1. Assistant Professor of Pharmacology and Toxicology
Pharmacology II
Lecture 3
Diuretics
Dr. Mahmoud H. Taleb
Assistant Professor of Pharmacology and Toxicology
Head of Department of Pharmacology and Medical Sciences, Faculty of Pharmacy- Al azhar University
Dr. Mahmoud H. Taleb

2. Diuretics
Diuretics are used to treat excessive water and sodium retention (edema states), hypertension, and electrolyte disorders, e.g., hypokalemia. These drugs are classified according to the renal tubular site of action.
To understand the therapeutic and side effects of diuretics, it is important to review renal tubular function and the maintenance of extracellular fluid and electrolyte homeostasis.
Dr. Mahmoud H. Taleb

3. Normal Regulation of Fluid and Electrolytes by the Kidneys
Approximately 16 to 20 percent of the blood plasma entering the kidneys is filtered from the glomerular capillariesinto the Bowman's capsule. The filtrate, although normally free of proteins and blood cells, does contain mostlow-molecular-weight plasma components in approximately the same concentrations as are found in the plasma. These include glucose, sodium bicarbonate, amino acids, and other organic solutes as well as electrolytes, such asNa+, K+, and Cl-. The kidney regulates the ionic composition and volume of urine by the active reabsorption orsecretion of ions and/or the passive reabsorption of water at five functional zones along the nephron—namely, the proximal convoluted tubule, the descending loop of Henle, the ascending loop of Henle, the distal convoluted
tubule, and the collecting tubule and duct .
Dr. Mahmoud H. Taleb

4. Figure Summary of diuretic drugs. .
Dr. Mahmoud H. Taleb
Figure Summary of diuretic drugs. .

5. REVIEW OF RENAL PHYSIOLOGY
The kidney regulates sodium and water excretion to maintain extracellular fluid (ECF) volume within narrow limits despite an irregular and often excessive dietary intake of sodium. The filtered load of sodium first entering the nephron is equal to the product of the glornerular filtration rate (GFR) and the plasma concentration of sodium.
Sodium reabsorption occurs at four major sites along the nephron: the proximal tubule, the ascending limb of the loop of Henle, the distal convoluted tubule and cortical collecting duct, and the medullary collecting duct . The first three nephron segments each reabsorb at least two-thirds of the sodium chloride that is delivered to them. The bulk of sodium reabsorption occurs in the proximal tubule and loop of Henle, whereas the final amount of sodium excreted is dependent on the fine-regulation at the distal sites.
Dr. Mahmoud H. Taleb

6. Figure 22.2 Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs.
Dr. Mahmoud H. Taleb

7. Dr. Mahmoud H. Taleb

8. DIURETICS
Diuretics (saluretics) elicit increase production of urine (diuresis). In the strict sense, the term is applied to drugs with a direct renal action. The predominant action of such agents is to augment urine excretion by inhibiting the reabsorption of NaCl and water
Diuretic agents have been classified according to chemical structure and/or site of action.
Dr. Mahmoud H. Taleb

9. 1- Loop Diuretics Mechanism and site of action
The loop diuretics directly inhibit the facilitated chloride, sodium, potassium transport at the luminal membrane of the medullary segment of the thick ascending limb of Henle's loop.
Dr. Mahmoud H. Taleb

10. Pharmacokinetics
Furosemide (Lasix, Furoside) is rapidly but incompletely absorbed from the gastrointestinal tract. In the circulation, it is 93% protein-bound. Excretion is primarily via proximal renal tubular secretion, at the organic-acid secretory site. As with most diuretics, renal tubular secretion of furosemide is necessary for pharmacological effect of the drug at the luminal membrane.
Bumetanide (Burnex) is a sulfamoyl benzoic acid derivative like furosemide. It is almost completely absorbed from the gastrointestinal tract, reaching peak blood concentrations within 30 minutes after an oral dose. In plasma, it is 90% protein-bound. The drug is partially metabolized by the liver, but more than 50% is excreted unchanged in the urine within 6 hours of administration.
Ethacrynic acid (RX Edecrin) is well absorbed from the gastrointestinal tract, and in the circulation it is 97% protein-bound. It undergoes partial hepatic metabolism. The major portion is secreted via the proximal renal tubular organic-acid transport sites and can then be reabsorbed at more distal nephron sites via pH-dependent nonionic diffusion.
Torsemide (RX Demadex), is very well absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 30 minutes. It is largely metabolized by the liver, only 20% being excreted unchanged in the urine, so it is less likely than the other drugs in this group to accumulate on repeated administration in patients with impaired renal function. It also has a longer half-life than the other agents of this class, so once-daily administration is sufficient.
Dr. Mahmoud H. Taleb

11. Pharmacological effects
Loop diuretics are highly efficacious natriuretic agents that have the capacity to inhibit reabsorption of up to 20-25% of the filtered sodium load. This efficacy is related to the relatively large magnitude of sodium chloride transport occurring in this nephron segment and to efficiency of the chloride transport blockade.
The kaliuresis observed with loop diuretics is proportional to the increased rate of urine flow caused by these agents.
Dr. Mahmoud H. Taleb

12. Adverse effects and toxicity
Ototoxicity: Hearing can be affected adversely by the loop diuretics, particularly when used in conjunction with the aminoglycoside antibiotics. Permanent damage may result with continued treatment. Ethacrynic acid is the most likely to cause deafness. Vestibular function is less likely to be disturbed, but it, too, may be affected by combined treatment with the antibiotic.
Hyperuricemia: Furosemide and ethacrynic acid compete with uric acid for the renal and biliary secretory systems, thus blocking its secretion and, thereby, causing or exacerbating gouty attacks..
Acute hypovolemia: Loop diuretics can cause a severe and rapid reduction in blood volume, with the possibility of hypotension, shock, and cardiac arrhythmias. Hypercalcemia may occur under these conditions.
Potassium depletion: The heavy load of Na+ presented to the collecting tubule results in increased exchange of tubular Na+ for K+, with the possibility of inducing hypokalemia. The loss of K+ from cells in exchange for H+ leads to hypokalemic alkalosis. Potassium depletion can be averted by use of potassium-sparing diuretics or dietary supplementation with K+.
Hypomagnesemia: A combination of chronic use of loop diuretics and low dietary intake of Mg2+ can lead to hypomagnesemia, particularly in the elderly. This can be corrected by oral supplementation.
Dr. Mahmoud H. Taleb

13. Dr. Mahmoud H. Taleb

14. Drug interactions
Three major groups of drug interactions are well recognized with loop diuretics. The most recently described, and likely the most common, is the blunting of the natriuretic effect of loop diuretics by most nonsteroidal anti-inflammatory agents. Inhibition of intrarenal prostaglandin synthesis by the latter is purported to be the mechanism of this interaction.
Less frequently, these diuretics potentiate the ototoxicity of aminoglycoside antibiotics and the nephrotoxicity of first-generation cephalosporins (cepha-loridine, cephalothin).
Drug interactions with other organic acids have been described and are due to competition between drugs for the secretory transport system. For example, probenecid, a uricosuric agent, delays the renal tubular secretion of the loop diuretics, thereby retarding their diuretic effect. High doses of furosemide have been reported to delay the excretion of tubocurarine and prolong its action.
Dr. Mahmoud H. Taleb

15. 2- Thiazide Diuretics
All thiazides affectthe distal tubule, and all have equal maximum diuretic effects, differing only in potency (expressed on a per milligram basis). [Note: They are sometimes called â€oeceiling diuretics,†because increasing the dose above normal does not promote a further diuretic response.] Like the actions of the loop diuretics, the thiazides partly depend on renal prostaglandin synthesis by a mechanism that is not yet understood.
Mechanism and site of action
Thiazide diuretics inhibit reabsorption of sodium from the lumen in the cortical ascending (diluting) limb of Henle's loop and the distal convoluted tubule. The exact cellular mechanism of action is uncertain. Inhibition of glycolysis and diminution of energy supplies (ATP) required for transport have been implicated.
Pharmacokinetics
Thiazide diuretics are rapidly absorbed from the gastrointestinal tract. The more substituted drugs (i.e., with hydrophobic side-chain) are more highly bound to plasma proteins. As well, they are more lipid-soluble and have a greater apparent volume of distribution. Protein binding decreases the rate of tubular secretion. Lipid solubility enhances reabsorption along the distal nephron. Most of these agents are excreted unchanged in the urine.
Dr. Mahmoud H. Taleb

16. Actions:
Increased excretion of Na+ and Cl-: Chlorothiazide causes diuresis with increased Na+ and Cl- excretion which can result in the excretion of a very hyperosmolar urine.
Loss of K+: Because thiazides increase the Na+ in the filtrate arriving at the distal tubule, more K+ is also exchanged for Na+, resulting in a continual loss of K+ from the body with prolonged use of these drugs. Therefore, it is imperative to measure serum K+ often (more frequently at the beginning of therapy) to assure that hypokalemia does not develop
Therapeutic uses:
a. Hypertension: Clinically, the thiazides have long been the mainstay of antihypertensive medication, because they are inexpensive, convenient to administer, and well tolerated. They are effective in reducing systolic and diastolic blood pressure for extended periods in the majority of patients with mild to moderate
essential hypertension. After 3 to 7 days of treatment, the blood pressure stabilizes at a lower level and can be maintained indefinitely by a daily dosage level of the drug, which causes lower peripheral resistance without having a major diuretic effect.
Many patients can be continued for years on the thiazides alone, although a small percentage of patients require additional medication, such as β-adrenergic blockers. [Note: Thehypotensive actions of angiotensin-converting enzyme inhibitors are enhanced when given in combination with the thiazides.]
Dr. Mahmoud H. Taleb

17. heart failure. If the thiazide fails, loop diuretics may be useful.
b. Heart failure: Thiazides can be the diuretic of choice in reducing extracellular volume in mild to moderate
heart failure. If the thiazide fails, loop diuretics may be useful.
c. Hypercalciuria: The thiazides can be useful in treating idiopathic hypercalciuria, because they inhibit urinary Ca2+ excretion. This is particularly beneficial for patients with calcium oxalate stones in the urinary tract.
d.Diabetes insipidus: Thiazides have the unique ability to produce a hyperosmolar d. urine. Thiazides can substitute for antidiuretic hormone in the treatment of nephrogenic diabetes insipidus. The urine volume of
such individuals may drop from 11 L/day to about 3 L/day when treated with the drug.
Dr. Mahmoud H. Taleb

18. Adverse effects
Most of the adverse effects involve problems in fluid and electrolyte balance.
Potassium depletion: Hypokalemia is the most frequent problem encountered with the thiazide diuretics, and it can predispose patients who are taking digitalis to ventricular arrhythmias (Figure 22.5). Often, K+ can
be supplemented by diet alone, such as by increasing the intake of citrus fruits, bananas, and prunes. In some cases, K+ salt supplementation may be necessary. Activation of the renin-angiotensin-aldosterone
system by the decrease in intravascular volume contributes significantly to urinary K+ losses. Under these circumstances, the K+ deficiency can be overcome by spironolactone, which interferes with aldosterone
action, or by administering triamterene, which acts to retain K+. Low-sodium diets blunt the potassium depletion caused by thiazide diuretics.
Hyponatremia
This serious adverse effect may develop due to elevation of ADH as a result of hypovolemia, as well as diminished diluting capacity of the kidney and increased thirst. Limiting water intake and lowering the dose of diuretic can prevent this condition.
Dr. Mahmoud H. Taleb

19. Sustained hypercalcemia is very occasionally seen with thiazide diuretic use. This is partly due to the increased calcium reabsorption by the kidney. Its presence should alert the physician to pathological states that cause increased serum calcium (hyperparathyroidism, neoplastic disease.
Volume depletion: This can cause orthostatic hypotension o d. r light-headedness.
Hypercalcemia: The thiazides inhibit the secretion of Ca2+, sometimes leading to elevated levels of Ca2+ in
the blood.
e . Hyperglycemia: Patients with diabetes mellitus who are taking thiazides for hypertension may become hyperglycemic and have difficulty in maintaining appropriate blood sugar levels. This is due to impaired release of insulin and tissue uptake of glucose.
f. Hyperlipidemia: The thiazides can cause a 5- to 15-percent increase in serum cholesterol as well as increased serum low-density lipoproteins. Lipid levels, however, may return to normal with long-term therapy.
g.. Hypersensitivity: Bone marrow suppression, dermatitis, necrotizing vasculitis, and interstitial nephritis are
Thiazide diuretics occasionally produce gastrointestinal intolerance (nausea and vomiting), pancreatitis, and allergic manifestations (e.g., skin rashes). Thrombocytopenia and agranulocytosis are rare toxic phenomena.
Dr. Mahmoud H. Taleb

20. Dr. Mahmoud H. Taleb
Figure Summary of some adverse effects commonly observed with thiazide diuretics.

21. 3- Carbonic Anhydrase Inhibitors: Acetazolamide
Mechanism and site of action
Acetazolamide inhibits proximal renal tubular and luminal brush-border carbonic anhydrase. Normally carbonic anhydrase catalyzes the reaction:
Inhibition of carbonic anhydrase results in delayed conversion of intraluminal carbonic acid (H2CO3) to CO2 and H2O. The rise in luminal H+ concentration provides a gradient against H+ secre­tion from the tubular cell. The intracellular hydration of CO2 to H2CO3 and subsequent production of H+ and HCO3– is retarded. Therefore, intracellular H+ available for secretion into the tubular lumen is also decreased. Proximal tubular reclamation of filtered bicarbonate (HCO3–) occurs indirectly by combina­tion of secreted H+ with filtered HCO3– to ultimately form CO2 and H2O, which are immediately reabsorbed. Carbonic anhydrase inhibition causes HCO3– to remain in the tubular fluid. Furthermore, since sodium is the cation that accompanies the entry of HCO3– into the peritubular circulation, carbonic anhydrase inhibition results in some natriuresis. This natriuresis is mild, partly because proximal sodium reabsorption is proportionately larger with other sol­utes, and because of sodium uptake at more distal sites.
Dr. Mahmoud H. Taleb

22. Figure Role of carbonic anhydrase in sodium retention by epithelial cells of renal tubule.
Dr. Mahmoud H. Taleb

23. Pharmacokinetics
Carbonic anhydrase inhibitors, like thiazide diuretics, are well absorbed from the gastrointestinal tract and excreted via proximal renal tubular secretion within 24 hours.
Dr. Mahmoud H. Taleb

24. Therapeutic uses
Treatment of glaucoma: The most common use of acetazolamide is to reduce the elevated intraocular pressure of open-angle glaucoma. Acetazolamide decreases the production of aqueous humor, probably by blocking carbonic anhydrase in the ciliary
body of the eye. It is useful in the chronic treatment of glaucoma but should not be used for an acute attack; pilocarpine is preferred for an acute attack because of its immediate action. Topical carbonic anhydrase inhibitors, such as dorzolamide and brinzolamide, have the advantage of not causing any systemic effects.
Mountain sickness: Less commonly, acetazolamide can be used in the prophylaxis of acute mountain sickness among healthy, physically active individuals who rapidly ascend above 10,000 feet. Acetazolamide given nightly for 5 days before the ascent prevents the weakness, breathlessness, dizziness, nausea, and
cerebral as well as pulmonary edema characteristic of the syndrome.
Dr. Mahmoud H. Taleb

25. Ad verse effects
The most frequent adverse effects seen with carbonic anhydrase inhibitors are hypokalemia and systemic metabolic acidosis.
Allergic and toxic effects are similar to those of other thiazide diuretics. Acute renal failure caused by nephrolithiasis (acetazolamide may crystallize in acidic urine) has been described during chronic acet­azolamide use in the treatment of glaucoma. A more recent congener, methazolamide (Neptazane), has not caused this side effect.
Drug interactions
No recognizable adverse drug interactions have been described for these agents. When carbonic anhydrase inhibitors are combined with thiazide and loop di­uretics, the natriuretic and kaliuretic effects of the drugs can be augmented.
Dr. Mahmoud H. Taleb

26. 4- Potassium-Sparing Diuretics Aldosterone antagonists: spironolactone
Mechanism and site of action:
Normally, aldosterone acts on nephron segments beyond the distal convoluted tubule, stimulating sodium reabsorption in exchange for potassium and hydrogen ions. Spironolactone and its major metabolite, canrenone, inhibit the effect of aldosterone on the kidney. Both bind competitively to cytosolic receptor sites for aldosterone prior to translocation into the nucleus.
Pharmacokinetics:
Spironolactone is well absorbed from the gastrointestinal tract and rapidly undergoes hepatic biotransformation to canrenone, the major metabolite. Canrenone is highly protein-bound and has an elimination half-life of approximately 18 hours, so it contributes to the total dura­tion of action of spironolactone. Excretion occurs via the kidneys and the gastrointestinal tract.
Pharmacological effects:
Aldosterone-stimulated sodium reabsorption in exchange for potassium and hydrogen ion, in the distal, collecting tubules and ducts, accounts for only 2-3% of total sodium reabsorption. Spironolactone therefore causes only a mild natriuresis.
Dr. Mahmoud H. Taleb

27. Adverse effects:
The most potentially dangerous adverse effect of spironolactone is hyperkalemia. This occurs frequently because of inadvertent admin­istration of spironolactone together with potassium supplementation, or because of administration to patients with moderate-to-severe renal insufficiency.
Other frequent side effects of spironolactone in­clude an unpleasant peppermint aftertaste and nau­sea/vomiting. Its steroid molecular structure has been implicated in painful gynecomastia, frequently noted in men. Other side effects related to the steroid structure include loss of libido, impotence, and men­strual irregularities.
Dr. Mahmoud H. Taleb

28. Other potassium-sparing diuretics: triamterene and amiIoride:
Mechanism and site of action:
Triamterene and amiloride inhibit sodium transport in nephron segments beyond the distal convoluted tubule. They do not interact with aldosterone receptors. The specific mechanism of action of triamterene is still unknown. Amiloride directly inhibits the luminal sodium channel. Since sodium uptake enhances potassium secretion in the collecting duct, inhibition of sodium uptake reduces potassium loss.
Pharmacokinetics:
Triamterene undergoes fast and essentially complete gastrointestinal absorption, whereas only 50% of amiloride is absorbed. Onset of diuretic effect is similar for the two drugs, occurring some 2 hours after ingestion. Duration of effect for triamterene is 7-9 hours and up to 24 hours for amiloride.
Pharmacological effects:
Since sodium uptake by the collecting tubules and ducts accounts for only 2-3% of total sodium reabsorption, only a mild natriuresis will occur with these potassium-sparing diuretics. The natriuresis is coupled with decreased potassium excretion.
Dr. Mahmoud H. Taleb

29. Adverse effects:
The major adverse effect is hyperkalemia, which frequently occurs because of inadvertent concurrent potassium supplementation, coadministration of ACE inhibitors, or because of moderate to severe renal insufficiency. Another fre­quent adverse effect is gastrointestinal intolerance.
Drug interactions:
Although not extensively studied, nonsteroidal anti-inflammatory agents op­pose the natriuretic effect of triamterene. Further­more, use of indomethacin together with triamterene has been reported to cause reversible renal insuffi­ciency.
Dr. Mahmoud H. Taleb

30. 5- Osmotic Diuretics:
Mannitol and urea have been utilized as osmotic diuretics. For this purpose these agents are adminis­tered intravenously; they are rapidly and freely filtered by the glomerulus. The hyperosmolality caused by the high intratubular concentration of these solutes prevents sodium reabsorption by effectively diluting the intraluminal sodium concentration and by markedly increasing the tubular fluid flow rate. The overall effect is increased sodium and water excretion.
The adverse effects encountered with osmotic diuretics include hypokalemia and acute intravascular volume overload. The latter effect occurs because the osmotic agent increases the transfer of fluid to the intravascular compartment from interstitial sites. The principal indications for the use of mannitol are to reduce brain edema (e.g., head trauma) and to acutely expand the intravascular volume (e.g., during cardiovascular surgery).
Dr. Mahmoud H. Taleb

31. THERAPEUTIC APPLICATIOn Edema Pulmonary edema:
Congestive cardiac failure:
Cirrhosis with ascites:
Renal diseases
Hypertension
Hyperparathyroidism:
Dr. Mahmoud H. Taleb