 Hello and welcome to Physiology Open. In this video we will see the physiological basis of mechanism of action of various diuretics. Dioretics are substances which increase the flow rate of urine. The flow rate of urine will increase when the volume of urine increases and volume will increase either due to only increase in volume of water or increase in solute as well as of water. Most of the classes of diuretics work by increasing both the solute as well as water loss. Rather this is important since for resolution of edema if total body sodium concentration decreases total blood volume also decreases thus decreasing the hydrostatic pressure in vessels which leads to resolution of edema. So obviously to understand the mechanism of action of diuretics you should know how sodium and water are reabsorbed from kidneys. Dioretics interfere with the mechanism of their reabsorption and hence promote their loss. So let's see the various parts of the nephron where sodium and water are reabsorbed and where diuretics act. Here is a diagram of the nephron. This is Bowman's capsule. This is a proximal convoluted tubule. This is the descending limb of loop of Henle. Then thin ascending limb, thick ascending limb, macular part of ascending limb which is just near the Bowman's capsule and has sodium chloride sensor that is macular denser which is responsible for tubular glomerular feedback. Then this is distal convoluted tubule connecting tubule and collecting dubs. Now sodium is absorbed here in proximal convoluted tubule, then in thick ascending limb of loop of Henle, then in distal convoluted tubule and in late distal tubule and collecting dubs by different mechanisms. And diuretics can block sodium reabsorption at any of these sites. Some fundamentals we'll see first. See the diuretics which prevents sodium reabsorption at sites before the macular denser, what they do is they will increase the delivery of sodium ions to macular denser. So the macular denser will sense more sodium and hence cause increased tubular glomerular feedback which will in turn decrease renal blood flow and glomerular filtration rate. Then second thing is the diuretics which act before the late distal tubule will lead to increased delivery of sodium to the late distal tubule and collecting duct. Now in collecting duct when sodium is reabsorbed what happens is that this causes potassium to move into the tubular lumen. So increased delivery of sodium to collecting duct will lead to loss of potassium in urine. Also here some potassium in the tubule is exchanged with hydrogen ions. Thus it causes loss of hydrogen ions also. So basically all these diuretics which act before this site will lead to loss of potassium and hydrogen from the body causing hypokalamic alkalosis. Fine with these fundamentals now let's discuss individual classes of diuretics. Well depending on where the diuretics act we have five classes of diuretics. Diuretics acting on proximal convoluted tubule are carbonic and hydrazine bitters. Then osmotic diuretics basically prevent water reabsorption mainly from descending limb of loop of henle. Then loop diuretics act on thick ascending limb. Thiazide diuretics act on distal convoluted tubule and potassium sparing diuretics act on late distal tubule and collecting duct. We will discuss each class while we move through mechanisms of sodium and water reabsorption segment by segment of nephron. But again one fundamental you should remember that from lumen to the cell sodium moves by different transporters in different segments of nephron. However across basolateral membrane sodium is moved out by sodium potassium at a pace at all places. We will be focusing on the transporters at the luminal membrane. Okay let's see the first segment. Well 65% of sodium is reabsorbed in proximal convoluted tubule. So let's magnify a portion of this PCT. Here sodium is reabsorbed along with glucose and amino acids by sodium glucose and sodium amino acid simporter. Then here it is also absorbed by sodium hydrogen exchanger by means of which sodium moves into the cells and hydrogen moves out of the cells. Now these cells have carbonic anhydrase enzyme. This enzyme is present intracellularly as well as at luminal membrane. Now this hydrogen which is secreted into the lumen of the nephron combines with the filtered bicarbonate in presence of this luminal membrane carbonic anhydrase and forms H2CO3 which dissociates into carbon dioxide and water. The carbon dioxide enters back into the cell combines with water inside the cell and forms H2CO3. In the presence of carbonic anhydrase enzyme H2CO3 dissociates into H plus ions and bicarbonate ions. The hydrogen ions again enter into the lumen by sodium hydrogen exchanger and bicarbonate ions here enter into the basolateral side and then into the circulation. In effect same hydrogen is being reabsorbed and then secreted into the tubular lumen. So what is happening is that recycling of hydrogen ions is leading to reabsorption of sodium ions and bicarbonate ions. Now this portion of nephron is permeable to water so with solute reabsorption water follows passively due to osmosis. This first class of diuretics acts by inhibiting this carbonic anhydrase enzyme. Well logically you can very well see that this will interfere with absorption of sodium ions and hence also of water. But you see here that this class of drug is also interfering with the absorption of bicarbonate. So basically alkaline blood is going to reduce causing decrease in pH that is metabolic acidosis. Indeed because of this these drugs are not used for resolution of edema. On the contrary they are used to block carbonic anhydrase enzyme elsewhere like for open-angle glaucoma where blocking carbonic anhydrase enzyme leads to decrease in the production of aqueous humor. Well one interesting thing is that they are used for the side affected causes that is metabolic acidosis. In high altitude sickness due to hyperventilation respiratory alkalosis occurs. Now these carbon dioxide and pH are a stimulus for maintaining respiratory drive. So when carbon dioxide decreases it leads to decrease in ventilation which will be very hazardous at high altitude since it can lead to dangerous hypoxia. So giving carbonic anhydrase inhibitors prevents the increase in pH and maintains ventilatory drive. Okay now let's move to next segment. In the thick ascending limb of loop of Henle approximately 25% of sodium is reabsorbed by the importer sodium potassium to chloride. Now this potassium which enters the cell moves back into the lumen by potassium channels while sodium and chloride enter into the medullary interstitium. The movement of potassium ions back into the lumen creates positivity at the luminal membrane which repels positive ions like calcium and magnesium which are absorbed by paracellar root. Now this thick ascending limb is impermeable to water. So as it reabsorbs the solute the tubular fluid becomes diluted since water is not moving along with solute. So this segment is known as diluting segment of nephron. This segment is also responsible for generating the hyper or smaller medullary gradient which in turn is responsible for concentration of urine when required. So if we block this transporter what will be the effects and side effects? Well loop diuretics act by blocking this transporter. Now see since this segment is responsible for approximately 25% of sodium reabsorption loop diuretics are rather very effective diuretics. These diuretics are so effective that they are used for acute emergency conditions like acute pulmonary edema. Apart from being used for edema due to various other causes like congestive heart failure, nephrotics syndrome, hepatic cirrhosis. Now we have discussed that generally drugs which act before macular denser tend to reduce renal blood flow and GFR. But that does not happen with these loop diuretics. Instead they block the sensor of macular denser also. So they block the feedback as well. Thus tubular glomular feedback decreases and renal blood flow and GFR increases. That's why they are preferred diuretics in presence of renal failure because they tend to maintain GFR. Well what could be its side effect? As already discussed one side effect will be hypokalamic alkalosis due to increased sodium delivery to collecting depth. Then since reabsorption of calcium and magnesium is indirectly dependent on this transporter their reabsorption will also decrease causing loss of the science hence hypocalcemia and hypomagnesemia will occur. Then it can also cause hyperuricemia. Why? Because to act on these transporters these diuretics need to be secreted into the lumen by organic acid transporters. These transporters are also required for secretion of uric acid. So due to competition between the drug and uric acid secretion of uric acid decreases and hence causes hyperuricemia. One dangerous complication can be that over zealous treatment with this diuretic can become very dangerous causing hypotension and circulatory shock. Since it can cause excessive water loss which cannot be compensated by the body also since it is interfering with kidney's ability to concentrate urine. We have seen that this segment is responsible for both dilution as well as concentration of urine right? One more side effect can be hearing loss. Since this importer has also been shown to have some role in hearing which can be blocked by lube diuretics. Okay, time to move on to next class on diuretics which act on distil convulated tubule. Around 5 to 10 percent of sodium is reabsorbed in distil convulated tubule by the sodium chloride importer. Well this segment is also impermeable to water. So this also forms the part of diluting segment. However it does not contribute to maintenance of hyper or smaller medullary gradient. So what will happen if we block this transporter? Thiozide group of diuretics act by blocking this transporter. You can see that since this segment is responsible for 5 to 10 percent of sodium reabsorption so it is not as effective as lube diuretics. So it is a moderately effective diuretics. It is a very good diuretic to be used for hypertension and for edema in moderate congestive heart failure. Well while we were talking about lube diuretics we did not mention it to be used for hypertension. Why? Well as a class lube diuretics have very fast elimination rates and have very low duration of action. So they will require more frequent dosing. However in presence of hypertension with the renal failure or hypertensive emergency lube diuretics will be required otherwise thiozide diuretics are used. Okay what could be the side effects of thiozide diuretics? Can we predict some side effects by now? Yeah obviously like other diuretics acting before late distil tubule they can cause hypokalamic alkalosis. Then like lube diuretics they can also cause hyperuricemia, hypomagnosemia but instead of hypocalcemia it causes hypercalcemia. Then similar to other diuretics overzealous use of thiozide diuretics may lead to hypotension. However you see this diuretic does not interfere with the ability of kidneys to concentrate urine in presence of adiate. Hence it's not as serious as lube diuretic in that regard. But if water can be reabsorbed but solute loss continues it can cause hyponatremia instead. Now can you predict its action on GFR? It will have no effect on GFR because it's acting further down the site of tubuloglomerular feedback and hence won't affect renal blood flow and GFR. Let's move on to the next class of diuretics which act on late distil convoluted tubule and collecting duct. Here there are two types of cells, principal cells and intercalated cells. Approximately one to two percent of sodium reabsorption takes place in principal cells by epithelial sodium channels. When sodium enters the cells potassium ions move into the lumen through potassium channels. In intercalated cells some of this luminal potassium is exchanged with hydrogen ions. Now these cells have mineralocorticoid receptors. Aldosterone a mineralocorticoid can enter into the cell bind to its receptor which in turn can increase expression of these epithelial sodium channels. So what will happen if sodium absorption is blocked here? See diuretic effect will not be much since only one to two percent of reabsorption of sodium is affected. But if you block these channels as a lateral effect potassium will not move out and hence hydrogen also will not move out. So basically these are sparing potassium and hydrogen from being secreted into the lumen. So these are potassium sparing diuretics. So we combine them with other diuretics they will prevent the development of hypokalamic alkalosis. Reabsorption here can be blocked by two ways. One block these epithelial sodium channels and second block these mineralocorticoid receptors. Now see both will have similar effects. However the effect of mineralocorticoid receptor antagonist will be pronounced in cases where aldosterone is high in body that is primary hyperaldosteronism. And aldosterone is also high in cases of congestive heart failure. So in case in congestive heart failure if edoma is refractory and not responding to thiozide and lube diuretics mineralocorticoid receptor antagonist may be given. But with these diuretics there is a danger of hyperkalemia because they are interfering with normal mechanism of potassium secretion. Now let's come back to final class of diuretics that is osmotic diuretics. Osmotic diuretics are filtered from the glomerulus but are not absorbed and tend to remain in the tubular fluid. Hence in descending limb of lube of Henle which is permeable to water they prevent the movement of water out from tubular lumen since they exert an osmotic pull on water. So basically osmotic diuretics are mainly interfering with water excretion only and not solute excretion. Hence they are not used for resolution of systemic edema but for reducing cerebral edema before and after neurosurgery and for reducing intraocular pressure for patients acquiring intraocular surgery. So that was the physiological basis of mechanism of action of five classes of diuretics. Hopefully now you understand that how they act. Okay, thanks for watching the video. If you liked it do not forget to subscribe to the channel Physiology Open. Thank you.