this is Dr busty and we're going to be doing a drug class review on aldosterone antagonist and to kind of get us started I just want to step back and just do basic uh information as far as the background and contributors to hypertension and we can see that it's multifactoral uh which is consistent with a lot of these topics we have the autonomic influence the heart's influence blood vessel anatomy and when we talk about that we're talking about the modeling process of what the vasculatures anatomy look like but also the diameter degree of uh restriction movement of blood and distribution of where it's located in the body and then the amount of uh hormone and plasma uh volume that is contributing and where we're going to be focusing our attention today are these two areas with as it relates to aldosterone antagonist we're going to be uh affecting it so that's why when you see drugs uh and many of these patients managed on multiple agents the reason is is because we're having to Target multiple mechanisms in order to get the blood pressure under control so to focus our attention we're going to be focusing in on spern lactone which is uh known as aldactone and ainon or inspra those are the two aldosterone antagonists that have been on the market for quite a while when we look at their mechanisms of action um it's important to recognize that there is a little bit of a multifactoral u perspective the first is that and it's listed here is that it competitively binds to inhibits the mineralic corticoid receptor and where that takes place is in the distal convoluted tubule of the nefron right before the collecting duct and this uh influences biochemical reactions that affects the sodium water permeability but on top of that it affects other receptors and this is one of the things that gives them their differences in their side effect profile one of the problems with spirolactone is that it also an appears to inhibit um and bind to the Androgen receptors which can cause gynecomastia which is enlargement of the breast tissue and then lastly the effect overall is this reduction in plasma volume but I would suggest that the other thing that happens with aldosterone is that it has remodeling effects on the vasculature uh not only blood vessels but also the heart tissue itself and so when we look at the nefron and where we're going to you know look at that first mechanism that we were talking about uh the first area is uh just to get oriented here this is your nefron the whole thing here uh we have the glomerulus where blood flow comes in filters in things into the urine filtrate in the proximal renal tubule as it moves through the proximal renal tubule it moves down in the loop of Henley and then it gets to the thick asending Loop of Henley where Loop Diuretics predominantly work okay uh then we come up here to the distal convoluted tubal where we have thides aldosterone antagonists work here Aces Inhibitors or angens receptor blockers indirectly and the the reason that they're indirectly is because of their impact on the release of aldosterone but aldosterone antagonists are going to be working working at this area here and they're going to block the uh effects at that that point and so let's kind of zoom in and look at some of the details of that so remember here's the Glarus at the beginning of the nefron the blood flow is coming in one of the things that influences the activation of Ras renin Angiotensin Reni Angiotensin aldosterone system is the release of renin from the JG cells that are present in this area and they sense profusion and when there's low Fusion Ren and goes up um as blood flow moves in it also is going to move out through the efferent arterial and at some level there's going to be a little bit of exertion down which generates U glome filtration pressure that per moves things across the basement membrane usually not large molecules and usually not proteins unless there's damage to the basement membrane and then the blood flow comes around the peritubular capillary system where there is in the beginning in the proximal renal tubule some creas of drugs and molecules including things like uric acid into the urine filtrate and this is where we begin the sodium water reabsorption pathway electrolytes uh management fluid shifts and all these things start to uh take place um and so once renin is released the way it does that is it converts angiotensinogen to Angiotensin one Angiotensin one gets converted to Angiotensin 2 via Ace and other Pathways and then um sorry brainin also gets metabolized um by Ace uh into inactive fragments but when brainen is allowed to be present um it does influence the release of local nitric oxide and pranin which has local antiplatelet and anti uh vasodilatory properties but if Angiotensin 2 is allowed to be formed it then goes on to bind to various Angiotensin 2 receptors and there are a number of different subtypes of receptors that out there they're subtype one subtype 2 three and four and on and on but the one where Angiotensin 2 binds to the subtype one receptor where it exerts all of the effects that we don't want um and one of the most highest components uh contributing to blood pressure management is the vasoconstrictive properties of angiotensin 2 when it binds to Angiotensin 2 subtype 1 receptor it causes an increase in vascular resistance because of Vaso restriction that increases the afterload that increases systemic vascular resistance and so that's a primary contributor of blood pressure management but also Angiotensin 2 stimulates the uh receptors within the adrenal glands that cause the release of aldosterone and that's where ACE inhibitors arbs and those things tend to work once aldosterone has been released even if it's physiologically you know being mediated because the RAS system was activated what happens is it goes to this distal comp vuto tubule and that's where it mediates the control of the amount of sodium and water being reabsorbed okay so as we zoom in over in onto the area of the distal convoluted tubule right before you get to the collecting tubule for elimination into the renal pelvis and into the and eventually urine uh we can see that we have the luminal side and the basolateral side and on the basil lateral side we see that we have the aldosterone receptor and when aldosterone is present it will activate that receptor stimulate a Cascade of intracellular or biochemical reactions that facilitate sodium in water reabsorption and when it does that that increases our plasma volume right and that will increase our return of volume back to the heart but also increase profusion to the kidney which affects the renin release that we were talking about um and so the way that this drugs these drugs work is that they obviously block The Binding of aldosterone to this receptor which blocks this pathway thereby preventing the reabsorption of of sodium water which has then no effect on the plasma volume or doesn't increase it and as a result it does not increase the release of uh potassium into the urine where it would normally go and so that's why patients with these drugs can develop hyperemia no different than they can develop hyperemia with ACE inhibitors Angiotensin receptor blockers uh renin Inhibitors all do the same thing but it's just whether or not it's direct or indirect okay indirect being that ACE inhibitors arbs prevent the release of aldosterone whereas Al aldosterone antagonists are working specifically at the level of the receptor uh to prevent the activity or The Binding of aldosterone so it can't influence the sodium water reabsorption and so this is just again in words what I said so when you get to the effect here of aldosterone the dist convoluted tubal we increase plasma volume that translates into an increase in blood pressure and if excessive can cause swelling fluid accumulation and edema and so when we think about conditions where we utilize these drugs where we may also utilize them for conditions where there's too much fluid on board things like sorosis where patients go on to develop aites patients with heart failure that have uh specifically problems with fluid overload and they develop systolic dysfunction because they have ineffective pumps and that fluid then accumulates and causes pulmonary fusions or edema and can go on create uh lower extremity edema and shortness of breath and so aldosterone antagonist because they're reducing sodium water reabsorption which translates into reduced plasma volume we will then reduce the preload which we know that the preload then reduces stroke volume and stroke volume plays a contributor to the cardiac output and when this formula if you just look at it if you change one of these variables uh the other one must compensate so if the systemic vascular resistance doesn't go up uh then there will be a reduction in the blood pressure so because it doesn't go up okay uh we have this reduction in plasma volume that can reduce cardiac output that can also reduce the blood pressure so that's one of the reasons why these drugs are used in part for hypertension uh now aldosterone as I mentioned early in the lecture also has other effects one of them is the anti-fibrotic effects and this is really important in the process of remodeling that can happen both in hypertension and in patients with congestive or known heart failure uh whether they have preserved EF or not uh specifically low EFS patients uh they tend to remodel and that contributes to the progression of their disease and it was the rails trial that was stopped early when uh spaone was being being used because the mortality benefit was so striking that important and obvious that it was unethical to continue the study there is also data with a pinone it's the Ephesus trial so they've both been shown to be beneficial in heart failure as a result of their anti- remodeling uh effects now as I also mentioned in the mechanism one unfortunately one of the biggest problems with bronol lactone or aldactone in adult and men in particular is gynecomastia which is painful enlargement of the breast tissue and that has to do with the fact that this drug um has a 911 epoxide group uh I'm sorry the pinone has a 911 epoxide group that prevents its binding to the and receptor spaone doesn't have that and what happens is its binding Affinity to the Androgen receptor is greater and so it antagonizes the effects of androgens in men which then causes the opposite effect so the breast tissue enlarges as a result that proliferation and this is the number one reason why people can't tolerate mainly adult men cannot tolerate spol lactone and that's the primary benefit of a pinone or inspra is that it lacks that effect okay so when we look at indications this is a table that just do a quick Cross comparison to help you to wrap your mind why do I pick one over the other what makes them similar what makes them different uh you see over here in the First Column we have the brand or generic name and then the Branded name or marketed name in the parenthesis so a plone is inspra spone is aldactone when you look at their indications you can see that a plone is predominantly for hypertension and heart failure specifically patients postm who have left ventricular systolic dysfunction uh spinal lactone in addition to those can be used to treat hypokalemia because they both of these drugs can increase potassium but you also see primary hyperaldosteronism you see serotic patients that develop alatis acne and then heroism which is you know abnormal facial hair growth mainly in in women and so if you think about that where they have too many androgens present and that's contributing to their facial hair to be more coarse and to grow a little bit more rapid uh one of the things that can be used is spironolactone because of its Androgen receptor inhibition again that works in favor of females with facial hair growth it does not work for men who typically don't want breast enlargement and painful um breast as a result of that stimulation and proliferation of the tissue so it's important to recognize differences in indication uh now you might say well why would it be used in therosis well therosis was specifically patients developing aites well where's all that fluid coming from from well it comes from the fact that they don't have enough Albin to maintain their oncotic pressure and when they're not maintaining the oncotic pressure they can't keep the fluid inside the vasculature so therefore it leaks out into the tissue and so they the vasculature looks like it's actually dehydrated well that reduces perfusion to the renal aparent arterial and those juular gar cells in that renal aperin arterial of the nefron sense that low profusion even though there's edema present in the tissue and it starts to rev up and reactivate that renin Angiotensin aldosterone system to the extent that there's so much sodium water reabsorption that they develop just morees because as that sodium water gets reabsorbed because there's no Albin presence it just leaks right back out into the tissue and so we use this to help manage patients with aites uh when you look at the doses uh they're fairly similar you do want to titrate to Target doses that were used in the trials again somewhere around 50 milligrams if they can tolerate it but remember one of the number one problems with being on these drugs is hyperemia well you're typically adding these drugs if you're using them for heart failure in patients already on ACE inhibitors or Angiotensin receptor blockers which also increase the risk of hyperium so hyperemia can be a big problem especially with patients with underlying renal impairment or renal failure because remember the kidneys are very important for maintaining electrolyte homeostasis and one of the number one problems in CKD or patients with renal impairment is the hyperkalemia risk uh you can see that a pinone is also a major substrate of 3a4 and as a result of that is high risk for drug drug interactions and as a result of being inhibited because there's a lot of Inhibitors at 384 there is a dose dependent increase in the risk of hyperemia so that's the biggest problem but it has the lowest incidence of gynacomastia compared to spol lactone and that's the only real benefit that a plin own really has to offer um if you're going to be using highd do spol lactone in aites management in stics you're going to be using doses up to 100 to 200 milligrams a day which is much higher than you would use in hypertension and heart failure as a result of that higher dose your risk of hyperemia goes up and and so many times these patients need to be put on low doses of feride or lasx to offset that hyperemia and the typical ratio is about 40 milligram of Lasix for every 100 milligrams of spironolactone that's being used um and so that's an important ratio many times people like to ask that question it's also clinically useful and very relevant within the context of that specific indication so side effect wise hyperemia gynacomastia greater in spinal lactone than a PL known because of that Androgen receptor inhibition um the other thing is we got to keep in mind this re avoiding salt substitutes and the reason the avoiding salt substitutes is relevant is the sodium is replaced with pottassium and so remember they're already at risk for hyperemia and so if you replace the sodium with potassium then you're only going to further increase the risk of hyperemia um this may be the firstline treatment and hypertension where the primary underlying cause is hyper aldosteronism that would be different than what is recommended by the initial monotherapy uh recommendations by the guidelines um that's because you're treating the underlying cause in that situation um again also in heart failure there's a risk of hyperemia because of the uses in Aces and arbs early on in the management of heart failure and then lastly one of the things you can see is uh insets can reduce the efficacy and that has to do with the fact that that Nets reduce prostate glandon production that have local vasodilatory effects if I reduce the pro the glands in the renal aeren arterial then I'm going to reduce profusion in the renal aarant arterial that's going to cause the JG cells to want to release renin that increases plasma volume um issues and so when you have nids on board the RAS system is overactivated and can sometimes overcompensate by making too much aldosterone for which the aldosterone antagonist cannot in inhibit so let's discuss in summary The Core Concepts one is spirolactone has many more indications and uses in clinical practice compared to a pinone and is also less likely to cause clinically relevant drug drug interactions remember pinone is a 3a4 substrate next is both agents are known to reduce mortality that was the Ephesus trial for a pinone rails trial with spirolactone a plone confers not only a risk of hype of um drug interactions but offers less risk of gynecomastia member spaone inhibits that Androgen receptor which would contribute to the gynacomastia uh risk and then lastly these drugs both can cause hyperemia because of the their mechanisms and as a result we have to be very careful with Aces arbs and salt substitute since salt substitutes supplement the sodium for potassium