AGENTS ACTING ON RENAL FUNCTION Dr.Sanjib Das MD.

AGENTS ACTING ON RENAL FUNCTION Dr.Sanjib Das MD

I. Diuretics and drugs acting on water excretion
Pharmacology Know the sites for water and solute transport along the nephron. Describe the sites & MOA of diuretics & other drugs i.e. glomerulus, proximal tubule, loop of Henle (thin limb; medullary and cortical thick ascending limb), distal tubule and collecting ducts. . For each class of diuretics, understand the important features of pharmacokinetics, pharmacodynamics and toxicity, including contraindications. Compare the effects of prototypical diuretics and other agents on excretion of various electrolytes and compare effects on cardiovascular system as to antihypertensive effects. Describe the therapeutic uses of these agents: e.g., edema causing dysfunction resulting from decreased cardiac, liver and renal function, and use in treatment of poisoning. State appropriate agents to be used in each condition.

Relate absorption distribution and excretion to particular therapeutic uses; e.g., the use of osmotic diuretics or vasodilators to increase urine flow in cases of impending renal failure. Describe the interactions of diuretics with other drugs such as cardiac glycosides, oral anticoagulants, oral hypoglycemics, uricosuric drugs, aminoglycoside antibiotics and non-steroidal anti-inflammatory drugs. State the adverse effects of diuretics related to and unrelated to water and electrolyte excretion. Relate effects of diuretics that would contraindicate their use in certain conditions, e.g., use of osmotic diuretics in pulmonary edema. Understand the combined use of loop agents and thiazides. Describe and understand the mechanisms whereby furosemide and thiazides are useful in the management of various calcium metabolism disorders. Understand how dietary management can influence diuretic efficacy or toxicity. Describe the site and mechanism of agents used to treat diabetes insipidus. Know that demeclocycline is used in water intoxication due to inappropriate secretion of antidiuretic hormone. Be aware how lithium compounds may cause a syndrome like diabetes insipidus.

Renal Physiology Review
Kidneys filter 180 L of plasma to form 1.5 L of urine per day 3 basic functions of kidneys: 1) filtration 2) reabsorption 3) secretion Nephron is the basic urine-forming unit consisting of: glomerulus = filtering apparatus; filtration is nonselective long tubular portion = reabsorbs and conditions glomerular filtrate. ( Principles of Osmolarity & Electronutrality. ) Urine composition is determined mainly by reabsorption and modified by secretion The main goals of renal function are to: reabsorb substances that the body needs, maintain acid-base balance, and excrete waste and foreign products that have to be eliminated

What happens as fluids pass through the nephron?
Glomerulus forms 120 mL of ultrafiltrate to produce 1 mL of urine per min All small plasma molecules (electrolytes, amino acids, drugs, glucose, metabolic wastes) are filtered while cells and large molecules (lipids, proteins) remain in the blood Most prominent filtered constituents are sodium and chloride ions with smaller amounts of bicarbonate and potassium Proximal convoluted tubule Absorbs Na (60 %),Cl, NaHCO3 (almost all), glucose, amino acids, organic solutes Water is reabsorbed passively to keep osmolarity constant NaHCO3 reabsorption depends on carbonic anhydrase activity

What happens as fluids pass through the nephron?
Loop of Henle - tubular segment between proximal and distal convolutions actively reabsorbs 35% of NaCl but is impermeable to water so that the tubular fluid becomes diluted Luminal membranes contain the Na+/K+/2Cl- transporter system Macula densa = specialized cells in the thick ascending limb act as chemoreceptors to influence renin secretion by sensing NaCl concentrations of tubular fluid leaving the loop Distal convoluted tubule - tubular segment between loop and collecting tubule contains the NaCl transporter which reabsorbs 10% of filtered NaCl Collecting tubule has principal and intercalated cells with ion channels for Na+ and K+ As the final site of NaCl reabsorption it determines the final Na+ concentration of urine Na+ reabsorption is coupled to K+ & H+ secretion (both processes are increased by aldosterone)→Hypokalemia & Alkalosis .

Diuretic Drugs Diuresis defined as Increase in urine volume or flow causing Natriuresis by blocking the transport functions of the renal tubules Most diuretics act by blocking sodium and chloride reabsorption to Increase intratubular osmotic pressure Prevent the passive reabsorption of water Increase urine flow Amount of solute (Na+) in tubular fluid decreases progressively as the fluid flows from proximal tubule to collecting duct: Drugs acting early (i.e., loop diuretics) will block solute reabsorption the most and produce the greatest diuresis Drugs acting late (i.e., potassium sparing diuretics) have little solute reabsorption to block, since most of the solute has already been reabsorbed and the ensuing diuresis will be weaker or relatively less Used clinically to adjust body fluid volume and/or composition in: Hypertension Acute and chronic heart failure Acute and chronic renal failure Nephrotic syndrome, and cirrhosis

100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day
DRUG C (Site 3) NBME DRUG A (Site 1) 5-10% Antikaliuretics DRUG D (Site 4) Thick Ascending Limb 60-70% 4.5% Collecting duct 20% 100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day DRUG B (Site 2) Arrange drug A,B,C & D according to diuretic efficacy……(high to low) 0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/day From Knauf & Mutschler Klin. Wochenschr :

Tubular Sites of Diuretic Action
Classification Five Main Diuretic Classes Based on site or mechanism of action: -CA inhibitors -Osmotic -Loop -Thiazides -K+ sparing Diuresis results from actions on different tubular segments, but never on the glomerulus

B. Know the Classification of Agents Acting on Renal Function
Diuretics Carbonic anhydrase inhibitors Osmotic diuretics Loop agents Thiazides Potassium-sparing diuretics Agents affecting water excretion Decreased by ADH Analogue Increased by ADH Antagonists

CARBONIC ANHYDRASE INHIBITORS
Oral Preparations: Acetazolamide (1) Dichlorphenamide Methazolamide Ophthalmic Preparations: Brinzolamide Dorzolamide Note: most have common ending -zolamide

Carbonic anhydrase (CA) is located in luminal membranes of proximal tubule cells where it catalyzes degradation of carbonic acid (H2CO3) for NaHCO3 reabsorption in the proximal tubule CA inhibitors produce diuresis by blocking NaHCO3 reabsorption CA inhibitors are well-absorbed following oral administration but diuretic effectiveness diminishes after several days because bicarbonate depletion eventually enhances NaCl reabsorption The prototype CA inhibitor is acetazolamide which is now rarely used as diuretic, but used to inhibit CA at sites other than the kidneys (i.e., aqueous humor or cerebrospinal fluid)

Acetazolamide: carbonic anhydrase inhibitor
NBME Counter-transport across the apical membrane moves Na+ into cell and H+ into lumen In the lumen, H+ reacts with HCO3- to produce carbonic acid (H2CO3) H2CO3 dissociates to form CO2 and H2O; this reaction is catalyzed by cytoplasmic CA (carbonic anhydrase) Acetazolamide inhibits CA to reduce reabsorption of Na+ and HCO3-

CA inhibitors for treatment of glaucoma: Acetazolamide, methazolamide and dichlorphenamide are given orally Brinzolamide and dorzolamide are applied topically to avoid metabolic effects or diuresis As CA in the ciliary body normally catalyzes HCO3 secretion into the aqueous humor CA inhibition reduces intraocular pressure by decreasing aqueous humor formation Other uses include: Urinary alkalinization Correction of metabolic alkalosis Prevention of acute mountain sickness Adjuvant epilepsy treatment To increase phosphate excretion during severe hyperphosphatemia NBME NBME A drug that is useful in glaucoma and high-altitude sickness is (A) Acetazolamide (B) Amiloride (C) Demeclocycline (D) Desmopressin (E) Ethacrynic acid Carbonic anhydrase inhibitors are useful in glaucoma and altitude sickness. The answer is (A). A 55-year-old patient with severe post-hepatitis cirrhosis is started on a diuretic for another condition. Two days later he is found in a coma. The drug most likely to cause coma in a patient with cirrhosis is (C) Furosemide (D) Hydrochlorothiazide (E) Spironolactone The carbonic anhydrase inhibitors cause metabolic acidosis and urinary alkalosis. Patients with severe impairment of liver function are unable to synthesize urea efficiently and become dependent on renal excretion of ammonium ion to rid the body of nitrogenous wastes. However, in alkaline urine the ammonium ion is rapidly converted to ammonia gas. which is very rapidly reabsorbed. Hyperammonemia results, with severe neurologic consequences. The answer is (A). 15

A/E: -Bicarbonaturia & Acidosis -Hypokalemia -Hyperchloremia
-Paresthesias -Renal stones -Sulfonamide hypersensitivity

Sample Vignettes Sample Vignettes
Explain how CAIs interfere physiological transport of water & electrolytes by acting at PCT Pt with glaucoma scenario------mechanism of therapeutic benefit by CAIs Sample Vignettes Mountain sickness scenario—mechanism of therapeutic benefit by CAIs. Patient receiving a diuretic developed signs & symptoms of hyponatremia first & then hypernatremia…which diuretics & what mechanism? Sample Vignettes Clockwise – 1.Syphillis—Pen G 2.Gonorrhoea-Ceftriaxone/Cefexime(oral) 3.Herpes 2+/- 1-all Acyclovir & “ovirs”except Gancyclovir 4.Trichomonas-Metronidazole & other ‘nidazoles”. Figure out predictable a/es of CAIs by visualizing physiological transport of water & electrolyte across PCT Discuss the concept of cross allergenicity between ‘S’ drugs & why is it imp. particularly while in prescribing a diuretic?

OSMOTIC DIURETICS Glycerin Isosorbide Urea
Mannitol (1) 5, 10, 15, 20, or 25% for injection

OSMOTIC DIURETICS Sugar alcohol (Mannose) ,a reduced product of endogenous Aldose reductase (other reduced sugar alcohols are Sorbitol ,Galactitol) Are freely filtered at the glomerulus, do not undergo limited tubular reabsorption, and are relatively inert Mannitol 5-25% injected IV in large amounts increases osmolarity of plasma and tubular fluid to produce diuresis by causing water retention in the proximal tubule and descending limb of Henle Some patients do not respond to osmotic diuretics, and a test dose of mannitol is used before starting continuous infusion. Which of the following diuretics would be most useful in a patient with cerebral edema'? (A) Acetazolamide (B) Amiloride (C) Ethacrynic acid (D) Furosemide (E) Mannitol An osmotic agent is needed to remove water from the cells of the edematous brain and reduce intracranial pressure. The answer is (E). Treatment options for rhabdomyolysis include: Intravenous fluids Diuretic medications for rhabdomyolysis: Furosemide (Lasix) Mannitol (Osmitrol) Medications to treat high potassium levels: Kayexalate Kidney dialysis for rhabdomyolysis To treat severe cases

OSMOTIC DIURETICS Used clinically to reduce:
Intracranial pressure in neurologic conditions Intraocular pressure before ophthalmic procedures Anuric stages(ARF): in anuresis due to Rhabdomyolysis Adverse side effects may include: Rapid expansion of extracellular fluid volume and hyponatremia before diuresis May worsen congestive heart failure and produce pulmonary edema Severe dehydration, loss of free water, and hypernatremia Headache, nausea, and vomiting NBME NBME Which of the following diuretics would be most useful in a patient with cerebral edema'? (A) Acetazolamide (B) Amiloride (C) Ethacrynic acid (D) Furosemide (E) Mannitol An osmotic agent is needed to remove water from the cells of the edematous brain and reduce intracranial pressure. The answer is (E). Treatment options for rhabdomyolysis include: Intravenous fluids Diuretic medications for rhabdomyolysis: Furosemide (Lasix) Mannitol (Osmitrol) Medications to treat high potassium levels: Kayexalate Kidney dialysis for rhabdomyolysis To treat severe cases

Sample Vignettes Discuss bi-phasic mech.of action of Mannitol
Patient with head injury scenario-which diuretic is the DOC & why…other drugs used? Sample Vignettes Clockwise – 1.Syphillis—Pen G 2.Gonorrhoea-Ceftriaxone/Cefexime(oral) 3.Herpes 2+/- 1-all Acyclovir & “ovirs”except Gancyclovir 4.Trichomonas-Metronidazole & other ‘nidazoles”. Patient receiving an osmotic diuretic developed signs & symptoms of CCF who was normal before….mechanism? Acidic drug poisoning scenario …………………mechanism of therapeutic benefit by CAIs through the application of concept of ionization

LOOP DIURETICS Bumetanide Furosemide (1) Torsemide Ethacrynic acid (2)
Lasix (furosemide) most common trade name----”six” of Lasix denotes half life. Bumetanide-more potent

LOOP DIURETICS Formerly referred to as 'high-ceiling' because they are the most effective diuretics now available Are all sulfonamide derivatives except ethacrynic acid Can be given orally, IV, or IM; produce extremely rapid diuresis following IV injection Actively secreted by proximal tubular cells, and then carried to their sites of action in the loop of Henle . Act by inhibiting Na+/K+/2Cl- cotransporter in the thick ascending limb of Henle's loop ® decreased NaCl reabsorption

LOOP DIURETICS NBME Block the Na+/K+/2Cl- cotransporter to prevent reabsorption of Na+ and Cl- and thereby increase tubular excretion Also decrease potential difference generated by recycling of K+ which normally drives divalent reabsorption The reduced electrical potential thus increases excretion of Ca2+ and Mg2+

LOOP DIURETICS Increased delivery of Na+ to the distal convoluted tubule ® will enhance K+ and H+ secretion ® hypokalemia & Alkalosis Reduced NaCl reabsorption will reduce NaCl influx in the macula densa ® increase renin secretion Reduced Ca2+ reabsorption in the loop ® increased Ca2+ excretion but hypocalcemia rarely occurs because Ca2+ is actively reabsorbed downstream in the distal tubule Also increase Mg2+ excretion ® hypomagnesemia May increase renal blood flow through direct vascular effects due to increased prostaglandin synthesis Many patients routinely consume NSAIDs for the management of fever, headache, or muscle aches due to inflammation. NSAIDs will inhibit the action of all of the following EXCEPT (A) aldosterone antagonists (B) carbonic anhydrase inhibitors (C) mannitol (D) thiazides (E) triamterene (Answer :C) The action of thiazides, loop diuretics, spironolactone, and triamterene are all dependent on renal prostaglandin production.

Clinical Uses of Loop Diuretics
Any condition when intensive diuresis is required. Most common use is for relief of edema due to congestive heart failure (including pulmonary edema), kidney disease or hepatic cirrhosis Other uses are for treatment of: Hypertension = use loop diuretics only if thiazides do not work Severe hyperkalemia = use loop diuretics (to enhance urinary K+ secretion) together with NaCl and water administration Acute renal failure = to convert oliguric to nonoliguric failure; are effective even when glomerular filtration rate is low Hypercalcemia NBME A 70-year-old man is admitted with a history of heart failure and an acute left ventricular myocardial infarction. He has severe pulmonary edema. Which of the following drugs is most likely to prove useful in the treatment of acute pulmonary edema? (A) Bumetanide (B) Ethacrynic acid (C) Furosemide (D) Hydrochlorothiazide (E) Torsemide Answer : Loop diuretics have a rapid onset of action, are very efficacious, and appear to have significant direct smooth muscle-relaxing effects in the pulmonary vessels. They are therefore drugs of choice in acute pulmonary edema. The only drug in the list that is not a loop agent is hydrochlorothiazide. The answer is (C). 2.A new diuretic is being studied in human volunteers. Compared with placebo, the new drug increases urine volume, increases urinary Ca2+,increases plasma pH, and decreases serum K+.If this new drug has a similar mechanism of action to an established diuretic, it probably A. blocks the NaCI cotransporter in the DCT B. blocks aldosterone receptors in the CT C. inhibits carbonic anhydrase in the PCT D. inhibits the Na+/K+/2Cl-cotransporter in the TAL E. acts as an osmotic diuretic Answer: D. The effects described are typical of loop diuretics, which inhibit the Na+K+2CI cotransporter in the thick ascending limb. This action prevents the reabsorption of Ca2+ from the paracellular pathway and provides for the use of these drugs in hypercalcemia. The increased load of Na+ in the collecting tubules leads to increased excretion of both K+ and H+, so hypokalemia and alkalosis may occur. 3. Which of the following therapies would be most useful in the management of severe hypercalcemia? (A) Amiloride plus saline infusion (B) Furosemide plus saline infusion (C) Hydrochlorothiazide plus saline infusion (D) Mannitol plus saline infusion (E) Spironolactone plus saline infusion Diuretic therapy of hypercalcemia requires a reduction in calcium reabsorption in the thick ascending limb. However, a loop diuretic alone would reduce blood volume around the remaining calcium so that serum calcium would not decrease appropriately. Therefore, saline infusion should accompany the loop diuretic. The answer is (B). NBME NBME NBME

Loop Diuretic Adverse Effects
Hypokalemic metabolic alkalosis = from enhanced K+ & H+ secretion ░Severe dehydration and hyponatremia leading to hypotension, circulatory collapse, reduced GFR, thromboembolic episodes Hypokalemia leading to cardiac arrhythmias especially in patients receiving digoxin Hyperuricemia and gout attacks = due to increased uric acid reabsorption in the proximal tubule & competition during active secretion. NBME NBME NBME 1.A 70-year-old woman is admitted to the emergency room because of a "fainting spell" at home. She appears to have suffered no trauma from her fall, but her blood pressure is 110/60 when lying down and 60/40 when she sits up. Neurologic examination and an ECG are within normal limits when she is lying down. Questioning reveals that she has recently started taking "water pills" (diuretics) for a heart condition. Which of the following drugs is the most likely cause of her fainting spell? (A) Acetazolamide (B) Amiloride (C) Furosemide (D) Hydrochlorothiazide (E) Spironolactone The case history suggests that the syncope (fainting) is associated with diuretic use. Complications of diuretics that can result in syncope include both postural hypotension (which this patient exhibits) due to excessive reduction of blood volume and arrhythmias due to excessive potassium loss. Potassium wasting is more common with thiazides (because of their long duration of action), but these drugs rarely cause reduction of blood volume sufficient to result in orthostatic hypotension. The answer is (C). In a patient with altered hearing, the agent most likely to exacerbate this deficit is (A) acetazolamide (B) furosemide (C) hydrochlorothiazide (0) mannitol (E) spironolactone (Answer :B) The loop diuretics cause a dose-related loss of hearing that is usually reversible. They should be avoided in patients with hearing loss or in patients who are on other ototoxic drugs such as gentamicin or aminoglycoside antibiotics. In a patient with CHF being treated with digoxin (A) a high intake of sodium should be avoided (B) diuretic therapy should be limited to loop diuretics (C) diuretics will prevent arrhythmias (D) oral mannitol is the agent of choice if diuretics are employed (E) potassium ion supplements should be administered routinely (Answer :A) The adherence to a low-sodium diet may prevent the development of hypokalemia. High sodium leads to increased potassium secretion. Hypokalemia in the presence of digoxin would be expected to cause arrhythmias. Administration of potassium is not routinely necessary. NBME

Loop Diuretic Adverse Effects
Allergic reactions = skin rash, eosinophilia, and interstitial nephritis; More common with sulfonamides than with ethacrynic acid Ototoxicity ( Ethacrynic acid>Furosemide)= as a reversible dose-related hearing impairment, tinnitus, deafness, and a sense of fullness in the ears; More common with ethacrynic acid than with other loop diuretics Probably due to inhibition of Na+/K+/2Cl- transport for endolymp production in the cochlea NBME NBME 1.A 70-year-old woman is admitted to the emergency room because of a "fainting spell" at home. She appears to have suffered no trauma from her fall, but her blood pressure is 110/60 when lying down and 60/40 when she sits up. Neurologic examination and an ECG are within normal limits when she is lying down. Questioning reveals that she has recently started taking "water pills" (diuretics) for a heart condition. Which of the following drugs is the most likely cause of her fainting spell? (A) Acetazolamide (B) Amiloride (C) Furosemide (D) Hydrochlorothiazide (E) Spironolactone The case history suggests that the syncope (fainting) is associated with diuretic use. Complications of diuretics that can result in syncope include both postural hypotension (which this patient exhibits) due to excessive reduction of blood volume and arrhythmias due to excessive potassium loss. Potassium wasting is more common with thiazides (because of their long duration of action), but these drugs rarely cause reduction of blood volume sufficient to result in orthostatic hypotension. The answer is (C). In a patient with altered hearing, the agent most likely to exacerbate this deficit is (A) acetazolamide (B) furosemide (C) hydrochlorothiazide (0) mannitol (E) spironolactone (Answer :B) The loop diuretics cause a dose-related loss of hearing that is usually reversible. They should be avoided in patients with hearing loss or in patients who are on other ototoxic drugs such as gentamicin or aminoglycoside antibiotics. In a patient with CHF being treated with digoxin (A) a high intake of sodium should be avoided (B) diuretic therapy should be limited to loop diuretics (C) diuretics will prevent arrhythmias (D) oral mannitol is the agent of choice if diuretics are employed (E) potassium ion supplements should be administered routinely (Answer :A) The adherence to a low-sodium diet may prevent the development of hypokalemia. High sodium leads to increased potassium secretion. Hypokalemia in the presence of digoxin would be expected to cause arrhythmias. Administration of potassium is not routinely necessary.

A pt. taking furosemide developed gout. what is the underlying mech
A pt. taking furosemide developed gout.. what is the underlying mech ? Which drugs if given with loop diuretic will cause D-D Interaction by the same mech? Explain how loop diuretic interfere physiological transport of water & electrolytes by acting at TALH What is the diuretic of choice in patient with acute renal shut down & why? Pt. with acute volume overload should be treated by which diuretics if not contraindicated? Sample Vignettes Clockwise – 1.Syphillis—Pen G 2.Gonorrhoea-Ceftriaxone/Cefexime(oral) 3.Herpes 2+/- 1-all Acyclovir & “ovirs”except Gancyclovir 4.Trichomonas-Metronidazole & other ‘nidazoles”. How does loop diuretic benefits in pt. with severe hyperkalemia and or hypercalcemia? Figure out predictable a/es of Loop diuretics by visualizing physiological transport of water & electrolyte across PCT

THIAZIDE (BENZOTHIAZIDE) DIURETICS
Names ending in “thiazide” Sulfonamides Bendroflumethiazide Chlorthalidone Benzthiazide Indapamide(2) Chlorothiazide Metolazone(3) Hydrochlorothiazide (1) Quinethazone Hydroflumethiazide Methyclothiazide Polythiazide Trichlormethiazide Note: thiazide like

THIAZIDE (benzothiazide) DIURETICS
All are absorbed orally but differ in metabolism, onset, and duration of action. Actively Secreted by proximal tubular cells, and then carried to their sites of action. Act by blocking NaCl transporter in the distal convoluted tubule ® inhibit NaCl reabsorption from lumen Only moderately effective in increasing NaCl excretion because 90% of filtered load has been reabsorbed before reaching the distal tubule Also increase K+ secretion to produce hypokalemia and decrease uric acid secretion to produce hyperuricemia Reduce Ca2+ excretion (effect opposite to that of loop diuretics) by enhancing reabsorption in the distal convoluted tubule. This process is regulated by parathyroid hormone Are ineffective (unlike loop diuretics) when glomerular filtration rate is low (could be PG mediated)

THIAZIDE DIURETICS NBME Inhibit the Na+/Cl- transporter to decrease reabsorption of Na+ and Cl- Reabsorption of Ca2+ also increases due to the Increased Na+ concentration gradient across the basolateral membrane which stimulates Na+/Ca2+ countertransport

Thiazides: Therapeutic Uses
Clinically used for treatment of: Hypertension = thiazides are still first choice Congestive heart failure = thiazides are second to loop diuretics Nephrolithiasis due to idiopathic hypercalciuria = to reduce urinary calcium concentration Nephrogenic diabetes insipidus To reduce polyuria and polydipsia Paradoxical effect due to plasma volume reduction NBME NBME 1.When used chronically to treat hypertension, thiazide diuretics have all of the following properties or effects EXCEPT (A) Reduce blood volume or vascular resistance, or both (B) Have maximal effects on blood pressure at doses below the maximal diuretic dose (C) May cause an elevation of plasma uric acid and triglyceride levels (D) Decrease the urinary excretion of calcium (E) Cause ototoxicity Thiazides do not cause ototoxicity; loop diuretics do. The answer is (E). 2.A 50-year-old man has a history of frequent episodes of renal colic with high-calcium renal stones. The most useful agent in the treatment of recurrent calcium stones is (A) Mannitol (B) Furosemide (C) Spironolactone (D) Hydrochlorothiazide (E) Acetazolamide The thiazides are useful in the prevention of calcium stones because these drugs inhibit the renal excretion of calcium. In contrast, the loop agents facilitate calcium excretion. The answer is (D). 35

Thiazides: Toxicity Adverse effects include:
Hypokalemic metabolic alkalosis and hyperuricemia (competition during active secretion) Impaired glucose tolerance and hyperglycemia due to decrease in pancreatic release of insulin and tissue glucose utilization Hyperlipemia shown by increases in serum cholesterol and low-density lipoproteins (LDL) Hyponatremia resulting from elevated ADH, reduced renal diluting capacity, and increased thirst can be prevented by reducing doses or restricting fluid intake NBME NBME Which of the following is not a complication of therapy with thiazide diuretics? (A) Hypercalciuria (B) Hyponatremia (C) Hypokalemia (D) Hypemricemia (E) Metabolic alkalosis Thiazides produce all of the effects listed except hypercalciuria. They reduce urine calcium and for this reason are useful in chronic stone-formers. The answer is (A). A 55-year-old male with kidney stones has been placed on a diuretic to decrease calcium excretion. However, after a few weeks, he develops an attack of gout. Which diuretic was he taking? A. Furosemide. B. Hydrochlorothiazide. C. Spironolactone. D. Triamterene. Answer: B. Hydrochlorothiazide is effective in increasing calcium reabsorption, thus decreasing the amount of calcium excreted, and decreasing the formation kidney stones that contain calcium phosphate or calcium oxalate. However, hydrochlorothiazide can also inhibit the excretion of uric acid and cause its accumulation, leading to an attack of gout in some individuals. Furosemide increases the excretion of calcium, whereas the K+-sparing diuretics, spironolactone and triamterene, do not have an effect. A 75-year-old woman with hypertension is being treated with a thiazide. Her blood pressure responds and reads at 120/76 mm Hg. After several months on the medication, she complains of being tired and weak. An analysis of the blood indicates low values for which of the following? A. Calcium. B. Uric acid. C. Potassium. D. Sodium. E. Glucose Answer: C. Hypokalemia is a common adverse effect of the thiazides and causes fatigue and lethargy in the patient. Supplementation with potassium chloride or with foods high in K+ corrects the problem. Alternatively, one may add a potassium-sparing diuretic like spironolactone. Calcium, uric acid, and glucose are usually elevated by thiazide diuretics. The sodium loss does not weaken the patient. NBME

Thiazides: Toxicity Allergic reactions include cross-reactivity with other sulfonamides, photosensitivity, and generalized dermatitis; rarely, may induce hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis Weakness, fatigability, paresthesias, and impotence may occur ░Thiazides cause impotence 4-times more often than beta-blockers but the mechanism is unknown; impotence may still be bothersome even with low doses, for example: with chlorthalidone 12.5 mg/day, the number of elderly men with erectile dysfunction was 17% compared with 8% for placebo NBME Which of the following is not a complication of therapy with thiazide diuretics? (A) Hypercalciuria (B) Hyponatremia (C) Hypokalemia (D) Hypemricemia (E) Metabolic alkalosis Thiazides produce all of the effects listed except hypercalciuria. They reduce urine calcium and for this reason are useful in chronic stone-formers. The answer is (A). A 55-year-old male with kidney stones has been placed on a diuretic to decrease calcium excretion. However, after a few weeks, he develops an attack of gout. Which diuretic was he taking? A. Furosemide. B. Hydrochlorothiazide. C. Spironolactone. D. Triamterene. Answer: B. Hydrochlorothiazide is effective in increasing calcium reabsorption, thus decreasing the amount of calcium excreted, and decreasing the formation kidney stones that contain calcium phosphate or calcium oxalate. However, hydrochlorothiazide can also inhibit the excretion of uric acid and cause its accumulation, leading to an attack of gout in some individuals. Furosemide increases the excretion of calcium, whereas the K+-sparing diuretics, spironolactone and triamterene, do not have an effect. A 75-year-old woman with hypertension is being treated with a thiazide. Her blood pressure responds and reads at 120/76 mm Hg. After several months on the medication, she complains of being tired and weak. An analysis of the blood indicates low values for which of the following? A. Calcium. B. Uric acid. C. Potassium. D. Sodium. E. Glucose Answer: C. Hypokalemia is a common adverse effect of the thiazides and causes fatigue and lethargy in the patient. Supplementation with potassium chloride or with foods high in K+ corrects the problem. Alternatively, one may add a potassium-sparing diuretic like spironolactone. Calcium, uric acid, and glucose are usually elevated by thiazide diuretics. The sodium loss does not weaken the patient.

Thiazide-like Diuretics
Indapamide and Metolazone are slightly different in structures from thiazide diuretics, but their actions and uses are similar to thiazides. Indapamide is generally used in the treatment of hypertension and congestive heart failure. Metolazone may be more effective than Thiazides in patients with impaired renal function. Metolazone is sometimes combined with loop diuretic to treat patients with diuretic resistance. Patients with diuretic resistance do not adequately respond to any single diuretic agent. Combined use of diuretics produces sequential nephron blockade.

Key Differences LOOP VS THIAZIDE Diuretics
NBME LOOP THIAZIDE Site of action Ascending limb Henle's loop Distal convoluted tubule NaCl reabsorption Na+/K+/2Cl- cotransporter NaCl transporter Diuretic efficacy ++++ ++ Anti-HT efficacy Calcium excretion Increased Reduced Low GFR Effective Ineffective

A pt. taking thiazide developed gout. what is the underlying mech
A pt. taking thiazide developed gout.. what is the underlying mech ? Which drugs if given with loop diuretic will cause D-D Interaction by the same mech? Explain how thiazides interfere physiological transport of water & electrolytes by acting at DCTs? How thiazide benefits hypertension , nephrolithiasis & nephrogenic diabetes insipidus ? An obese pt. was prescribed a thiazide .His lipid profile was deranged during 1st visit . Consider the justification for thiazide therapy? Sample Vignettes Clockwise – 1.Syphillis—Pen G 2.Gonorrhoea-Ceftriaxone/Cefexime(oral) 3.Herpes 2+/- 1-all Acyclovir & “ovirs”except Gancyclovir 4.Trichomonas-Metronidazole & other ‘nidazoles”. Pt. on long term thiazide therapy developed Diabetes Mellitus . What is the probable mechanism? Figure out predictable a/es of Loop diuretics by visualizing physiological transport of water & electrolyte across PCT

POTASSIUM-SPARING DIURETICS
Aldosterone antagonists Eplerenone Spironolactone (1) Na+ channel blockers Amiloride (2) Triamterene (3)

Are generally weak diuretics, seldom used alone, but used to counteract hypokalemia caused by loop or thiazide diuretics Reduce K+ secretion at the cortical collecting tubule and late distal tubule Inhibition of K+ secretion results from either Direct pharmacological antagonism of mineralocorticoid receptors (spironolactone or eplerenone) Indirect Reduction of K+ flux through ion channels (triamterene or amiloride) Aldosterone regulates Na+ reabsorption and enhances K+ secretion in collecting tubules; it acts by increasing activity of: [a] Na+/ K+ ATPase, and [b] Na+ and K+ channels Spironolactone and eplerenone act as competitive aldosterone antagonists by binding to cytoplasmic mineralocorticoid receptors Slow onset because of hepatic inactivation and aldosterone kinetics in target tissues Triamterene and amiloride are not aldosterone antagonists, but act by blocking Na+ channels in apical membranes of the collecting tubule; K+ is spared because its secretion is coupled with Na+ entry

NBME POTASSIUM-SPARING DIURETICS Amiloride and triamterene block apical Na+ channels [ENaC] to cause loss of potential (decreases the driving force for K+ secretion) and reduce K+ and H+ secretion Aldosterone receptors (MR) that decrease Na+ excretion, and increase K+ and H+ secretion will produce opposite effects when blocked by spironolactone & eplerenone

POTASSIUM-SPARING DIURETICS Therapeutic Uses
Used for treatment of: Primary mineralocorticoid hypersecretion as in Conn’s syndrome or ectopic ACTH production Secondary aldosteronism due to congestive heart failure, hepatic cirrhosis, nephrotic syndrome, and other conditions associated with salt retention and reduced fluid volume Often used together with thiazide or loop diuretics to minimize or prevent potassium depletion Spironolactone has been used to reduce digoxin toxicity during treatment of CHF NBME NBME Amiloride is used in the treatment of Lithium induced Diabetes Insipidus. Spironolactone is used in the treatment of Polycystic ovary disease because it antagonizes androgen & progesterone Rcs. Eplerenone(Inspra)-weak diuretic+ fewer antiandrogenic adverse effects.Hence it has mortality benefit in post MI patient with LV dysfunction Dospirenone(Yaz) is a synthetic progestin having contraceptive+weak anti aldosterone effect(diuretic)---given to reduce water retention during menstruation in some women. An alcoholic male has developed hepatic cirrhosis. To control the ascites and edema, he is prescribed which one of the following? A. Hydrochlorothiazide. B. Acetazolamide. C. Spironolactone. D. Furosemide. E. Chlorthalidone. Answer: C. Spironolactone is very effective in the treatment of hepatic edema. These patients are frequently resistant to the diuretic action of loop diuretics, although a combination with spironolactone may be beneficial. The other agents are not indicated. NBME NBME

POTASSIUM-SPARING DIURETICS Side Effects
Toxic effects include: Hyperkalemia may be mild, moderate, or even life threatening; risk of this complication increases in the presence of renal disease or drugs that reduce renin-angiotensin activity (i.e., b-blockers, ACE inhibitors, or angiotensin antagonists); the risk is less when used in combination with thiazide diuretics Hyperchloremic metabolic acidosis due to inhibition of H+ secretion with the reduced K+ secretion Gynecomastia due to the steroid chemical structure (only spironolactone) Acute renal failure may occur when triamterene is combined with indomethacin Kidney stones may occur with triamterene which is poorly soluble NBME Most diuretics have the potential to cause hypokalemia; however, in the presence of beta blockers or ACE inhibitors, hyperkalemia would be expected with the administration of (A) acetazolamide (B) furosemide (C) hydrochlorothiazide (D) mannitol (E) Spironolactone (Answer :E) The aldosterone antagonists may cause severe hyperkalemia in the presence of altered renal function, agents that inhibit rennin formation (beta blockers), or agents that reduce angiotensin II activity (ACE inhibitors, angiotensin receptor blockers). Which side effect is associated with spironolactone? A. Alkalosis B. Hirsutism C. Hyperkalemia D. Hypercalcemia E. Hyperglycemia Answer: C. Spironolactone blocks aldosterone receptors thereby inhibiting the production of Na+ channels in the collecting duct and is used as a K+-sparing agent because the reabsorption of Na+ in the CT is coupled (indirectly) to the secretion of K+ ions. Hyperkalemia is characteristic of this drug and may lead to clinical consequences at high doses, or if patients fail to discontinue K+ supplements or ingest foodstuffs high in K+. Because Na+ reabsorption is associated with secretion of protons, spironolactone causes retention of H+ ions, leading to acidosis. It has no significant effect on the renal elimination of Ca2+ or on the plasma level; of glucose.

Explain how K+ sparing diuretics interfere physiological transport of water & electrolytes by acting at CDs? How these drugs benefits in primary & secondary mineralocorticoids hypersecretion? What is the pharmacological basis of combination of a loop diuretic or thiazide with a K+ sparing diuretic in most of the pharmaceutical preparations? Why spironolactone is given in digoxin toxicity> Sample Vignettes Clockwise – 1.Syphillis—Pen G 2.Gonorrhoea-Ceftriaxone/Cefexime(oral) 3.Herpes 2+/- 1-all Acyclovir & “ovirs”except Gancyclovir 4.Trichomonas-Metronidazole & other ‘nidazoles”. Why K+ sparing diuretics are to be cautiously used with BBs, ACEIs or ARAs? Which drug from these drug group has anti-androgenic activity?

Sulfur (S) containing drugs- Allergy Issues
NBME Cross allergenicity with -All CA Inhibitor -All loop diuretics EXCEPT Ethacrynic acid -All Thiazides -All Sulfa antibiotics -Celecoxib How to recognize S containing drugs ? -Have ‘sulfo’ or ‘sulfa’ or ‘thio’ or ‘thia’ inside chemical name.eg.Sulfonamide,sulfonylurea,thiazide,phenothiazine etc.

Clinical Uses of Diuretics
The two most common clinical uses are for reducing fluid volume in edematous states (CHF, kidney or hepatic disease) or treatment of hypertension. In CHF diuretics will reduce extracellular fluid volume ® reduce preload ® reduce cardiac work Chronic treatment is reserved only for patients with advanced CHF First-choice drugs are loop diuretics like furosemide, bumetanide, and torsemide; use ethacrynic acid only in patients allergic to sulfonamides Thiazides being weaker diuretics are used only for mild CHF Spironolactone reduces mortality from CHF Concurrent treatment with any vasodilator may reduce renal blood flow and inhibit diuretic effectiveness Treating electrolyte abnormalities (eg.Hyperkalemia,Hyper & Hypocalcemia etc) is 3rd important indication of diuretics

Clinical Uses of Diuretics
For treatment of hypertension: thiazides are first choice as they are more effective than loop diuretics in lowering BP and antihypertensive doses are much lower than those for diuresis (e.g., hydrochlorothiazide doses are: mg for diuresis versus 6-12 mg for hypotension) Recommended for monotherapy of mild to moderate hypertension, lower BP in 40-60% of patients, can enhance efficacy of other antihypertensive drugs, and can be given as a single daily dose (slower onset but longer duration of action than loop diuretics) Low cost (e.g., three cents daily for generic hydrochlorothiazide versus $ for an ACE inhibitor) Diuretics are most effective in: (A) African Americans, and (B) the elderly Use loop diuretics only in presence of renal insufficiency or cardiac failure Potassium-sparing diuretics are weak and used only in combinations to avoid hypokalemia

Agents affecting water excretion
Antidiuretic hormones (discussed in Autacoids chapter) -Vasopressin(ADH) -Desmopressin Osmotic Diuretics (discussed earlier in this chapter)

ADH Antagonists Two nonselective agents, -Lithium and (1)
-Demeclocycline (2). Both reduces the formation of cAMP in response to ADH. ADH antagonists inhibit the effects of ADH in the collecting tubule. ADH antagonists are used to manage Syndrome of Inappropriate ADH secretion (SIADH). Water restriction is the treatment of choice for this condition. ADH is also elevated in response to hypovolemia. When fluid replacement is not possible due to heart failure or liver disease, and hyponatremia is a possibility; ADH antagonists may be used. Adverse effects: Severe hypernatremia and nephrogenic diabetes insipidus; acute renal failure and chronic interstitial nephritis. A drug that increases the formation of dilute urine in water-loaded subjects and is used to treat SIADH is (A) Acetazolamide (B) Amiloride (C) Demeclocycline (D) Desmopressin (E) Ethacrynic acid Inability to form dilute urine in the fully hydrated condition is characteristic of SIADH. Antagonists of ADH are needed to treat this condition. The answer is (C).

Summary of Diuretics Thiazide diuretics inhibit NaCl reabsorption from the distal tubule, and decrease Ca2+ excretion. Thiazides are chiefly used to treat Hypertension, Edema, Hypercalciuria, and Nephrogenic Diabetes Insipidus. Loop diuretics inhibit the Na+,K+,2Cl- symporter in the ascending limb, and increase Na+, K+, Ca+ and Mg+ excretion. Loop diuretics are used to treat Congestive Heart Failure, Renal failure, Pulmonary Edema and Hypercalcemia. Thiazide and Loop diuretics may cause hypokalemia, as well as hyperglycemia and hyperuricemia. Potassium-sparing diuretics inhibit K+ secretion in the collecting duct and are used to prevent hypokalemia.

Osmotic diuretics increase the osmotic pressure of plasma and retain water in the nephron, causing water diuresis. They are used to treat Cerebral Edema, Glaucoma and Oliguria of Acute Renal Failure. Carbonic Anhydrase Inhibitors are weak diuretics, inhibit sodium bicarbonate reabsorption from the proximal tubule and may cause a mild metabolic acidosis. They reduce aqueous humor secretion and are primarily used to treat glaucoma.

C) Hydrochlorothiazide D) Mannitol E) Triamterene
Which of the following diuretics would be most appropriate for the treatment of a 59-year-old man with pulmonary edema and congestive heart failure? Acetazolamide B) Furosemide C) Hydrochlorothiazide D) Mannitol E) Triamterene ANS = B Loops are most effective and osmotics would be contraindicated for this patient!! 54

C) Hydrochlorothiazide D) Mannitol E) Triamterene
Which of the following diuretics would be most appropriate for the treatment of a 41-year-old African/American woman with mild hypertension? A) Acetazolamide B) Furosemide C) Hydrochlorothiazide D) Mannitol E) Triamterene ANS = C Thiazdes are very effective in African Americans 55

A) Bendroflumethiazide B) Candesartan C) Enalapril D) Furosemide
A 60-year-old man treated with digoxin for congestive heart failure requires an additional drug to relieve peripheral edema. Which of the drugs listed below would be most effective in getting rid of excess fluid volume but would also be most likely to precipitate cardiac arrhythmias in this patient? A) Bendroflumethiazide B) Candesartan C) Enalapril D) Furosemide E) Spironolactone ANS = D Loops are most effective for CHF 56

Final drug List (Total No.16)
SIADH  Ca excretion  Ca excretion Hypokalemia, hyperurcemia, hyperglycemia  HCO3- excretion  NH4+ excretion Contraindicated in Hepatic cirrhosis Hyperkalemia 57

Hypertension Hyperuricemia Hypokalemia Hyponatremia Pulmonary edema
A 65-year-old man with congestive heart failure develops cerebral edema after an automobile accident. Mannitol would be contraindicated for relieving cerebral edema in this patient because it is likely to cause which of the following adverse effects in this patient? Hypertension Hyperuricemia Hypokalemia Hyponatremia Pulmonary edema Answer: E Loops increase extracellular volume 58

Acetazolamide Furosemide Hydrochlorothiazide Mannitol Triamterene
Three months after an obese 48-year-old African-American woman begins therapy for hypertension, her laboratory results show a low serum potassium level and high levels of glucose, calcium and uric acid. Which of the following medications is most likely responsible for these findings in this patient? Acetazolamide Furosemide Hydrochlorothiazide Mannitol Triamterene Answer: C Everything fits for a Thiazide 59

SKIP THIS SLIDE FINISHED FILES ARE THE RESULT OF YEARS OF SCIENTIFIC STUDY COMBINED WITH THE EXPERIENCE OF YEARS...

PowerPoint Slides Several of the PowerPoint slides are Copyright © , the American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved. Some of slides in this session are from the above mentioned format and are free for use by members of ASPET. Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA). Core concepts of various USMLE High yield review series like Kaplan ,BRS etc. are thoroughly explored & integrated where ever necessary

AGENTS ACTING ON RENAL FUNCTION Dr.Sanjib Das MD.

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