I. Intro a. What’s the primary use of diuretics in medicine today? a. Control of high blood pressure. Many patients, especially over the age of 50, need blood pressure control and diuretic agents are usually looked to first by physicians. b. Dr. Pillion looks at the kidney as a river system that flows down to the sea. As in many rivers the tributaries that feed into this gradually become wider and have greater capacity, and as the fluid flows down to the tip of the kidney and into the ureter and ultimately into the bladder, the salinity changes. For a river, the NaCl concentration where the river and ocean merge is similar to the human blood stream (around 300, Na in blood is typically ~140, and Cl is ~90-110 - other anions make up the rest of the negative charge). c. Blood pH is usually ~7.40, we call this neutral, when it gets above this we call it basic and when it gets below this we call it acidic. We maintain this pH very aggressively. Saline solution is composed of NaCl dissolved in water – about 0.9% NaCl, so 0.9 grams NaCl per 100 mL water. 1 liter of blood has about 9 grams of NaCl so this is the amount that goes in the saline. d. In a river system, the concentration of NaCl upstream (away from the ocean) is essentially 0, and when it gets down close to the ocean it’s about 0.9%, and in between its mixed – so there’s a gradient. In the kidney, when stuff gets filtered across the glomerulus, the Na concentration there is – i.e. at the very beginning of the proximal tubule – the fluid is just like the blood stream ~140 milimolar or miliequivalents of Na. So, 140 milimolar is what you start with at the beginning of the proximal tubule. The proximal tubule reabsorbs 2/3 of the sodium so the concentration of sodium in the lumen of the proximal tubule stays about the same because water follows Na out of the proximal tubule (2/3 of water is also reabsorbed here). e. The fluid moves down the loop of Henle and is exposed to very high concentrations of Na, and the fluid in the lumen of the descending loop the concentration gets high and as you go back up the loop water cannot leave the lumen and you reabsorb Na so the concentration of Na is now getting lower and lower. When you reach the collecting duct the concentration of Na is very low – we excrete about 100 miliequivalents in 24 hrs and filter 25,000 meq in that same time span. f. Along the way there are specialized Na reabsorption channels – these channels are what the drugs we’ll talk about today act upon. Different parts of the tubule have different Na carriers, and these drugs inhibit specific carriers. Where the carriers are located geographically has a big effect on how effective they are. a. Theoretically, since 2/3 of the Na gets absorbed in the proximal tubule, do you think that the drug that inhibits Na transport in the proximal tubule would be the most effective for naturesis? It would be. b. What drug affect Na uptake in the proximal tubule – NONE OF THEM. c. Most of the diuretics got discovered by accident – they were developed for some other reason and dieresis was observed as a side effect so they became diuretics. We figured out how and where they worked later on.
II. Objectives: Diuretics [S2] a. Describe renal tubule physiology b. Discuss the pharmacology of the different classes of diuretic agents c. The kidney plays an important role in all of our lives a. Na is the major extracellular ion b. K is the major intracellular ion c. We will always take into account what happens to K when we discuss Na movement d. On the urine side stuff wants to run down hill, on the blood side the stuff wants to run down hill, so the cell needs a pump or a channel to make stuff move in any way other than downhill
III. Kidneys [S3] a. The kidney plays an important role in all of our lives a. Na is the major extracellular ion b. K is the major intracellular ion c. We will always take into account what happens to K when we discuss Na movement d. On the urine side stuff wants to run down hill, on the blood side the stuff wants to run down hill, so the cell needs a pump or a channel to make stuff move in any way other than downhill
IV. What electrolytes are reabsorbed from the urine by the kidney? [S4] a. Is there anything besides Na that we reabsorb? a. Yes – K, Mg, Cl, Phosphate b. You have to know about all of these things because when we give drugs we have to be aware of its effects on all of these other substances c. If you think about phosphate for example 1. If you have a drug that causes you to lose phosphate what might the impact of that be on your body? a. Blood pH may be altered b. If you lose phosphate it may have an impact on bone 2. Calcium as another example a. Bone and teeth affected here
V. Renal Tubule Transport System [S5] a. This is his favorite cartoon of the kidney because it shows where all the different drugs work b. Memorize this cartoon and you’ll have all the answers you need for a test c. Proximal tubule on the left side of the cartoon a. As the fluid travels through the proximal tubule we reabsorb Na, bicarbonate, and some hydrogen as well 1. We also reabsorb glucose, uric acid, amino acids, and many other organic acids (Not shown on chart) 2. Under normal condition the amount of glucose and amino acids that enter the nephron get reabsorbed in the proximal tubule 3. This is where osmotic diuretics work – these really work through the whole tubule system as they are impermeable through the entire length of the tubule transport system 4. Carbonic anhydrase inhibitors work in the proximal tubule, they are not used as often d. As the fluid comes back up the loop of Henle the area is impermeable to water and as Na and Cl leave the tubule water is not able to travel with it so, you have an effect on the osmolarity on the fluid e. The thick ascending limb is where the reabsorption of Na and Cl is coupled and this is where loop diuretics work f. Loop and thiazide diuretics are most often used a. Should commit side effects and physiological effects to memory b. Loops are the most effective in emergency setting 1. If you give someone an infusion of a loop diuretic intravenously you can get a massive dieresis in a very short amount of time 2. Useful in situations such as a seriously high blood pressure 3. Would give a loop diuretic (such as flurosamide) orally in the instance of a middle aged man with congestive heart failure – not usually given this way due to cost 4. Thiazide diuretics usually given for everyday control of blood pressure a. Cheap, relatively non-toxic, have been around for a long time b. Can lead to complications such as K wasting – can end up with hypokalemic situation a. This is bad because skeletal and cardiac muscle require 4 milimolar K in the blood, if it gets down around 2 milimolar the heart doesn’t want to beat anymore b. Usually combine thiazide therapy with a K sparing diuretic a. K sparing diuretic work on different cells and cause and increase K level so you get a neutral effect when you combine with the thiazide diuretics g. At the very end of the collecting duct we have water channels and aldosterone sensitive transporters a. Only a few drugs work here b. Relatively expensive and not that common
VI. Proximal Tubule [S6] a. There is a Na/K ATPase in this cell, it’s just not pictured (this pump present in every cell in body even though it’s not pictured – will see it in some of the other cartoons) b. This cartoon highlights a Na/Hydrogen exchanger a. This is the most important transporter in the proximal tubule, it moves about 2/3 of the Na from the lumen and brings it into the cell and then it gets actively pumped out c. Na/K ATPase plays a role in Na regulation as it drives Na out of the cell and this allows the gradient to be maintained d. Carbonic acid is dehydrated to water and CO2 a. Carbonic anhydrase on the surface of the proximal tubule b. There is also a carbonic anhydrase inside the tubule 1. This sets up a little cycle (not shown) a. Outside the cell bicarbonate comes floating in form our blood stream and it reacts with hydrogen that gets pumped out of the cell to form H2CO3 – this is more permeable as it is uncharged, can actually readily diffuse across the membrane b. To make things go even better an enzyme called carbonic anhydrase breaks H2CO3 down to H2O and CO2 a. CO2 is a gas and can literally diffuse across the cell b. H2O can diffuse across the cell in this part of the kidney c. Some of this goes into the blood and some goes into the cell, once inside the cell the H2O and CO2 can actually reform H2CO3 and this dissociates in to H+ and CO3- a. So the bicarbonate indirectly gets into the cell and is then reformed and pumped out into the blood stream b. The hydrogen just keeps cycling around and the bicarbonate has a net transfer from the lumen to the blood and the sodium has a net transfer from the lumen to the blood as well – so in the proximal tubule we reabsorb Na and bicarbonate
VII. Carbonic Anhydrase Inhibitor [S7] a. One of the drugs that was discovered by accident was that a carbonic anhydrase inhibitor had an impact on Na reabsorption and an impact on bicarbonate as well b. The net effect is a little bit of dieresis – we lose a little bit of Na and a little bit of water if we take this drug c. Modest affect, primarily because it happens at the beginning of the kidney and the rest of the kidney has ample time to compensate for it d. Carbonic anhydrase also plays a role in fluid movement in the aqueous humor a. Carbonic anhydrase inhibitors are useful in the treatment of glaucoma b. If you inhibit the carbonic anhydrase you have the net effect of lowering the intraocular pressure e. Some people are prone to altitude sickness, it is useful to take a carbonic anhydrase inhibitor as it appears to lower cerebrospinal fluid pressure and this happens in altitude sickness 1. Can also use another drug to decrease this pressure (will be discussed later) f. Carbonic anhydrase inhibitors are principally used for mountain sickness, can be used for a cerebral crisis, can be used for glaucoma (other drugs are better) g. Make the urine more alkaline a. What is the urine pH usually? 1. 6.8 b. If you make the urine more alkaline than the pH is going up, if we make it 8.8 what will get reabsorbed? 1. What is it that limits the reabsorbtion of stuff back into your body? Charge a. Neutral things get reabsorbed better, if you affect a change in the pH form 6.8 to 8.8 you have less hydrogen so a chemical that can exist as an HA or A-, the A- form is favored in more basic conditions b. If you have an overdose of aspirin (a weak acid) you will reabsorb more aspirin under the acidic condition so to excrete the aspirin you want to make the urine more alkaline a. So in the case of an overdose with a weak acid alkalizing the urine would be a good thing to help them excrete it b. In the case of an overdose with amphetamine (a weak base) making the urine more acidic will help to excrete the amphetamine c. THIS WILL BE A TEST QUESTION – h. Not a mainline drug for hypertension i. Toxicities a. Can cause low sodium and a low potassium b. Can encourage the formation of calcium phosphate stones because when urine is more alkaline you have the same amount of calcium phosphate but they come out of solution and precipitate c. Skin rashes, allergic reactions, and bone marrow depression may occur
VIII. Proximal tubule [S8] a. Proximal tubule has high water permeability. b. The urine osmolality and fluid concentration don’t change because the sodium and water get reabsorbed at the same time.
IX. Osmotic Agents [S9] a. Presence of large insoluble substances in the tubule results in low water reabsorption because water stays with it. b. A drug like mannitol or glycerin- you can’t reabsorb it. They get filtered by the kidneys, the tubules can’t reabsorb them, so you excrete it with a lot of water. a. When is this a good thing? If you didn’t have lasix or furosemide and you had a severely high BP then you give one of these instead. c. These are called osmotic diuretics. d. Mannitol and glycerine are the most common. e. They increase urine volume. They reduce intercranial pressure. f. If you give too much then you can get dehydrated. You have to titrate how much you give. You want your sodium concentration to stay around 140 mmol or all the cells in your body won’t be able to work like they should. g. Not usually used for high BP, but used in emergency situation.

X. Thick Ascending Limb [S10] a. Ascending limb of loop of henle is impermeable to water. b. It has a specific transporter that carries Na+, K+, and Cl-. c. What is in the lumen here: salt water. What is inside the cell here: low Na+, high K+. d. The gradient doesn’t favor K+ but it does Na+. Add Cl- to make the charge neutral. e. Sodium gradient is 140:5. Potassium gradient is 4:40. The gradient is greater for Na+ going downhill than for K+ going uphill. f. On the other side of the cell you have a pump pumping Na+ right back out, so this keeps the gradient there. g. Under normal circumstances, the K+ wants to leak back out again, so the process that was once electroneutral is now leaking positive charge back into the lumen. h. This is important because this positive charge normally helps to drive other positive charges back into the body such as calcium and magnesium. Electrical charge causes some reabsorption of Ca2+ and Mg2+ under normal circumstances. i. Furosemide blocks this transporter. What happens to everything else? The Na+, K+ and Cl- doesn’t get in. K+ doesn’t have to leak back out and this causes the lumen to remain neutral and inhibits the reabsorption of Ca2+ and Mg2+.
XI. Loops [S11] a. The direct action of furosemide is that it blocks Na+ uptake and increases urine formation. But it also decreases the uptake of Ca2+ and Mg2+. You should worry about them losing Ca+. Furosemide and ethacrynic acid- you should know these drugs they are big ones. b. They are useful for HTN and pulmonary edema (water in the lungs). If you have a high level of Ca2+ in their urine then you can give these drugs and they could lose some. This happens in people that are on cancer therapy- good way to treat their BP and Ca2+ at same time. It could also be used if you have a lot of K+ (Hyperkalemia). c. If you take too much then you are going to lose K+ and Mg2+ and Ca2+. You can get high levels of Ca2+ or uric acid in your urine. Uric acid is in your blood. Where does uric acid play a role? in gout. If you have someone that comes in with gout and high BP, is this (a loop diuretic) is a good drug to give them? NO, because it causes high levels of uric acid. This is your next test question. d. Ototoxicity- ear problems. Diuretics can be helpful for people with inner ear balance problems because there is fluid in the ear canal. It could be by some mechanism that we don’t know that cause an effect of the osmolality of the fluid in the back of the ear. But loop diuretics cause ototoxicity. (2nd hour audio begins here)
XII. Renl tubule Transport System [S12] a. So far we’ve traveled through the loop and we get to the DCT where we have thiazide diurectics.
XIII. Distal Convoluted Tubule [S13] a. The primary transporter here that is the thiazide sensitive carrier is the NaCl cotransporter. b. Sodium is getting pulled out. c. Na+/K+ ATPase is on the other side. d. The net effect is that you establish a negative charge under normal circumstances. If you blocked the activity then the negative charge wouldn’t develop as strongly. e. Thiazide inhibits the reabsorption of NaCl through the Na/Cl cotransporter. f. Two test questions for thiazides is what channel do they impact and what are the side effects. The Na/Cl cotransporter in the DCT is the channel and the other answer is on the next slide g. They reduce the negative transport potential. They increase urine NaCl and K+ but not Ca+ excretion. h. Thiazides [S14] a. HCTZ is the cardinal thiazide used b. Primary indication for hypertension and CHF c. It’s toxicities include hyperlipidemia d. People that go on thiazide therapy, particularly with diabetes, often co-present with CV complications and get up on an antihypertensive medication. Those that take thiazides end up with a worse lipid pattern than those that don’t. e. ACE inhibitors, such as lisinopril, are drugs used in the kidney, they are anti-diuretic and anti-HTN, they have a positive effect on the kidney in diabetics f. They are the first drug of choice for diabetes due to the side effect for hyperlipidemia in thiazides g. They decrease Na+, K+, Cl-, and Mg2+ levels in the blood stream h. A few people have allergic reactions- very uncommon i. Collecting tubule [S15] a. Site of final regulation of salt, water, and acid/base balance b. By this time there is not much left- 95% of sodium has been reabsorbed already c. The Na+ that is left here is sucked back inside and K+ is excreted. 1:1 situation. d. If you’ve given a diuretic upstream, then the sodium level is higher in the lumen because you have blocked the reabsorption upstream. e. What is the net effect? The sodium get absorbed as much as possible and K gets dumped out. f. People who take those drugs have K+ wasting. g. What can you do about this? If you block the sodium channel here with amiloride then you block that. If you block this then you get a lot of sodium going out and you retain the potassium, so this is called a potassium sparing diuretic
XIV. K+ Sparing Agents [S16] a. Amiloride and Triamterene are the two drugs in this category. b. They inhibit sodium influx in the collecting duct and decrease potassium secretion c. Usually used in combination with HCTZ. The combination of the two is probably the most commonly prescribed diuretic. d. Combination with the K+ wasting diuretics and you end up with potassium neutral situation e. Toxicities: too high potassium and metabolic acidosis (unusual)
XV. Aldosterone Antagonist [S17] a. What does aldosterone do? Sodium retention hormone secreted by the adrenal gland. Adrenal gland helps the kidney respond to changes in fluid and electrolyte abnormalities like with a severe loss of blood. b. Aldosterone binds to the mineralocorticoid receptor in response to a fall in blood volume and then you increase the activity of the sodium postassium ATPase and you increase the reabsorption of sodium and thus more water. You retain fluid. c. Aldosterone antagonist- Spironolactone is a competitive inhibitor for aldosterone. It would compete with aldosterone in a situation where you don’t want to retain water. d. When someone has a tumor on their adrenal gland then they secrete a lot of aldosterone. So you can give this drug that would compete with aldosterone for receptors. It is a competitive antagonist e. Side effects: high K+ in the blood f. Aldosterone is closely related to progesterone and testosterone so other side effects include breasts in males and hirsutism (mustaches) in females. It can be a secondary sex characteristic. It can also lead to impotence and GI effects. g. Spironolactone is not a routine drug for HTN. Used for situations like high levels of testosterone present.
[Total 56:10]