Diuretics Flashcards
- What is the general function of diuretics?
Diuretics act by blocking specific transport functions of the renal tubules leading to an increased excretion of urinary sodium chloride and water. By increasing the amt of NaCl and water there is a decrease in both blood volume and venous pressure leading to a decreased preload, fall in CO and fall in arterial pressure. Diuretics decrease blood pressure or eliminate edema.
- Discuss the role of the proximal tubule of the kidney.
Proximal tubule → reabsorbs 65% filtered Na, 85% NAHCO3, 65% K+, 60% water, all glucose and AA. The most important ions in regards to diuretic actions are NaHCO3 (sodium bicarb) and NaCl (sodium choride). The Na+-H+ antiporter movement from lumen then into blood via Na+-K+ transporter is the main driving force for water reabsorption. HCO3- wants to be reabsorbed as well but has poor permeability so via the carbonic anhydrase enzyme it is converted to H2CO3 → OH- + CO2. CO2 quickly diffuses into cell and OH- turns to water with the addition of a proton. CO2 in the cell quickly turns back to H2CO3 then intracellular carbonic anhydrase dissociates it to H+ (for the antiporter) and HCO3-.
- Discuss the role of thick ascending limb of the loop of henle in the kidney.
The thick ascending loop of henle receives hypertonic filtrate and allows for reabsorption of NaCl without water. Na+ is reabsorbed via Na+/K+/2Cl- cotransporter (NKCC2). Cl- exits basolateral side of cell, Na+ exits via Na+/K+ ATPase on basolateral side and K+ is recycled back to the lumen for the NKCC2 function. There is also additional reabsorption of Na+, Ca2+ and Mg2+ from lumen to the interstitium driven by K+ recycling.
- Discuss the role of the distal convoluted tubule in the kidney.
Distal convoluted tubule activity reabsorbs4-8% of filtered NaCl. Na+ enters via Na+/Cl- cotransporter (NCCT) and Na+ exits on basolateral side via Na+/K+ ATPase. Ca2+ is reabsorbed via Na+/Ca2+ exhcnagers.
- Discuss the role of the cortical collecting duct in the kidney.
The collecting duct is the final site of NaCl reabsorption and this determines the final Na+ concentration in the urine. Luminal Na+ enters cell via ENaC and exits basolateral side via Na+/K+ ATPase. K+ is secreted into the lumen. ENaC and K+ movement is under the control of aldosterone. Collecting duct also expresses vasopressin (ADH) channels that controls the permeability of the collecting tubule to water. (without ADH the urine is dilute)
- What is the action of Furosemide?
Furosemide is a loop diuretic that selectively inhibits NaCl reabsorption in the thick ascending loop of henle by inhibiting the luminal Na+/K+/Cl- cotransporter (NKCC2). This is called a high-ceiling diuretic b/c water is unable to be reabsorbed therefore it is extremely effective. By inhibiting the reabsorption of NaCl, there is a lowered lumen-positive (K+) potential that would usually come from K+ recycling. The positive potential usually drives divalent cation reabsorption in the loop and therefore by reducing potential, loop diuretics Mg2+ and Ca2+ are unable to be reabsorbed and remain in the filtrate to be excreted. Loop diuretics increase urinary excretion of K+ and titratable acid due to increased delivery of Na+ to the distal tubule and therefore increased action of Na+/K+ exchanger. This predisposes the pt to hypokalemia and metabolic acidosis. All together by decreasing sodium and water reabsorption there is a decrease in renal vascsular resistance and an increase in renal blood flow.
- What is the interaction of loop diuretics (furosemide) with Eicosanoids?
Loop diuretics induce expression of COX-2 which synthesizes prostaglandins from arachidonic acid. The prostaglands appear to mediate the diuretic/natriuretic actions to help increase the electrolyte and fluid excretion. It also has an effect on increased renal blood flow.
- What are the clinical uses of Furosemide?
- edema associated with heart failure and hepatic/renal disease
- acute pulmonary edema
* NOT a first like drug in the tx of HTN, only indicated when thiazide is not sufficient
* IV and oral administration with half life of 2-4hrs
- What are the adverse side effects of Furosemides?
- Ototoxicity → manifesting as tinnitus and hearing impairment
- Hyperuricemia → precipitating gout
- Acute hypovolemia → depletion of Na+ leading to hyponatremia and hypotension
- K+ depletion → leading to cardiac arrhythmias
- Hypomagnesemia and hypocalcemia
- Hypersensitivity, hyperglycemia, hyperlipidemia, photosensitivity, parasthesias, bone marrow depression, GI disturbances
- What is the mechanism of Thiazide diuretics?
Thiazides inhibit NaCl reabsorption in the distal convoluted tubule by blocking the Na+/Cl- cotransporter (NCCT). By allowing more Na+ to make it to the collecting duct, there is the same effect as what happens with loop diuretics where increased action of Na/K ATPase and therefore increased excretion of K+ and acid. By increasing the sodium and water excretion there is a decrease in extracellular volume and a decrease in CO and renal blood flow. Unlike loop diuretics, thiazides are able to increase the reabsorption of calcium preventing kidney stones.
Taken orally with half life of 40hrs – takes 1-3 weeks to produce stable effect. Long term treatment with thiazides will allow for normal plasma volume, but a sustained decrease in peripheral resistance therefore lowering blood pressure.
- What are examples of Thiazide diuretics?
- Hydrochlorothiazide
- Chlorthialidone – long duration of action (half life = 40-60hrs), used to treat HTN once daily
- Metolazone – most potent, causes Na+ excretion in advance kidney failure
- What are Thiazides used for clinically?
- mild to moderate HTN – first-line anti-hypertensive in black/elderly pts who do not respond well to treatment with ACEIs or ARBs.
- treatment of edema due to heart failure
- used off label for tx of diabetes insipidus – thinking is that the antidiuretic effect of thiazides is a result of induced sodium deficit causing reduced serum osmolality and decreased thirst
- HypercalciURIA → inhibits Ca2+ excretion therefore decreases amt of calcium being excreted that can precipitate in the tubules therefore particularly useful for kidney stones
- Premenstrual edema
- Counteract sodium and water retention drugs – therefore are useful in combination therapy
- What is hydrochlorothiazide?
Hydrochlorothiazide is a thiazide diuretic that used to be the treatment of edema for hepatic cirrhosis, but has since been replaced by spironolactone. Hydrochlorothiazide also used to be used in the management of edema in patients with renal dysfunction, but has since been replaced with loop diuretics (ex. furosemide).
- What are the adverse side effects of thiazide diuretics?
- Hypokalemia
- Hyponatremia
- Hyperuricemia → due to competition for organic secretory pathway in proximal tubule by thiazides and uric acid
- Hypercalcemia
- Hyperglycemia → thiazides decrease glucose tolerance
- Hyperlipidemia → b/c they increase plasma levels of LDL cholesterol, total cholesterol and total triglycerides
- Hypersensitivity
- What are K+ sparing diuretics?
Potassium sparing diuretics are competitive aldosterone antagonists (inhibitors). Therefore these diuretics act on the aldosterone receptors [that activate ENaC (Na+ reabsorber) and ROMK (K+ excreter)] at the late distal and cortical collecting ducts causing salt and water retention. These drug antagonize aldosterone at intracellular cytoplasmic receptor sites preventing the translocation of receptor complex into the nucleus. The levels of aldosterone determine effect of diuretics. The higher the amt of aldosterone the greater the effect of the antagonist/diuretic.