Pharmacology of Diuretics Flashcards
clinical uses of diuretics
*edema tx
*HTN tx
*hyperkalemia, hyponatremia, hypercalciuria, hypercalcemia tx
*prevention of stone precipitation in urinary tract
*increase in urine flow to reduce tubular toxicity of a drug or toxin
*tx of chronic hyponatremia in states of inappropriate antidiuretic hormone excretion
*increase urine glucose excretion and lower plasma glucose in type 2 DM
if ion transporters are expressed in other epithelial, why are diuretics relatively selective for the kidneys?
*transporters are drug-specific targets, expressed on apical membranes, and level of expression in kidney is high
*drug concentration is higher in the kidney
mannitol (osmotic diuretic) - MOA
*inert sugar, filtered but not reabsorbed
*works in PCT & distal loop of Henle
*causes increased serum osmolality → fluid shift from interstitium to intravascular space → increased urine flow (large volume of dilute fluid) and decreased intracranial/intraocular pressure
mannitol (osmotic diuretic) - uses
*cerebral edema
*nephroprotective (diluting renal toxins helps to maintain urine flow in AKI)
mannitol (osmotic diuretic) - ADEs
*volume overload; worsening of CHF or cause acute pulmonary edema
*volume depletion
*hypernatremia
*tubule toxicity
SGLT2 inhibitors - MOA
*inhibits Na+/glucose symporter in PCT
*results in:
-glycosuria: decreases blood sugar, osmotic diuresis
-natriuresis: increases NaCl delivery to macula densa → downregulation of RAAS
recall: “-gliflozins” are SGLT2 inhibitors
SGLT2 inhibitors - examples
*canagliflozin
*empagliflozin
*dapagliflozin
SGLT2 inhibitors - uses
*adjunct treatment for type 2 DM
*prevents CKD progression
*HF symptoms
*HTN
recall: “-gliflozins” are SGLT2 inhibitors
SGLT2 inhibitors - ADEs
*urinary tract infections
*genital infections (fungal)
*volume depletion
*euglycemic DKA (ketoacidosis with normal blood sugar)
recall: “-gliflozins” are SGLT2 inhibitors
acetazolamide - MOA
*inhibits carbonic anhydrase enzyme → decreased reabsorption of Na+, H2O, and HCO3- in the PCT → increased excretion of Na+, HCO3-, K+, and Cl-
*alkalinizes urine
*causes mild metabolic acidosis
acetazolamide - uses
*increased urine pH
*glaucoma
*treat/prevent high altitude sickness (acclimatization; by offsetting respiratory alkalosis)
*treat METABOLIC ALKALOSIS IN CHF
recall: acetazolamide is a carbonic anhydrase inhibitor
acetazolamide - ADEs
*ceiling effect: bicarb can only drop down so much
*allergy
*tolerance
*metabolic acidosis
*slight increased risk for stones
recall: acetazolamide is a carbonic anhydrase inhibitor
secretion of loop and distal diuretics by PCT S3
*loop diuretics & distal diuretics are protein-bound, and need to get into the tubule to work
*in S3 segment of proximal tubule, OAT transporter & MDRP secrete diuretics and other drugs into our tubular lumen
*note - some drugs or conditions interfere with the function of OAT transporter (cimetidine, NSAIDs, probenacid, uremia, and CKD)
loop diuretics - examples
*FUROSEMIDE
*bumetanide
*torsemide
loop diuretics - MOA
*inhibit Na+/K+/2Cl- (NKCC) symporter in thick ascending loop of Henle
*results in increased Na+, Cl-, K+, Ca2+, and Mg+ delivery and excretion
*MOST POTENT AND EFFECTIVE DIURETICS
loop diuretics - uses
*edema (pulmonary, systemic)
*heart failure
*hypercalcemia
*hypertension (thiazides are better)
loop diuretics - ADEs
- electrolyte abnormalities:
-volume depletion, metabolic alkalosis
-hypokalemia, hypomagnesemia, hypocalcemia, hyponatremia - hyperglycemia, hyperuricemia
- allergy (sulfa drug)
- ototoxicity: NKCC cotransporters in inner eras
- diuretic resistance
starting dose of furosemide =
*20x creatinine
*the lower the GFR, the higher dose is needed
thiazide diuretics - examples
*hydrochlorothiazide (HCTZ)
*chlorthalidone
*indapamide
*metolazone
thiazide diuretics - MOA
*inhibit Na+/Cl- symporter in DCT → increased delivery and excretion of Na+, Cl-, and K+
thiazide diuretics - uses
*HYPERTENSION
*edema
*prevention of kidney stones
*hypercalciuria
thiazide diuretics - ADEs
*electrolyte abnormalities:
-volume depletion
-HYPONATREMIA
-hypokalemia
-metabolic alkalosis
*hyperglycemia, hyperuricemia
*allergy
hyperuricemia in loop & thiazide diuretics
*uric acid is freely filtered but it it both reabsorbed and secreted
*parallel relationship between Na+ and urate reabsorption in proximal tubule
HYPERCALCIURIA in loop diuretics
*Loops LOSE calcium (increased urinary excretion)
*Ca2+ absorption is dependent on voltage generated by NKCC and K+ backleak
*loop diuretics turn off NKCC → no positive lumen → NO REABSORPTION OF Ca2+ → hypercalciuria
decreased calcium excretion (hypercalcemia) in thiazide diuretics
*increased reabsorption of Ca2+ with THIAZIDE diuretics due to less NCC action → more calcium reabsorption
hypokalemia with loop & thiazide diuretics
- higher delivery of Na+ and Cl- to distal nephron (principal cell) enhances K+ secretion by DCT2 and CD
- volume depletion leads to secondary hyperaldosteronism enhancing K+ secretion by ROMK
metabolic alkalosis with loop & thiazide diuretics
*diuretics result in increased distal Na+ and Cl- delivery, leading to:
-increased Cl- excretion
-increased K+ excretion
-increased H+ excretion
-decreased ECV
*results in hypokalemic, hypochloremic alkalosis
potassium-sparing diuretics - MOA
- ENaC inhibitors: epithelial Na+ channel inhibitors (amiloride, triamterene)
- mineralocorticoid antagonists (spironolactone, eplerenone)
*all work in the late DCT and the cortical collecting duct
potassium-sparing diuretics - uses
*adjunct agent HTN/edema
*prevent hypokalemia
*refractory edema
*ascites with secondary hyperaldosteronism
potassium-sparing diuretics - ADEs
*HYPERKALEMIA
*GYNECOMASTIA (from spironolactone)
*volume depletion
*stones (triamterene)
aquaretics - MOA
*V2 receptor antagonists; inhibit ADH response
*selective WATER DIURESIS without effect on Na+ or K+
*excrete dilute urine
*increase thirst, need to monitor Na+
aquaretics - examples
*tolvaptan
*satavaptan
*lixivaptan
*conivaptan
aquaretics - uses
*hyponatremia with SIADH
*cirrhosis with ascites
*CHF
*ADPKD
