Diuretics

Front 1

Definition of Diuretics

Back 1

Drugs that increase urine flow and/or Na+/Cl- excretion
-Sustained imbalance between Na+/Cl- intake or loss is fatal
-Too much: volume overload, pulmonary edema
-Too little: volume depletion, CV collapse

Front 2

Renal compensatory mechanisms that prevent volume depletion and CV collapse

Back 2

-"Diuretic braking"
-Activation of SNS and RAAS
-Decrease BP (decrease pressure natriueris)
-Decrease ANP, increase ADH
-Renal cell hypertrophy

Front 3

Filtration

Back 3

-16 to 20% fluid and solutes filtered (glucose, Na, K, Cl, HCO3, amino acids)
-150 to 180 liters filtered per day, 1 to 2 liters excreted
-Plasma filtered ~50 to 60 times per day

Front 4

Proximal Tubule

Back 4

-Reabsorption of glucose, amino acids and organic solutes (Na 66%, NaHCO3 85%, K 65%, H20 60%)
-Weak acids and bases excreted into lumen, site where diuretics enter tubule
-60 to 70% of filtrate reabsorbed

Front 5

Loop of Henle

Back 5

-Concentrate urine and Na reabsorption
-Descending loop: water leaves lumen (helps concentrate urine)
-Ascending loop: 25% of Na reabsorbed, impermeable to water
-LOOP DIURETICS work at this site

Front 6

Distal Tubule

Back 6

-~5% of Na reabsorbed
-Water movement controlled by aldosterone
-Site of THIAZIDE diuretics
-Macula densa at interfact between ascending loop and distal tubule regulates Na. If Na too high constricts afferent arteriole to decrease filtration through nephron.

Front 7

Collecting Duct

Back 7

-2 to 3% of sodium reabsorbed
-Water movement controlled by aldosterone and ADH
-Site of Potassium Sparing Diuretics (less effective than others)

Front 8

Loop Diuretics

Back 8

-Inhibit the Na-2Cl-K carrier on the luminal membrane of the thick ascending loop of Henle
-Furosemide, Bumetanide, Torsemide, Ethacrynic acid

Front 9

Major Actions of Loop Diuretics

Back 9

-Inhibit NaCl reabsorption by 20-25%, increase urine output up to 4 liters per day
-Decrease medullary hypertonicity, reduces countercurrent concentration
-Increase K+ excretion, will decrease K adsorption in TAL and will increase K secretion in LDT and Collecting Ducts
-Increase Ca and Mg excretion (decrease potential across tubular cell)

Front 10

Other actions of Loop Diuretics

Back 10

-Hyperglycemia: hypokalemia leads to impaired insulin release; reflex mediated catecholamine release (a2 decreases insulin release, B2 increases glycogenolysis); impaired peripheral glucose uptake (insulin resistance)
-Systemic vasodilator actions: stimulate prostaglandins (PGE2)- blocked by NSAIDs; direct relaxant effect on muscle although mechanism is not understood

Front 11

Other activities of Loop Diuretics

Back 11

-Reflex activity due to volume depletion: increase renin-angiotensin system; increase aldosterone; increase ADH
-Uric Acid: decrease excretion and increase plasma uric acid levels (Gout): acute increase in PCT reabsorption, chronic decrease in tubular excretion, and increased concentration due to plasma volume contraction

Front 12

Other actions of Loop Diuretics

Back 12

-Mild metabolic alkalosis: volume depletion due to increased HCO3 reabsorption (minor) and enhanced H+ ion secretion (major)
-Mild hyperlipidemia: increased sympathetic activity leads to increased triglycerides
-Block transporter in macula densa to effect feedback signal to regulate GFR and AngII
-Loops effective in patients with CrCl below 30 ml/min

Front 13

Therapeutic indications of Loops

Back 13

-Pulmonary edema
-Nephrotic syndrome (protein loss can't regulate plasma fluids)
-Cirrhosis of the liver (Ascites)
-Hypercalcemia (used with saline)
-Heart failure
-Renal failure/insufficiency
-Hypertension

Front 14

Adverse Effects of Loops

Back 14

-Volume depletion- reflex mechanisms
-Hypokalemia- cardiac arrhythmias
-Hyperglycemia: diabetogenic effects
-Contraction alkalosis
-Hyperuricemia: gout
-Ototoxicity: damages hair cells in cochlea
-Hyponatremia: seizures
-Allergic reactions: rash, photosensitivity
-Azotemic: increase BUN

Front 15

Drug Interactions with Loops

Back 15

-NSAIDs: blunt the natriuretic and BP response
-Aminoglycosides: potentiates ototoxicity
-Weak organic acids: compete for anion transporter, decrease lumen concentration
-Warfarin: competes for plasma protein binding
-Lithium: decreased clearance, increase toxicity
-Digitalis: hypokalemic + hypomagnesium - arrhythmias