, up to 10% of people suffer gynecomastia, breast pain, or sexual dysfunction. It is metabolized by the liver and the metabolites, e.g., canrenone, are also active and are responsible for the long half-life.
Trial work has suggested that spironolactone does not act as a diuretic at doses up to 8 mg/kg in healthy Beagles as no increase in diuresis or increase in sodium excretion could be detected.[12] In preclinical studies, an effect on sodium and water diuresis was demonstrated in the face of raised aldosterone levels. These also suggested that a dose of 2 mg/kg once daily provides effective aldosterone antagonism (87%) and that it should be ………………………as bioavailability increases by 80% to 90%. Spironolactone has also been shown to attenuate the effects of aldosterone on ……………. reflex. A randomized, double-blinded placebo controlled field trial has been completed in Europe for licensing purposes. This trail involved dogs with both dilated cardiomyopathy and degenerative mitral valve disease and showed improvements in clinical indices, which were significant by 3 month, as well as longer term improvements in morbidity and mortality. In addition, decreases in syncope were observed. Side effects were not apparent and although potassium levels rose in the treated group, they were not outside the reference intervals.[14] However, monitoring of…………… function and serum …………..levels is recommended in dogs with renal impairment.
Trial work has suggested that spironolactone does not act as a diuretic at doses up to 8 mg/kg in healthy Beagles as no increase in diuresis or increase in sodium excretion could be detected.[12] In preclinical studies, an effect on sodium and water diuresis was demonstrated in the face of raised aldosterone levels. These also suggested that a dose of 2 mg/kg once daily provides effective aldosterone antagonism (87%) and that it should be given with food as bioavailability increases by 80% to 90%.[13] Spironolactone has also been shown to attenuate the effects of aldosterone on baroreceptor reflex.[6] A randomized, double-blinded placebo controlled field trial has been completed in Europe for licensing purposes. This trail involved dogs with both dilated cardiomyopathy and degenerative mitral valve disease and showed improvements in clinical indices, which were significant by 3 month, as well as longer term improvements in morbidity and mortality. In addition, decreases in syncope were observed. Side effects were not apparent and although potassium levels rose in the treated group, they were not outside the reference intervals.[14] However, monitoring of renal function and serum potassium levels is recommended in dogs with renal impairment.
As it is antiandrogenic, it is not recommended in ………… dogs or those used for ………….. Concern has been raised that the combination of spironolactone with an ACE inhibitor could result in significant electrolyte changes. However, in 50 dogs with degenerative mitral valve disease and left atrial enlargement given the two drugs for a mean of 23 weeks, there were no significant changes in sodium or potassium. Serum magnesium was slightly elevated but this was not clinically significant.[15]
In view of the effects of aldosterone on myocardial fibrosis and the fact that it is elevated in cats with hypertrophic cardiomyopathy (HCM), spironolactone may have a role in slowing the progression of HCM in cats.[10] A trial involving 23 Maine Coon cats from a colony affected by HCM using a dose of spironolactone of 2 mg/kg BID showed no change in diastolic function or any other parameter of heart disease.[16] Aldosterone levels were elevated in the treated group, which is a common finding. In people, improvements in diastolic function only occur if there is a decrease in myocardial fibrosis. Worryingly, 4 of 13 cats developed severe ulcerative facial dermatitis after an average of 2.5 months. In our clinic, we use a dose of 5 mg or 6.25 mg SID per cat increasing to BID in severely affected cases and have not witnessed this.
As it is antiandrogenic, it is not recommended in growing dogs or those used for reproduction. Concern has been raised that the combination of spironolactone with an ACE inhibitor could result in significant electrolyte changes. However, in 50 dogs with degenerative mitral valve disease and left atrial enlargement given the two drugs for a mean of 23 weeks, there were no significant changes in sodium or potassium. Serum magnesium was slightly elevated but this was not clinically significant.[15]
In view of the effects of aldosterone on myocardial fibrosis and the fact that it is elevated in cats with hypertrophic cardiomyopathy (HCM), spironolactone may have a role in slowing the progression of HCM in cats.[10] A trial involving 23 Maine Coon cats from a colony affected by HCM using a dose of spironolactone of 2 mg/kg BID showed no change in diastolic function or any other parameter of heart disease.[16] Aldosterone levels were elevated in the treated group, which is a common finding. In people, improvements in diastolic function only occur if there is a decrease in myocardial fibrosis. Worryingly, 4 of 13 cats developed severe ulcerative facial dermatitis after an average of 2.5 months. In our clinic, we use a dose of 5 mg or 6.25 mg SID per cat increasing to BID in severely affected cases and have not witnessed this.
Spironolactone may have a specific role in treating ascites due to chronic liver failure where loop diuretics should be used with caution as the resulting …………….. and ………………..encourage the ammonia …… and hepatic ………………….. (see Chapter 276).
Spironolactone may have a specific role in treating ascites due to chronic liver failure where loop diuretics should be used with caution as the resulting hypokalemia and alkalosis encourage the ammonia trap and hepatic encephalopathy (see Chapter 276).
EPLERENONE
Eplerenone is a more selective aldosterone antagonist which does not have the side effects seen with spironolactone.[2] Its metabolites are not metabolically active, shortening the half life. In the human EPHESUS trial, 6632 patients with acute myocardial infarction, left ventricular dysfunction, and heart failure were randomized to receive 25 to 50 mg eplerenone or placebo.[17] Patients receiving eplerenone showed reduced left ventricular hypertrophy and blood pressure. There was a slight risk of hyperkalemia in the eplerenone group but the risk of hypokalemia, which was twice as high, was significantly reduced in the eplerenone group.
In veterinary trials, eplerenone has been used at 10 mg/kg BID. In 14 dogs with experimentally induced ejection fractions of 30% to 40% randomized to receive eplerenone or placebo, eplerenone was associated with a 38% decrease in left ventricular cross sectional area, and a 34% to 37% decrease in fibrosis.[18] The progression of both systolic and diastolic dysfunction seemed to be slowed and capillary density in the myocardium was increased. In a second trial of 12 dogs with experimentally induced heart failure, eplerenone normalized the expression of cytoskeletal proteins and matrix metalloproteinases.[19] This may reduce the stiffness of the ventricle, reducing diastolic dysfunction. This exciting area is currently the subject of several human trials such as TOPCAT and PREDICT.
EPLERENONE
Eplerenone is a more selective aldosterone antagonist which does not have the side effects seen with spironolactone.[2] Its metabolites are not metabolically active, shortening the half life. In the human EPHESUS trial, 6632 patients with acute myocardial infarction, left ventricular dysfunction, and heart failure were randomized to receive 25 to 50 mg eplerenone or placebo.[17] Patients receiving eplerenone showed reduced left ventricular hypertrophy and blood pressure. There was a slight risk of hyperkalemia in the eplerenone group but the risk of hypokalemia, which was twice as high, was significantly reduced in the eplerenone group.
In veterinary trials, eplerenone has been used at 10 mg/kg BID. In 14 dogs with experimentally induced ejection fractions of 30% to 40% randomized to receive eplerenone or placebo, eplerenone was associated with a 38% decrease in left ventricular cross sectional area, and a 34% to 37% decrease in fibrosis.[18] The progression of both systolic and diastolic dysfunction seemed to be slowed and capillary density in the myocardium was increased. In a second trial of 12 dogs with experimentally induced heart failure, eplerenone normalized the expression of cytoskeletal proteins and matrix metalloproteinases.[19] This may reduce the stiffness of the ventricle, reducing diastolic dysfunction. This exciting area is currently the subject of several human trials such as TOPCAT and PREDICT.
CLINICAL APPLICATION
Spironolactone (Prilactone 10, 40, and 80 mg) has a license in Europe for the treatment of degenerative mitral valve disease. Eplerenone is significantly more expensive, may need to be given more frequently, and in view of the lack of side effects from spironolactone in dogs offers few advantages. Aldosterone levels rise when heart failure develops, so it is logical to start at that point as ACE inhibition alone is insufficient to control aldosterone levels. Current dosage recommendations are 2 mg/kg once daily with food in dogs. In cats the dose is not well established but a similar dose has been suggested. Clinical improvements are likely to be modest, although a reduction in syncope was an unexpected early observation in the clinical trials. However, trial data is emerging to suggest that spironolactone confers significant advantages in terms of long-term survival.[14]
CLINICAL APPLICATION
Spironolactone (Prilactone 10, 40, and 80 mg) has a license in Europe for the treatment of degenerative mitral valve disease. Eplerenone is significantly more expensive, may need to be given more frequently, and in view of the lack of side effects from spironolactone in dogs offers few advantages. Aldosterone levels rise when heart failure develops, so it is logical to start at that point as ACE inhibition alone is insufficient to control aldosterone levels. Current dosage recommendations are 2 mg/kg once daily with food in dogs. In cats the dose is not well established but a similar dose has been suggested. Clinical improvements are likely to be modest, although a reduction in syncope was an unexpected early observation in the clinical trials. However, trial data is emerging to suggest that spironolactone confers significant advantages in terms of long-term survival.[14]
