Block 1 Cvrr Spring Oms1 2010: Diuretics (Klapstein)

Front 1

Name a carbonic anhydrase inhibitor.

Back 1

Acetazolamide (not for block 1: Dorzolamide, Dichlorphenamide, Methazolamide)

Front 2

Where does Acetazolamide act in the kidney tubule, and what is its mechanism?

Back 2

Acetazolamide acts in the Proximal Convoluted Tubule, and acts as a Carbonic Anhydrase inhibitor. When inhibited, CA does not catalyze HCO3- + H+ --> H2O + CO2, which then enter the kidney epithelial cell (Inhibits reabsorption of HCO3-).

Front 3

Inhibition of carbonic anhydrase causes...

Back 3

HCO3- diuresis, reduction in total HCO3- stores, alkaline diuresis, hyperchloremic metabolic acidosis, reduction in volume and pH of eye fluid and CSF.

Front 4

For what is Acetazolamide indicated?

Back 4

Glaucoma (primarily), also Acute Mountain Sickness, to achieve urinary alkalinization, to correct metabolic alkalosis.

Front 5

This drug is taken PO, is well absorbed, lasts ~12 hours, secreted by the kidney, and achieves 45% inhibition of Na-HCO3- reabsorption.

Back 5

Acetazolamide (or other carbonic anhydrase inhibitor)

Front 6

What are the side effects of Acetazolamide?

Back 6

hyperchloremic metabolic acidosis, renal stones (phosphaturia, alkalinization favor calcium phosphate stone formation), renal potassium wasting (administer KCl).

Front 7

When is Acetazolamide contraindicated?

Back 7

hepatic cirrhosis (decreases NH4+ excretion, causing hyperammonemia and hepatic encephalopathy)

Front 8

Name two Loop Diuretics

Back 8

Furosemide (sulfonamide), Ethacrynic Acid (non-sulfonamide)

Front 9

Where do Loop Diuretics act, and what do they do?

Back 9

They selectively inhibit NaCl reabsorption in the Thick Ascending Limb of the loop of Henle.

Front 10

What group of diuretics are the most efficacious ("high ceiling")?

Back 10

Loop Diuretics, like Furosemide and Ethacrynic Acid

Front 11

What are the effects of Loop Diuretics?

Back 11

They inhibit the Na+/K+/2Cl- transport system, thus inhibiting NaCl from being reabsorbed from the lumen, inhibiting K+ recycling, and decreasing paracellular reabsorption of Ca2+ and Mg2+.

Front 12

For what would one use Furosemide and Ethacrynic Acid? Which would you prescribe if someone had a sulfa allergy?

Back 12

Clinical indications include Acute Pulmonary Edema, other edemas, Hypercalcemia, Acute Renal Failure, Anion Overdose. Furosemide is a sulfonamide, so Ethacrynic Acid is used if patient has sulfa allergies.

Front 13

What are the side effects of Loop Diuretics?

Back 13

Hypokalemic metabolic alkalosis, dose-related reversible ototoxicity (more often with weak renal function or with aminoglycoside antibiotics), Hyperuricemia, Hypomagnesemia, Skin Rash (sulfa rxn), Dehydration, Hyponatremia, rarely interstitial nephritis (reversible).

Front 14

Contraindications of Loop Diuretics?

Back 14

Sulfonamide sensitivity (except Ethacrynic Acid), caution in Cirrhosis, CHF (CO maintained by high filling volume, diuretics decrease venous return). NSAIDs may interfere with action of loop and thiazide diuretics.

Front 15

Where do Thiazides act, and what to they do (basic)?

Back 15

Thiazides act in the distal convoluted tubule, and inhibit NaCl transport.

Front 16

Can any Thiazide drug be prescribed to a person with a sulfa allergy?

Back 16

No, all Thiazides contain a sulfonamide group.

Front 17

What are two Thiazides?

Back 17

Chlorothiazide, Hydrochlorothiazide (prototype drug). (others: Bendroflumethiazide, Hydroflumethiazide, Polythiazide, Trichlormethiazide)

Front 18

This group of diuretics acts in the distal convoluted tubule, is well absorbed orally (some better than others), and are secreted by the kidney by the organic acid secretory system (thus they compete with uric acid and may cause hyperuricemia).

Back 18

Thiazides (prototype: Hydrochlorothiazide)

Front 19

Describe the specific mechanism of Thiazide drugs.

Back 19

Thiazides inhibit NaCl reabsorption from the distal convoluted tubule by acting on an Na+Cl-Cotransporter on the lumen side. Secondary effects - it also increases Ca2+ resorption because there is lower intracellular Na+. Hypercalcemia will not occur if patient not predisposed but it is useful in hypercalcuria and kidney stones.

Front 20

For what conditions would one prescribe Thiazides?

Back 20

Hypertension, Heart Failure, Nephrolithiasis (from idiopathic calciuria), Nephrogenic Diabetes Insipidis

Front 21

List a few of the toxic side effects of Thiazides

Back 21

Hypokalemic metabolic acidosis, hyperuricemia, impaired carbohydrate tolerance (from impaired pancreatic insulin, diminished glucose utilization), hyperlipidemia (10% increase in cholesterol, LDL), hyponatremia, sulfa reaction. Rarely: hemolytic anemia, thrombocytopenia. Others: weakness, fatigue, rarely impotence.

Front 22

For which conditions should Thiazide use be more carefully administered and monitored?

Back 22

Cirrhosis, Borderline Renal Failure, Congestive Heart Failure

Front 23

Name a sulfonamide that is similar to Thiazides

Back 23

Indapamide (Chlorthalidone, Metolazone, Quinethazone)

Front 24

Name two K+ Sparing Diuretics and the site of action of K+ Sparing Diuretics.

Back 24

Spironolactone (Eplerenone), Amiloride (Triamterene). K+ Sparing Diuretics act in the collecting tubule and late distal tubule.

Front 25

This drug is a K+ Sparing Diuretic and acts as an aldosterone antagonist.

Back 25

Spironolactone (Eplerenone)

Front 26

This K+ Sparing Diuretic acts by blocking Na+ channels.

Back 26

Amiloride (Triamterene)

Front 27

What class is Spironolactone and by what mechanism does it effect diuresis?

Back 27

Spironolactone is a K+ Sparing Diuretic that acts as a competitive antagonist to aldosterone at the mineralocorticoid receptor. It has slow onset.

Front 28

What class is Amiloride and by what mechanism does it effect diuresis?

Back 28

Amiloride is a K+ Sparing Diuretic that acts by inhibiting Na+ transport channels in the luminal membrane (recall K+ secretion is coupled to Na+ reabsorption).

Front 29

For what are K+ Sparing Diuretics indicated?

Back 29

Most useful in mineralocorticoid excess to prevent depletion of K+ stores. Examples include primary hypersecretion (Conn's syndrome) and secondary aldosteronism from salt retention (in HF, cirrhosis, nephrosis).

Front 30

What are some toxicities associated with K+ Sparing Diuretics?

Back 30

Hyperchloremic metabolic acidosis (inhibition of H+ secretion), hyperkalemia. Combination with other diuretics reduces risks.

Front 31

What are some specific side effects of Spironolatone?

Back 31

It is a steroid, so it may cause gynecomastia, impotence, or benign prostatic hyperplasia.

Front 32

When would a K+ Sparing Diuretic be contraindicated?

Back 32

Fatal hyperkalemia can occur with PO K+ administration, chronic renal insufficiency, use of beta-blockers or ACE inhibitors, liver disease (impaired drug metabolism, adjust dose).

Front 33

Name an Osmotic Diuretic and where it acts in the kidney.

Back 33

Mannitol, sites of action are the proximal tubule and descending loop.

Front 34

What are some things to keep in mind when administering Mannitol?

Back 34

It must be given parenterally due to poor PO absorption (will cause diarrhea), it is not metabolized, it is excreted via glomerular filtration in 30-60 minutes, and there is no reabsorption or secretion.

Front 35

How does an Osmotic Diuretic work?

Back 35

Mannitol, an Osmotic Diuretic, increases the osmotic pressure in the lumen, causing net osmosis of water into the lumen where it is permeable (proximal tubule, thin descending tubule). Increased flow rate also decreases Na+ reabsorption.

Front 36

What are the clinical indications for an Osmotic Diuretic?

Back 36

Osmotic Diuretics are used to increase urine volume (water) - when patients are unresponsive to other diuretics due to compromised renal hemodynamics or avid Na+ retention, or to prevent anuria from pigment load (hemolysis, rhabdomyolysis). Also used to reduce intracranial or intraocular pressure by reducing intracellular volume.

Front 37

What are the toxicities/side effects of an Osmotic Diuretic?

Back 37

Extracellular volume expansion (before filtration) due to extraction of intracellular water - may enhance CHF or cause PE, N/V, headache. Dehydration and Hypernatremia due to excessive use of mannitol without water replacement. *Monitor ions, fluid balance*

Front 38

What class is Vasopressin?

Back 38

Vasopressin is an ADH antagonist

Front 39

What is the mechanism of action for Vasopressin?

Back 39

Vasopressin inhibits the effect of ADH at the collecting tubule by blocking the ADH receptor, thereby preventing activation of cAMP, which would then initiate recruitment of aquaporin 2 to the lumen to increase water permeability. Overall effect: no recruitment of aquaporins, no increased water permeability.

Front 40

When would one use Vasopressin?

Back 40

Syndrome of Inappropriate ADH Secretion (SIADH) if water restriction is not applicable, or when there is unwanted elevation of ADH (e.g. from dimished effective circulating blood volume) - Vasopressin is indicated when water replacement is not possible due to HF or liver disease.

Front 41

What toxicities are associated with Vasopressin?

Back 41

Nephrogenic Diabetes Insipidus, Renal Failure

Front 42

What is the benefit to combining a Loop Agent with a Thiazide?

Back 42

Refractoriness to a Loop Agent (by itself) develops quickly. The two drugs work at different sites and show synergy, because the compensation mechanism for each drug is blocked by the other drug. Significant diuresis even if patient is refractory to either agent.

Front 43

What precautions must be taken when combining a Loop Agent and a Thiazide?

Back 43

Monitoring is necessary in case of excessive diuresis - no outpatient use. Potassium wasting is common, so parenteral K+ is often necessary.

Front 44

Why would one add a K+ Sparing Diuretic to a Loop Agent/Thiazide combination?

Back 44

Many patients on a Loop Agent/Thaizide combo develop hypokalemia, and dietary salt restriction (Na+ is coupled with K+ secretion) or dietary KCl supplementation is useful, but if that doesn't work then K+ Sparing Diuretics can be used to lower K+ excretion.

Front 45

When would adding a K+ Sparing Diuretic to a Loop Agent/Thiazide combination be contraindicated?

Back 45

It is contraindicated in renal insufficiency (Hyperkalemia may result).

Front 46

List four edematous states treated with diuretics.

Back 46

Heart Failure, Kidney Disease and Renal Failure, Hepatic Cirrhosis, Idiopathic Edema

Front 47

List four non-edematous states for which diuretics may be indicated.

Back 47

Hypertension, Nephrolithiasis, Hypercalcemia, Diabetes Insipidus

Front 48

What is the most common indication for an edematous state? What risks are associated with using diuretics?

Back 48

Pulmonary Edema (secondary to heart, kidney, or vascular disorder). Diuresis may reduce arterial blood volume, and thus the perfusion of vital organs. Always analyze the pathophysiology and monitor the hemodynamic status.

Front 49

How does Congestive Heart Failure result in interstitial and pulmonary edema?

Back 49

CHF results in decreased heart function. If the heart is unable to maintain good contractile force, there is decreased BP and decreased flow to the kidney, which the body senses as hypovolemia - causing it to up salt and water retention in an attempt to increase blood volume. If it continues, the kidney continues to retain water and salt, and it begins to leak from the vasculature and cause edema, necessitating diuretics.

Front 50

What is the most important thing to remember about diuretics and heart failure?

Back 50

Excessive diuresis may result in decreased venous return, especially in right ventricular failure with systemic congestion, and cardiac output will decrease. High filling pressure is necessary to ensure cardiac output.

Front 51

What drugs are usually used with CHF?

Back 51

As an adjunctive therapy, diuretics reduce pulmonary vascular congestion and may improve oxygenation and cardiac function. Loop Diuretics, or a Loop Diuretic/Thiazide combination may be used.

Front 52

In addition to decreased CO, what are some risks associated with diuretics and CHF?

Back 52

Diuretic-induced metabolic alkalosis (may becorrectable with acetazolamide), hypokalemia may exacerbate arrhythmias - reverse by decreasing Na+ intake, supplementing with KCl, adding a K+ Sparing Diuretic, discontinue the Thiazide or Loop Diuretic.

Front 53

What conditions are included within Kidney Diseases?

Back 53

Glomerular diseases (in DM, systemic lupus), Hyperkalemia (diabetic nephropathy), Nephrotic syndrome (diuretics would cause orthostatic hypotension).

Front 54

What diuretics are good to use for Kidney Diseases?

Back 54

Loop Agents are often the best. Avoid acetazolamide since it may exacerbate acidosis, and K+ Sparing Diuretics may exacerbate hyperkalemia. Thiazides are ineffective when GFR < 30mL/min; Overuse of diuretics will cause decline in renal function.

Front 55

When would diuretics be indicated for Hepatic Cirrhosis, and what are the consequences of too aggressive a therapy?

Back 55

Hepatic Cirrhosis is associated with edema, ascites, portal hypertension, and reduced plasma oncotic pressure. With decreased renal perfusion, there is a lower plasma volume and lower oncotic pressure, which triggers an increase in aldosterone levels. If ascites and edema are severe, diuretics are indicated. It is frequently resistant to Loop Agents. Spironolactone is very effective. Aggressive therapy may cause hepatorenal syndrome and hepatic encephalopathy.

Front 56

Which diuretics should be used to treat Hypertension, why?

Back 56

Thiazides are effective in essential hypertension, and are similar/better than ACE inhibitors or Ca2+ blockers. Also cheap and effective. Vasodilators may cause water and salt retention, necessitating diuretics. Diuretics also enhance the ability of ACE inhibitors.

Front 57

Why are diuretics indicated for nephrolithiasis?

Back 57

Kidney stones tend to contain Calcium (phosphate, oxalate). Renal Ca2+ leak can be treated with Thiazides, which enhance Ca2+ reabsorption in the distal convoluted tubule. NaCl intake must be limited.

Front 58

How would one use diuretics to treat hypercalcemia?

Back 58

Loop Diuretics promote calcium diuresis, but may cause volume contraction and thus Ca2+ reabsorption in proximal tubule. therefore, Loop Diuretics are combined with Saline and administered per IV - effective treatment.

Front 59

How would one use diuretics to treat Diabetes Insipidus?

Back 59

If the problem is deficient ADH production, ADH (or an analog) can be supplemented. If patients do not respond to that, then Thiazides are beneficial. Amiloride may also be used. Lithium may be used, but it may also cause Diabetes Insipidus, and diuretics reduce Li+ clearance.