Diuretics F23.2 PDF

Diuretics Basic nephron function With ADH Without ADH Drug Classes Carbonic Anhydrase Inhibitors Loop Diuretics Thiazides Potassium Sparing Diuretics Osmotic Diuretics Overview of drug classes and sites of action Indications Hypertension Mobilization of edematous fluid...

Diuretics Basic nephron function With ADH Without ADH Drug Classes Carbonic Anhydrase Inhibitors Loop Diuretics Thiazides Potassium Sparing Diuretics Osmotic Diuretics Overview of drug classes and sites of action Indications Hypertension Mobilization of edematous fluid CHF Cirrhosis Kidney Disease Kidney stones Hypercalcemia  In general many Block solute reabsorption Water remains in tubule Carbonic Anhydrase inhibitors Block CA enzyme Act primarily in PCT Leaves Bicarb and sodium in tubular fluid (becomes urine) Water remains in tubule with sodium and is excreted Bicarbonate loss and less H+ excretion results in metabolic acidosis Not very potent diuretics and diuretic effects diminish after several days Often used for other actions Sulfonamide Derivatives Allergies Acetazolamide (Diamox) is the prototype Dozolamide (Trusopt) Brinzolamide (Asopt)  Edema due to heart failure (Acetazolamide when other diuretics have failed) Glaucoma due to reduction in Indications intraocular pressure secondary to of Carbonic reduced aqueous humor production Epilepsy Anhydrase Diminished Inhibitors seizures and CNS excitability Due to acidosis Altitude sickness (prophylactic ) Offsets respiratory alkalosis characteristic of acclimating to high altitudes  Drowsiness Metabolic Acidosis Paresthesia Uticaria Photosensitivity Adverse Effects (CA Sodium and inhibitors) Potassium loss Renal Stones Contraindicated in hepatic Cirrhosis  Most potent Effects are potent but brief Furosemide (Lasix) (prototype) Ethacrynic Acid, Bumetanide (Bumex), Torsamide (Demadex) All are sulfonamides except Ethacrynic acid Loop (Edecrine) Diuretics Inhibit Sodium, Potassium, 2 Chloride exchanger in ascending limb This reduces osmotic medullary gradient, keeps sodium in tubular lumen, and halts calcium and magnesium reabsorption Also increases distal sodium load, which stimulates potassium excretion Potassium loss can have clinical consequences  Actions of Loop Diuretics inhibit reabsorption of sodium, potassium and chloride in the ascending limb, increasing urine levels and loss High Ceiling diuretics : Cause water and sodium excretion of up to 20% filtered load inhibit the reabsorption of calcium and magnesium, thus increasing urine levels, and decreasing blood levels Increase renal blood flow by decreasing renal vascular resistance Effects on bp greater than what would be expected just through diuresis NSAIDS may reduce this action Over time they reduce uric acid excretion (cause hyperuricemia) Compete with Uric acid for excretion Mechanism of Hypokalemia 2. As a re sul t t he re i s a n + l o a d de l i ve re d i ncre a se d Na t o t he di st a l t ubul e s + 1. Thi a zi de s a nd o t he r po t a ssi um wa st i ng di ure t i cs Na K sparing + bl o ck t he re a bso rpt i o n o f so di um i n t he t hi ck Na BLO CKED diuretics block a sce ndi ng po rt i o n o f t he l o o p o f He nl e + Na 3. The re sul t i s a n i ncre a se d a bso rpt i o n o f Mechanism of + i n t he di st a l t ubul e s + K +loss with Na K diuretics. wi t h a co nse que nt + ( Adapted from i ncre a se i n t he se cre t i o n K o f po t a ssi um Klein, 1982).  Acute Pulmonary edema secondary to heart failure They act quickly Hypertension Useful when other drugs do not provide an adequate response Thiazides are first line Hypercalcemia Increase calcium excretion Indications Edema of Nephrotic Syndrome Drug of choice Edema from Cirrhosis Diuretic of choice in heart failure  Administered orally and parenterally Rapid onset of diuresis with short duration of action ( 30 min – 4 hours) useful for pulmonary edema when quick response is needed Torsemide has a longer half-life ( 6 hours) Pharmacokine Chronic use can result in diuretic tics resistance Addition of thiazide can offset Adverse Effects Fluid and electrolyte imbalances Lowered BP Lowered GFR Can be profound to point of circulatory collapse Hyponatremia and hypokalemia Low potassium of significant concern in patients also taking cardiac glycosides May result in digoxin toxicity Hypocalcemia Tetany if severe Hypomagnesaemia Cardiac arrhythmias Hyperglycemia Problem in diabetics or prediabetics Ototoxicity May manifest as tinnitus and vertigo Can result in deafness Exacerbated with concurrent use of other Ototoxic drugs (aminoglycosides) Ethacrynic acid has most ototoxicity , deafness may be permanent Hyperuricemia Can precipitate gout attacks Hypovolemia Shock , hypotension and arrhythmias Allergies and photosensitivity Skin rashes Hypokalemia Concurrent use of potassium supplements or addition of Potassium sparing diuretic Elevated LDL and Triglycerides  Interactions Other diuretics Additive effects Digitalis Increased risk of digoxin toxicity due to hypokalemia Sulfonylureas ( used for Diabetes) oppose action due to elevating blood glucose NSAIDS Diminish effects on TPR due to prostaglandin inhibition Aminoglycosides, other ototoxic drugs Probenecid ( Gout treatment) Diminished effects ( stimulate excretion of diuretics) Lithium and propranolol Increased plasma levels Lithium has narrow TI , hyponatremia can stimulate lithium reabsorption Thiazides Inhibit sodium chloride exchanger in DCT Hydrochlorothiazide (HCTZ) is the prototype Other Examples: Chlorothiazide (Diuril), Cyclothiazide (Anhydron), Polythiazide (Renese), Benzthiazide (EXNA), Bendroflumethiazide (Naturetin), Hydrochlorothiazide (HCTZ, Hydrodiuril), Hydroflumethiazide (Saluron), Methyclothiazide (Enduron), Polythiazide (Renese), Chlorthalidone (Hygroton), Indapamide (Lozol), Metolazone (Mykrox, Zaroxolyn), Quinethazone (Hydromox), Trichlormethiazide (Aquacot, Diurese, Metahydrin, Naqua, Niazide, Trichlorex)  Thiazides Most widely used diuretics Sulfonamide derivatives Inhibit peripheral vascular resistance Adds to BP reduction Transporter they inhibit is on the luminal side Must have adequate GFR to act, not useful in reduced renal function ( Metolazone is the exception) Increase distal sodium delivery Hypokalemia Cause magnesium loss but calcium retention Reduce uric acid excretion with long term use Gout can occur Thiazide like Diuretics Metolazone Can be used in impaired renal function Indapamide Often used in advanced renal failure to increase diuresis in combination with loop diuretics Indications Hypertension Cheap and effective Heart Failure to reduce edema Edema due to reduced renal function If loop diuretics fail metolazone in conjunction with a loop diuretic Hypercalciuria (Prevent kidney stones by reducing urine calcium)  Adverse Effects Hypokalemia Can offset by diet, supplements, or K sparing diuretic Can exacerbate dig toxicity Hypovolemia Hyperuricemia Periodic monitoring Hypercalcemia Usually only unmask an underlying condition Hyperglycemia Caution in diabetics and prediabetics Hyperlipidemia Hyponatremia, Hypomagnesiumemia, Hypochloremia Allergies due to sulfonamide Other: CNS hematological, GI , dermatological  Interactions Other diuretics Additive effects Digitalis Increased risk of digoxin toxicity Sulfonylureas Thiazides oppose action due to elevating blood glucose NSAIDS Diminish effects due to prostaglandin inhibition Aminoglycosides, other ototoxic drugs Probenecid Diminished effects ( stimulate excretion of diuretics) Lithium and propranolol Increased plasma levels Lithium has narrow TI , hyponatremia can stimulate lithium reabsorption Potassium Sparing Diuretics  In general, antagonize effects of aldosterone in distal nephron Two general mechanisms 1. antagonize aldosterone receptors Spironolactone(Aldactone), eplerenone(Inspra) 2. Inhibit sodium influx through ion channels Amiloride(Midamor), triamterene (Dyrenium) Reduce sodium reabsorption and increase Potassium reabsorption Will also reduce hydrogen ion excretion ( increase hydrogen ion reabsorption)  Spironolactone,Eplerenone Amiloride, Triamterene Indications Most useful for states of aldosterone excess Primary states : hypersecretory conditions Secondary : Heart failure, cirrhosis, nephrotic syndrome Often used In conjunction with other diuretics to offset potassium losses (most common use) Thiazides or loop diuretics No potassium supplements Spironolactone has shown usefulness in severe heart failure Increased overall survival and reduced hospitalization when added on to other therapies Adverse Effects Hyperkalemia Can be life threatening Risk higher in renal disease or in presence of drugs that reduce renin ARBs ACE inhibitors, beta blockers or NSAIDS Metabolic acidosis Due to reduced hydrogen ion excretion Gynecomastia Spironolactone is a synthetic steroid binds other steroid receptors Impotence and BPH also Menstrual irregularities in females Eplerone is more specific for Aldosterone receptor Kidney stones Osmotic Diuretics Hypertonic Solution Hypotonic Solution Nonabsorbable and freely filtered at glomerulus Must be given parenterally Remain in tubule raise osmotic pressure and hold water in tubule Used to remove renal toxins Reduction of intracranial pressure ( Cerebral edema) Act in most water permeable regions of nephron PCT and descending limb Also antagonize ADH Hypernatremia over time Water loss is greater than sodium loss Mannitol (Osmotrol) is the prototype Indications Cause greater water excretion than sodium excretion Not useful in conditions of sodium retention Maintain urine flow with ingestion of nephrotoxic substances to prevent acute renal failure Reduction of intracranial and intraocular pressure Primary use is reduction of intracranial pressure or prevention of acute renal failure due to shock, drug toxicity or trauma ( rhabdomyolysis or hemolysis)  Adverse effects ECF volume expansion Dehydration and electrolyte imbalances Muscle cramps PVCs Headache N/V are common ADH antagonists Covered later in more detail Allow selective water diuresis Plasma sodium rises Urine osmolarity falls