1. Diuretics
Abnormalities in fluid volume and electrolyte composition are common and important clinical disorders. Drugs that block specific transport functions of the renal tubules are valuable clinical tools in the treatment of these disorders. Although various agents that increase urine volume (diuretics) have been described since antiquity, it was not until 1957 that a practical and powerful diuretic agent (chlorothiazide) became available for widespread use.

3. Figure 15–1.Tubule transport systems and sites of action of diuretics.
The nephron is divided structurally and functionally into several segments.
Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells.
Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers).
The physiology of each segment is closely linked to the pharmacology of the drugs acting there.
Figure 15–1.Tubule transport systems and sites of action of diuretics.

4. Introduction "diuresis" = ↑ urine volume
"natriuresis" = ↑ renal sodium excretion.
Renal Tubule Transport Mechanisms
Proximal Tubule
NaHCO3 (85%), NaCl (40%), glucose, amino acids, & other organic solutes are reabsorbed via specific transport systems in the early proximal tubule.
Water (60%) is reabsorbed passively so as to maintain nearly constant osmolality of proximal tubular fluid.
Technically, a "diuretic" is an agent that increases urine volume, while a "natriuretic" causes an increase in renal sodium excretion. Because natriuretics almost always also increase water excretion, they are usually called diuretics.
Potassium ions (K+) are reabsorbed via the paracellular pathway. As tubule fluid is processed along the length of the proximal tubule, the luminal concentrations of these solutes decrease relative to the concentration of inulin, a marker that is filtered but neither secreted nor absorbed by renal tubules. Approximately 66% of total sodium ions (Na+, but 85% of the filtered NaHCO3), 65% of the K+, 60% of the water, and virtually all of the filtered glucose and amino acids are reabsorbed in the proximal tubule
Of the various solutes reabsorbed in the proximal tubule, the most relevant to diuretic action are NaHCO3 and NaCl. Of the currently available diuretics, only one group (carbonic anhydrase inhibitors, which block NaHCO3 reabsorption) acts predominantly in the PCT. In view of the large quantity of NaCl absorbed in this segment, a drug that specifically blocked proximal tubular absorption of NaCl would be a particularly powerful diuretic. No such drug is currently available
Paracellular transport refers to the transfer of substances across an epithelium by passing through the intercellular space between the cells. It is in contrast to transcellular transport, where the substances travel through the cell, passing through both the apical membrane and basolateral membrane.

5. Proximal convoluted tubule
Apical membrane Na+/H+ exchange (via NHE3) and bicarbonate reabsorption in the proximal convoluted tubule cell. Na+/K+ ATPase is present in the basolateral membrane to maintain intracellular sodium and potassium levels within the normal range. Because of rapid equilibration, concentrations of the solutes are approximately equal in the interstitial fluid and the blood.
1. NaHCO3 reabsorption by the proximal tubule is initiated by the action of a Na+/H+ exchanger located in the luminal membrane→ Na enters the cell from the tubular lumen in exchange for a proton from inside the cell → Na+/K+ ATPase in the basolateral membrane pumps the reabsorbed Na+ into the interstitium so as to maintain the normal intracellular concentration of this ion.
2. Protons secreted into the lumen combine with bicarbonate to form carbonic acid, H2CO3 →is rapidly dehydrated to CO2 & H2O by carbonic anhydrase.
3. CO2 produced by dehydration of H2CO3 enters the proximal tubule cell by simple diffusion where it is then rehydrated back to H2CO3 → after dissociation of H2CO3, the H+ is available for transport by the Na+/H+ exchanger, and the bicarbonate is transported out of the cell by a basolateral membrane transporter. Bicarbonate reabsorption by the proximal tubule is thus dependent on carbonic anhydrase (inhibited by acetazolamide).
4. In the late proximal tubule, as bicarbonate & organic solutes have been largely removed from the tubular fluid, the residual luminal fluid contains predominantly NaCl →Na+ reabsorption continues, but the protons secreted by the Na+/H+ exchanger can no longer bind to bicarbonate.
5. Free H+ causes luminal pH to fall, activating a still poorly defined Cl-/base exchanger. The net effect of parallel Na+/H+ exchange & Cl-/base exchange is NaCl reabsorption.
6. Because of the high water permeability of the proximal tubule, water is reabsorbed in direct proportion to salt reabsorption in this segment. Thus, luminal fluid osmolality & sodium concentration remain nearly constant along the length of the proximal tubule. If large amounts of an impermeant solute such as mannitol are present in the tubular fluid, water reabsorption will cause the concentration of the solute to rise to a point at which further water reabsorption is prevented. This is the mechanism by which osmotic diuretics act.

6. Proximal Tubule (cont’d)
Organic acid secretory systems located in the middle third of the proximal tubule (S2) secrete a variety of organic acids (uric acid, nonsteroidal anti-inflammatory drugs - NSAIDs, diuretics, antibiotics, etc) into the luminal fluid from the blood→ help deliver diuretics to the luminal side of the tubule
Organic base secretory systems (creatinine, choline, etc) are present in the early (S1) & middle (S2) segments of the proximal tubule.

7. Loop of Henle Thin descending water permeable
Thin and Tick Ascending (TAL)  water impermeable (Diluting Segment) – Hypertonicity
NKCC2 & Loop Diueretics
lumen-positive potential
Water is extracted from the thin descending limb of the loop of Henle by osmotic forces created in the hypertonic medullary interstitium.
2. The thick ascending limb of the loop of Henle actively reabsorbs NaCl from the lumen (~ 35% of the filtered Na), but unlike the proximal tubule & the thin limb, it is nearly impermeable to water→Salt reabsorption in this part dilutes the tubular fluid ="diluting segment." Medullary portions of the thick ascending limb contribute to medullary hypertonicity and thereby also play an important role in concentration of urine.
3. The NaCl transport system in the luminal membrane of the thick ascending limb is a Na+/K+/2Clcotransporter (blocked by "loop" diuretics). Although this transporter is electrically neutral (2 cations+ 2 anions cotransported), the action of the transporter contributes to excess K+ accumulation within the cell→ back diffusion of K+ into the tubular lumen & development of a lumen-positive electrical potential which provides the driving force for reabsorption of cations—including Mg2+ & Ca2+—via the paracellular pathway (between the cells) → inhibition of salt transport in the thick ascending limb by loop diuretics causes ↑ in urinary excretion of divalent cations in addition to NaCl.

8. Distal Convoluted Tubule
Only 10% of filtered NaCl reabsorbed at DCT
DCT impermeable to water
K+ does not recycle NO lumen positive potential
Ca2+ actively reabsorbed
1. Only ~10% of the filtered NaCl is reabsorbed here. This segment is also relatively impermeable to water → NaCl reabsorption further dilutes the tubular fluid.
2. The mechanism of NaCl transport here is electrically neutral Na+ & Cl- cotransport (blocked by thiazides).
3. Because K+ does not recycle across the apical membrane of the distal convoluted tubule as it does in the loop of Henle, there is no lumen-positive potential in this segment, & Ca2+ & Mg2+ are not driven out of the tubular lumen by electrical forces.
4. However, Ca2+ is actively reabsorbed by the distal convoluted tubule epithelial cell via an apical Ca2+ channel &basolateral Na+/Ca2+ exchanger (This process is regulated by parathyroid hormone).

9. Collecting Tubule (CCT)
This part is responsible for only 2–5% of NaCl reabsorption by the kidney, but still is important for fluid volume regulation & for determining the final Na+ concentration of the urine.
Mineralocorticoids exert a significant influence here.
3. The collecting tubule is the major site of K secretion by the kidney.
4. The mechanism of NaCl reabsorption in the collecting tubule is distinct: the principal cells are the major sites of Na+, K+, & H2O transport, & the intercalated cells are the primary sites of proton secretion. Unlike cells in other nephron segments, the principal cells do not contain cotransport systems for Na+ & other ions in their apical membranes, but exhibit separate ion channels for Na+ & K+. These channels exclude anions →transport of Na+ or K+ leads to a net movement of charge across the membrane.
5. Because the driving force for Na+ entry into the principal cell greatly exceeds that for K+ exit, Na+ reabsorption predominates, & a 10–50 mV lumen-negative electrical potential develops.
6. Na+ that enters the principal cell from the urine is then transported back to the blood via the basolateral Na+/K+ ATPase.
7. The lumen-negative electrical potential drives the transport of Cl- back to the blood via the paracellular pathway & also pulls K+ out of the cell through the apical membrane K+ channel →there is an important relationship between Na+ delivery to the collecting tubule & the resulting secretion of K+.
8. Diuretics that act upstream of the collecting tubule will ↑ Na+ delivery to this site & ↑ K+ secretion.
9. If the Na+ is delivered with an anion which cannot be reabsorbed as readily as Cl- (eg, bicarbonate), the lumen negative potential is ↑, & K+ secretion will be ↑. This mechanism, combined with enhanced aldosterone secretion due to volume depletion, is the basis for most diuretic-induced K+ wasting.
10. Reabsorption of Na+ via the epithelial Na channel (ENaC) & its coupled secretion of K+ is regulated by aldosterone (↑ the activity of both apical membrane channels & the basolateral N+/K+ ATPase →↑ transepithelial electrical potential & ↑ both Na+ reabsorption & K+ secretion.

10. Collecting Tubule and ADH
Water transport across the luminal and basolateral membranes of collecting duct cells.
Above, low water permeability exists in the absence of antidiuretic hormone (ADH).
Below, in the presence of ADH, aquaporins are inserted into the apical membrane, greatly increasing water permeability.
(V2, vasopressin V2 receptor; AQP2, apical aquaporin water channels; AQP3, 4, basolateral aquaporin water channels.)
The collecting tubule is also the site at which the final urine concentration is determined.
Antidiuretic hormone (ADH, also called arginine vasopressin, AVP) controls the permeability of this segment to water by regulating the insertion of preformed water channels (aquaporin-2, AQP2) into the apical membrane via a G protein-coupled cAMP-mediated process.
In the absence of ADH, the collecting tubule (and duct) is impermeable to water and dilute urine is produced. ADH markedly increases water permeability and this leads to the formation of a more concentrated final urine.
ADH also stimulates the insertion of urea transporter UT1 molecules into the apical membranes of medullary collecting tubule cells. Urea concentration in the medulla plays an important role maintaining the high osmolarity of the medulla and in the concentration of urine.
ADH secretion is regulated by serum osmolality and by volume status.

11. Basic Pharmacology

12. Carbonic Anhydrase Inhibitors
predominant location of the enzyme is the luminal membrane of the proximal tubule cells, where it catalyzes dehydration of H2CO3, (critical step in reabsorption of HCO-3).
inhibitors block NaHCO3 reabsorption & cause diuresis.
they are now rarely used as diuretics, but are used for other applications.
acetazolamide is a prototype.
they are sulfonamide derivatives,

13. Carbonic Anhydrase Inhibitors (cont’d)
Pharmacokinetics & Pharmacodynamics
well absorbed after oral administration.
Inhibition of CA →↓ HCO3 reabsorption in the PCT → HCO3 losses & hyperchloremic metabolic acidosis
diuretic efficacy ↓ with use over several days (because ↓ HCO3 in the glomerular filtrate & also due to HCO3- depletion leading to ↑ NaCl reabsorption by the remainder of the nephron).
Because of reduced HCO3- in the glomerular filtrate and the fact that HCO3- depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with use over several days.
excreted by secretion in the proximal tubule S2 segment → dosing must be ↓ in renal insufficiency.

14. At present, the major clinical applications of acetazolamide involve carbonic anhydrase-dependent HCO3- and fluid transport at sites other than the kidney
Eye: ciliary body secretes bicarbonate from the blood into the aqueous humor.
Formation of cerebrospinal fluid (CSF) by the choroid plexus involves bicarbonate secretion into the CSF.
These processes remove bicarbonate from the blood (opposite to proximal tubule), but inhibition of carbonic anhydrase in both cases dramatically alters the pH & quantity of fluid produced.

15. Carbonic Anhydrase Inhibitors Used Orally in Treatment of Glaucoma

16. Carbonic Anhydrase Inhibitors (cont’d)
Clinical Indications & Dosage
Glaucoma: the most common indication for use of carbonic anhydrase inhibitors- topically active agents (dorzolamide, brinzolamide)
Urinary Alkalinization (to ↑excretion of uric acid, cystine, & some other weak acids).
Metabolic Alkalosis (due to excessive use of diuretics in patients with severe heart failure, due to respiratory acidosis).
Acute Mountain Sickness: rapidly progressing pulmonary or cerebral edema
As adjuvants for the treatment of epilepsy etc.
GLAUCOMA The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma, making it the most common indication for use of carbonic anhydrase inhibitors. Topically active carbonic anhydrase inhibitors (dorzolamide, brinzolamide) are also available. These topical compounds reduce intraocular pressure, but plasma levels are undetectable. Thus, diuretic and systemic metabolic effects are eliminated for the topical agents.
B. URINARY ALKALINIZATION Uric acid, cystine, and other weak acids are most easily reabsorbed from acidic urine. Therefore, renal excretion of cystine (in cystinuria) and other weak acids can be enhanced by increasing urinary pH with carbonic anhydrase inhibitors. In the absence of continuous HCO3- administration, these effects of acetazolamide last only 2-3 days. Prolonged therapy requires HCO3- administration. C. METABOLIC ALKALOSIS Metabolic alkalosis is generally treated by correction of abnormalities in total body K+, intravascular volume, or mineralocorticoid levels. However, when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, replacement of intravascular volume may be contraindicated. In these cases, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. Acetazolamide can also be used to rapidly correct the metabolic alkalosis that may develop in the setting of respiratory acidosis. D. ACUTE MOUNTAIN SICKNESS Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m. The symptoms are usually mild and last for a few days. In more serious cases, rapidly progressing pulmonary or cerebral edema can be life-threatening. By decreasing cerebrospinal fluid formation and by decreasing the pH of the cerebrospinal fluid and brain, acetazolamide can increase ventilation and diminish symptoms of mountain sickness. E. OTHER USES Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of epilepsy, in some forms of hypokalemic periodic paralysis, and to increase urinary phosphate excretion during severe hyperphosphatemia.

17. Toxicity of Carbonic Anhydrase Inhibitors
Hyperchloremic Metabolic Acidosis.
Renal Stones: Calcium salts are relatively insoluble at alkaline pH →renal stone formation
Renal Potassium Wasting: NaHCO3 presented to the collecting tubule ↑ the lumen-negative electrical potential in that segment & ↑ K+ secretion.
Hyperchloremic Metabolic Acidosis: results from chronic reduction of body bicarbonate stores & limits the diuretic efficacy of these drugs to 2 or 3 days.
Renal Stones: phosphaturia & hypercalciuria occur during the bicarbonaturic response to these drugs. Renal excretion of solubilizing factors (eg, citrate) may also ↓. Calcium salts are relatively insoluble at alkaline pH →renal stone formation.
Renal Potassium Wasting: NaHCO3 presented to the collecting tubule ↑ the lumen-negative electrical potential in that segment & ↑ K+ secretion.

18. Carbonic Anhydrase Inhibitors (cont’d)
Other Toxicities
Drowsiness & paresthesias (with large doses)
Accumulation in renal failure →nervous system toxicity
Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis)
Contraindications
Liver cirrhosis: alkalinization of the urine may ↓ urinary excretion of NH4 + & contribute to the development of hyperammonemia & hepatic encephalopathy

20. Loop Diuretics
Selectively inhibit NaCl reabsorption in the TAL of the loop of Henle.
(1) Due to the large NaCl absorptive capacity of this segment & (2) the fact that diuresis is not limited by development of acidosis, these drugs are the most efficacious diuretic agents available.
2 prototypes: furosemide & ethacrynic acid.
Furosemide, bumetanide, & torsemide (but not ethacrynic acid) are sulfonamide derivatives.

21. Loop Diuretics (cont’d)
Pharmacokinetics
Rapid absorption (more rapid with torsemide: 1 hr vs furosemide 2-3 hrs).
Elimination by tubular secretion as well as by glomerular filtration.
Diuretic response is extremely rapid following IV injection.
Duration of effect for furosemide is usually 2– 3 hrs & that of torsemide is 4–6 hrs.
Reduction in secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule.

22. Loop Diuretics Pharmacodynamics
Inhibit the luminal Na+/K+/2Cl- transporter in the TAL of Henle's loop→↓reabsorption of NaCl & also ↓ lumen-positive potential that derives from K+ recycling (normally drives divalent cation reabsorption in the loop)→↑ Mg2+ and Ca2+ excretion→ hypomagnesemia in some patients.
do not generally cause hypocalcemia (Ca2+ is actively reabsorbed in the distal convoluted tubule).
However, in disorders that cause hypercalcemia, Ca2+ excretion can be greatly enhanced by combining loop agents with saline infusions.
Other effects (PGs, blood flow?)
Since vitamin D-induced intestinal absorption of Ca2+ can be increased and Ca2+ is actively reabsorbed in the DCT, loop diuretics do not generally cause hypocalcemia
Induce renal prostaglandin synthesis→NSAIDs (eg, indomethacin) can interfere with actions of the loop diuretics by reducing prostaglandin synthesis in the kidney (may be significant in patients with nephrotic syndrome or hepatic cirrhosis).
Furosemide ↑ renal blood flow. Furosemide &ethacrynic acid also ↓ pulmonary congestion & left ventricular filling pressures in heart failure, & in anephric patients.
The main treatment for hypercalcemia is Saline Diuresis mL/h of saline to reverse dehydration & restore urine flow + loop diuretic to ↑urine flow but also ↓Ca reabsorption in ascending limb of loop of Henle
Loop diuretics induce synthesis of renal prostaglandins, which participate in the renal actions of these diuretics. NSAIDs (eg, indomethacin) can interfere with the actions of the loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis. In addition to their diuretic activity, loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs, and in anephric patients.

23. Loop Diuretics (cont’d)
Clinical Indications
Acute pulmonary edema
Other edematous conditions
Acute hypercalcemia
Hyperkalemia (how to facilitate response?)
Acute renal failure (risks vs benefit?)
Hyperkalemia
In mild hyperkalemia—or after acute management of severe hyperkalemia by other measures—loop diuretics can significantly enhance urinary excretion of K+. This response is enhanced by simultaneous NaCl and water administration
Acute Renal Failure
Loop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. However, they do not seem to shorten the duration of renal failure. If a large pigment load has precipitated acute renal failure or threatens to do so, loop agents may help flush out intratubular casts and ameliorate intratubular obstruction. On the other hand, loop agents can theoretically worsen cast formation in myeloma and light chain nephropathy.
C. ANION OVERDOSE Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the thick ascending limb. Saline solution must be administered to replace urinary losses of Na+ and to provide Cl-, so as to avoid extracellular fluid volume depletion

24. Toxicity of Loop Diuretics
Hypokalemic Metabolic Alkalosis: ↑ renal secretion of K+ & H+ (can be reversed by K+ replacement & correction of hypovolemia).
Ototoxicity: dose-related hearing loss, usually reversible. Most common in patients who have ↓ renal function or who are also receiving other ototoxic agents such as aminoglycoside antibiotics.
A. HYPOKALEMIC METABOLIC ALKALOSIS By inhibiting salt reabsorption in the TAL, loop diuretics increase delivery to the collecting duct. Increased delivery leads to increased secretion of K+ and H+ by the duct, causing hypokalemic metabolic alkalosis (Table 15-2). This toxicity is a function of the magnitude of the diuresis and can be reversed by K+ replacement and correction of hypovolemia.

25. Toxicity of Loop Diuretics
Hyperuricemia (how?): can precipitate attacks of gout. May be avoided by using lower doses
Hypomagnesemia:
Allergic Reactions: skin rash, eosinophilia, interstitial nephritis-less common with ethacrynic acid
Severe dehydration: more common than with other diuretics
Hyponatremia may become severe in patients who increase water intake in response to hypovolemia-induced thirst
Hypercalcemia: is it common?
Hyperuricemia is caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule.
Loop agents are sometimes used for their calciuric effect, but hypercalcemia can occur in volume-depleted patients who have another¾previously occult¾cause for hypercalcemia, such as metastatic breast or squamous cell lung carcinoma.
Hypotension and cardiac arrhythmia can also happen with loop diuretics

26. Loop Diuretics (cont’d)
Contraindications
Furosemide, bumetanide, & torsemide: cross-reactivity in patients who are sensitive to other sulfonamides
Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure

27. Thiazides
Inhibit NaCl transport predominantly in the DCT (Some members inhibit CA enzyme)
Prototype is hydrochlorothiazide (HCTZ).
All have unsubstituted sulfonamide group
All can be administered orally, chlorothiazide is the only thiazide available for parenteral use.
Chlorthalidone is slowly absorbed and has a longer duration of action.
Are secreted by the organic acid secretory system in the proximal tubule & compete with the secretion of uric acid by that system →uric acid secretion may be ↓→ hyperuricemia
Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration.
Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the DCT.

28. Thiazides (cont’d) Pharmacodynamics
Inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the NCC transporter.
↓ cell Na+ →↑ Na+/Ca2+ exchange in the basolateral membrane→↑overall reabsorption of Ca2+ in the distal convoluted tubule
Rarely cause hypercalcemia, but can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis).
Are useful in the treatment of kidney stones caused by hypercalciuria.
Action depends in part on renal prostaglandin production→can be inhibited by NSAIDs
In contrast to the situation in the TAL, where loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubule:
(1) In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. (2) In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca2+.

29. Thiazides (cont’d) Clinical Indications & Dosage hypertension,
heart failure,
nephrolithiasis due to idiopathic hypercalciuria,
(4) nephrogenic diabetes insipidus.

30. Table 15–3. Thiazides and Related Diuretics: Dosages

31. Toxicity of Thiazides
Hypokalemic Metabolic Alkalosis and Hyperuricemia- similar to loop diuretics
Impaired Carbohydrate Tolerance & hyperglycemia in patients who are diabetic or who have mildly abnormal glucose tolerance tests. How? (1) + (2)
Hyperlipidemia: 5–15% ↑ in serum cholesterol & ↑ low-density lipoproteins (LDL). May return toward baseline after prolonged use.
Hyponatremia: due to a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, & ↑ thirst. Can be prevented by ↓ dose or limiting water intake.
Impaired carbohydrate tolerance: is due both to (1) impaired pancreatic release of insulin and to (2) diminished tissue utilization of glucose. Hyperglycemia may be partially reversible with correction of hypokalemia.
Hyponatremia is an important adverse effect of thiazide diuretics. It is due to a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake
Hypotension and cardiac arrhthmia may alos occur

32. Thiazides (cont’d) Toxicity (cont’d)
Allergic Reactions: cross-reactivity with sulfonamides. Photosensitivity, dermatitis, hemolytic anemia, thrombocytopenia, acute necrotizing pancreatitis-all are rare.
Weakness, fatigability, paresthesias
Impotence: probably related to volume depletion.
Contraindications
Excessive use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure

33. Potassium-Sparing Diuretics
Antagonize effects of aldosterone at late DCT & CCT either by:
1. direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone)
2. inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene).
Spironolactone is a synthetic steroid with slow onset of action (several days)
Eplerenone, a new spironolactone analog with high selectivity for aldosterone receptor - recently approved for treatment of hypertension.
Triamterene is extensively metabolized, has shorter half-life & must be given > frequently than amiloride.
Amiloride and triamterene are direct inhibitors of Na+ influx in the CCT. Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites. Because triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized).

34. Potassium-Sparing Diuretics (cont’d)
Pharmacodynamics
Na+ absorption (& K+ secretion) in collecting tubules & ducts is regulated by aldosterone,
aldosterone antagonists interfere with this process.
Similar effects are observed with respect to H+ handling by the intercalated cells of the collecting tubule, in part explaining metabolic acidosis
Spironolactone & eplerenone bind to aldosterone receptors & may also ↓ formation of active metabolites of aldosterone
Potassium-sparing diuretics reduce Na+ absorption in the collecting tubules and ducts. Na+ absorption (and K+ secretion) at this site is regulated by aldosterone, as described above. Aldosterone antagonists interfere with this process. Similar effects are observed with respect to H+ handling by the intercalated cells of the collecting tubule, in part explaining the metabolic acidosis seen with aldosterone antagonists (Table 15-2). Spironolactone and eplerenone bind to aldosterone receptors and may also reduce the intracellular formation of active metabolites of aldosterone. Amiloride and triamterene do not block the aldosterone receptor but instead directly interfere with Na+ entry through the epithelial sodium ion channels (ENaC) in the apical membrane of the collecting tubule. Since K+ secretion is coupled with Na+ entry in this segment, these agents are also effective potassium-sparing diuretics. The actions of the aldosterone antagonists depend on renal prostaglandin production. As described above for loop diuretics and thiazides, the actions of K+-sparing diuretics can be inhibited by NSAIDs under certain conditions.

35. Potassium-Sparing Diuretics (cont’d)
Pharmacodynamics (cont’d)
Triamterene & amiloride directly interfere with Na+ entry through Na+ -selective (ENaC) ion channels in apical membrane of collecting tubule. K+ secretion is coupled with Na+ entry in this segment→ K+ -sparing effect
Actions of triamterene & spironolactone depend on renal prostaglandin production→ actions can be inhibited by NSAIDs as described for loop diuretics & thiazides

36. Potassium-Sparing Diuretics (cont’d)
Clinical Indications
States of mineralocorticoid excess, due either to primary hypersecretion (Conn's syndrome, ectopic ACTH production) or to secondary aldosteronism (from heart failure, hepatic cirrhosis, nephrotic syndrome)
Diuretic-induced (thiazides or loop agents) hypokalemia: volume contraction may intensify secondary aldosteronism. Continuing delivery of Na+ to distal nephron sites, renal K+ wasting occurs.
Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. In the setting of enhanced mineralocorticoid secretion and excessive delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response.

37. Table 15–4. Potassium-Sparing Diuretics & Combination Preparations.

38. Potassium-Sparing Diuretics
Toxicity
Hyperkalemia: risk ↑ in the presence of renal disease or of other drugs that reduce renin ( ß-blockers, NSAIDs) or angiotensin II activity ( [ACE] inhibitors, ARBs), especially in patients with renal insufficiency.
Hyperchloremic Metabolic Acidosis: by inhibiting H+ secretion in parallel with K+ secretion
Gynecomastia, impotence, & benign prostatic hyperplasia with spironolactone but not with eplerenone.
Acute Renal Failure: triamterene + indomethacin
Kidney Stones: triamterene is poorly soluble & may precipitate in the urine, causing kidney stones.
D. ACUTE RENAL FAILURE The combination of triamterene with indomethacin has been reported to cause acute renal failure. This has not been reported with other K+-sparing diuretics.

39. Potassium-Sparing Diuretics (cont’d)
Contraindications
Oral K+ administration should be discontinued if aldosterone antagonists are administered.
Should be generally avoided in patients with chronic renal insufficiency
Concomitant use of other agents that blunt the renin-angiotensin system ( ß-blockers or ACE inhibitors) ↑ risk of hyperkalemia.
Patients with liver disease may have impaired metabolism of triamterene & spironolactone, & dosing must be carefully adjusted.
Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole) can ↑ blood levels of eplerenone.

40. Osmotic Diuretics
Proximal tubule & descending limb of Henle's loop are freely permeable to water. An osmotic agent that is not reabsorbed causes water to be retained in these segments & promotes a water diuresis.
Prototype is mannitol.
Poorly absorbed → must be given parenterally.
If administered orally, mannitol causes osmotic diarrhea.
Mannitol is not metabolized and is excreted primarily by glomerular filtration within 30–60 min.

41. Osmotic Diuretics (cont’d)
Pharmacodynamics
act in those segments of the nephron that are freely permeable to water: proximal tubule & descending limb of the loop of Henle.
also oppose the action of ADH in the collecting tubule.
The presence of nonreabsorbable solute such as mannitol prevents normal absorption of water by interposing osmotic force. → urine volume ↑→ ↓contact time between fluid & the tubular epithelium→↓Na+ reabsorption.
Resulting natriuresis is of lesser magnitude than water diuresis→ hypernatremia.
The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ as well as water reabsorption. The resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatremia.

42. Osmotic Diuretics (cont’d)
Clinical Indications
to ↑ urine volume & to prevent anuria that might otherwise result from presentation of large pigment loads to kidney (eg, from hemolysis or rhabdomyolysis)
Reduction of Intracranial & Intraocular Pressure (ICP & IOP)
Osmotic diuretics alter Starling forces so that water leaves cells & ↓ intracellular volume→ used to ↓ ICP in neurologic conditions & to ↓ IOP before ophthalmologic procedures
Test dose of mannitol (12.5 g IV) should be given prior to starting continuous infusion.
Mannitol should not be continued unless there is ↑ in urine flow rate to > 50 mL/h during the 3 hours.
Mannitol can be repeated every 1–2 hrs to maintain urine flow rate > 100 mL/h.
Prolonged use of mannitol is not advised
A dose of 1–2 g/kg mannitol is given IV.
IOP, which must be monitored, should fall in 60–90 minutes.

43. Toxicity of Osmotic Diuretics
Extracellular Volume Expansion: mannitol is rapidly distributed in extracellular compartment & extracts water from cells→ expansion of extracellular volume & hyponatremia prior to diuresis.
This effect can complicate heart failure & may produce pulmonary edema.
Headache, nausea, & vomiting are commonly observed.
Dehydration & Hypernatremia: can be avoided by careful attention to serum ion composition & fluid balance.

44. Antidiuretic Hormone (ADH) Agonists
Vasopressin & desmopressin are used in the treatment of pituitary diabetes insipidus.

45. Antidiuretic Hormone (ADH) Antagonists
Two nonselective agents, lithium & demeclocycline (a tetracycline derivative), are of limited use in some situations.
Both are orally active.
Lithium is excreted by the kidney, & demeclocycline is metabolized in the liver.
Inhibit ADH effects in collecting tubule by (1) ↓ formation of cAMP in response to ADH & also (2) interfere with actions of cAMP in collecting tubule cells.

46. Antidiuretic Hormone (ADH) Antagonists (cont’d)
Clinical Indications
Syndrome of Inappropriate ADH Secretion (SIADH): Lithium carbonate has been used to treat this syndrome, but response is unpredictable & Li+ is toxic. Demeclocycline yields a more predictable result & is less toxic.
Other Causes of Elevated Antidiuretic Hormone (ADH) e.g., diminished effective circulating blood volume. When treatment by volume replacement is not possible, as in heart failure or liver disease, hyponatremia may result → demeclocycline may be used.
Antidiuretic hormone is also elevated in response to diminished effective circulating blood volume, as often occurs in congestive heart failure. When treatment by volume replacement is not desirable, hyponatremia may result. As for SIADH, water restriction is the treatment of choice, but if it is not successful, demeclocycline or conivaptan may be used

47. Antidiuretic Hormone (ADH) Antagonists (cont’d)
Toxicity
Nephrogenic Diabetes Insipidus Lithium-induced nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride.
Acute Renal Failure. Long term lithium therapy may also cause chronic interstitial nephritis.
Other ADRs of lithium: tremulousness, mental obtundation, cardiotoxicity, thyroid dysfunction, & leukocytosis.
Demeclocycline should be avoided in patients with liver disease & in children younger than 12 years.
If serum Na+ is not monitored closely, ADH antagonists can cause severe hypernatremia and nephrogenic diabetes insipidus. If lithium is being used for a psychiatric disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride (see below).

48. Diuretic Combinations: Loop Agents & Thiazides
Some patients are refractory to usual dose of loop diuretics or become refractory after initial response.
Loop agents & thiazides in combination will often produce diuresis when neither agent acting alone is even minimally effective.
Reasons:
1. salt & water reabsorption in either thick ascending limb or distal convoluted tubule can ↑ when the other is blocked.
2. thiazides may produce a mild natriuresis in proximal tubule that is usually masked by ↑ reabsorption in thick ascending limb.

49. Diuretic Combinations: Loop Agents & Thiazides (cont’d)
Metolazone is the usual choice of thiazide-like drug in patients refractory to loop agents alone, given PO only
chlorothiazide can be given parenterally.
Combination of loop diuretics & thiazides can mobilize large amounts of fluid→ close hemodynamic monitoring is essential.
Routine outpatient use is not recommended.
K+-wasting is extremely common & may require parenteral K+ administration with careful monitoring of fluid & electrolyte status.
The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Therefore, close hemodynamic monitoring is essential. Routine outpatient use is not recommended. Furthermore, K+-wasting is extremely common and may require parenteral K+ administration with careful monitoring of fluid and electrolyte status

50. Potassium-Sparing Diuretics & Loop Agents or Thiazides
Hypokalemia eventually develops in many patients who are placed on loop diuretics or thiazides. This can often be managed with dietary NaCl restriction.
When hypokalemia cannot be managed in this way, or with dietary KCl supplements, the addition of a potassium-sparing diuretic can significantly lower potassium excretion.
This approach should be avoided in patients with renal insufficiency in whom life-threatening hyperkalemia can develop in response to potassium-sparing diuretics.

52. Clinical Pharmacology of Diuretic Agents
Edematous States
Are the most common use, as a result of cardiac, renal, or vascular diseases, or abnormalities in the blood oncotic pressure.
Judicious use of diuretics can mobilize interstitial edema fluid without significant reductions in plasma volume.
However, excessive diuretic therapy may lead to further compromise of the effective arterial blood volume with reduction in perfusion of vital organs → requires careful monitoring of the patient's hemodynamic status & understanding of pathophysiology of underlying condition.
INTRODUCTION A common reason for diuretic use is for reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases that reduce blood delivery to the kidney. This reduction is sensed as insufficient "effective" arterial blood volume and leads to salt and water retention and edema formation. Judicious use of diuretics can mobilize this interstitial edema without significant reductions in plasma volume. However, excessive diuretic therapy may lead to further compromise of the effective arterial blood volume with reduction in perfusion of vital organs. Therefore, the use of diuretics to mobilize edema requires careful monitoring of the patient's hemodynamic status and an understanding of the pathophysiology of the underlying illness.

53. Clinical Pharmacology of Diuretic Agents (cont’d)
Heart Failure
Cardiac output is ↓ → changes in blood pressure & blood flow to the kidney are sensed as hypovolemia → renal retention of salt & water→ initially expands intravascular volume & venous return to the heart & may partially restore the cardiac output toward normal.
If the underlying disease deteriorates, the kidney continues to retain salt & water, which then leaks from the vasculature & becomes interstitial or pulmonary edema.
Reduction of pulmonary vascular congestion with diuretics may actually improve oxygenation & improve myocardial function.

54. Clinical Pharmacology of Diuretic Agents (cont’d)
Heart Failure (cont’d)
Edema associated with heart failure is generally managed with loop diuretics.
In severe cases combination of thiazides & loop diuretics is necessary.
Excessive use of diuretics may ↓ venous return & impair cardiac output.
Diuretic-induced metabolic alkalosis may further compromise cardiac function. It is generally treated with replacement of K+ & restoration of intravascular volume with saline, severe heart failure may preclude the use of saline → acetazolamide can help correct alkalosis.

55. Clinical Pharmacology of Diuretic Agents (cont’d)
Heart Failure (cont’d)
Diuretic-induced hypokalemia can exacerbate underlying cardiac arrhythmias & contribute to digitalis toxicity. This can be avoided by ↓Na+ intake→↓Na+ delivery to the K+-secreting collecting tubule or by taking oral KCl supplements or a potassium-sparing diuretic
Drugs that improve myocardial contractility or reduce peripheral vascular resistance are more direct approaches to the basic problem.

56. Clinical Pharmacology of Diuretic Agents (cont’d)
Kidney Disease
Most kidney diseases cause retention of salt & water.
Patients with mild degrees of renal insufficiency can be treated with diuretics when they retain Na+.
Cause of sodium retention is not precisely known, but it probably involves disordered regulation of the renal microcirculation & tubular function through release of vasoconstrictors, prostaglandins, cytokines, &other mediators.
A variety of renal diseases interfere with the kidney's critical role in volume homeostasis. Although some renal disorders cause salt wasting, most kidney diseases cause retention of salt and water. When loss of renal function is severe, diuretic agents are of little benefit, because there is insufficient glomerular filtration to sustain a natriuretic response. However, a large number of patients with milder degrees of renal insufficiency can be treated with diuretics when they retain sodium. Many glomerular diseases, such as those associated with diabetes mellitus or systemic lupus erythematosus, exhibit renal retention of salt and water. The cause of this sodium retention is not precisely known, but it probably involves disordered regulation of the renal microcirculation and tubular function through release of vasoconstrictors, prostaglandins, cytokines, and other mediators. When edema or hypertension develops in these patients, diuretic therapy can be very effective. If heart failure is also present, see the warnings mentioned above

57. Clinical Pharmacology of Diuretic Agents (cont’d)
Kidney Disease (cont’d)
Certain forms of renal disease, e.g., diabetic nephropathy, are associated with development of hyperkalemia at a relatively early stage of renal failure.
Thiazide or loop diuretic will enhance K+ excretion by ↑ delivery of salt to K+-secreting collecting tubule.

58. Clinical Pharmacology of Diuretic Agents (cont’d)
Kidney Disease (cont’d)
Patients with nephrotic syndrome may have ↓ plasma volume in conjunction with ↓plasma oncotic pressures→ diuretic use may cause further ↓ in plasma volume that can impair glomerular filtration rate and lead to orthostatic hypotension.
Most other causes of nephrotic syndrome are associated with retention of salt & water by kidney→expanded plasma volume & hypertension despite the low plasma oncotic pressure→diuretic therapy may be beneficial
Patients with renal diseases leading to the nephrotic syndrome often present complex problems in volume management. These patients may exhibit fluid retention in the form of ascites or edema but have reduced plasma volume due to reduced plasma oncotic pressures. This is very often the case in patients with "minimal change" nephropathy. In these patients, diuretic use may cause further reductions in plasma volume that can impair glomerular filtration rate and may lead to orthostatic hypotension. Most other causes of nephrotic syndrome are associated with primary retention of salt and water by the kidney, leading to expanded plasma volume and hypertension despite the low plasma oncotic pressure. In these cases, diuretic therapy may be beneficial in controlling the volume-dependent component of hypertension.

59. Choice of Diuretics in Kidney Disease
Acetazolamide & potassium-sparing diuretics must usually be avoided because of their tendency to exacerbate acidosis and hyperkalemia, respectively.
Thiazide diuretics are generally ineffective when glomerular filtration rate is < 30 mL/min.
Loop diuretics are often the best choice in treating edema associated with kidney failure.
although excessive use of diuretics can impair renal function in all patients, the consequences are more serious in those with underlying renal disease.
Lastly, although excessive use of diuretics can impair renal function in all patients, the consequences are more serious in those with underlying renal disease.

60. Clinical Pharmacology of Diuretic Agents (cont’d)
Hepatic Cirrhosis
Is often associated with edema, ascites in conjunction with ↑ portal hydrostatic pressures & ↓ plasma oncotic pressures.
Retention of Na by the kidney is due to ↓ renal perfusion, ↓ plasma volume as the result of ascites formation, & ↓ oncotic pressure from hypoalbuminemia.
Plasma aldosterone levels are usually high in response to the reduction in effective circulating volume.
Cirrhotic edema is unusually responsive to spironolactone.

61. Clinical Pharmacology of Diuretic Agents (cont’d)
Hepatic Cirrhosis (cont’d)
Cirrhotic patients are often resistant to loop diuretics, in part because of a ↓ secretion of the drug into the tubular fluid & in part because of high aldosterone levels leading to ↑collecting duct salt reabsorption.
Loop diuretics+spironolactone may be useful.
Overly aggressive use of diuretics can cause marked depletion of intravascular volume, hypokalemia, & metabolic alkalosis→ hepatorenal syndrome & hepatic encephalopathy
It is important to note that, even more than in heart failure, overly aggressive use of diuretics in this setting can be disastrous. Vigorous diuretic therapy can cause marked depletion of intravascular volume, hypokalemia, and metabolic alkalosis. Hepatorenal syndrome and hepatic encephalopathy are the unfortunate consequences of excessive diuretic use in the cirrhotic patient.

62. Clinical Pharmacology of Diuretic Agents (cont’d)
Hypertension
Thiazides are useful in treating virtually all patients & may be completely sufficient in 2/3.
Moderate restriction of dietary Na+ intake (60–100 meq/d) potentiates the effects of diuretics in essential hypertension & to ↓ renal K+ wasting.
Results of ALLHAT study?
Diuretics ↑ efficacy of many agents, particularly ACEI.
Patients on vasodilators such as hydralazine or minoxidil usually require diuretics because the vasodilators cause significant salt & water retention.
A recent very large study (over 30,000 participants) has shown that inexpensive diuretics are similar or superior in outcomes to ACE inhibitor or calcium channel blocker therapy (ALLHAT, 2002). This important result reinforces the importance of thiazide therapy in hypertension.
Loop diuretics are usually reserved for patients with renal insufficiency or heart failure

63. Clinical Pharmacology of Diuretic Agents (cont’d)
Nephrolithiasis
~2/3 of all renal stones contain Ca phosphate or Ca oxalate.
Many patients with such stones exhibit renal defect in Ca PCT reabsorption that causes hypercalciuria
This can be treated with thiazide diuretics, which ↑ Ca reabsorption in DCT
Salt intake must be ↓, as excess dietary NaCl will overwhelm hypocalciuric effect of thiazides.
Ca stones may also be caused by ↑ intestinal absorption of Ca - thiazides are also effective, but should be used with ↓calcium intake.

64. Clinical Pharmacology of Diuretic Agents (cont’d)
Hypercalcemia
Loop of Henle is an important site of Ca reabsorption→loop diuretics can be quite effective in promoting calcium diuresis.
Loop diuretics can cause volume contraction→Ca reabsorption in the proximal tubule is ↑→ saline must be administered simultaneously
Normal saline+furosemide (80–120 mg) are given IV.
Potassium may be added to the saline infusion as needed.
Hypercalcemia can be a medical emergency. Because loop diuretics reduce Ca2+ reabsorption significantly, they can be quite effective in promoting Ca2+ diuresis. However, loop diuretics alone can cause marked volume contraction. If this occurs, loop diuretics are ineffective (and potentially counterproductive) because Ca2+ reabsorption in the proximal tubule would be enhanced. Thus, saline must be administered simultaneously with loop diuretics if an effective Ca2+ diuresis is to be maintained. The usual approach is to infuse normal saline and furosemide ( mg) intravenously. Once the diuresis begins, the rate of saline infusion can be matched with the urine flow rate to avoid volume depletion. Potassium chloride may be added to the saline infusion as needed.

65. Clinical Pharmacology of Diuretic Agents (cont’d)
Diabetes Insipidus
Thiazide diuretics can ↓ polyuria & polydipsia in patients who are not responsive to ADH.
Effect is mediated through plasma volume ↓, with associated ↓ GFR, ↑ proximal reabsorption of NaCl & water, & ↓ delivery of fluid to the diluting segments→ maximum volume of dilute urine that can be produced is ↓& thiazides can significantly ↓ urine flow in the polyuric patient.
Dietary Na restriction can ↑ the beneficial effects of thiazides
What is the common cause of drug-induced diabetes insipidus?
Lithium, used in the treatment of manic-depressive disorder, is a common cause of drug induced
diabetes insipidus
Diabetes insipidus is due either to deficient production of ADH (neurogenic or central diabetes insipidus) or inadequate responsiveness to ADH (nephrogenic diabetes insipidus). Administration of supplementary ADH or one of its analogs is only effective in central diabetes insipidus. Thiazide diuretics can reduce polyuria and polydipsia in both types of diabetes insipidus. This seemingly paradoxic beneficial effect is mediated through plasma volume reduction, with an associated fall in glomerular filtration rate, enhanced proximal reabsorption of NaCl and water, and decreased delivery of fluid to the downstream diluting segments. Thus, the maximum volume of dilute urine that can be produced is lowered and thiazides can significantly reduce urine flow in the polyuric patient. Dietary sodium restriction can potentiate the beneficial effects of thiazides on urine volume in this setting. Lithium (Li+), used in the treatment of manic-depressive disorder, is a common cause of nephrogenic diabetes insipidus and thiazide diuretics have been found to be helpful in treating it. Serum Li+ levels must be carefully monitored in these patients, because diuretics may reduce renal clearance of Li+ and raise plasma Li+ levels into the toxic range (see Chapter 29). Lithium-induced polyuria can also be partially reversed by amiloride, which blocks Li+ entry into collecting duct cells, much as it blocks Na+ entry.