---start---- pharm 2/9/98 Fluharty Diuretics this morning's lectures deal with diuretics. we're going to spend the first lecture reviewing some principles of kidney function, esp the processes which regulate Na+ and H2O reabsorption in the nephron. all diuretics basically act by altering these mechanisms that govern sodium reabsorption, some water reabsorptoin. so you have to understand the underlying mechanisms. we won't discuss glomerular filtration or GFR, really, because the diuretics we use clinically don't really affect GFR. then, after this overview, we'll discuss classes of diuretics that act on different areas of the kidney diuretics are both pharmacological and nonpharmacological agents that increase urine flow. they're used clinically to tx edema, of cardiac/liver/kidney dysfunction; cerebral edema; glaucoma; hypertension. virtually all current diuretics increase urinary sodium excretion. as such, they increase total fluid excretion by inhibiting reabsorptive processes. diuretics generally have a single predominant site of action in the nephron - proximal tubular diuretics, LOH diuretics, esp. however, if they act in one area of the nephron, their action will have influence on other areas of the nephron as well. so the diuretic may interfere with a process that is centered in one area of the nephron, but when it acts in that region, there are repercussions for other areas of the nephron. also, because these drugs are powerfully acting and alter in significant ways the composition and volume of body fluids, sometimes the consequences are opposed by homeostatic adjustments within the patient. so potency is affected by nephron actions, and total body homeostatic adjustment. when you affect renal function, this may impact other systems, causing other things to kick in. generally, diuretics are drugs that mainly affect sodium reabsorption through the nephron, generally by affecting one particular process. if you affect reabsorptoin of sodium, you inhibit water absorption, increasing urinary flow. ok. renal physiology see handout "functional organization of the nephron" chart. the nephron starts with the glomerulus, a capillary bed that gets blood from renal blood flow. it filters it basically based on starting equilibrium. blood enters capillary beds, hydrostatic pressure is very high, and it forces fluid out of the capillaries, into bowman's capsule. that fluid then travels through the nephron. drugs can affect GFR, but most diuretics don't. as the fluid enters the tubular network, it first goes into the proximal tubular region, large and reabsorptive area where over 65% of the filtrate is reabsorbed. the remaining 35% of the fluid then enters the LOH, which is really 2 parts - the thin descending limb, which has high permeability to H2O and less to ions, so water flows out of the tubule, concentrating the fluid, and at the tip of the LOH, you're about 4x the osmolarity of plasma. the LOH is the concentrator. then, as you go back up, you are in the thick ascending limb of the LOH, which has virtually no water permeability, and uses Cl- transport. now, the lumenal fluid gets dilute again, because the water can't leave. remember the LOH dips deep into the renal medulla, where osmolarity of interstitial fluid is very high. LOH and vasa recta have kind of a counter current exchange thing going on. ok, so now you're at the distal tubule, also largely impermeable to water. then, you get into late distal tubule and collecting duct, also impermeable unless vasopressin is present - then, the tubular cells dramatically increase permeability to water, then water is efficiently reabsorbed, powerfully drawn out by the medullary tubular osmotic gradient. all along the nephron, the key to understadning is to recognize the properties that govern reabsorption across the peritubular cells. any fluid that can leave the lumen and be reabsorbed across these cells will be picked up by the capillary network (peritubular capillaries), because the protein in blood attracts the fluid. when the glomerulus filters fluid, it doesn't filter protein, so the protein exerts oncotic pressure, drawing in the fluid and electrolytes that make it across the peritubular epi cells. the key to understanding diuretics is to focus on the processes that govern reabsorbtion across the peritubular epi cells. there are five active - no six active processes, and then some passive mechanisms, governing absorption. these are - Na+ entry, per se - across very permeable areas like brush border - Na+ cotransport with glucose, organic acids, phosphate - Na+ H+ proton exhcange mechanisms - Na+ K+ 2Cl- cotransport - Na+ Cl- cotransport - Cl- diffusion, Na+ following - Active Na+ extrusion (sodium potassium pump) these are the ways you get fluid out of the lumen, into the peritubular cells - and the last thing is the way it gets out of the cell, available to get sucked into the blood. so, sodium is the major mover. the proximal tubule has a brush border on the lumenal side, is very active with mitochondrial-driven sodium pumps, is very permeable with lots of surface area. the top three mechanisms in the list above are the main mechanisms. all work in the proximal tubular region. in the late proximal tubular region, Na+ entry is now joined by some Cl- diffusion with Na+ following along. in LOH, when ions move actively, the major mechanism is always the Cl- cotransport. all the drugs affecting LOH as diuretics, affect Cl- transport. in distal convolution, Na+ Cl- cotransport is involved in late distal tubule and collecting system, Na+ entry and Na+/H+ exchange are the main mechanisms. permeability to water is virtually nonexistant unless vasopressin levels are high. key to understanding diuretics is to know where it acts. you know how it acts by knowing what mechanism it affects. once you know what it affects, you can ID the regions it will affect and predict how much it will increase water and sodium excretion. there are other factors affecting diuretic efficacy. as a general rule, if a drug acts where only a little sodium is reabsorbed, it has minimal effects. typically, 90% of water and sodium are already absorbed by the time it gets to collecting system, so if you affect teh collecting system, there's little effect it can have. the later a drug acts within the nephron, the less effect it can have - but they can still be potent and useful diuretics. drugs that act early, affecting proximal tubule, usually are compensated for by events later in teh nephron. if you fail to absorb as much as usual in the proximal tubule, and you send more sodium to the distal nephron, the distal portions increase their absorption, as more fluid is sent to them. so there can be compensatory increases in absorption. so, the most potent diuretics turn out to be the ones that act in the middle - in the LOH. there's still a lot of absorption to inhibit, and there's less time for nephron to compensate. because parts of the nephron can compensate for blocked absorption, sometimes combinations are used. a diuretic that acts in proximal tubule, and one that acts in late distal tubule, might be used together, to get maximal diuresis. this prevents the compensatory mechanisms. also, the physiological state of the animal can impact the efficacy of diuretics. the volume and composition of ECF, and status of renin/ATII system, and so forth. also, many diuretics act on receptors in membrane that are reached via the luminal fluid. the drug has to be filtered by glomerulus, and affect receptors from luminal side. this means that anything diminishing glomerular filtration will diminish delivery of drug to site of action. not all of them work this way, but carbonic anhydrase inhibitors, and others, do. so this is important - drug delivery may be influenced by glomerular filtration. see table in handout. there is one other thing - some parts of the nephron, eg proximal tubular region, the spaces b/w peritubular epi cells are large. this is the zona occludens. ions can flow between the cells, not through them, but between them. this isn't unidirectional, and can go in either direction. this isn't carrier mediated, it's just diffusion. diuretics don't affect that so much. now: where they act how they influence reabsorption when they are used contraindications Osmotic diuretics: probably simplest to understand. these are not really drugs. these are compounds that are freely filtered by the glomerulus, usually large macromolecules, that remain in the luminal fluid in high concentrations. they largely are not reabsorbed, or are reabsorbed very very slowly. therefore they build up a large osmotic gradient w/in the lumen of the nephron, holding on to water and ions that might otherwise be reabsorbed. they're not pharmacologically ctive, just osmotically active. by creating this gradient, they interfere w/many of the processes we listed - especially the ones that are diffusional. for this reason, they've got a big site of action in the proximal tubular region. they interfere w/water and sodium reabsorption there. sometimes these diuretics are exogenous - mannitol - or sometimes endogenous, like glucose or urea, which increase osmolarity of luminal fluid, holding water. something like glucose is eventually metabolized and absorbed - so duration of action of glucose is less than something like mannitol, which lasts much longer. these compounds act in proximal tubule, mainly. they prevent reabsorptoin of water and sodium. they disrupt what's typically known as a favorable electrochemical gradient for the flow of sodium in proximal tubular region. as sodium flows into the proximal tubular cells, it is always immediately pumped out, so intracellular sodium levels stay low. when you have the osmotic diuretics in the lumen, they counter balance this, and prevent the easy flow. they hold on to the water, and indirectly to the sodium. they do not directly influence the cellular processes, they just change osmotic balance. there is some evidence that these diuretics also affect the LOH. they increase inner medullary flow. by preventing reabsorption in proximal tubule, more fluid is delivered to LOH, and vasa recta. the whole way the vasa recta and LOH establish the area of hypertonicity is by being a sluggish system, with little fluid flowing through. when stuff moves through more quickly, it disrupts the system, reducing the hypertonicity of inner medullary region of kidney, which in turn affects reabsorptive processes later in the nephron, b/c the hypertonicity of medulla is what pulls water and ions out later in the nephron. also, generally speaking, osmotic diuretics have a greater effect on overall water reabsorption than ion reabsorption - you tend to lose a bit more water than solutes. uses: when you want to maintain a relatively dilute urine at high flow rate. early tx of ARF, under many conditions; reduction of cerebral edema; glaucoma toxicity/contraindications: b/c they are so effective at inhibiting reabsorption in proximal tubule and also b/c they later affect LOH/distal regions, they can produce too much fluid loss and volume depletion. you have to be careful, esp with mannitol which isn't metabolized and has long action. because this is a dilute diuresis, you may create hypernatremia, drawing fluid from cells, dehydrating them. therefore you must make certain that any animal on these drugs is conscious and behaviorally competent, because hypernatremia triggers thirst, and animal will drink water. you shouldn't use mannitol in an unconscious animal. obviously, you don't use these drugs in animals that have longterm compromised renal function, because eventually they are removed by lumenal flow, and with compromised function you may not be able to get rid of it. Carbonic anhydrase inhibitors: these are some of the oldest and most popular diuretics, esp for tx of glaucoma and motion sickness. they really aren't as potent as many other diuretics. as clinicians we have better tools available. however, they do illustrate how the nephron works. they mainly act in the proximal tubular region, b/c they are reversible inhibitors of carbonic anhydrase, which breaks down bicarbonate, and greatly influences the level of H+ in lumenal and surrounding interstital fluid. carbonic anhydrase is membrane bound and cytosolic. 99% of it must be blocked for the diuretic to be effective. by blocking this enzyme, the diuretic lowers the availability of H+ for the sodium/proton exchanger to work, thereby inhibiting sodium reabsorption across the peritubular epi. the LOH is totally unaffected by these drugs, because the reabsorptive processes in the LOH aren't affected by carbonic anhydrase inhibitors. so this area compensates, lowering the relative potency of these drugs. in addition, b/c they increase flow to more distal regions, they tend to increase potassium excretion. this is because the level of aldosterone tends to influence potassium excretion, and any diuretic that promotes fluid delivery to distal areas of nephron, promotes potassium excretion. people on longterm diuretics get K+ levels checked a lot. sometimes you have to also use another drug to promote K+ reabsorption. K+ sparing diuretics might be used together with another diuretic or something. so the carbonic anhydrase inhibitors may cause hypokalemia. uses and toxicity: these drugs are used to tx glaucoma, to reduce aqueous humor production and to pull fluid away from the chamber, reducing pressure on optic nerve. also to tx metabolic alkalosis, by increasing excretion of bicarbonate. also may be used with LOH diuratics, or late distal tubular diuretics. these drugs, however, may also produce a metabolic acidosis by causing too much bicarb lost, and also create hypokalemia - significant and severe reduction in plasma potassium levels. so they act in similar area as osmotic type, but through blockade of an enzyme that ends up reducing availability of protons for the Na+ H+ exchanger LOH diuretics/high ceiling diuretics: in LOH, the main mechanism for reabsorption is chloride transport. so basically, all the LOH diuretics mainly inhibit chloride transport, thereby affecting all the sodium/fluid cotransport mechanisms that involve Cl-. these are very very potent drugs. there is a lot of fluid left whose reabsorption can be inhibited and there is less nephron left to compensate for it. it's the middle ground thing we discussed before. these are very very potent, rapid acting (less than 30 min) and generally short lived - 2-8 hrs of diuresis. major area of action is thick ascending limb of LOH, where Cl- cotransporters are the main mechanism. furosemide/lasix is one of these. this inhibits water reabsorption and electrolyte reabsorption. also an increase in renal blood flow occurs, which reduces reabsorption in proximal tubular region - but over longterm use, the main mechanism is really the LOH part. these are the most potent diuretics - can increase Na+ excretion 15-20 fold. these have another affect - b/c they interfere w/reabsorption in LOH, they deprive animals of ability to concentrate urine. these animals can't concentrate OR dilute their urine. you're interfering with the mechanism. you produce isoosmotic urine (300 mOsm). use/abuse: they're used to tx edema due to CHF, nephrotic syndrome, kidney dz, and also as antihypertensives. they are abused by wrestlers for wt loss, and by anorexics - very dangerous. deaths are associated with it among high school and college wrestlers. can produce profound abnormalities of ECF, K+ depletion, metabolic alkalosis, hyponatremia, perturbations of many blood electrolytes, ototoxicity (damage to hair cells/cochlear function). so LOH diuretics are most potent, very useful, and most abused. ---break--- thiazide diuretics - act in distal tubular region. less potent than LOH diuretics, b/c more fluid has already been reabsorbed. only 15% of original filtrate remains. however, these have longer half lives, and are useful for longterm maintenance of fluid excretion of a milder type, with fewer risks of severe volume depletion. some of these compounds may have proximal tubular action also. the mechanism is to interfere w/sodium/chloride transport mechanisms, and some of those are shared with PCT and DCT. so some of these drugs have action in both areas. action is to reduce sodium transport across epi cells, promoting water and electrolyte excretion. very popular in vet med b/c they're mild, but effective, for all states of edema and fluid accumulation, and are much less expensive than most other diuretics. like all diuretics that act just before late DCT area, they can cause hypokalemia. they are useful to treat edema and hypertension, esp in humans who are on drugs that cause fluid retention. they have some toxicity, not as severe as LOH diuretics though. can reduce plasma K+ levels, you'd almost always use these with K+ sparing diuretics simultaneously. longterm may cause slow, very slow but steady increase in plasma sodium, can promote cell dehydration in some instances. very popular drugs, work pretty well, minimal risks. potassium sparing diuretics - these do not promote potassium excretion; they promote K+ reabsorption. these act very late in reabsorptive process. about 98% of luminal fluid has already been reabsorbed. you don't use these to produce diuresis - that's not going to work. you use them to promote Na+ excretion and preserve K+. you use a different diuretic to promote diuresis, and use this drug to prevent K+ losses. two main types of K+ sparing diuretics - the aldosterone antagonists, and sodium channel blockers. the aldosterone antagonists block the aldosterone receptors in the late DCT and collecting system. the peritubular epi cells in these areas express aldosterone receptors. aldosterone comes from zona glomerulosa in adrenal cortex, and acts on cytosolic mineralocorticoid receptor to promote Na+ absorption and K+ excretion. so aldosterone causes sodium absorption at the expense of potassium. high plasma potassium levels stimulate aldosterone release. so aldosterone is not only a sodium conserving hormone, it's also a K+ excreting hormone. blocking the receptor promotes K+ reabsorption and Na+ excretion. these antagonists only work if there is aldosterone in the systeym. wouldn't work in animal with Addison's or something. but if aldosterone is present, this is going to work. also adds a tiny bit to the diuresis that's present from the other drug. the Na+ channel blockers block channels that would promote sodium entry into the peritubular cells. these drugs are less specific than aldosterone antagonists. throughout the nephron, Na+ channels are important. so they aren't as specific, and if there is an obvious need for a K+ sparing diuretic, and you know aldosterone levels in animal are pretty normal, then you use an aldosterone receptor antagonist preferentially. you only use the Na+ channel blockers if you know the animal has an adrenal insufficiency or something, and there's nothing going on to block. all K+ sparing diuretics can be dangerous if high K+ level already exists. the last thing you do then is promote potassium reabsorption! you can get a dangerous hyperkalemia. so with renal failure, diabetes, or other anti-aldosterone drugs (ACE inhibitors, etc), you must be very careful to check for this. so if you're using ACE inhibitor to tx CHF, you must not use a K+ sparing diuretic. they are clearly contraindicated when K+ levels are elevated or when aldosterone levels have been inhibited. other diuretics we haven't discussed do exist. these are just the main ones. there are drugs that block vasopressin (which promotes late water absorption in collecting duct), which could produce increased urinary excretion. but the main drugs affect sodium transport, as discussed. there's a table on the site and mechanism of these diuretics: LOH - act on thick ascending limb, affect Cl- transport, huge effect on Na+ excretion, very powerful, increased risk of volume depletion and electrolyte perturbation Thiazides - milder, longer acting, early DCT/some PCT. inhibit NaCL transport. mild, popular, less dangerous but may promote K+ excretion K+ sparing/natriuretic: late distal tubule and collecting sytem; antagonize aldosterone and block Na+ channels osmotic: minimal side effects except hypernatremia. not real drugs. removed via nephron function so be careful with reduced renal function. PCT and LOH. these all work under conditions of renal, liver, heart failure which cause fluid accumulation. tx hypertension, glaucoma, other edema/fluid retention, etc. some drugs we use to tx people with hypertension actually promote fluid retention, so you can treat that side effect with diuretics. side effects: distortions of ECF composition/volume. degree of risk is directly related to effect of drug - LOH most dangerous. ---end---