Outline Chapter 15 — Clinical Use of Diuretics- Among most commonly used drugs- Block NaCl reabsorption at different sites along the nephron- The ability to induce negative balance has made them useful in multiple diseases- Edematous states- Hypertension- Mechanism of action- Three major classes- Loop- NaK2Cl- Up to 25% of filtered sodium excreted- Thiazide- NCC- Up to 3-5% of filtered sodium excreted- Potassium sparing- ENaC- Up to 1-2% of filtered sodium excreted- Each segment has a unique sodium channel to allow tubular sodium to flow down a concentration gradient into the cell- Table 15-1 is interesting- Most of the sodium 55-655 is reabsorbed in the proximal tubule- Proximal diuretics would be highly effective if it wasn’t for the loop and other distal sites of Na absorption- Loop Diuretics- Furosemide- Bumetanide- Torsemide- Ethacrynic acid- NaK2Cl activated when all four sites are occupied- Loop diuretic fits into the chloride slot- In addition to blocking Na reabsorption results in parallel decrease in calcium resorption- Increase in stones and nephro albinos is especially premature infants which can increase calcium excretion 10-fold- Thiazide- Even though they are less potent than loops they are great for hypertension- “Not a problem in uncomplicated hypertension where marked fluid loss is neither necessary nor desirable”- Some chlorothiazide and metolazone also inhibit carbonic anhydrase in the proximal tubule- Increase Calcium absorption. Mentions that potassium sparing diuretics do this also- Potassium sparing diuretics- Amiloride- Spironolactone- Triamterene- Act at principal cells in the cortical collecting tubule,- Block aldosterone sensitive Na channels.- Discusses the difference between amiloride and triamterene and spiro- Mentions that trimethoprim can have a similar effect- Spiro is surprisingly effective in cirrhosis and ascites- Talks about amiloride helping in lithium toxicity- Partially reverse and prevent NDI from lithium- Trial Terence as nephrotoxin?- Causes crystaluria and casts- These crystals are pH independent- Faintly radio opaque- Acetazolamide- Blocks carbonic anhydrase- Causes both NaCl and NaHCO3 loss- Modest diuresis de to distal sodium reclamation- Mannitol- Nonreabsorbable polysaccharide- Acts mostly in proximal tubule and Loop of Henle- Causes water diuresis- Was used to prevent ATN- Can cause hyperosmolality directly and through the increased water loss- This hyperosmolality will be associated with osmotic movement of water from cells resulting in hyponatremia, like in hyperglycemia.- Docs must treat the hyperosmolality not the hyponatremia- Time course of Diuresis- Efficacy of a diuretic related to- Site of action- Dietary sodium action- 15-1 shows patient with good short diuretic response but other times of low urine Na resulting in no 24 hour net sodium excretion.- Low sodium diets work with diuretics to minimize degree of sodium retension while diuretic not working- Also minimizes potassium losses- Increase frequency- Increase dose- What causes compensatory anti-diuresis- Activation of RAAS and SNS- ANG II, aldo, norepi all promote Na reabsorption- But even when prazosin to block alpha sympathetic and capto[pril to block RAAS sodium retention occurs- Decrease in BP retains sodium with reverse pressure natriuresis- Even with effective diuresis there is reestablishment of a new steady state- Diuresis is countered by- Increases in tubular reabsorption at non-diuretic sensitive sites (neurohormonal mediated)- Flow mediated in creases in Tubular reabsorption distal to the diuretic from increased sodium delivery.- Hypertrophy- Increased Na-K-ATPase activity- Decreased tubular secretion of diuretic if renal perfusion is impaired- Getting to steady state requires- Diuretic dose and sodium intake be constant- Sodium balance is reestablished with 3 days of a fixed diuretic dose- K balance in 6-9 days- Figure 15-2- Which means that people on stable doses of diuretics don’t need regular labs, t