this is Dr busty and we're going to do a drug class review with a focus being on uh thide diuretics but before we dive into the individual drugs I think it's important that we have a baseline conversation of uh information regarding the physiology of the kidneys and so we'll be kind of zooming in on the areas where the nephrons are located um in this area here that I just circled on the kidney so we zoom in here and we see that we have nephrons uh where the Glarus is right here and that's where the blood flow coming in through the renal aeren arterial then hits the Glarus there's urin filtrate starting to be filtered across but then there's also in the proximal renal tubule secretion of things electrolytes and acidbase balance and reabsorption of sodium and water happening at that level that starts to form the initial urine filtrate and then it heads down the loop of Henley and then it comes up here to the distal convoluta tubule now there's a differen is as you go through the k and the reabsorption of sodium and water so in the proximal renal tubule it's about 40 to 60% okay uh when you go to the uh thick ascending Loop of Henley which is where the Loop Diuretics work that's about 20 to 20 to 40% roughly okay and then when you come up here to the distal convoluted tubal this is where our our thigh ey diuretics work and that's about 5 to 10% okay and so you can see that we don't get a significant amount of diuresis uh when you inhibit uh sodium water reabsorption at the distal convoluted tubule but you'll get a mild diuresis but once you ex uh pass the distl convoluted tubule it then enters into the collecting system where the water free water um uh control is in the urine filtrate so this is where we concentrate urine before it gets emptied out into the renal pelvis and into the uror and into your bladder so this is where concentration occurs once urine uh sodium uh passes by here it really doesn't have a chance to get reabsorbed anymore and so it's going to be lost um from the body which contributes to one of the reasons you develop more hyponatremia in these patients so there's a lot of thide diuretics on the market not just HCTZ or hydrochlorizide um but we'll talk about chlorthalidone which is actually one of the maybe more effective agents actually in this group chloride hydrochlorizide or HCTZ and dap and mosone indapamide and Mone being a little bit more potent as far as the amount of drug that you have to give to exert the pharmacologic effect so let's talk a little bit more about that mechanism so we were generally talking about the area of the dlomo tubal where that 5 to 10% of sodium water is being reabsorbed now in order for that to happen or to block that mechanism the drug has to get inside of the renal tubule all right that means it has to work on the luminal side of the kidney and the nefron of that tubule that means it gets secreted and so it's very important that once it's been absorbed and it moves throughout the body then it undergoes active secretion in that proximal renal tubule to get into the Lumen where the urine filtrate is located it then passes through the nefron and makes its way up to the distal convoluted tubule will it will block the sodium chloride Cod transporter at that level which is again where about 5 to 10% of sodium and and water is being reabsorbed now that is a traditional mechanism and we're going to look at that here in a minute there is one exception to that rule and that's chlorthalidone chlorthalidone not only does everything listed on this slide but it also has some Carbonic and hydr activity that is present in the proximal renal tubu and this may confer in part why chlorthalidone has been in the evidence when you take the totality of the evidence may be a little bit more effective at providing not only 24-hour blood pressure lower but also um improved cardiovascular outcomes compared to other thigh diuretic so core thalidone is separate separates itself um from a pharmacologic standpoint but also maybe even from an Evidence standpoint because of that Carbonic and Hydra inhibition activity that is present um in its use compared to the other agents um and so we're going to be uh uh now we're going to be um zooming in into this area of the DCT where the thighs I diuretics work on that sodium chloride co-transporter again on the luminal side so here's the Lumin of the uh tubule and here's the basolateral side where the blood flow and peras perivascular tubu blood flows are and this is looking at the proximal renal tubule so this is where you look here you see that there are are influx and e-lux cell membrane Transporters that are going to move thide diuretics and I just used HCTZ here as an example but all of thide diuretics move through this Pathway to get into the urine filtrate and it doesn't remember it has to be on the luminal side or inside the Lumin in order to exert its effect and so if you have poor um blood flow to the kidney or poor renal profusion or damage to the kidney and these nephrons have been damaged then you won't get that movement and so you will lose the efficacy so as the renal function declines so does the clinical efficacy of the thide diuretic class now once it makes its way to the distal convoluted tubules remember it's in the urine filtrate on the luminal side it blocks the sodium chloride co-transporter um and when it does that it not only blocks the reabsorption of about 5 to 10% of sodium but that also then sodium what follows sodium is water and so that's where you increase the amount of sodium and water staying in the urine filtrate as it then makes its way way to the collecting tubule and once it makes its way to the collecting tubule it really the nefron has lost most of its chance to reabsorb any sodium at that point and this is one of the reasons why this drug class in particular causes more hyponatremia now remember the diuresis here is much less than that of a loop diuretic because you're not you're only doing that 5 to 10% of the reabsorption versus in the asending loop of Henley where the Loop Diuretics work that's where you get under the 20 up to as much as 40% of reabsorption so their greater amount of curin filtrate uh stays higher in concentration of sodium now one of the things that happens when you block some of these cations and anions from moving into the cells is that you change the electrical chemical gradient and that influences the movement of calcium um absorption and but one of the things that you see when you you block this sodium chloride Co transporter with thite is that you also um increase okay the reabsorption of calcium and so you see this movement of calcium inside and so the calcium concentrations in the body go up and there are even case reports of of hyper calcemia as a result of that this is also the mechanism that is in play where some patient clinicians Advocate the use of thides maybe even preferentially in some patients with osteoporosis because again you're going to be facilitating the reabsorption of calcium now this is also where parathyroid hormone works to reabsorb calcium in the kidneys um which is also playing a role in all of this but the point is to show you that that hyper calcemia can happen with aai diuretics and it's because of that effect right there now when they when the urine filtrate has taken the turn and now it's heading for the collecting tubules remember this is where aquaporin would be upregulated and in the upregulation of aquaporins that's where free water is being reabsorbed and the urine filtrate is going to be concentrated we have very little ability to reabsorb sodium at this point unless there's a lot of aldosterone being released um but otherwise you're really not going to reabsorb much sodium that means the sodium is going to be making it down this way as well as a little bit of potassium and so as a result of that there's a lot there's other things happening in here this is a this is a brief summary of the area uh but you can also see a little bit of reabsorption of potassium and you can also be seeing some kicking out of the hydrogen ions and that's where you can develop a very mild case of metabolic alcalosis with thid diuretics it's not very common but it has occurred um and that's just described here and when you decrease the amount of sodium that's staying in the body okay because remember when it makes the collecting tubule it's pretty much going to be lost so we're going to see a slow depletion of the sodium coming out of the body over a period of time and these these are the patients to develop can develop pretty significant asymptomatic hyponatremia and the reason I said asymptomatic is that it occurs gradually over time and when you have changes in the serum sodium that is gradual they're less likely to cause symptoms until it gets to very critical levels if you change someone's serum sodium levels quickly then they become altered very quickly as well but when we decrease sodium in water of absorption and we get rid of it into the urine then we're depleting the total body sodium and water and what ends up happening is that we see a reduction in both an extracellular volume as well as the plasma volume that reduces some of our our cardiac output uh that initially causes a increase in the total peripheral resistance but over time you see a reverse Auto regulation kicking in plus we reduce perivascular edema occurring around these blood vessels where there's a lot of sodium accumulation and when you have edema around the blood vessels they're squeezing down and make them less compliant to changes in in blood pressure and so that reduction in the compliance of the vessel makes it more rigid and more likely to contribute to overall blood pressures and so you have this dual effect that happens when you use these drugs so we can see a small reduction in preload because we're reducing the plasma volume that will reduce the stroke volume and in reducing the stroke volume we will reduce the card output which assuming that systemic vascular resistance doesn't change very much you will see an overall reduction in blood pressure for that reason and this is the hemodynamics that happens and if you look at this this is time down here and as you go over from left to right the time goes by so when you first start someone on a thide diuretic what you see is you'll see that their systolic and diastolic blood pressure do decline like they're supposed to the plasma volume initially de increases and then there's a slight increase compensatory mechanism you see that reduction in cardiac output initially but then again it stabilizes itself but that um initially you see an increase in vascular resistance but as you reduce that per vascular edema then the overall peripheral vascular resistance goes down and so when you go look at this formula you see systemic vascular resistance goes down cardiac output goes down so there's a nice reduction in blood pressure and that again that effect may be more effective when you look at drugs like chlorthalidone which have also car Carbonic in hydrates inhibition now this table is a side by-side comparison with each of the thy diuretics HCTZ being listed first simply due to the fact that we are more commonly using it in practice it's just cheap and available but if you're a purist and you're an evidence-based medicine kind of person you really we should be using more chlorthalidone not only because of the differences in mechanism and the evidence supports it but there's another benefit to this drug um but which has to do with the halflife so down here when you look at these agents we have HCTZ chloride chlorthalidone and damid and metazone um and you look down here one of the things that makes them different is their long duration of action you can see that many of these have a me a duration of minutes some of them for hours but the one with the longest uh duration or halflife um is chal so chlorthalidone lasts longer probably provides a greater 24-hour blood pressure control with once a day dosing and has the Carbonic and hydrat activity which further facilitates the uh any hypertensive effect so chalone you know is not only where the evidence is but mechanistically is different and offers that Advantage although some people may argue well is that Vantage really worth the extra cost and that's where you do pharmacoeconomics analysis and that kind of stuff um but from a purist standpoint there's suggest that codon probably is the preferred agent um so the usual doses are listed here you can see that indapamide and metazone have the smallest doses that are necessary to achieve an effect that's because they're more potent that doesn't mean they're more effective that means I just have to give less drug to exert the pharmacologic effect so their ed50 or ec50s are really small um you can see that there is a sealing effect you don't really get much bang for the buck once you go above above that and particularly when you look at the max effective clinical dose of HCTZ that's around 25 Mig a day so pushing somebody up to 25 milligrams twice a day or 50 milligrams once a day of HCTZ is not really giving you much bang for the buck and is only increasing side effects including increase uric acid as well as uh increases in sugar or glucose um I mentioned before that these drugs have to get renally uh secreted uh into the proximal renal tubule to work and as the renal function declines so does the efficacy so once the CL crat and clearance really drops below 40 the effectiveness really starts to decline in the utilization of these drugs and practice begins to wne uh more so you can see that there's a variability in in bioavailability or absorption with indapamide having one of the highest okay uh when you look at as I mentioned the duration of action uh chlorthalidone not only has the longest halflife but has the longest ation of hour uh action by hours um and then when you see the pregnancy risk category you might think wow I could use these safely in pregnancy and the reality is that ACOG and other groups don't recommend their use if someone took one and they were pregnant it wouldn't probably teratogenic but one of the things that you saw is a reduction in plasma volume which actually is a physiologic in increase during pregnancy for the purpose of a perusing another organ I.E the placenta so most would agree that we probably don't want a diar IC on board while someone is pregnant because we actually do want increased plasma volume and this is not the preferred drug of choice in these patients um and so we tend to avoid them given the fact that thy diuretics have been around for a long time they are very useful even in monotherapy in most patients including African-Americans and blacks you see that they are combined with a lot of different agents on the market and I listed those here for you for those of you that want to study the brand name generic names but also to get an idea it's across the board many of these drugs are used and you'll see that HCTZ is one of the more common thy diuretics that's combined but a few agents do use chlorthalidone uh which I said is probably the more appropriate evidence-based uh decision clinical pearls so these are little things little factoids or things that you need to think about in CL like clinical integration of the pharmacology so they can be used as monotherapy U and as initial therapy so the first line treatments for many patients assuming their renal function is intact U this drug this drug class will work even in blacks and African-Americans many times as I said they're combined so it's convenient for compliance and adherence to other medications when you can combine medications into one pill as I mentioned it can be useful in blacks and African-Americans many of them are now cheap uh and cost more cost effective because of their generic status there may be a small benefit in osteoporosis due to the increase in calcium absorption but just recognize that you can also develop hypercalcemia in some of these patients um we mentioned the decline in the efficacy with poor renal function and it actually serves as a treatment in patients with lithium induced nephrogenic diabetes incipits um and the reason for that um and this is a classic sort of you know trivia question uh lithium um basically blocks the upregulation of aquaporins and so what ends up happening is these patients end up losing large amounts of free water and so by giving them thy diuretics you actually facilitate the proximal renal tubule reabsorption of water and sodium which then decreases the amount that's going to be lost in the Pro in the distal tubule down towards where the collecting duct is um it sounds uh not clear I I know that but it seems a little maybe counterintuitive uh but that's what actually has happening why we use it sometimes lithium induced diabetes and citus CU you may not always be able to stop the lithium there is a small risk of hypokalemia it's not near what it is for Loop Diuretics but it is obviously smaller there is a risk in hyperglycemia in fact one of the old thide diuretics diazoxide uh is used because it increases glucose levels and we use it in insulinomas basically tumors that secrete insulin and cause hypoglycemia so we give this thide like diuretic and it increases the blood blood sugar uh in patients who are having trouble with maintaining their blood sugar um and if you look at epidemiologic data quite honestly patients on thide diuretics end up developing more diabetes than patients not on thide diuretics and you may be like why would I want to give a drug that causes diabetes in a patient population that's not probably a good idea and it's not but the reality is when you think about the cost and the effectiveness of these drugs and maintaining blood pressure uh they work very well in the risk of hyperglycemia or diabetes is still relatively low but it's recognized that it does exist um there is a increase in uric acid this has to do with competition at the renal approximal renal tubule and uh if you go back to that slide where there the proximal renal tubule is that uric acid is also moving through there so there's a competition of U for movement of uric acid into the urine filtrate and so you can increase the uric acid levels okay and in doing so you can worse and the risk of gout okay uh hyponatremia and as I mentioned because there's not much chance for the kidneys to regain that that that loss sodium uh once it hits the collecting tubule the risk of of hyponatremia can sometimes be greater than that of other diuretics and even including Loop Diuretics and I know that doesn't also make sense it may sound counterintuitive but remember with a loop diuretic even though it's inhibiting more of the reabsorption of sodium water than a thide is there's still a chance that I can reabsorb it at that distal convoluted tubule and Pull It in that is not the case with th diuretics once we block that 5 to 10% in that distal convoluted tubule it makes it towards the collecting tubule there's not much left to be able to recoup and so you lose it it's just slower and that's why I said before those patients sometimes end up becoming more asymptomatic but severely hypo uh nmic now the uric acid elevations can are are here you can see that 8 CZ and again it's all thy diuretics I just used HCTZ in this example but quite honestly it's with all of the different drugs but you can see that HCT Z oride diuretics will compete U for this transporter and therefore we will block it and that will increase the uric acid concentrations causing um gout flares in certain high-risk patients we talked about hyper calcemia and that uh that reabsorption issue well I briefly mentioned the risk of metabolic alkalosis because again right before the collecting tubule there's a little effort to try to pull in some of that potassium so it doesn't lose too much and in doing so there's a elimination of hydrogen ions we see the same thing happen with Loop Diuretics um for the for the same mechanism as well uh possible orthostasis especially in the elderly these are uh something to consider because they can be easily volume uh deficient already or be dehydrated from pore or Al intake and so that's something to be uh aware of now if you read certain uh drug information you may see that it says that if you're allergic to sulfa or have a sulfonamide allergy that you should avoid thy diuretics and the reason they say that is because thy diuretics contain a sulfonamide mo they have the same sulfonamide MOA found in drugs like Baum now Baum being an antimicrobial agent um has a specific orientation associated around the sulfonamide and more recent evidence has shown that the antimicrobial containing sulfonamide drugs tend to have uh the problems with allergies whereas nonantimicrobial drugs that contain sulfonamides don't experience that same degree of reactivity and so what I mean by that is if someone is allergic to a drug like batrum sulfamethoxazol uh trimethoprim suom oxol and they're allergic to sulfa that if you used a loop diuretic or used a thide diuretic in that patient they're probably not going to have an allergic reaction and the reason for that has to do with the orientation of the sulfonamide in the structure so this is an example of the sulfonamide mo it's this S2 nh2 but in the in the antimicrobial drugs okay so drugs like trimethoprim sulfamethoxazol sulfa okay being right here sulfamethoxazol this is sulfoxy this is the actual structure and so in this antimicrobial agent we have the N1 substituent it's a five member ring and we have the N4 aramine which is a six member ring oriented in this fashion and that's the one that seems to be problematic when you have that orientation and when you look at the thigh ey diuretics you see that they don't have that same orientation now granted they're not antimicrobial drugs right they're thigh ey diuretics but when you look at the solonamide containing drugs that are antimicrobial agents they have different functional groups and orientation than do nonantimicrobial agents and so you look here and you can see that there's a difference here in the sulfonamide groups okay we lack that N4 aramine for sure and we also lack the N1 substituent um that's a five member ring and so what the point here is is that if you somebody who's truly sua allergic to an antibiotic then using a thide diuretic is probably okay I didn't say it was absolutely non-existent I just said it's probably okay and not going to be clinically relevant okay because the sodamide group and the orientation is not the same compared to other drugs and there's evidence that has recently come out over the past decade to show that that cross reactivity is very low if not non-existent and there have only been a few case reports ever published and so the overall risk does seem to be pretty low all right to summarize thiy diuretics work in the distal convoluted tubal they work on the sodium chloride co-transporter which is different from Loop Diuretics which works on the sodium chloride uh sodium potassium to Chloride transporter um in the loop of Henley so this works in the distal convoluta tubule only 5 to 10% reabsorption there but once it's lost it's gone and that's why they can develop pretty severe asympto itic hyponatremia compared to Loop Diuretics they're known to increase sugar or glucose calcium and uric acid and those are important side effects and monitoring parameters we know that once the Craton clearance drops below 30 to 40 the efficacy is really going to decline because these drugs have to get secreted in the luminal tubule in order to work and then the risk of Steven Johnson's or severe allergic uh reactions to sulfa is pretty pretty low but not zero um it just warrants probably a little extra attention but really probably nothing is going to happen clinically which is not only my experience but is also based on the evidence as well