Diuretics

A 65-year-old man comes to the emergency department with severe shortness of breath. His wife reports that he has long known that he is hypertensive but never had symptoms, so he refused to take antihypertensive medications. During the last month, he has noted increasing ankle edema, reduced exercise tolerance, and difficulty sleeping lying down, but he reports no episodes of chest pain or discomfort. He now has pitting edema to the knees and is acutely uncomfortable lying down. Vital signs include blood pressure of 190/140 mm Hg, pulse 120/ min, and respirations 20/min. Chest auscultation reveals loud rhonchi, but an electrocardiogram is negative except for evidence of left ventricular hypertrophy. He is given a diuretic intravenously and admitted to intensive care. What diuretic would be most appropriate for this man's case of acute pulmonary edema associated with heart failure? A. Amiloride B. Furosemide C. Hydrochlorothiazide D. Mannitol E. Spironolactone

B

A patient with long-standing diabetic renal disease, hyperkalemia, and recent-onset heart failure requires a diuretic. Which of the following agents would be the safest in a patient with severe hyperkalemia? A. Amiloride B. Hydrochlorothiazide C. Mannitol D. Spironolactone E. Triamterene

B

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. Mannirol plus saline infusion E. Spironolactone plus saline infusion

B

What are the possible toxicities of this therapy in the previous question? A. Hypouricemia B. Hypoglycemia C. Hypokalemia D. Hyperchloremic acidosis E. Hypertension

C

Carbonic anhydrase (CA) MOA, the drugs that inhibit carbonic anhydrase-what are these drugs used for?

CA is located in proximal portion of nephron (*PCT*) & normally performs 2 actions, all driven by Na+/K+ ATPase 1. Lumen: catalyzes H2CO3 → H2O + CO2 2. PCT: CO2 diffuses into PCT, where it reacts with water (catalyzed by CA) to re-form H2CO3 → H+ + HCO3- 3. HCO3- & Na+ are reabsorbed via a secondary cotransporter into the interstitium/peritubular capillaries These drugs can be used for *metabolic alkalosis*. Less bicarb formation/reabsorption via inhibition of carbonic anhydrase → more alkaline urine.

Acetazolamide

Carbonic anhydrase inhibitors 1. Main action at PCT, where the drug's sulfonamide group inhibits CA → weak diuretic effect 1. *Use: glaucoma (↓ aqueous humor formation & ↓ intraocular pressure), metabolic alkalosis* 2. (but can also induce metabolic acidosis): Inhibits dehydration of H2CO3→CO2 + H2O → ↑ loss of HCO3- in urine along with Na+ ↑ excretion NaHCO3 makes urine alkaline & blood acidic → metabolic acidosis

A 50-year-old man has a history of frequent episodes of renal colic with high-calcium renal stones. The most useful diuretic agent in the treatment of recurrent calcium stones is (A) Mannitol (B) Furosemide (C) Spironolactone (D) Hydrochlorothiazide (E) Acetazolamide

D

Formation of urine

Diagram illustrates filtration (glomerulus, Bowman's capsule), proximal tubule, peritubular capillaries (reabsorption of Na+, glucose, amino acids; also secretion)

Which of the following is an important effect of chronic therapy with loop diuretics? A. Metabolic acidosis B. Elevation of blood pressure C. Elevation of pulmonary vascular pressure D. Decreased urinary excretion of Ca2+ E. Ototoxicity

E

Renal function

He wants us to focus on renal function with respect to water reabsorption & decreasing extracellular fluid volume (anti-Hypertension effect). Regulate fluid/electrolyte & acid/base balance, eliminate metabolic/nitrogenous waste products. Nephron is the functional unit: composed of glomerulus and tubule which forms a U - shaped tube (loop of Henle) and terminates as a collecting duct.

Conivaptan/demeclocycline: MOA

Inhibits Anti-diuretic hormone (ADH) , which normally ↑ cAMP, making this portion of the collecting tubule permeable to water (forms pore channels) Alcohol also inhibits ADH → ↑ urine output

Structure of juxtaglomerular apparatus (JGA)

JG cells are secretory cells that sense changes in blood flow & respond by releasing renin. JG cells are present in both afferent & efferent arterioles. This area is sensitive to β-adrenergic stimulation. Renin begins cascade that ultimately produces angiotensin II, a potent vasoconstrictor leading to ↑BP.

Tubuloglomerular Feedback (TGF) Reflex

Macula densa cells at juncture of ascending limb/distal tubule sense increased Na+ loss → chemical signal to afferent arteriole to vasoconstrict → ↓ RBF/GFR to protect from salt/water wasting *Decreased renal blood flow (RBF) activates RAA system to generate angiotensin II (a potent vasoconstrictor) to release aldosterone/ADH → ↑ Na+ & water retention in distal portion of distal tubule and collecting ducts*

Amiloride-triamterene

Similar potency as spironolactone, not dependent on aldosterone level; *non-steroidal (no anti-androgen effects)* Block luminal Na+ channels, produces Na+ loss, K+ retention, hence K+-sparing Used mostly in combination with other diuretics to prevent hypokalemia Adverse: GI (n-v-d), rash, headache, *hyperkalemia* (especially when used in conjunction with ACEIs, angiotensin blockers, or K+ supplementation)

Thiazides: mechanism of action

Used to manage HTN via inhibition of Na+-Cl- cotransporter & ↓ incidence of renal stones by ↓ Ca2+ excretion in urine

Tubular secretion

active secretion of organic acids (diuretics, penicillins, uric acid) and bases, K+ into tubule lumen/urine - Concern with bioavailability of drugs

Spironolactone & Amiloride: mechanism of action

diuretic drugs that do not promote the secretion of potassium into the urine (Potassium-sparing diuretics) Aldosterone receptor antagonists; potassium-sparing diuretics Affect 2-5% of Na+ reabsorption (in exchange for K+ secretion) Intercalated cells: alpha & beta Secrete H+ & reabsorb HCO3- Beta intercalated cells do same reaction in opposite direction

Acetazolamide

inhibits carbonic anhydrase (enzyme that usually allows for the reabsorption of HCO3-) →HCO3- wasting → potentiation of metabolic acidosis (or treatment metabolic alkalosis) Used to reduce aqueous humor in glaucoma

Mannitol

osmotic agent; can't be reabsorbed and thus draws water OUT of the cells; principally used in *cerebral edema*

Loop diuretics

prototype: Furosemide promote metabolic alkalosis via potassium wasting; inhibit cotransporter in thick ascending limb that is responsible for reabsorbing Na+ (25%), K+, & Cl- →Wherever Na+ goes, water follows →Exchanger is driven by Na+/K+ ATPase →Used for heart failure and severe hypertension

*Tubular reabsorption*

solutes and water inside lumen transported back to blood; diuretics mainly block reabsorption of Na+.

Thiazides

work in the distal convoluted tubule, where 5-10% of the Na+ is reabsorbed. Use: hypertension, moderate edema, early heart failure (↓ preload) Unique uses: ↓ development of *renal stones* (Ca2+ salts) by promoting active Ca2+ reabsorption (less urinary Ca2+ wasting/excretion); also used to treat *osteoporosis*

ADH antagonists

(Conivaptan): used principally in treatment of inappropriately high ADH secretion, which leads to ↓ uric acid excretion

Aldosterone antagonists

(Spironolactone, Amiloride [non-steroidal]): inhibit aldosterone, a hormone normally released by adrenal gland in response to angiotensin II → ↑ absorption of Na+, K+ → secretion of H+ Spironolactone & Amiloride are *K+-sparing diuretics* and are therefore helpful in treating patients with *hypokalemia* or *secondary hyperaldosteronism* due to over-use of a loop diuretic

Spironolactone

*Competitive antagonist of aldosterone*, a hormone that normally stimulates Na+ reabsorption & K+ secretion. Drug therefore causes Na+ loss & K+ retention; acts on collecting ducts and late distal tubule. Limited diuretic action (2-5% Na+ load), depends on level of aldosterone activity. Active metabolite, canrenone, long t1\2 Uses: in mineralocorticoid excess, Conn's syndrome, secondary aldosteronism from CHF, cirrhosis, nephrotic syndrome ADRs: nausea, gastric ulceration, drowsiness, *hyperkalemia* because blocks potassium reabsorption, antiandrogenic effects (gynecomastia, male impotence)

Mannitol

*Know that its main use is to ↓ ICP in cerebral edema* & that it is *NEVER used in heart failure*! (because it expands the extracellular fluid volume) 1. Osmotic diuretic - adm IV, excreted unchanged in urine, requires mandatory osmotic amount of water, therefore urine volume increased with minimal Na excretion. 2. Action mainly in PCT/descending limb of loop Henle, holds H2O within lumen → excretion. 3. *Does not eliminate edematous fluid, can cause fluid overload in CHF* Extracts intracellular water → expansion of extracellular volume Use: *↓ intracranial pressure (cerebral edema*, ↓ intraocular pressure (ophthalmologic procedures), maintains urine flow in low urine flow states (e.g. drug OD, nephrotoxic drugs) OD toxicities: hypernatremia, hyperkalemia, volume depletion

Conivaptan

1. ADH receptor blocker (V1A & V2 receptors) 2. ↓water reabsorption by inhibiting V2 receptor 3. Blocks vasoconstrictive effects of V1A receptor, and used (P.O.) in clinical trials for heart failure pts.(results pending) Indicated for *Syndrome of Inappropriate of ADH (SIADH)*→ very low urine output as well as hypothyroidism, adrenal insufficiency, & potentially heart failure ADRs: hypokalemia, injection site reactions

Loop diuretics: mechanism of action

1. Furosemide inhibits NKCC2 transport mechanism (driven by Na+/K+ ATPase). This transport mechanism drives an outward potential into lumen, which drives a paracellular reabsorption of Mg2+ & Ca2+ 2. Leads to Na+, K+, Mg2+, Ca2+ wasting → metabolic alkalosis (opposite of carbonic anhydrase inhibitors). Furosemide can induce this metabolic alkalosis in patients with severe pulmonary edema (treatment: Acetazolamide)

Excessive diuresis/Adverse H's of Furosemide- KNOW THIS

1. Hyponatremia - excessive diuretic effect 2. Hypotension - loss of fluid volume 3. Hypokalemia - cardiac arrhythmias (↑ resting membrane potential) 4. Hypocalcemia - muscle cell excitability/tetany (rare). PTH attempts to counteract this. 5. Hypomagnesemia - twitching / convulsions 6. Hypochloremic alkalosis - excessive loss Cl- 7. Hyperuricemia - competes with tubular secretion uric acid; can lead to gout 8. Hyperglycemia - interferes with release of insulin (related to hypokalemia)

Thiazides: Hydrochlorothiazide

1. Less potent than loop diuretics; lower ceiling 2. Action in DT; inhibits Na\Cl cotransporter Usually can affect ~ 5-10 % of Na load 3. ↑ excretion of Na, K, Cl, Mg, water; but *NOT* Ca2+ *Ca2+ is actively reabsorbed in DT via PTH* Uses: edema/pulmonary edema, hypertension, early CHF, renal failure, diabetes insipidus (neurogenic vs. nephrogenic), hypocalcemia, kidney stones ADRs: H's (but not hypocalcemia), ↑ LDL, cholesterol, triglycerides, allergy

Loop diuretics: Furosemide

1. Potent high-ceiling diuretic 2. Inhibits Na\K\2Cl carrier, affects ~20-30% Na+ 3. ↑ excretion: Na, K, Cl, Ca, Mg, & water Uses: acute CHF, pulmonary edema, acute/chronic renal failure, hypercalcemia, hypertensive crises ADRs: *adverse H's* & related symptoms, *ototoxicity* (pain, vertigo, tinnitus, hearing loss), ↑ cholesterol/triglycerides, allergic reactions (Furosemide = sulfonamide derivative)

Na+ & water reabsorption

1. Proximal convoluted tubule (PCT): 65% of Na+ & water reabsorbed (*acetazolamide*) 2. Thick ascending limb: 25% (*loop diuretics*) 3. Distal tubule: 5-10% (*thiazides*) 4. Collecting duct: 2-5%

Glomerular filtration

20% of blood (about 1 L) through glomerulus forms ultrafiltrate renal blood flow=glomerular filtration rate

A 60-year-old patient complains of paresthesias and occasional nausea associated with one of her drugs. She is found to have hyperchloremic metabolic acidosis. She is probably taking? A. Acetazolamide for glaucoma B. Amiloride for edema associated with aldosternism C. Furosemide for severe hypertension and heart failure D. Hydrochlorothiazide for hypertension E. Mannitol for cerebral edema

A

Which of the following is associated with use of thiazide diuretics? A. Hypocalciuria B. Hypernatremia C. Hyperkalemia D. Hypouricemia E. Metabolic acidosis

A

Demeclocycline

A tetracycline that antagonizes ADH by inhibiting cAMP (downstream of receptor) in the collecting tubules. Indicated for SIADH and has 60-80% bioavailability after oral administration ADRs: nephrogenic diabetes insipidus, renal failure, photosensitivity (contraindicated in children under 12)

Acetazolamide ADRs

ADRs: GI n-v, allergy/rash (sulfa moiety), CNS depression (drowsiness/headache/ confusion), paresthesias, teratogenic (contraindicated in pregnancy)