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27 Cards in this Set
- Front
- Back
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uses of diuretics
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Treatment of edema
Treatment of hypertension Treatment of hyperkalemia, hyponatremia, hypercalciuria, and other electrolyte disturbances Prevent precipitation in urinary tract Maintain output in chronic kidney disease and CHF with edema Increase in urine flow to reduce tubular toxicity Use as a tool in the molecular and cellular biology of transporters |
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Diuretic drugs are classified according to
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nephron site of action
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Proximal Diuretics
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Carbonic Anhydrase inhibitors, Actezolamide-not very effective, but has particular uses like lowering ocular pressure
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Loop Diuretics
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Na, K 2Cl inhibitors.
Furosimide, Bumetanide, Torsemide, Ethacrynic acid |
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DCT Diuretics
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"thiazides" NaCl inhibitors
HCTZ, metolazone, Chlorthalidone, Indapamide |
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CD Diruetics
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Na channel Blockers- ENaC inhibitors: amiloride, triamterene
Aldosterone antags: spironolactone, eplerenone |
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6 classes of diuretics and nephron sites
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osmotics and carbonic anhydrase inhibitors in the proximal tubule.
Loop diuretics (thick ascending limb) and thiazide diuretics K sparing diuretics and Aquaretics |
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Proximal Tubule
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glucose is a diuretic. We can administer mannitol as a diuretic that works in the proximal tubule
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Cellular mechanism of action of mannitol and carbonic anhydrase
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Cabonic anhydrase inhibitition shuts down bicarb reabsorption
Mannitol is not reabsorbed in the renal tubule |
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Mannitol as an osmotic diuretic
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Mannitol is the most commonly used osmotic diuretic
Inert sugar, filtered but not reabsorbed. IV use only. Retains water in PT and early loop so that a large volume of dilute fluid enters the DT Glucosuria from DM and contrast media also are osmotic diuretic states Use: dilute renal toxins (cisplatin), maintain urine flow in acute kidney injury. Brain edema, not generalized edema or in CHF patients Side effects: Volume overload, CHF, tubule toxicity |
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Carbonic Anhydrase 4
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adheres to brush border membrane, exposed to apical side. inhibitied by acetozolamide
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Carbonic Anhydrase 2
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inside the cell. inhibited by acteozolamide
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Carbonic Anhydrase Inhibitors: Acetazolamide
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Acetazolamide (Diamox)
Sulfanilamide prototype with –SO2NH2 excretion of Na, HCO3 and K ↑; Cl ↔ alkaline urine and systemic acidosis Use: ↑urine pH (aspirin intoxication), correct severe metabolic alkalosis in patients with CHF, glaucoma, epilepsy, mountain sickness, occasionally to potentiate other diuretics S/E, limitations: allergy, tolerance, metabolic acidosis alternate H+/HCO3- pathways |
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"Loop Diuretics" Furosemide
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bumetanide, torsemide, ethacrynic acid
Most potent and effective diuretics since downstream transporters can’t compensate Inhibit Na,K,2Cl symporter (NKCC2) ↑Na, Cl, K, Ca, Mg excretion Use: mainstay in kidney disease with ↓eGFR (CHF, edema), hypertension, pulmonary edema, hypercalcemia. Used alone or combined with other diuretics S/E, limitations: short action, volume depletion, hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalcemia, hyperglycemia, hyperuricemia, may cause hyponatremia*. All but EA are sulfa derivatives – allergy potential Ototoxicity, esp with aminoglycosides and higher with EA |
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Thiazides and similar drugs
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Hydrochlorothiazide [HCTZ], HydroDiuril® +
Others: chlorthalidone, indapamide, metolazone Inhibit the apical Na-Cl symporter (NCCT) Sulfonamide derivatives do have minor CAI activity and ↑bicarbonate excretion Slight renal vasoconstriction limits use below GFR <30 ml/min Ca+2 retention esp with chronic use Use: First-line drug in hypertension, edema, ± other diuretics, hypercalciuria, nephrogenic DI. Several drugs are long acting and can be given 1x/day. S/E, limitations: hypokalemia, hyperglycemia, hyperuricemia, metabolic alkalosis, volume depletion Potential allergy to sulfas |
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Why should thiazides decrease Ca+2 excretion while loop diuretics increase Ca+2 excretion ??
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inhibiting the na cl transporter causes decr in ca
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Distal Regulation of K Secreteion
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Aldosterone
Na delivery to the distal tubule Potential difference (lumen negative voltage) across the tubule Tubular fluid flow rate |
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Amiloride, traimterene and spironolactone
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These drugs are often useful in treating “refractory” edema associated with avid distal Na reabsorption which may compensate for the action of more proximally acting drugs, and in ascites associated with secondary hyperaldosteronism accompanying hepatic cirrhosis.
Spironolactone may be effective in low renin-low aldosterone hypertension, perhaps because of inhibition of aberrant mineralocorticoid other than aldosterone, or through mineralocorticoid-like receptors in the brain. Major hazard: hyperkalemia. |
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If ion transporters are expressed in other epithelia, why are diuretics relatively selective for the kidney?
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Transporters: specific renal transporters are targets, most on apical membrane, and level of expression in kidney is high
Drug concentration is higher in the kidney Filtration of free vs. bound drug Secretion of drug stripped of binding protein Luminal conc. ↑ by Na, water reabsorption Filtered albumin [nephrotic syndrome] can re-bind diuretics and ↓effect |
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Why may loop and thiazide diuretics cause hypokalemia?
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Increased delivery of Na, water, sometimes HCO3- to distal nephron enhances K secretion
Volume depletion leads to secondary hyperaldosteronism Better dietary Na control less diuretic required less distal nephron Na delivery less K loss and hypokalemia |
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How may loop and thiazide like diuretics cause metabolic alklosis
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Diuretics distal Na delivery:
Cl loss (relative to bicarbonate as an anion) K loss (eventually transcellular K/H exchange also contributes to lower pH) H loss (distal Na delivery and aldosterone contribute) ECV (aldosterone to K, H loss) Hypokalemic, hypochloremic alkalosis corrected with KCl replacement |
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Physiological Compensation limiting diuretic effects (homeostasis)
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Increased downstream reabsorption may reduce the effect of more proximally acting drugs (e.g., CAI are weak natriuretics)
Increased proximal reabsorption can compensate for more distally acting drugs (e.g., ↑ proximal reabsorption in response to ECV contraction produced by loop or DT-acting drugs) Dietary salt intake |
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V2 Receptor Antagonists: Aquaretics
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The V2 receptor mediates the antidiuretic response of ADH.
The vasopressin receptor antagonists are a new class of agents that produce a selective water diuresis without affecting sodium and potassium excretion. The ensuing loss of free water will correct hyponatremia in patients with the syndrome of inappropriate ADH secretion (SIADH). Thirst increases significantly with these agents, which may limit the rise in serum sodium. Some oral formulations — tolvaptan, satavaptan, and lixivaptan — are selective for the V2 receptor, while an intravenous agent, conivaptan, blocks both the V2 and V1a receptors. Tolvaptan and conivaptan are currently available in the United States and both are approved for the treatment of hyponatremia due to SIADH, but broader application is anticipated: hyponatremia with advanced CHF, cirrhosis. |
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Clinical uses of diuretics
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Relatively small doses of diuretics, esp. thiazides, are effective in hypertension
Diuretic therapy provides symptomatic relief of edema; reduces ascites slowly but can induce hypokalemia, severe volume depletion (often used together with K-sparing diuretics) Loop diuretics i.v. provide dramatic relief in pulmonary edema and severe volume overload Less Na intake →less hypokalemia and more benefit for hypertension Side effects may be useful for treatment strategy of electrolyte abnormalities (amelioration of hyperkalemia by furosemide) Benefits may extend beyond kidney (improved outcomes in post MI patients with low EF from aldactone and epelerenone); RALES and EPHESUS trials. |
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Complications of Diuretic Therapy
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Proximal Diuretics (Carbonic Anhydrase Inhibitors)
Hypokalemia, metabolic acidosis Distal Tubule Diuretics (NCCT inhibitors) Volume depletion, hypokalemia, metabolic alkalosis, hypercalcemia Loop Diuretics (NKCC-2 inhibitors) Volume depletion, hypokalemia, metabolic alkalosis, hypocalcemia, hypomagnesemia K+-Sparing Diuretics (amiloride, triamterene, spironolactone) Hyperkalemia (especially with CKD), metabolic acidosis Spironolactone: gynecomastia, impotence, menstrual abnormalities (endocrine effects of non-selective MC antagonist) |
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Gitelmans Syndrome
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inherited loss of NCCT fxnGenetic basis: loss of function mutation of the NCCT in the DCT (thiazide).
Defect causes renal salt wasting, hypokalemia, metabolic alkalosis, volume depletion, and relative hypotension. Inverse relationship between salt intake and BP. Higher salt intake in these patients associated with lower BP Inescapable conclusion is that these patients have salt hunger. Provides clue to what happens in HBP patients on diuretics. Overcompensate by eating more salt. |
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Liddles Syndrome
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Volume Expansion
Hypertension Hypokalemia Metabolic Alkalosis Cause: Inherited gain of function mutation of ENaC Example of monogenic hypertension Respond to amiloride |
