This chapter is relevant to the aims of Section H2(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to have "an understanding of the pharmacology of diuretics". It is less relevant to the answering of actual CICM Primary Exam questions, because this chapter is not about furosemide, and all of the exam questions somehow are. Theoretically, this furocentric bias means that it should be possible to know no other diuretic, and still pass. Nonetheless, some crude workmanlike understanding of broad diuretic pharmacology is probably called for. At least a couple of past paper questions asked to compare two agents, and in the distant past the college had asked for the sites and mechanisms of these drugs, as well as their side effects.
The classification question was passed by 57% of that early cohort, and it has never been repeated again, perhaps because it was too fair.
Classification of Diuretic Agents
by Mechanism of Action
Site Mechanism of diuretic effect Representative drug & its side effects Glomerulus Increased glomerular filtration rate due to afferent arteriolar vasodilation
- Hypotension and vasodilation
Increased glomerular filtration rate due to increased cardiac output
Proximal tubule Carbonic anhydrase inhibition: decreased reabsorption of bicarbonate and sodium; therefore increased tubular fluid osmolality
- Metabolic acidosis
Unresorbable fully filtered solute, therefore markedly increased tubular fluid osmolality
(all electrolytes are lost as a side effect, but to different degrees)
Thick ascending limb
NKCC2 sodium-chloride-potassium transport inhibition; therefore "disruption of the counter current multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid".
- Hypotension (esp.orthostatic)
- Metabolic alkalosis (hypochloraemia)
- Hypernatremia (as sodium is retained by ENaC)
- Acidification of the urine
Distal convoluted tubule NCC sodium and chloride transporter inhibition; therefore increased delivery of sodium to the distal nephron, preventing the reabsorption of urinary water by decreasing the tubulo-medullary osmotic gradient
- unexplained vasodilatory antihypertensive effects in the long term
Collecting duct Aldosterone receptor inhibition, leading to decreased ENaC channel expression and therefore decreased sodium reabsorption
- Metabolic acidosis (Type 4 RTA),
- gynaecomastia (by cross-reactivity with other steroid receptors, eg. sex hormones)
ENaC channel blockade, therefore decreased sodium reabsorption and decreased tubulo-medullary osmotic gradient
Blockade of vasopressin receptors (V2), decreasing the expression of aquaporins and thereby decreasing the reabsorption of water
Blockade of water reabsorption by inducing a conformational change in aquaporin proteins
In terms of peer-reviewed resources, the best single reference for this topic would have to be "Discovery and development of diuretic agents" by Lang & Hropot (1995). In fact, if one can get a hold of the entire Diuretics book from which it originates, one would have no need of any other diuretic-related literature for the rest of one's life, provided one plans to lead a relatively normal life. Diuretics , by Rainer Knauf & Mutschler (1995) is Volume 117 from the Springer Handbook of Experimental Pharmacology series, and is basically 500 or so pages which describe each class of agent with a tear-inducing level of detail. That this is not essential for the CICM primary exam goes without saying, but it would have been amiss not to list it. Obviously, nothing of this sort of quality could ever be free for anybody who really needs it, and the resource-poor candidate will have to resort to open journal reviews like Wile (2012) or Clarke & Simpson (2001).
|Drug||Year of availability|
|Caffeine||Pre-dates the dawn of Man|
|Carbonic anhydrase inhibitors|
|Aldosterone receptor antagonists|
|ENaC channel antagonists|
|Vasopressin receptor blockers|
There is no widely accepted Vaughan Williams-like system of classification for these drugs, but that does not seem to matter very much, because they all have fairly discrete mechanisms of effect that do not overlap (i.e there's no "amiodarone" of diuretics which defies classification by acting simultaneously on all possible mechanisms). Because of this, the most important structural choice for the exam-going candidate is how to order their thoughts logically to enhance their recollection of the various classes. The approach taken here will be to follow the course of urine through the nephron, taking note of any scenic diuretic processes along the way.
Carbonic anhydrase inhibitors are represented by acetazolamide, which is discussed elsewhere in much more detail. Fortunately, virtually all of those details are completely unnecessary, and all that is required for exam purposes is listed in the table below:
|Class||Carbonic anhydrase inhibitor|
|Routes of administration||IV, oral|
|Absorption||Oral bioavailability of about 60-100%|
|Solubility||pKa 7.2; slightly soluble in water|
|Distribution||VOD = 0.3L/kg, 90% protein bound|
|Target receptor||Acetazolamide binds to and blocks the activity of carbonic anhydrase in the proximal tubule, thereby preventing thr reabsorption of filtered bicarbonate|
|Metabolism||No metabolism occurs|
|Elimination||All of the administered dose is cleared renally; half-life is about 6-10 hours|
|Time course of action||Duration of effect is ~ 8-12 hrs|
|Mechanism of action||Produces diuresis by increasing the concentration of osmotically active bicarbonate in the proximal tubule. Also decreases the secretion of aqueous
humour and results in a drop in intraocular pressure. By preventing the reabsorption of bicarbonate, alkalinises the urine and acidifies the body fluids (by decreasing the amount of available buffer)
|Clinical effects||Hypotension (extension of the diuretic effect)
- Metabolic acidosis
- May inhibit folate metabolism
- Inhibits the clearance of amphetamines, salicylates, phenytoin, quinidine
|Single best reference for further information||INCHEM article|
That the inhibition of bicarbonate reabsorption should lead to metabolic acidosis should not surprise anybody, and that's probably the most important mechanism to understand from an exam perspective. Moreover, in the modern era acetazolamide is rarely used for its diuretic effect. Without going into extensive detail about the diuretic mechanism of action, one can simply say that it is poorly understood, and ascribed to the increased delivery of osmotically active bicarbonate to the distal tubule, which is somehow also associated with natriuresis. The exact molecular mechanism by which this happens is not well explained in peer-reviewed literature, and therefore cannot possibly be expected to be well explained by CICM trainees.
Furosemide, or frusemide for the староверы, is the main representative of this class. Being the drug most frequently mentioned in exams and used in clinical environments, it has enjoyed a significant amount of attention in a dedicated chapter all to itself. Again, nothing more than a summary table is required here, as anybody who really wants to read a 5,000 word thesis on furosemide can do so by following that link.
|Chemistry||Anthranilic acid derivative|
|Routes of administration||IV, IM, oral, sublingual, and as a neb|
|Absorption||Variable oral bioavailability, between 10 and 100% (interindividual variability).
Mainly absorbed in the stomach
|Solubility||Acidic drug; pKa 3.6. Highly ionised (therefore poorly lipid soluble) in the relatively alkaline small intestine, as well as in the blood|
|Distribution||VOD = 0.1-0.2L/kg, i.e. mainly confined to the circulating volume. 95% protein bound. Decreased albumin levels increase the volume of distribution and decrease the delivery of the drug to its useful site of action (tubular lumen)|
|Target receptor||Binds competitively to the chloride binding site of the NKCC2 sodium-potassium-0chloride transport protein in the thick ascending limb of the loop of Henle|
|Metabolism||50% of the dose is metabolised in the kidney into an active glucouronide (which has only 25% of the parent drug activity)|
|Elimination||Cleared renally - 50% of the administered dose is eliminated in this way, mainly by active secretion via the OAT organic anion transport proteins in the proximal convoluted tubule|
|Time course of action||Effect lasts for six hours; half life is about 30-120 minutes|
|Mechanism of action||Blockade of the NKCC2 transporter decreases the reabsorption of sodium potassium and chloride in the thick ascending limb
This increases the delivery of sodium potassium and chloride to the distal nephron. The increased solutes in the collecting duct lumen decrease the osmotic gradient between the duct and inner medulla, preventing water reabsorption in the collecting duct, resulting in diuresis.
Because of the main site of sodium reabsorption being the proximal tubule, theoretically only up to 20% of filtered sodium can be excreted by the blockade of all NKCC2 channels, which means loop diuretic therapy has a ceiling effect.
|Clinical effects||Hypovolemia (diuretic effect)
- Hypotension (esp. orthostatic)
- Metabolic alkalosis (hypochloraemia)
- Hypernatremia (as sodium is retained by ENaC)
- Acidification of the urine
|Single best reference for further information||FDA PI data sheet|
Important points to note and then regurgitate include the dependence of furosemide on active proximal tubular secretion. In order to have its effect at the thick ascending limb, this drug needs to be available at the apical surface, i.e. it needs to get into the lumen of the tubule. And it certainly isn't going to get there by glomerular filtration, as it is highly protein-bound and only about 3-5% of it is available as free molecules for filtration. Fortunately, the proximal tubule is highly interested in excreting it actively, to the point where high-affinity basolateral transport proteins will actually strip the frusemide off the albumin as it passes them. This makes furosemide one of the few drugs that enjoy an increase in their clearance rate and in their clinical effect as their protein-bound fraction increases.
Following the realisation that sulfonamide antibiotics and acetazolamide have diuretic effects related to their containing a sulfonamide group led to the pursuit of diuretic effects in other similar molecules, and ultimately led to the development of thiazides when Novello & Sprague (1957) modified sulfanilamide by adding a chlorine atom into the ortho position. They called their variants "benzothiadiazines". These daughter substances still had some carbonic anhydrase inhibitor effects, but these were minor and inconspicuous.
Chlorothiazide and the more potent hydrochlorothiazide became an instant hit in the cardiology community, and basically killed the older mercurial diuretics. However, older agents remained in the formulary for situations where rapid control of fluid overload was called for. Because of their pharmacodynamic effect, the thiazides are limited in how much water excretion they can produce. Lang & Hropot (1995) give 5% as the diuresed fraction of glomerular filtrate which can be maximally achieved by these substances.
Hydrochlorothiazide is a reasonable representative of its class. Or rather, Australian ICU trainees probably do not need to learn about metolazone or bendroflumethiazide. As you can see from the table below, the pharmacokinetics of hydrochlorothiazide are unimpressive, and the bulk of examinable knowledge is mainly in the pharmacodynamic mechanisms.
|Routes of administration||Oral only|
|Absorption||Oral bioavailability 65-75%|
|Solubility||pKa 9.09; practically insoluble in water|
|Distribution||VOD= 1.5-4.2L/kg; 40-68% protein bound|
|Target receptor||NCC sodium/chloride cotransporter in the distal convoluted tubule|
|Metabolism||Does not undergo any hepatic metabolism|
|Elimination||Virtually all of the dose is eliminated renally; half life is 6-9 hours|
|Time course of action||With oral dosing, peak effect is seen within 1-2 hours; mortality-reducing antihypertensive effects develop over months and years|
|Mechanism of action||By decreasing the reabsorption of sodium and chloride in the distal convoluted tubule, thiazides block the reabsorption of up to 5% of the total filtered sodium. This increases the delivery of sodium and chloride to the distal nephron. The increased solutes in the collecting duct lumen decrease the osmotic gradient between the duct and inner medulla, preventing water reabsorption in the collecting duct, resulting in diuresis.|
|Clinical effects||Hypokalemia, hyponatremia, unexplained vasodilatory antihypertensive effects in the long term|
|Single best reference for further information||FDA PI data sheet|
The mechanism of action of thiazides involves the inhibition of the thiazide-sensitive NCC sodium/chloride cotransporter in the distal tubule. The activity of this channel is responsible for 5-10% of the total sodium reabsorption in the nephron and represents a sort of "fine-tuning" of sodium handling (the bulk of which has already occurred by this point).
Logically, to block this channel would mean to decrease the reabsorption of sodium, which leads to two of the most important side effects of thiazide therapy, hyponatremia and hypokalemia. Like with anything that increases the delivery of sodium to the distal nephron, thiazides will increase the elimination of potassium in the collecting duct. This happens because of the reabsorption of sodium through the ENaC channel, which produces a transmembrane potential difference and forces potassium out of the cells along an electrochemical concentration gradient. As loop diuretics are better known for this side effect, it is discussed in greater detail in the furosemide chapter. For thiazides, this is not something we see clinically, mainly because of the relatively restrained way in which we use them (even in the ICU). According to Ellison & Loffing (2009), back in the sixties it would have been routine to start patients on something like 150mg/d of hydrochlorothiazide, and hypokalemia became a major problem for those people.
For the ICU trainee, the hyponatremia is of greater interest, both from a "learn your job" and "pass the exam" perspective. Specifically, their tendency to increase sodium excretion as well as water excretion leads to hypovolemic hyponatremia, which has come up in the Second Part exam (Question 5.1 from the second paper of 2011). The mechanism of this is related directly to their diuretic effect (Hwang & Kim, 2010). The loss of body water, which is desirable, leads to undesirable compensatory endocrine responses: specifically, the release of vasopressin and the subsequent reabsorption of water at the collecting duct. Sure, aldosterone activity also increases, but the extra ENaC action really cannot keep up with the increased sodium delivery to the distal nephron, and the sodium is still lost. The result is a state of water excess and sodium paucity, which produces a hyponatremia with a relatively high urine sodium and a concentrated urine (unless you literally just gave the diuretic, in which case it will probably be dilute). This for some reason seems to fascinate the examiners. Perhaps because the solution is to administer isoosmolar saline, and because the intensivist must carefully watch for the point where the volume is corrected and the vasopressin release is turned off by euvolaemia. At that stage, a profound diuresis abruptly occurs, and the patient may rapidly self-correct their sodium with potentially disastrous neurological consequences.
There are other, much weirder effects that take place over months and years of therapy, and which are probably the main reason we use these drugs in the chronic management of heart failure and hypertension. Sica (2004) goes through these in some detail, in case anyone is interested. In brief, they seem to be related to some sort of poorly defined antihypertensive vasodilator effect which seems entirely unrelated to the diuretic mechanism. Even more weirdly, it still seems to be related to the presence of functioning kidneys (as end-stage renal failure patients do not seem to derive the same benefit), and it seems to persist for months even after the thiazide is discontinued. Intelligent people work themselves into physiology pretzels trying to explain this in terms of RAAS activation and sodium depletion, awaiting further data. Whatever its cause, this effect has earned these drugs a highly recommended first-line status among big cardiology societies, and has led to the proliferation of ubiquitous combination antihypertensives where a small amount of thiazide is conveniently incorporated with other agents.
Spironolactone and eplerenone are the two most widely available aldosterone receptor antagonists which exert their diuretic effect by blocking the action of aldosterone on the collecting duct cells which express ENaC sodium channels on their apical surface. Of these, spironolactone is the oldest, best known, most widely used, and therefore the most likely to become the subject of an exam question. In fact, that's already happened in Question 10 from the 1st paper of 2013, where it was for some reason compared to carvedilol.
|Class||Mineralocorticoid receptor antagonist|
|Routes of administration||Oral only|
|Absorption||95% bioavailability, when taken with food|
|Solubility||pKa 18.01; practically insoluble in water|
|Distribution||VOD= about 2L/kg; 90% protein bound|
|Target receptor||Aldosterone receptors everywhere (particularly in the collecting duct and distal convoluted tubule)|
|Metabolism||100% of spironolactone is metabolised in the liver - some of the metabolites are active and have long half-lives|
|Elimination||Elimination of inactive metabolites is renal. Half-life of spironolactone itself is only 2-3hours, whereas the metabolites have half-lives of 10-20 hrs|
|Time course of action||Some effect is seen withn 3-4 hours, but the maximum effect takes up to 2 days to develop|
|Mechanism of action||By decreasing the reabsorption of sodium via the ENaC channel, aldosterone receptor antagonists increase the loss of sodium. The increased sodium concentration in the lumen of the collecting duct creates a positive charge which repels potassium ions and therefore leads to potassium retention.|
|Clinical effects||Decreased blood pressure and circulating volume, hyponatremia, hyperkalemia, metabolic acidosis (Type 4 RTA), gynaecomastia (by cross-reactivity with other steroid receptors, eg. sex hormones)|
|Single best reference for further information||FDA PI data sheet|
Spironolactone became available for medical use in 1959, and so the relatively old article by Ochs et al (1978) is still good, because our understanding of its main actions has not changed very much since then. From the pharmacokinetic standpoint, the only interesting points of note are its metabolism and chemical structure. Spironolactone is technically a synthetic steroid. Its main metabolite, canrenone, also seems to have some considerable anti-aldosterone activity, and has a longer half life (~20 hours). The onset of the diuretic effect, and the peak effect of regular doses ends up being somewhat delayed because the mechanism of action requires a change in the population of apical proteins.
By competitive inhibition of aldosterone, these drugs influence the synthesis of ENaC protein channels at a nuclear level. The result is the decreased expression of these channels. At the time you give your first dose of spironolactone there are still plenty of channels which have already been expressed and are already active on the apical membrane, which means that realistically spironolactone should not be expected to have an immediate effect on urine output, and its maximum effect develops slowly, over the first 24-48 hours.
So, how does reducing the number of ENaC channels actually produce diuresis? Well. There is a surprising amount of sodium left in the tubular fluid at this point in the tubule. It's only about 2% of the total filtered sodium, but it can increase with water reabsorption via aquaporins, or with concomitant use of other diuretics. This increase in sodium concentration increases the osmolality of the tubular fluid. This, in turn, has the effect of increasing the excretion of water, as aquaporin-mediated reabsorption of water here is a completely passive process that relies on the osmotic gradient between the tubular fluid and the inner medulla. Because there's not much sodium to work on here (normal urinary sodium being something around 20mmol/L), changing its concentration even by ten times will have little effect on the total magnitude of that osmotic gradient, when the inner medullary osmolality is something like 1400 mOsm/kg. From this, it logically follows that spironolactone is not an especially potent diuretic.
Fortunately, it has many other effects, some of which make it highly attractive to long term cardiovascular care. For one, it appears that binding to the aldosterone receptors everywhere and inhibiting them tends to counteract many of the unpleasant side-effects of chronic RAAS activation, including the destructive vascular and ventricular remodelling seen in chronic heart failure. Spironolactone also bears a close enough resemblance to other steroids that it can easily confuse their supposedly specific receptors, posing as (for example) sex hormones. For example, the actions of spironolactone as the antagonist of androgen hormones could lead to hair regrowth and gynecomastia, which could be good and bad, depending on your take.
Together with the likes of spironolactone, these drugs are occasionally referred to as "potassium-sparing" diuretics, owing to the fact that their mechanism of action includes the retention of potassium. In fact their mechanism of action is basically identical to that of spironolactone and eplerenone, except without the aldosterone antagonism, and therefore without the hirsutism and gynecomastia. Common examples include triamterene and amiloride, of which the latter was selected as a class representative for no reason other than it being more familiar to the author.
|Class||ENaC channel blocker|
|Routes of administration||Oral only|
|Absorption||50% bioavailability, which is reduced when it is taken with food|
|Solubility||pKa 8.67; sparingly soluble in water|
|Distribution||VOD = 5L/kg; 23% protein-bound|
|Target receptor||Amiloride and triamterene both bind to and inhibit the ENaC sodium channel in the collecting duct|
|Metabolism||Does not undergo any hepatic metabolism|
|Elimination||All of the administered dose is cleared renally; half-life is about 6-9 hours|
|Time course of action||Peak activity is about 2 hours after administration; effect last about 24 hours|
|Mechanism of action||By decreasing the reabsorption of sodium via the ENaC channel, amiloride and triamterene increase the loss of sodium. The increased sodium concentration in the lumen of the collecting duct creates a positive charge which repels potassium ions and therefore leads to potassium retention.|
|Clinical effects||Hyperkalemia, hyponatremia|
|Single best reference for further information||TGA PI data sheet|
As mentioned above, the blockade of the ENaC channel is functionally indistinguishable from the inhibition of mineralocorticoid receptors, with the exception of the fact that blocking the receptor does not have to wait for nuclear transcription and protein synthesis. This makes these drugs more rapidly effective than the older aldosterone antagonists. Because they do not resemble steroids and do not interfere with aldosterone, they lack both the positive and the negative long-term effects of spironolactone. However, the ENaC channel does exist outside the kidney, and many positive antihypertensive and general survival-promoting effects of amiloride can be attributed to its extrarenal action.
These agents exert their effect by blocking V2 receptors in the collecting duct, thereby decreasing the insertion of aquaporins into the apical membrane. Predictably, this causes a decrease in the reabsorption of water, and therefore diuresis. Currently available agents consist of tolvaptan and conivaptan, of which only conivaptan is available for IV use. The (rather boring) pharmacokinetic details for these drugs are offered here for no specific reason:
|Class||Vasopressin receptor antagonist||Vasopressin receptor antagonist|
|Routes of administration||Oral only||IV, oral|
|Absorption||Oral bioavailability 56%||Oral bioavailability 40%|
|Solubility||pKa 13.4; practically insoluble in water||pKa 11.4; slightly soluble in water|
|Distribution||VOD=3L/kg; 99% protein-bound||VOD=0.5L/kg; 99% protein bound|
|Target receptor||Binds to V2 vasopressin receptors, inhibiting the insertion of aquaporins||Has affinity for both V2 and V1A receptors|
|Metabolism||99% metabolised in the liver, mainly by CYP3A||99% metabolised in the liver, mainly by CYP3A|
|Elimination||Half life is 12 hours||Half life is 5 hours|
|Time course of action||Duration of effect is about 24 hrs||Duration of effect is about 12 hours|
|Mechanism of action||By decreasing the insertion of aquaporins into the apical membrane of collecting duct cells, prevents the reabsorption of water. This distal site of action means this class of drugs is free from electrolyte-depleting side effects (i.e. only water is excreted)||By decreasing the insertion of aquaporins into the apical membrane of collecting duct cells, prevents the reabsorption of water. This distal site of action means this class of drugs is free from electrolyte-depleting side effects (i.e. only water is excreted)|
|Clinical effects||Hypernatremia, hyperkalemia, LFT derangement||Hypernatremia, hyperkalemia|
|Single best reference for further information||Tvaptan brochure||FDA PI data sheet|
As this class acts on such a distal site, and only on the mechanism of water reabsorption, only water is eliminated and so these are diuretics of a very pure form - in the sense that they produce "aquauresis" only. Because all of the hard work of handling electrolytes and other solutes has already been done by that stage, the resulting diuresis does not produce undesirable electrolyte depletion like the loop diuretics and thiazides. Instead undesirable accumulation of electrolytes may result by the loss of body water and the subsequent concentration of these substances. Depending on one's renal wherewithal, one may successfully self-regulate this hypernatremia and hyperkalemia, or one may not.
These drugs seem like natural solutions to the problem of water retention, and they would logically be expected to work harder in scenarios where endogenous vasopressin release is increased (such as SIADH and heart failure). Unfortunately, most oedema is the consequence of the retention of water and sodium. In fact sodium retention is how most oedema-generating mechanisms operate, particularly in heart failure. Ergo, if one were serious about treating heart failure, one would usually be interested in getting rid of both. Moreover, the normal compensatory mechanisms which respond to hypovolemia produced by diuresis would crank up the sodium reabsorption even more. Perhaps for this reason, or perhaps because of unimpressive trial data, the uptake of these substances into the CCF recommendations has been sluggish and reluctant. "May be considered", the society guidelines mutter inaudibly.
Beyond this point, even the most bullshit-resistant reader may wish to abandon this chapter, as its already threadbare quality degenerates markedly from here on. None of these digressions on obscure diuretic agents and weird urine experiments are going to help you pass your exams. Here is a convenient link to act as your emergency exit.
Dopamine needs to be mentioned here but fenoldopam will be the focus because it truly is a drug that cannot decide whether it is a vasodilating antihypertensive or a short-acting diuretic, whereas the dopamine is very clearly an inotrope and vasopressor which just happens to have some random diuretic side-effects. Fenoldopam is a selective dopamine-1 receptor agonist, also classified as a benzazepine (same as the vaptan drugs). In case anybody for some reason requires a one-stop study solution, the article by Brogden & Markham (1989) will satisfy all of their fenoldopam learning needs.
Of all the diuretic substances, this is the only one with the sort of half-life that might make a continuous infusion necessary (10 minutes). It has terrible oral bioavailability, but that did not stop people from trying to market it as an oral preparation (a commercial failure). It is only polite to warn the reader that its other pharmacokinetic properties are boring, so they can scroll past the table of them:
|Class||Dopamine receptor agonist|
|Routes of administration||IV infusion, but also has been trialled orally|
|Absorption||Oral bioavailability only 5.7% due to extensive first-pass metabolism|
|Solubility||pKa 8.12; slightly soluble in water, and highly soluble in organic solvents|
|Distribution||VOD =0.3-07L/kg; 88% protein bound|
|Target receptor||Has affinity for peripheral DA1 receptors and alpha-2 adrenoceptor|
|Metabolism||99% metabolised in the liver, into a variety of metabolites|
|Elimination||Half life is 10 minutes|
|Time course of action||Duration of effect is similar to half life|
|Mechanism of action||Diuretic effect is partly due to afferent renal vascular vasodilation (which increases the glomerular filtration rate) and partly due to natriuresis. The natriuresis is produced by Na+/K+ ATPase inhibition in the proximal tubile and the thick ascending limb results in the decreased reabsorption nof sodium, due to a decreased transmembrane gradient|
|Clinical effects||Hypokalemia, hypotension, tachycardia, flushing, vasodilation|
|Single best reference for further information||Brogden & Markham (1989)|
One part of the diuretic effect of fenoldopam seems to be related to its direct effects on cardiac output and glomerular filtration. When Simmons et al (2006) gave fenoldopam to cats, they found that diuresis coincided with an increase in glomerular filtration rate, and subsided as the glomerular filtration rate returned to normal. This appears to be related to the DA-1 receptor activation, which are the main dopamine receptors in the renal circulation (spread from the main renal artery to the afferent arteriole) and which facilitate vasodilation (they are G-protein coupled, so all this vasodilation is related to the increased cAMP). To vasodilate all of that afferent circulation would increase the blood flow into the glomeruli, provided the systemic arterial pressure remains the same. The result is the increased production of glomerular filtrate.
This same cAMP activation is thought to produce the natriuretic effect seen with dopamine and fenoldopam (Jose et al, 1992). DA-1 receptors are also expressed on proximal and distal tubular cells. Increased cAMP and protein kinase A activity result in the inhibition of Na+/K+ ATPase at the proximal tubule and in the thick ascending limb. As the function of these pumps is the main driver of the sodium reabsorption (it generates and maintains a transmembrane sodium gradient), to disable them will mean to decrease sodium reabsorption, and this indeed what you see.
The side effects of fenoldopam, if you are using it as a diuretic, are vasodilation and hypotension with a compensatory tachycardia. As a natriuretic drug, it should be expected to cause some kind of hypokalemia by increasing the delivery of sodium to the distal nephron, just like loop diuretics - and indeed that is what it does. As far as one can tell from cruising the literature for ten minutes, this drug does not appear to have any other serious or hilarious side effects.
Osmotic diuretics are substances that achieve their diuretic effect mainly by their effect on the osmolality of the tubular fluid, rather than by any effect on ion channels or other reabsorption mechanisms. Most of them share the same properties, which is that they are generally small molecules that are freely filtered at the glomerulus and not reabsorbed in the tubule. Mannitol and urea are the most well known osmotic diuretics, but theoretically anything that fits the above description could act as an osmotic diuretic, including glucose (in HHS) and iodinated IV contrast media. We have had people using urea as a diuretic since 1892, and mannitol has been around since 1802 but only in 1940 did we recognise its potential as a diuretic, when Homer Smith used it to encourage urine flow in the dog, and thought - hey, why not try this on humans.
The first thing one is struck by is just how large the doses have to be in order to achieve the desired effect. Mannitol diuretic doses resemble the doses given to control raised intracranial pressure, in the range of 50-100g. It undergoes no absorption in the GIT, which means all of this dose has to be given IV. Urea does get absorbed orally, but somehow this does not make it any easier, as this only means the poor patient has to regularly ingest vast quantities of this unpalatable substance. Crawford & McIntosh (1925) reported using doses in the range of 40-100g, which raised the blood urea to about 30 mmol/L; they remarked that it "has a peculiar metallic taste and is not pleasant to take", but that "the patients soon become accustomed to it" presumably because it was better than dying of heart failure. It was also spectacularly ineffective: with doses around 45-60g, the urine output of these patients increased by only about 1L/day. The main reason for this poor response is the fact that about 50% of the filtered urea is reabsorbed in the proximal tubule, defeating the purpose of the exercise.
Mannitol diuresis is far more vigorous, because it is administered intravenously, and unlike urea it undergoes no reabsorption anywhere in the nephron. The effect on the urine output is dramatic. Within minutes, urine output increases to 8-10ml per minute. With large doses, 20-30% of the filtered water are excreted during the peak of the diuretic effect, producing a urine output of 15-2.0 L/hr. That's actually not even the maximum possible diuresis - Wesson & Anslow (1948) report cruel experiments from the 1940s where humans were given enough glucose to produce a urine output of 41ml/min, and others where humongous doses of sodium sulfate caused dogs to hose out 57% of their glomerular filtrate as urine. These are obviously extremes, but they illustrate the basic fact that osmotic diuresis is potentially highly potent, which could be an unpleasant surprise if your plan was to use the mannitol for raised ICP.
If anybody ever had to spell out exact how diuresis happens with osmotic agents, one could do so by means of a point form list of arguments:
This movement of water also results in the loss of non-water solutes. The water that does not get reabsorbed in the proximal tubule travels deeper into the tubule and dilutes the fluid in the ascending thin limb of the loop of Henle. That's where you would normally rely on a high concentration of solute to drive its reabsorption; so if the concentration of the solute ends up being low, no reabsorption occurs, and the solute is lost through the urine. This accounts for the loss of all sorts of electrolytes which is usually seen with mannitol diuresis, and each electrolyte may be affected slightly differently. Of the reviews describing these mechanisms, Matheson et al (1981) and Gennari & Kassierer (1974) are probably the most comprehensive, and the latter includes detailed notes on the effect of osmotic diuretics at every segment of the nephron.
Caffeine, theophylline, theobromine and all of their various relatives are well known for their diuretic effect, and stimulants from this chemical class have been used as diuretics from times immemorial. Now, when one says "time immemorial" about the history of xanthine use, one of course is referring to the fact that caffeine and its ilk have formed a core part of folk pharmacology probably since before the development of bipedal locomotion (as modern forest chimpanzees are seen to eat caffeine-containing kola nuts). Unfortunately, we do not have back issues of the Palaeolithic Journal of Heart Failure to refer to. The next best thing are papers like Marvin (1926) which describe these drugs being used as diuretics in congestive heart failure during the early decades of the twentieth century. It begins with a list of everything everybody else has said on the subject, mainly quoting lines from textbooks by eminent-sounding people like some "late Sir James Mackenzie", concluding that there was no agreement between experts as to how and when to use these drugs.
The author then proceeded to describe their own case series of heart failure patients. Theobromine (2.6-5.3g/day) and theophylline (300mg orally tds) were administered. The vast majority of the patients were completely relieved of their peripheral oedema, even as "theophylline caused undesirable symptoms in the vast majority of those who received it" and had to be ceased in several patients "because of the appearance of distressing symptoms which could not be ignored". One cannot help but wonder how much of the benefit was directly related to the diuretic effect and how much as related to the positive inotropy and afterload reduction derived from their phosphodiesterase inhibitor effects. That confounder notwithstanding, these drugs are clearly diuretics, and can be quite potent when used in decent doses. For caffeine, the dose required to elicit diuresis is about 300mg according to Passmore et al in 1987 (3-4 big cups of strong coffee), and this does not produce much diuresis on its own. However, when you give people truly gamer-level amounts of caffeine, this effect is amplified to the point where "proper" diuresis occurs. Neuhäuser-Berthold et al (1997) measured the effects of giving about 700mg to their healthy volunteers and determined that they lost about 2.7% of their body weight in the form of water, corresponding to a diuresis of about 1900ml - which almost sounds like the sort of effect you'd expect from a dose of loop diuretic.
Speaking of the mechanisms of effect. These drugs are definitely cardiovascular stimulants, and some authors have found it difficult to separate the origins of their diuretic effect from the origins of their cardiovascular effects. By increasing the cardiac output, they certainly do increase the blood flow to the kidneys, and some authors dismiss their diuretic effect as being purely based on this increase in flow. However, on closer inspection, this defies logic - as the renal circulation has developed rather clever mechanisms to to maintain a stable blood flow in the face of changing systemic cardiovascular conditions, and it would be unexpected for a cup of coffee to completely overwhelm these ancient mechanisms with just a talkative tachycardia.
Clearly, there is some sort of intrinsic diuretic effect. Coulson & Scheinman (1989) posed that these drugs probably exert their effect by acting on adenosine receptors in proximal tubular cells. They used a potent synthetic adenosine receptor antagonist to do this, which - some might argue - is more caffeine than caffeine - but it illustrated the point nicely. The inhibition of adenosine receptors was associated with a marked increase in the volume of urine and excreted electrolytes - mainly sodum, calcium and phosphate. Another later study by Shirley et al (2002) confirmed that this is a proximal tubular phenomenon, that it is associated with significant natiuresis, and that there is minimal renal microvascular change associated with normal doses of caffeine (i.e. there does not need to be any increase in the cardiac output and renal blood flow for this to happen). Still, many textbooks insist that the main reason for caffeine diuresis is the increase in renal blood flow, and that's what used in the summary at the top of this chapter.
. The exact molecular mechanism of its effect remains to be established, but all are now in agreement that it is definitely a direct tubular effect. Osswald & Schnermann (2011) speculate that it might have something to do with NHE3 sodium/hydrogen exchanger, which is thought to be modulated through adenosine receptors. There is so little direct evidence to support this, or any other competing theory, that it seemed inappropriate to represent it using color:
Again, one needs to reinforce that this is complete speculation, and that there is no data to directly support the assertion that methylxanthines somehow interfere with NHE3 function. Certainly, there is other adenosine-related malarkey going on in the renal cortex, but it is mainly related to tubuloglomerular feedback- specifically, the mechanism of controlling glomerular filtration and salt delivery to the macula densa is through to be mediated by the release of ATP and adenosine receptor activation. At this stage, the molecular effects of caffeine on the proximal tubule remain a promising PhD topic, which sounds like the most perfect reason to fill a lab with some extremely jittery rats.
In spite of their horrific toxicity rapidly becoming obvious to even uneducated feudal peasants, mercury compounds had for centuries occupied a whole shelf at the local pharmacy, probably next to the mummia and laudanum. Their diuretic effect was noted during the sixteenth century, when Europe was thrown into a devastating syphilis crisis by the return of Columbus, whose infected sailors, upon disembarking their ships, immediately made vigorous use of the local sex industry. Apparently, the effects of this early strain on those affected were so "loathsome and conspicuous" that even lepers refused to live near them. When that's your vibe, a bit of drooling neurotoxicity will seem like a small price to pay, and diuresis will go unnoticed as a minor inconvenience.
The diuretic mechanism of these drugs is not completely understood, as they fell out of favour just as we developed instruments to investigate them with. It appears that the mercury ion, rather than the whole molecule, is the most important functional element. Clarkson et al (1965) measured the liberation of radiolabeled mercury ions in the rat kidney and determined that the peak of diuresis was roughly matched to the peak availability of ionised mercury. This makes sense, as even very basic mercury-containing molecules appear to produce some diuretic effect. Mercurous chloride (Hg2Cl2), otherwise referred to as calomel, is a naturally occurring salt of mercury which was among the first antisyphilis drugs used during the Renaissance, and which had a measurable diuretic effect. Clarkson (1972) noted that the highest concentration of deposited mercury seems to occur in the proximal tubule, and so for the longest time it was thought that some sort of pars recta channel blockade or interference with Na+/K+ ATPase activity was responsible for their effect. However, just because the bulk of the mercury is deposited there does not mean that the diuretic effect originates in that segment. It is now thought that mercury binds to sulfhydryl groups of aquaporin proteins, inducing a conformational change which renders these channels inactive (Zalups, 2000).
In the unlikely case that anybody ever needs more detail about the clinical use and pharmacokinetic behaviour of these drugs, excellent reviews by Ray (1958) and Dale & Sanderson (1954) are available, written towards the end of the mercurial diuretic era. Erratic and unpredictable oral absorption made intramuscular injection the most popular mode of delivery. Volume of distribution must be reasonably large as mercury is highly protein-bound and circulates in a complex with albumin. Most of the metal ion was excreted in the urine, and the diuretic effect was brief in duration, petering out over about two hours (though some authors reported a "copious and protracted" diuresis in some heart failure patients)