RCS 14 - Diuretics Flashcards
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What MOA do all diuretics share?
They all inhibit some kind of renal ion transporter in order to decrease the reabsorption of Na+ at different site in the nephron.
They are all natriuretics
List the segments of the nephron and what they secrete and reabsorb.
- Glomerulus - just filters
- Proximal Tubule (PT) - both segments reabsorb Na+, K+, and H2O while secreting organic acids and bases
- Proximal Convoluted Tubule (PCT)
- Proximal Straight Tubule (PST)
- Descending Loop of Henle (DLH) - reabsorbs H2O
- Ascending Loop of Henle (ALH) - reabsorbs Na+, Cl-, and K+
- Distal Convoluted Tubule (DCT) - reabsorbs Cl-, and Na+
- Cortical Collecting Duct (CCD) - reabsorbs Na+ and H2O while secreting H+ and K+
List the primary transporters and drug targets present in each segment of the nephron.
- Glomerulus - none
- PT Segments - Na+/H+ exchanger 3 (NHE3), carbonic anhydrase, organic acid and base transporters
- DLH - aquaporins
- ALH - Na+/K+/2Cl- cotransporter 2 (NKCC2)
- DCT - Na+/Cl- cotransporter (NCC)
- CCD - epithelium Na+ channel (ENaC), K+ channels, H+ transporter, aquaporins
Describe the effects most diuretics have on uric acid levels and explain why.
Most dirutecs will cause hyperuricemia (an excess of uric acid in the blood)
This is because many diuretics utilize the organ acid secreting enzymes in the PT, the same enzymes used to secrete uric acid. As a result, not as much uric acid is secreted, causing the plasma levels to rise.
List the different classes of diuretics, briefly describe their MOAs, and name the drugs we need to know in each class.
- Loop Diuretics - block NKCC2 - furosemide (Lasix), -mide drugs
- Thiazides - block NCC - hydrochlorothiazide, chlorthalidone, metolazone
- Potassium-Sparing Diuretics - block aldosterone - spironolactone, eplerenone, triamterene, amiloride
- Carbonic Anhydrase Inhibitors - acetazolamide
- Osmotic Agents - raise osmotic pressure of the plasma to draw H2O out of the tissues and increase diuresis - mannitol
- ADH antagonist - antagonize the V1 and V2 receptors - conivaptan
Which class of diuretics is the most efficacious in removing Na+ and Cl- from the body?
Loop diuretics
Describe and explain the effects of furosemide.
- Increases Ca++, Mg++, Na+, Cl-, K+, and H2O excretion
- Increases prostaglandin synthesis which increases renal blood flow which decreases renal vascular resistance
The NKCC2 on the apical side of the cell transports Na+/K+/2Cl- into the cell. The Na+/K+ ATPase on the basolateral side of the cell transports the Na+ out of the cell but also transports more K+ into the cell. Cellular K+ overload is prevented by the renal outer medullary K+ channel (ROMK) on the apical side of the cell which allows for K+ recycling. This causes the apical side of the cell to be (+) and the basolateral side to be (-), which drives paracellular movement of Mg++, Ca++, and Na+ from the lumen to the interstitium. Loop diuretics will reverse this polarity and drive secretion of Na+, Ca++, and Mg++ in addition to preventing Na+/K+/2Cl- reabsorption.
Describe the clinical applications and administration routes for Furosemide. What is its half-life?
- Clinical Applications
- DOC for managing sever edema (usually due to HF or hepatic/renal disease)
- Treat HTN when first line drugs fail
- Administration - both orally and parenterally
- Half-life of 2-4hrs
What are the adverse effects of furosemide?
- Ototoxicity (toxic to the inner ear structures) - effects fluid flow in cochlea
- Hyperuricemia
- Acute hypovolemia
- K+ depletion
- Hypomagnesemia
- Allergic reactions - furosemide is a sulfur based drug which some patients are allergic to
Describe and explain the effects of hydrochlorothiazide
- Increases Na+, Cl-, K+, Mg++, and H2O excretion
- Decreases Ca++ excretion and PVR
The DCT cells have the NCC and a Ca++ channel on their apical surface and a Na+/K+ ATPase, Cl- channel, and Na+/Ca++ exchanger on their basolateral surface. When a thiazide blocks the NCC, Na+ & Cl- reabsorption is blocked. Because intracellular [Na+] drops, the Na+/Ca++ exchanger works more efficiently, which is why thiazides decrease Ca++ excretion. Because thiazides lead to an increase in [Na+] in the CCD, the Na+/K+ ATPases work more efficiently, which is why thiazides increase K+ excretion. The increase in Mg++ excretion is not understood. Decrease in PVR is due to derease in blood volume at first but with continued therapy, volume recovery occurs and hypotensive effects remain. This is believed to be due to vasodilation (MOA not known)
List the clinical applications, administration routes, and half-life of thiazides.
- Clinical Applications
- First line agent for HTN
- HF (mild-moderate)
- Treat hypercalciuria
- Only administered orally
- Half-life of 40hrs (40-60 for chlorthalidone)
List the differences amongst the thiazides
- Chlorthalidone has a longer half life and is therefore only taken once daily
- Metolazone is more potent and is therefore used in patients with advanced kidney failure.
What are the adverse effects of thiazides?
- Hypokalemia
- Hyponatremia
- Hyperuricemia
- Mild hyperglycemia - secretion of insulin is K+ dependent, and since thiazides have a stronger than usualy hypokalmeic effect, this is believed to be why they can cause hyperglycemia
- Hyperlipidemia (MOA unknown, easily countered with statins)
- Hypersensitivity - thiazides are sulfur based
- Sexual Dysfunction (MOA unknown)
Describe and explain the effects of K+ sparing diuretics.
- Increase in Na+ and decrease in K+ excretion
Aldosterone acts to stimulate the recruitment of ENaC and ROMK channels in the CCD. Spironolactone and Eplerenone antagonize aldosterone, preventing this. Amiloride and Triamterene block ENaC.
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