Diuretics

• drugs that increase the output of urine
• –most actually work by increasing sodium excretion, and could therefore be referred to more accurately as natriuretics (natrium = sodium, reason abbr. is Na)
• –diuresis (water loss) follows the sodium loss
• these drugs are used to treat hypertension, to mobilize edematous fluid, and to prevent renal failure

• •most work by blocking net sodium reabsorption; this tubular solute creates osmotic pressure that prevents water from being reabsorbed, and water that is not reabsorbed is excreted
• •since the early parts of the nephron are concerned more with bulk reabsorption and the later parts are more concerned with fine-tuning, the closer to the beginning of the nephron that a diuretic works, the greater its ability to increase salt and water excretion

maintain volume and composition of the body fluids constant despite wide variation in the daily intake of water and solutes.

• •cleanse extracellular fluid (ECF) and maintain ECF volume and composition; the function most affected by diuretics
• •together with the lungs, maintain acid-base balance
• •excrete metabolic wastes and foreign substances

• •the prototype for the class and is the most frequently prescribed
• –mechanism of action:
• •blocks Na+-K+-2Cl- cotransporter in thick segment of ascending limb of Henle’s loop, which leads to dissipation of the medullary interstitial gradient and a profound diuresis
• –other loop diuretics: ethacrynic acid, bumetanide and torsemide

• –pharmacokinetics:
• •PO, IV, and IM formulations; PO action begins in ~60 minutes and lasts 8 hours, while IV route effects begin within 5 minutes and last for 2 hours
• •eliminated by hepatic metabolism

• –therapeutic uses:
• •used when rapid and massive fluid removal needed (e.g., pulmonary edema and edema of hepatic, cardiac, or renal origin)
• •hypertension that is unresponsive to other diuretics; it still works when renal blood flow and glomerular filtration rate are low

• –adverse effects:
• •oops too much --> hyponatremia, hypochloremia and dehydration, and hypotension
• •hypokalemia (i.e., it is a K+-losing diuretic)
• •others: ototoxicity, hyperglycemia, hyperuricemia, reduces HDL cholesterol and raises LDLs and triglycerides, increases excretion of magnesium and calcium, dangerous to use during pregnancy

• –drug interactions
• •digoxin: toxicity is increased by low potassium due to the diuretic
• •ototoxic drugs: increased chance of hearing loss if combined with drugs having similar toxicity (e.g., gentamicin)
• •potassium-sparing diuretics can counterbalance potassium-wasting effects
• •others: increases lithium toxicity, potentiate effects of other antihypertensive agents, diuretic effects can be antagonized by NSAIDs

• –mechanism of action:
• •blocks reabsorption of sodium and chloride (Na+-Cl- cotransporter) in early segment of the distal convoluted tubule
• •this location means it can cause less diuresis than loop diuretics but more than the downstream-acting potassium- sparing diureticsthiazides do not work well when renal blood flow and glomerular filtration rate are low

• –pharmacokinetics:
• •diuresis begins ~ 2 hours after oral ingestion with peak at ~ 4–6 hours and effects lasting ~12 hours
• •drug is excreted unchanged in urine

• –therapeutic uses:
• •primary hypertension and edema
• •(paradoxically) treats diabetes insipidus
• •decreases excretion of calcium which can decrease risk of kidney stones (opposite of loop diuretics)

• –adverse effects:
• •“oops to much” effects similar to loop diuretics
• •also a K+-losing diuretic
• •like loop diuretics, increases plasma glucose, urate, and lipid levels and should not be used during pregnancy
• •lacks the ototoxicity of loop diuretics

• –drug interactions:
• •often combined with antihypertensive medications from other drug classes to potentiate the blood pressure lowering effects
• •potassium loss can be offset by combining with potassium-sparing diuretics
• •increases risk of digoxin and lithium toxicity

• –mechanism of action:
• •blocks ability of aldosterone to bind to its receptor and increase sodium reabsorption in the cortical collecting ductleads to increased sodium excretion
• and decrease potassium excretion

• –pharmacokinetics:
• •this drug can take up to 48 hours to work because steroid hormones produce effects with a slow onset (i.e., takes time for protein synthesis) and slow offset (proteins last for awhile)

• –therapeutic uses:
• •used to treat hypertension and edema, often in combination with a loop or thiazide diuretic
• •primary hyperaldosteronism
• •also known to greatly reduce mortality rate in patients with severe heart failure

• –adverse effects:
• •hyperkalemia (causes excitable tissues to fire when they should not)
• •endocrine effects include gynecomastia, menstrual irregularities, impotence, hirsutism and deepening voice

• –drug interactions:
• •often combined with thiazide and loop diuretics to counteract their potassium lossshould never be given with drugs that increase plasma potassium levels (e.g., ACE inhibitors)

• –mechanism of action:
• •directly blocks the sodium channel through which Na+ can normally be reabsorbed from the tubular fluid in the cortical collecting duct
• •if sodium cannot get into the cell, potassium cannot get out of the cell into the tubular lumen, so urinary sodium excretion is increased and potassium excretion is decreaseddue to location, only produces a modest increase in urine volume but decrease K+ excretion

• –pharmacokinetics:
• •since channel is blocked, effects are seen more rapidly than with spironolactone (e.g., 2-4 hrs) and last 12-16 hrs

• –therapeutic uses:
• •used to treat hypertension and edema, often in combination with a loop or thiazide diuretic

• –adverse effects
• •hyperkalemia
• •nausea, vomiting, leg cramps, and dizziness are common; blood dyscrasias are rare

• –mechanism of action:
• •mannitol is a non-metabolized 6-carbon sugar, freely filtered, minimal reabsorption
• •the inability to reabsorb this solute keeps water in the proximal tubule lumen; this water is delivered to the distal portions of the nephron where much of it is ultimately excreted
• •mannitol acts throughout the body to pull water out of the cells (gets rid of intracellular water while other diuretics get rid of extracellular volume)
• •the net effect after administering mannitol is to excrete total body water in excess of plasma electrolytes agents used similarly include urea, glycerin, and isosorbide

• –pharmacokinetics:
• •mannitol must be given IV in amounts sufficient to raise extracellular fluid osmolarity (grams vs mg of other drugs)
• •effects are noticeable within 30–60 minutes, and mannitol is eliminated unchanged in the urine over a period of 6-8 hours

• –adverse effects:
• •extracellular volume is acutely increased because mannitol sucks water out of the cells, which can exacerbate heart failure
• •headache, nausea, vomiting, and fluid and electrolyte imbalances also occur

• –therapeutic uses
• •prophylaxis of renal failure
• •reduction of intracranial pressure
• •reduction of intraocular pressure (treating glaucoma) when patients haven’t responded to other therapy