Diuretics

Diuretics Carbonic Anhydrase Inhibitors (-zolamide): Acetazolamide is the prototype Notes Pharmacology - Well absorbed orally. - Carbonic anhydrase (CA) plays a role in the reabsorption of Na+ and HCO3- from the proximal convoluted tubules. - HCO3- diuresis causes an increase in urine pH, it is apparent within 30 minutes, maximal at 2 hours, and persists for 12 hours after a single dose. - Excretion of the drug is by - CA is predominantly secretion to the PCT. located in the luminal membrane of the PCT - 85% of the HCO3where it breaks H2CO3 into reabsorption in the PCT is CO2 and H2O. inhibited. Some can still be absorbed in other sites by CA–independent mechanisms, thus, the overall effect is only about 45% inhibition. Indications - Glaucoma: used to control intraocular pressure during acute attacks of glaucoma and for short-term reductions in intraocular pressure both preoperatively and postoperatively. Acetazolamide is effective orally & topically. Topically, dorzolamide, brinzolamide reduce intraocular pressure without systemic effects. Toxicity Hyperchloremic metabolic acidosis: acidosis results from chronic loss of bicarbonate and persists as long as the drug is continued (2). - Urinary alkalization: to increase renal excretion of weak acids e.g. cysteine and uric acid.  Prevents the formation of - Renal Stones: calcium and cystine and uric acid phosphate salts stones. - HCO3- depletion leads to are relatively enhanced NaCl reabsorption, - Metabolic Alkalosis: insoluble at therefore, the diuretic efficacy acetazolamide produces alkaline pH, of acetazolamide decreases metabolic acidosis (loss of thus, renal stone significantly with use over 2 HCO3-) → useful in formation from - CA inhibitors cause: or 3 days. correcting blood alkalosis. these salts is a- ↓ Na+ and HCO3enhanced. - The ciliary body of the eye - Acute Mountain Sickness: reabsorption. secretes HCO3 from the weakness, dizziness, - Renal K+ b- ↓ Na+ /H+ transporter blood into the aqueous insomnia, headache, and wasting. activity. humor – playing a role in its nausea can occur in mountain formation. climbers. Acetazolamide can - Drowsiness,  HCO3- loss, mild paresthesia and increase ventilation natriuresis (1-3%), and  CAIs decrease the hypersensitivity diminishing the symptoms of diuresis. aqueous humor. (1) reactions may mountain sickness . - CA inhibitors are now also occur. - HCO3 secreted by the Epilepsy: acidosis rarely used as diuretics, choroid plexus plays a role ↓seizures. their major clinical use is in the formation of the for glaucoma. cerebrospinal fluid. - Severe hyperphosphatemia: they  CAIs decrease CSF increase urinary phosphate formation and pH. excretion. 1- Altitude leads to hypoxemia → hyperventilation → hypocapnia → alkalosis → limits ventilation → Mountain sickness symptoms. Acetazolamide corrects alkalosis and ventilation which reduces Mountain sickness symptoms. 2- When HCO3- - dependent Na+ reabsorption is reduced, the activity of other receptors responsible for Na+ reabsorption is increased, e.g. Na+/Cl- co-transporter activity increases → Hyperchloremia. Loop Diuretics: Furosemide, Bumetanide, Torsemide, and Ethacrynic acid Notes Pharmacology - Absorption of oral torsemide in 1 hour, duration 4–6 hrs, furosemide 2–3 hrs, duration 2–3 hrs. - Loop diuretics selectively inhibit Na+/K+/2Cl- transporter in the TAL, causing: a- ↓ Lumen-positive potential b- ↓ Reabsorption of Ca+2 and Mg+2 - They are the most efficacious diuretic agents currently available (high ceiling diuretics). - Furosemide, Bumetanide, and Torsemide are sulfonamide loop diuretics, whereas Ethacrynic acid is not a sulfonamide. - Elimination by the glomerular filtration and PCT secretion.  They compete with drugs and weak acids (uric acid) secreted at the PCT.  They may cause hyperuricemia worsening gout. - They cause 10-25% loss of filtered Na+ - Loop diuretics induce the expression of - ↑ dose → ↑ diuretic COX-2, which synthesizes prostaglandins effect; however, from arachidonic acid, thus, they have over-treatment vasodilating effects. PGE2 inhibits salt causes dehydration. transport in the TAL and thus participates - Decreased luminalin the renal actions of loop diuretics. positive potential,  NSAIDs interfere with the actions of which drives cations loop diuretics by reducing reabsorption, prostaglandin synthesis and by induces the loss of reducing the secretion of loop Ca+2 and Mg+2. diuretics; due to the competition for However, since Ca+2 secretion in the proximal tubule. is actively - Both furosemide and ethacrynic reduce reabsorbed in the pulmonary congestion and left ventricular DCT, loop diuretics filling pressures in heart failure before a do not generally measurable increase in urinary output cause hypocalcemia. occurs. These effects on peripheral vascular tone may be due to the release of prostaglandins. Indications - Acute pulmonary edema: loop diuretics are the drug of choice here. Decreasing blood volume reduces left ventricular filling pressures and rapidly relieves pulmonary edema. - Hyperkalemia: loop diuretics enhance urinary excretion of K+. - Acute Renal Failure: Loop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. They are the most effective diuretics in patients with renal insufficiency as they are effective even at GFR below 10 ml/min. - Anion Overdose: Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the TAL. Toxicity - Hypokalemic Metabolic Alkalosis: due to increased K+ and H+ secretion (1). - Ototoxicity: doserelated hearing loss, usually reversible. - Hyperuricemia: common, but painful episodes of gout are rarely reported. - Hypomagnesemia: in patients with dietary magnesium deficiency. - Hypercalcemia can occur in volumedepleted patients - Allergic Reactions: less common with ethacrynic acid (2). - Severe dehydration. - Hyponatremia is less common than with the thiazides. - Loop agents increase renal blood flow. 1- Aldosterone’s, secreted secondary to hypovolemia, the net effect is to excrete potassium and hydrogen ions for sodium ions reabsorption → eventually causing hypokalemic metabolic acidosis. 2- Sulfa-containing drugs can cause hypersensitivity, e.g. Furosemide, Bumetanide, and Torsemide. - Thiazides: Hydrochlorothiazide and Indapamide Notes - Some members of this group retain significant carbonic anhydrase inhibitory activity. - They are the most frequently used diuretics and the least expensive. - The action of thiazides depends in part on renal prostaglandin & can also be inhibited by NSAIDs under certain conditions (similar to loop diuretics). - They inhibit NaCl reabsorption by blocking the Na+/Cl- co-transporter in the DCT → ↑ Na+, K+, Cl-, HCO3-, and H2O excretion. - Thiazides enhance Ca+2 reabsorption but rarely cause hypercalcemia (1). - Thiazides lead to ≈ 5-10% loss of filtered Na+. - High doses will not lead to a further increase in their diuretic effect (low ceiling – unlike loop diuretics). - They are ineffective in pts with impaired renal function or pts with GFR< 20 ml/min (unlike loop diuretics). - They are highly effective in lowering BP when combined with other antihypertensive drugs (synergistic effect). Pharmacokinetics - All thiazides can be administered orally, but there are differences in their metabolism: Indications Toxicity - Hypertension - Edema of heart failure - Hypokalemic Metabolic Alkalosis (CHF). - Nephrolithiasis (calcium renal stones); due to idiopathic hypercalciuria. - Hyperuricemia could precipitate gout. a- Chlorothiazide is not very lipid-soluble and - Hyperglycemia due to must be given in both impaired release relatively large doses. of insulin and - Nephrogenic diabetes It is the only thiazide decreased tissue insipidus: inability to available for parenteral utilization of glucose concentrate urine due to (2) administration. . Hyperglycemia is impaired renal tubule partially reversible response to ADH which b- Chlorthalidone is with the correction of leads to the excretion of slowly absorbed and hypokalemia. large amounts of dilute has a longer duration urine. of action. - Hyperlipidemia 5– 15%: increase in total → i.e. Diabetes c- Indapamide is serum cholesterol and insipidus causes the excreted primarily by LDL. These levels excretion of more water the biliary system, but may return to baseline than sodium (i.e., dilute enough of the active after prolonged use. urine ), t his results in a form is cleared by the net effect of increasing - Hyponatremia. kidney to exert its serum osmolarity. This diuretic effect in the - Allergic Reactions: high serum osmolarity DCT. thiazides are stimulates polydipsia in - All thiazides are secreted sulfonamides and an attempt to dilute the by the organic acid share cross-reactivity serum back to normal secretory system in the with other members of and provide free water PCT and compete with the this chemical group. for excreting the excess secretion of uric acid. As a serum solutes. However, - Photosensitivity or result, thiazides may blunt since the patient is generalized dermatitis uric acid secretion and unable to concentrate occurs rarely. cause hyperuricemia urine to excrete the (similar to loop diuretics). - Weakness, fatigability, excess solutes, the impotence, and - Diuretic of choice in resulting urine fails to paresthesia may occur. treating hypertension. decrease serum Their early hypotensive osmolarity and the cycle - Contraindications: effect is related to a repeats itself, hence Excessive use of any reduction in blood volume. polyuria. diuretic is dangerous Their long-term effect is in patients with  Thiazides allow related to a reduction in hepatic cirrhosis, increased solute peripheral vascular borderline renal excretion in the resistance through direct failure, or heart urine, breaking the vasodilating effect failure. polydipsia-polyuria (Indapamide). cycle. 1- In the DCT, Ca+2 is reabsorbed through Na+/ Ca+2 channels on the basolateral membrane, which is dependent on the Na+ gradient. Thiazides blocking Na+ reabsorption leads to decreased intracellular Na+ levels → increasing the gradient and activity of the channel → increased Ca+2 reabsorption. 2- It is postulated that hypocalcemia leads to decreased insulin release. Potassium-Sparing Diuretics (low efficacy diuretics): Spironolactone, Eplerenone, Amiloride and Triamterene Notes Indications - K+-Sparing diuretics act on the distal portion of the distal tubule and the cortical collecting tubule: where Na+ is exchanged for K+ or H+. - Spironolactone is particularly useful in hyperaldosteronism states, i.e. in the treatment of resistant hypertension due to primary hyperaldosteronism and of refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and severe ascites). - The actions of the aldosterone antagonists depend on renal prostaglandin production; thus, their activity can be inhibited by NSAIDs under certain conditions (similar to loop diuretics and thiazides). - Hypokalemia; since they decrease K+ excretion. - They are two types: 1- Aldosterone antagonists: Spironolactone and Eplerenone. - The aldosterone net effect is ↑ Na+ reabsorption, ↑ K+, and H+ excretion.  Aldosterone antagonists →↑ Na+ excretion, ↓ K+, and H+ excretion. - They are only effective in the presence of aldosterone (competitive antagonists). - Given orally; have delayed onset of action requires several days. - Weak diuretics, usually combined with other diuretics. They have great benefits in improving myocardial function in patients with heart failure. - Spironolactone is an aldosterone antagonist with antiandrogenic activity (has side effects). - Hirsutism (antiandrogenic effect of aldosterone antagonists). - They are available alone or combined with thiazides: thiazide-induced hypokalemia and metabolic alkalosis are ameliorated. Toxicity - Hyperkalemia: can cause mild, moderate, or even life-threatening hyperkalemia → cardiac arrhythmias. It is more severe with eplerenone and more common in patients with diabetes, chronic renal disease or patients on ACE inhibitors - Hyperchloremic Metabolic Acidosis: by inhibiting H+ secretion in parallel with K+ secretion, the K+sparing diuretics can cause acidosis. - Gynecomastia: Spironolactone may cause Gynecomastia, impotence, benign prostatic hyperplasia in males and breast tenderness in females (rare with Eplerenone as they are side effects due to the antiandrogenic activity). - Acute Renal Failure: the combination of triamterene with indomethacin (NSAID) may cause acute renal failure. This has not been reported with other K+sparing diuretics. - Eplerenone is a spironolactone analog with much greater - Kidney Stones: Triamterene is only slightly soluble selectivity and potency for the aldosterone receptor. It is and may precipitate in the urine, causing kidney much less active on androgen and progesterone receptors stones. than spironolactone and therefore has fewer adverse - Contraindications: effects. a- Oral K+ administration should be discontinued if 2- ENaC Blockers: Amiloride and triamterene. K+-sparing diuretics are administered. - They are none steroidal potassium-sparing diuretics. b- Concomitant use of other agents that blunt the They do not block aldosterone receptors, but instead renin-angiotensin system (β blockers or ACE directly interfere with Na+ entry through the epithelial inhibitors) increases the likelihood of Na+ channels (ENaC) in the apical membrane of the hyperkalemia. collecting tubule. c- Patients with liver disease may have impaired - Triamterene is metabolized in the liver, but renal metabolism of triamterene and spironolactone, so excretion is a major route of elimination for the active dosing must be carefully adjusted. form. It has a shorter half-life and must be given more d- Strong CYP3A4 inhibitors (e.g., ketoconazole) frequently than amiloride (not metabolized). can markedly increase blood levels of eplerenone. Agents that alter water excretion: 1- Osmotic Diuretics and 2- ADH 1- Osmotic diuretics: Mannitol, urea, and glycerol Notes - The proximal tubule and descending limb of Henle's loop are freely permeable to water. Any osmotically active agent that is filtered by the glomerulus but not reabsorbed promotes a water diuresis due to increased tubular osmolarity.  Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle's loop; where water is freely reabsorbed mostly. - Mannitol is a sugar, not absorbed by kidney tubules, has no systemic effects and not metabolized. Pharmacology - Mannitol is not absorbed by the GI tract; thus, it must be given parenterally. - Mannitol is not metabolized and is excreted by glomerular filtration within 30–60 minutes, without any important tubular reabsorption or secretion. - Through osmotic effects, they also oppose the action of ADH in the collecting tubule. As a result, urine volume increases. 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. Indications Toxicity - Increase of Urine Volume: used to maintain urine volume and to prevent anuria/oliguria states due to large pigment loads to the kidney (rhabdomyolysis) (1). - Extracellular Volume Expansion: Mannitol extracts water from cells before reaching the kidney and causing diuresis. This leads to the expansion of extracellular volume and hyponatremia. - Reduction of Intracranial and Intraocular Pressure Osmotic: diuretics are used to reduce intracranial pressure, cerebral edema and brain mass before and after neurosurgery, and to reduce intraocular pressure in glaucoma before ophthalmologic procedures.  The above therapeutic uses are based on the fact that osmotic diuretics increase the osmotic pressure of plasma thus extract water from the eye and brain. - Hyponatremia: in patients with diminished renal function, mannitol is retained intravenously and causes osmotic extraction of water from cells, leading to hyponatremia. - Dehydration, Hyperkalemia, and Hypernatremia: as water is extracted from cells, intracellular K+ concentration rises, leading to hyperkalemia. - Headache, nausea, and vomiting. 1- Pigment nephropathy is an abrupt decline in renal function as a consequence of the toxic action of endogenous hemecontaining pigment on the kidney tubules. Such pigments include myoglobin, released from skeletal muscle in rhabdomyolysis, and hemoglobin, released during intravascular hemolysis. ➔ 2- ADH: Vasopressin and desmopressin Notes Pharmacology - They are used in the treatment of central diabetes insipidus. - Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. - Their renal action is mediated primarily via V2 receptors → ADH stimulates water reabsorption through stimulating insertion of "water channels" or aquaporins into the membranes of kidney tubules. - Conivaptan is a pharmacologic antagonist at V1a and V2 receptors. It is only available for IV use. - Other nonselective agents are Lithium and Demeclocycline (a tetracycline antimicrobial drug that has anti-ADH effects). These channels transport solute-free water through tubular Both lithium and cells and back into demeclocycline the blood, leading to a reduce the formation decrease in plasma of cAMP in response osmolarity and an to ADH. increased osmolarity - Conivaptan and of urine. demeclocycline have half-lives of 5–10 hrs. Indications Toxicity - Syndrome of Inappropriate ADH Secretion (excessive insuppressible release of ADH): - Nephrogenic Diabetes Insipidus: ADH antagonists can cause severe hypernatremia and nephrogenic diabetes insipidus (a disorder caused by complete or partial resistance of the kidneys to vasopressin). Nephrogenic diabetes insipidus can be treated with a thiazide diuretic.  Lithium carbonate is used to treat this syndrome, but the response is unpredictable.  Demeclocycline yields a more predictable result and is less toxic.  Conivaptan is administered by IV injection, so it is not suitable for chronic use in outpatients.  Water restriction is often the treatment of choice. - ADH is also elevated in response to diminished effective circulating blood volume, as often occurs in congestive heart failure, dangerous hyponatremia may result.  Conivaptan may be particularly useful because blockade of V1a receptors by this drug leads to decreased peripheral vascular resistance and increased cardiac output. - Renal Failure: both lithium and demeclocycline have been reported to cause acute renal failure. Long-term lithium therapy may also cause chronic interstitial nephritis. - Demeclocycline should be avoided in liver disease and children younger than 12 years. Diuretic Combinations Loop Agents + Thiazides - The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Salt reabsorption in either the TAL or the DCT can increase when the other is blocked. Inhibition of both produces more than an additive diuretic response. - K+-wasting is extremely common and may require parenteral potassium administration with careful monitoring of fluid and electrolyte status. K+-Sparing Diuretics + Loop Agents or Thiazides - Hypokalemia develops in many patients taking loop diuretics or thiazides. This can usually be managed by taking dietary KCl supplements. - When hypokalemia cannot be managed through supplements, the addition of a K+-sparing diuretic can significantly lower K+ excretion. - It should be avoided in patients with renal insufficiency and in those receiving ACE inhibitors, in whom lifethreatening hyperkalemia can develop in response to K+-sparing diuretics. Useful Notes     All diuretics increase Na+ excretion. HCO3- in urine → CAIs ↑ Ca+2 in urine → Loop diuretics ↑ Ca+2 in urine → Thiazides - Mannitol is contraindicated in CHF and pulmonary edema because it draws water from the cells and increases the filling pressures of the heart. - Combining K+-sparing diuretics with ACEIs or ARBs may cause hyperkalemia (contraindicated). - Eplerenone is a selective aldosterone receptor blocker devoid of antiandrogenic effect. - An important difference between loops and thiazides is that loops promote calcium excretion, while thiazides decrease calcium excretion. - Allergies to Sulfonamide containing drugs, cross-allergenicity with: abcd- Carbonic anhydrase inhibitors All loop diuretics, except ethacrynic acid Thiazides Sulfa antibiotics - Diuretic of choice for acute pulmonary edema are loop diuretics, if the patient has sulfonamide allergies, then the drug of choice is ethacrynic acid. - Thiazides are the diuretics of choice for hypertensive patients. They also treat nephrogenic diabetes insipidus. - Oliguria states → Mannitol - High ceiling diuretics (most efficacious) / in acute renal failure → Loop diuretics - NSAIDs inhibit their actions → Thiazides, Loop, and K+ sparing diuretics. - Hyperuricemia → Thiazides and Loop diuretics.