Pharmacology: D I U R E T I C S

CARBONIC ANHYDRASE INHIBITORS

ACETAZOLAMIDE Sulfonamide derivative diuretic action was observed as a side effect of Sulfanilamide (an

OSMOTIC DIURETICS
MANNITOL inert freely filtered at the glomeruli

LOOP DIURETICS
FUROSEMIDE

THIAZIDE DIURETICS

RENAL EPITHELIAL SODIUM CHANNEL INHIBITORS

TRIAMTERENE Non-steroidal in structure inhibits Na+ reabsorption in the mineralocorticoid independent portion of the collecting duct NOT dependent upon presence of Aldosterone

MINERALOCORTICOID RECEPTOR ANTAGONISTS

SPIRONOLACTONE structurally related to Aldosterone clinical efficacy correlates with levels of endogenous Aldosterone

antibiotic)

now rarely used as a Diuretic

Primary Site of Action: Proximal tubule

Primary Site of Action: Descending limb of the Loop of Henle also acts at the proximal tubules

HYDROCHLOROTHIAZIDE DESCRIPTION contains a sulfonamide moiety Sulfonamide derivatives High ceiling diuretic: Low ceiling Diuretic blocks 25% reabsorption of Na+ exhibit a ceiling of Diuretic effect TAL has greater reabsorptive surface Usual dose is 12.5-25 mg >25 mg dose does NOT result in increase in (increasing the dose increases the diuresis) Diuretic effect usual dose is shown to be more effective in reducing Cardiovascular events SITE OF ACTION Site of Action: Thick ascending limb (TAL) of Major Site of Action: Distal convoluted tubules the Loop of Henle

Site of action of Potassium-sparing diuretics is the Sodium channel in the late distal tubule and collecting ducts blocks reabsorption of only about 2% of filtered load of Na+ competitively inhibits Aldosterone binding to Mineralocorticoid receptors in the late distal tubules and collecting duct system promotes modest Na+ excretion and K+ retention

inhibition of Carbonic anhydrase almost complete stop of NaHCO3 reabsorption

increase urinary excretion of Na+ bound to HCO3- (can lead to

Increase osmolality of plasma and tubular fluid extraction of water from intracellular compartments increase urinary excretion of electrolytes

Mannitol is a sugar

metabolic acidosis)
also affects Carbonic anhydrase in the: eyes gastric mucosa pancreas CNS erythrocytes

MECHANISM OF ACTION Inhibits Na+ K + 2Cl- symporter in the thick inhibition of Na+-Cl- symporter at the apical Block Na+ channels in the ascending limb (TAL) of the Loop of Henle membrane of the Distal convoluted tubule cells luminal membrane of cells in weak Inhibitor of Carbonic anhydrase which the late distal tubule and PHARMACOLOGIC ACTIONS: accounts for its weak proximal tubular effects collecting duct 1. Diuretic (this action is also found in Furosemide) increase urinary Na+ and Cl excretion INCREASE excretion of Na+ prevents reabsorption of 5% of filtered Sodium marked increases in Ca2+ and Mg2+ and Clload + + excretion (The reabsorption of Ca++ and approximately 90% of filtered Sodium load is INHIBIT secretion of K , H , Ca++ and Mg++ reabsorbed before reaching the DCT Mg++ parallels the absorption of sodium in the enhanced K+ excretion Loop of Henle but this is mediated by

paracellular pathway.) metabolic alkalosis)

enhanced K+ and H+ excretion (can

cause

NOT absorbed from GI tract given INTRAVENOUSLY Onset of action: 10 minutes after infusion Duration: 1-3 hrs Half-life: 100 minutes (therefore given

via continuous infusion)

metabolized minimally in the liver to glycogen rapidly excreted in the urine

2. Direct vascular action Mechanism is related to prostaglandin Venodilatation decrease in left ventricular filling pressure useful in patients with pulmonary edema relief of congestive symptoms before diuretic action PHARMACOKINETICS available for ORAL and PARENTERAL 70% ORAL bioavailability administration Half-life: ~2.5 hrs approximate oral bioavailability: 60% NOT metabolized Onset: rapid (20 min) excreted through the kidneys by tubular Half-life: 11.5 hours secretion highly bound to plasma proteins so not filtered through the glomeruli (it reaches the

15-25% ORAL bioavailability Half-life: ~ 21 hours renal excretion of the intact drug

tubules by tubular secretion) Probenecid)

secreted in the proximal tubules through an active transport process (can compete with 35% undergoes conjugation with glucuronic acid in the kidneys 65% excreted unchanged in the kidneys

The H+ ion produced by the breakdown of H2CO3 is usually exchanged for Na+ and is also used to combine with HCO3 in the lumen of the PCT. Without the H+, there is decreased reabsorption of Na+ and HCO3-, this results in diuresis.

given orally; 65% ORAL bioavailability extensive first pass hepatic metabolism undergoes enterohepatic recirculation Half-life: short (1.6 hrs) Highly protein bound (>90%) excretion is primarily in the urine; secondarily in the bile undergoes metabolism by both deacylation and dethioacetylation to a variety of metabolites with prolonged T : 7--(thiomethyl) spirolactone (TMS): 13.8. hrs (SHORTEST) 6--hydroxy-7--(thiomethyl) spirolactone (HTMS): 15 hrs Canrenone: 16.5 hrs (LONGEST)

ACETAZOLAMIDE 1. Edema low efficacy 2. Glaucoma to intraocular pressure (IOP) Carbonic anhydrase is responsible for production of aqueous humor in the ciliary process Dorzolamide and Brinzolamide TOPICAL carbonic anhydrase inhibitors

MANNITOL 1. Acute renal failure due to Acute tubular necrosis 1. 2. 3. 4.

(secondary to shock, drug, acute severe infections)

Increase renal blood flow open up the kidneys 2. Cerebral edema secondary to trauma or surgery 3. Reduction of intraocular pressure in: acute attacks of glaucoma pre and post Ocular surgery (short term use) 4. Dialysis Disequilibrium syndrome rapid reduction in the osmolality of ECF due to rapid removal of solutes after hemodialysis and peritoneal dialysis S/S: hypotension, muscle cramps, headache, nausea, restlessness, depression, convulsions

5. 6. 7.

FUROSEMIDE HYDROCHLOROTHIAZIDE THERAPEUTIC USES / CLINICAL INDICATIONS Acute pulmonary edema 1. Hypertension blood volume Congestive heart failure TPR (direct effects on vascular smooth Edema of Nephrotic syndrome Hypertension muscle) Oral: Moderate to Severe used as monotherapy IV or IM: Severe hypertension; additive or synergistic effects when hypertensive encephalopathy combined with other classes of antihypertensive drugs Hypercalcemia (since it enhances excretion of best initial therapy for uncomplicated Calcium by preventing its reabsorption) hypertension Peripheral edema and Ascites of Liver 2. Edema 2o to: cirrhosis Cardiac: CHF Acute Renal Failure (acts the same way as Hepatic: Cirrhosis Mannitol; increases renal blood flow) Renal: Nephrotic syndrome, Chronic renal failure, Acute Glomerulonephritis INEFFECTIVE if GFR is less than 30-40 ml/min

TRIAMTERENE

SPIRONOLACTONE 1. Primary hyperaldosteronism adrenal adenoma bilateral adrenal hyperplasia 2. Congestive heart failure reduce mortality if added to standard therapy 3. DOC for ascites secondary to Hepatic cirrhosis 4. Nephrotic syndrome 5. Essential hypertension 6. Hypokalemia

(this is a sign of renal dysfunction renal secretion is altered drug is not able to reach the distal tubules)

1. Dilutional hyponatremia (due

to

1.

increased ECF volume)

Headache Nausea Vomiting 2. Hypernatremia and dehydration 3. Expansion of ECF volume pulmonary edema worsening of CHF 2.

3.

4.

reabsorption of Na and Cl detected by JG cells triggers renin secretion activates RAAS aldosterone Na and H2O reabsorption 5.

3. Nephrogenic Diabetes Insipidus 4. Calcium nephrolithiasis ADVERSE EFFECTS Hypersensitivity reactions (due to Sulfonamide 1. Dermatologic skin rashes component) Photosensitivity skin rashes 2. Gastrointestinal interstitial nephritis anorexia Ototoxicity (due to its effect on Na-Cl-K nausea, vomiting symporter found on the inner ear) diarrhea/constipation tinnitus, deafness, disequilibrium 3. CNS vertigo, sense of fullness in the ears headache associated with high IV doses (> 240 paresthesias, vertigo mg/day) 4. Hematologic (due to Sulfonamide component) Fluid and electrolyte imbalance blood dyscrasias Hyponatremia 5. Fluid and Electrolyte abnormalities Hypotension ECF volume depletion hypotension Hypokalemia Hypokalemia Metabolic alkalosis (Hypochloremia) increased risk for Digitalis-induced Hypocalcemia arrhythmia Hypomagnesemia if combined with Quinidine Torsades Metabolic effects des pointes; usually self-limiting but may Uric acid excretion deteriorate into fatal ventricular fibrillation Acute: enhance excretion Hyponatremia: can be fatal or nearly-fatal Chronic: reduce excretion (can trigger Hypochloremia acute attacks of gout) Hypomagnesemia Hypercalcemia Hyperglycemia (not useful in DM Metabolic alkalosis patients) 6. Metabolic Dyslipidemia Hyperuricemia HDL Hyperglycemia LDL Hyperlipidemia triglycerides 7. Sexual dysfunction Braking Phenomenon impotence / erectile dysfunction tolerance to the diuretic effect CONTRAINDICATIONS

1. Hyperkalemia 2. GIT Nausea Vomiting Diarrhea 3. CNS headache

1. Hyperkalemia may be mild, moderate or lifethreatening 2. Anti-androgenic effects:

(Spironolactone has some affinity toward progesterone and androgen receptors)

Males: gynecomastia, decreased libido and impotence Females: menstrual irregularities, hirsutism, deepening of voice 3. Gastrointestinal Diarrhea Gastritis Bleeding peptic ulcer 4. CNS Confusion Headache Ataxia Drowsiness Lethargy 5. Skin rashes

1. Anuric patients due to severe renal disease or unresponsive to test dose of the drug 2. Active intracranial bleeding

DIURETICS
increase rate of urine flow increase rate of Na+ excretion accompanied by an anion usually Cl- (where sodium goes, water follows) reduce extracellular fluid volume by decreasing total NaCl content also modify renal handling of other electrolytes such as K+, H+, Ca++, Mg++, Cl-, HCO3-, H2PO4-, glucose and uric acid

SUMMARY

Best time to give diuretics is in the morning. Giving diuretics in the evening can disturb sleep.

CLASSIFICATION OF DIURETICS
1. 2. Carbonic Anhydrase Inhibitors Acetazolamide Osmotic Diuretics Mannitol Glycerin Urea Loop Diuretics Furosemide * Has sulfonamide component Bumetamide Ethacrynic acid Torsemide Thiazide Diuretics Hydrochlorothiazide Chlorothiazide Thiazide-like Inhibitors of Na+-Cl- Symport Chlorthalidone Indapamide Metolazone Potassium Sparing Diuretics 6.1. Renal epithelial sodium channels Inhibitors a. Triamterene b. Amiloride 6.2. Mineralocorticoid receptors Antagonists a. Spironolactone b. Elprenolone

3.

4. 5.

6.

Dose-response curve of loop diuretics (high-ceiling) vs thiazide diuretics (low-ceiling)

1. 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 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. Spironolactone. c. Hydrochlorothiazide. d. Triamterene. Which of the following drugs is contraindicated in a patient with hyperkalemia? a. Acetazolamide b. Chlorothiazide c. Spironolactone d. Ethacrynic acid e. Chlorthalidone 4. Which would be the initial treatment choice to manage the hypertension in an African-American woman with a past medical history of gout and severe hypokalemia? a. Hydrochlorothiazide b. Valsartan c. Spironolactone d. Atenolol e. Enalapril An elderly patient with a history of heart disease and who is having difficulty breathing is brought into the emergency room. Examination reveals that she has pulmonary edema. Which of the following treatments is indicated? a. Spironolactone. b. Acetazolamide. c. Furosemide. d. Chlorthalidone. e. Hydrochlorothiazide.

HORMONAL CONTROL OF THE COLLECTING DUCT SYSTEM

(in relation to Potassium sparing diuretics)

1. Aldosterone Na+ reabsorption and K+ secretion adjusts electrolyte composition Antidiuretic Hormone modulates permeability to water

2.

5.

2.

GLOSSARY: RENAL PHYSIOLOGY

3.

Glomerular filtration: First step in urine formation; involves the ultrafiltration of plasma in the glomerulus Tubular reabsorption: process by which solutes and water are removed from the tubular fluid and transported into the blood Tubular secretion: transfer of materials from peritubular capillaries to renal tubular lumen; caused mainly by active transport. Excretion: elimination via the urine. In general, the amount excreted is expressed by the following equation: Excreted = Filtered Reabsorbed + Secreted

TIM RUSSERT