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30 Cards in this Set

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Diuretic drugs are primarily used to treat?
Edema as a result of organ dysfxn

Also useful in treatment of glaucoma, pulmonary edema, and increased intracranial pressure
Renal dysfxn is not always the cause of edema. other causes?
Ex: low cardiac output associated w/ cardiac failure decreases renal perfusion and results in fluid retention (via increased filtration fraction and increased Aldo and ADH)
Best way to treat edema?
Treat the primary disease causing the edema.

Treating edema is useful and necessary, but therapy should be aimed at overcoming the pathophys of the primary disease.
What is loculated fluid?
- patients w/ severe hepatic damage develop edema in peritoneal cavity as result of:
1. increased hepatic portal pressure and
2. lack of plasma proteins

ASCITES may be accomp by vascular hypovolemia which activates RAAS to produce secondary hyperaldosteronism.
-- excess fluid equilibrates slowly w/ fluid of vascular space, so rate of diuresis must be very slow in order to prevent further decrease plasma volume
Adverse effects of diuretic drugs are mostly related to...?
Dose -- use smallest effective dose in order to prevent:
-- hypokalemia
-- hypomagnesemia
-- disorders of acid/base imbalance
What are the possible mechanisms of action of diuretic drugs?
1. decrease Na absorption in proximal tubule by alterating renal hemodynamics
2. Decrease epithelial transport
3. Decrease Na reabsorption in thick ascending limb of L of H
4. Decrease Na reabsorption in the distal tubule
5. Decreased Na reabsorption in the late distal tubule and collecting duct
Theophylline, dopamine, caffeine MOA?
Alter renal hemodynamics (act in proximal tubule)

-- cause natriuresis/diuresis via dilation of the afferent arterioles
-- causes increase RBF w/ less of increase in GFR, so the filtration fraction (FF = GFR/RBF) is decreased
-- smaller percentage of total RPF is filtered, the protein conc in the peritubular caps is decreased
-- decreased oncotic pressure decreases the osmotic forces which keep reabsorbed Na and water from leaking back into the lumen of the PT
-- Greater back leak of Na and water translates into less net reabsorp of Na and water into prox tubule
**relatively weak natriuretic agents b/c more distal segs of the nephron reabsorb much of the sodium which is not absorbed in the prox tubule
Acetazolamide MOA?
Carbonic Anhydrase inhibitor causing decreased epith Na transport in the proximal tubule

1. blockade of CA prevents reabsorp of filtered HCO3 and thus reabsorp of Na and H20.
-- urinary pH increases from 6 to 8.2
2. Since L of H not perm to HCO3, this segment cannot completely compensate for loss of Na reabsorp in prox tubule
-- urine reaching distal tubule still high in Na and HCO3
3. K secretion is markedly INCREASED
-- ascending limb of L of H captures almost all excess Cl and part of Na coming from PT
-- increased Na reaching early distal tubule (EDT) is accomp by nonperm anion HCO3 instead of perm anion Cl, so less Na is reabsorbed
-- Na can be conserved only by cation exchange w/ K in late distal tubule/collecting duct
4. Increased urine vol accomp by increased excretion of Na, K, and HCO3. Cl excretion falls.
Acetazolamide pharmacological effects?
1. decreases rate of bicarb reabsorption in the prox tubule (80%) and early distal tubule (20) by inhibiting CA
2. relatively weak diuretic agent both filtered and secreted into tubule via organic acid transport system
3. Inhibits 85-90% of the CA in the prox tubule, but only 35% of total HCO3 reabsorption is inhibited
Acetazolamide therapeutic uses?
1. Glaucoma

2. Altitude sickness -- works best when given prophylactically

3. Alkalinization of urine to increase loss of acidic drug in drug intoxication
- ex: aspirin poisoning
Acetazolamide intoxication?
-- hyperchloremic metabolic acidosis due to loss of HCO3 and impairment of H secretion

-- when HCO3 is lost, body retains Cl, and vice-versa
Mannitol MOA?
unknown
-- surrounded by layer of water molecules which are tightly bound and thus lost in urine when mannitol is excreted
-- can increase RBF and GFR, but MAIN DIURETIC EFFECT is to increse urine flow by preventing reabsorp of water in thin descending L of H
-- water retention decreases NaCl conc of urine entering ascending L of H
-- causes decreased Na gradient which norm drives NaCl reabsorp in ascending limb so LESS is reabsorbed in ascending L of H
-- increases medullary blood flow which reduces interstitial osmotic gradient by washing out NaCl and urea.
-- water loss enhanced b/c interstit osmotic gradient is factor which drives water reabsorp in presence of ADH
Mannitol net effect on Na/H20 excretion?
1. Urine flow rate can increase from 1 ml/min to 10 ml/min

2. Increases urinary excretion of Na, K, Mg, Ca, Cl, HCO3, and PO4

3. Magnitude of Na/H2O loss is directly proportional to amount of mannitol excreted in urine
Therapeutic use of mannitol?
1. must be given IV so it's use limited to inpatients
2. to prevent complete renal failure in patients w/ ARF
3. to decrease intraocular pressure in glaucoma
4. to decrease intracranial pressure if intracranial bleeding is NOT involved
5. to prevent renal toxicity of certain cmpds such as cisplatin, ampho B, cyclosporin, and myoglobin
Toxicity, side effects of mannitol?
1. overexpansion of vascular volume leading to CHF and pulmonary edema
2. headache, nausea, hyponatremia
Furosemide, bumetanide, ethacrynic acid properties?
-- loop diuretic drug
-- filtered and secreted into prox tubule via the organic acid transport system, must enter tubule to exert action
-- activity NOT affected by acidosis or alkalosis
-- effective orally and parentally
-- produce rapid diuresis (15 minutes) of short duration (2-3 hrs)
-- Effective if GFR <25ml/min...therefore GOOD DRUG IF GFR IS LOW!!
Furosemide, bumetanide, ethacrynic acid MOA?
1. Inhibits active Na/K/2Cl transport in medullary and cortical segs of L of H resulting in decreased absorp NaCl
-- vigorous natriuresis (25-30% filtered load) occurs since distal tubule cannot compensate by greatly increasing Na reabsorp
2. FUROSEMIDE may inhibit CA in large doses
3. Inhib Na/K/2Cl symporter in macula densa causing immed increase GFR b/c tubuloglomerular feedback is blocked.
-- stim renal synth PGs in addition which contrib to immed increase RBF and GFR
4. Inhib of Na/K/2Cl symporter in macula densa causes immed increase renin secretion. Resulting increase in AgII causes chronic, secondary hyperaldosteronism
5. K secretion and urinary loss increases due to inc Na deliver to distal tubule, increased distal tubular flow, and secondary hyperaldosteronism
-- hyperaldosteronism enhances K loss and leads to metabolic alkalosis which can be corrected w/ KCl
6. Enhanced Ca and Mg excretion
7. Increased urate reabsorp in prox tubule
8. ability of kidney to make conc or dilute urine lost due to decreased reabsorp of NaCl in L of H
9. increased excretion of Na, K, Mg, Ca, Cl, HCO3, and PO4 accomp increased urine volume
Therapeutic uses furosemide, bumetanide, ethacrynic acid?
1. Acute pulmonary edema

2. Management of edema in cardiac, hepatic and renal disease.
3. Since RBF and GFR increased, useful in treating chronic renal failure and nephrotic syndrome
4. Hypercalcemia (furosemide and NaCl infusion)
Toxicity and S/Es from furosemide, bumetanide, ethacrynic acid?
1. 2NDARY HYPERALDOST -- from increased renin and subseq increase in plasma AgII conc
2. HYPOKALEMIA -- hypochloremic metabolic alkalosis can develop due to excessive loss of NaCl and KCl.
-- secondary hyperaldost contributes to hypokalemia
-- muscular weakness, mental confusion, cardiac dysrrhythmias
3. HYPOMAGNESEMIA - can cause cardiac dysrrhythmias
4. Hyperuricemia - can precip attack of gouty arthritis
5. ORTHOSTATIC HYPOTENSION from volume depletion
6. DILUTIONAL HYPONATREMIA -- cannot excrete excessive water intake
7. TINNITUS and possibly reversible hearing loss w/ large doses, espec w/ ethacrynic acid.
8. HYPERGLYCEMIA -- furosemide only
9. AZOTEMIA and COMA in severe renal and hepatic disease. Hypokalemia stims renal ammonia production.
Hydrochlorothiazide and metolazone general properties?
1. orally active and efficacious in inhibiting NaCl reabsorp in distal tubule
-- metolazone also inhibs Na reabsorp in proximal tubule by mech not involving CA
2. Diuretic action not modified by acidosis or alkalosis
3. Less efficacious than "loop" diuretics; only 5-6% of filtered sodium load is excreted
4. Diuresis is rapid onset and LONG duration (12h)
5. Secreted into prox tubule by organic acid transport system; must enter tubule to exert their action
6. Variable effects on RBF, but GFR is consistently reduced
7. INEFFECTIVE if GFR is <25ml/min w/ exception of metolazone
Hydrochlorothiazide and metolazone MOA?
1. Inhib NaCl reabsorp in distal tubule by blocking symporter
2. At larger doses, some thiazides inhib CA and exert some activity on Na reabsorp in prox tubule
-- urinary pH rises from 6 to 7.4; rarely occurs since the dose is usually kept small to limit hypokalemia
3. Impair ability of kidney to produce dilute urine, so urine is always hypertonic. Excessive water intake can cause dilutional hyponatremia
4. Enhanced urate reabsorp in prox tubule
5. DECREASED excretion of Ca: plasma Ca rises only slightly if Ca metab is normal
6. Increased excretion Mg
7. Progressive contraction of ECF volume leads to activation sympth NS and increased renin. Causes 2ndary hyperaldost due to increased AgII
8. K excretion is increased due to a greater presentation of Na to the distal tubule and 2ndary hyperaldost
9. Increased excretion H2O, Na, Cl, K, Mg. HCO3 excretion w/ large doses
Therapeutic uses hydrochlorothiazide and metolazone?
1. First line drug in treatment HTN
2. Management of edema due to CHF, mild chronic renal failure, hepatic cirrhosis, premenstrual weight gain, and hormone therapy w/ estrogen
3. Management of hypercalcinuria in patients w/ renal calculi composed of Ca salts
4. Diabetes insipidus -- decrease in plasma volume caused by the natriuresis increases the efficiency of solute/water reabsorpt in the prox tubule.
-- As result, less volume sent to the CD.
-- In addition, inhibition of NaCl reabsorp in the EDT further impairs renal dilution
Toxicity, SEs of hydrochlorothiazide and metolazone?
1. 2NDARY HYPERALDOST -- results from increased renin-AgII conc
2. HYPOKALEMIA -- hypochloremic metabolic alkalosis can develop due to excessive loss of NaCl and KCl. 2ndary hyperaldost contributes to the hypokalemia
-- muscular weakness, mental confusion, cardiac dysrhythmias
3. HYPOMAGNESEMIA -- can cause cardiac dysrrhythmis
4. HYPERURICEMIA
5. DILUTIONAL HYPONATREMIA -- cannot excrete excessive water intake
6. HYPERGLYCEMIA and AGGRAVATION DM -- due to blockade of insulin secretion
7. AZOTEMIA and COMA in severe renal and hepatic disease -- hypokalemia stims renal ammonia production
Spironolactone MOA?
**K-sparing diuretic drug

1. Blocks Aldo receptors in DT
2. Diuretic activity requires presence of Aldo
3. A weak diuretic--only 2-3% of filtered Na is excreted
4. Increased excretion of H20, Na, Cl, HCO3, and decreased excretion of K
5. LONG duration of action (half-life 24 hours)
Therpeutic uses spironolactone?
1. Primarily used w/ thiazide diuretic to enhance diuresis and lessen hypokalemia caused by the thiazide
2. Refractory edema (nothing else works)
3. Primary hyperaldosteronism
4. Cirrhosis and nephrotic syndrome -- intravasc hypovolemia produces 2ndary hyperaldost and thus K loss
5. Heart failure -- decreases left ventricular wall stiffness
Toxicity, SEs of spironolactone?
1. HYPERKALEMIA -- do not use w/ oral K supplements or give to patients w/ renal insufficiency
2. Partial agonist at androgen, estrogen, progesterone receptors; partially inhib testosterone synth (weakly inhib CYP17)
MALES -- gynecomastia, azoospermia
FEMALES -- menstrual irregularity, hirsutism
Triamterene and amiloride MOA?
1. Inhib Na reabsorp by blocking Na channels on the luminal mbrns of principal cells in the DT and CD
2. Natriuresis is not dependent on presence of endogenous Aldo
3. Weak diuretics; only 2-3% of filtered load is excreted
4. Inhib secretion H ions (does not involve CA inhib)
5. INCREASE excretion H20, Na, Cl, and HCO3; DECREASE excretion K and H
Therapeutic use of triamterene and amiloride?
1. Use w/ loop diuretic or a thiazide to enhance Na loss and lessen hypokalemia caused by thiazide
2. Cystic Fibrosis - inhalation of AMILORIDE slows mucus accum and increases mucus clearance from lungs
Toxicity and SEs or triamterene and amiloride?
1. HYPERKALEMIA - should not be given w/ K supplements
2. Can cause hyperkalemia in severe renal insufficiency
How do we gove combo diuretic agents?
1. Thiazide or loop diuretic + a K-sparing diuretic
-- K-sparing prevents or limits K wasting caused by other two drugs

2. Loop diuretic + metolazone
-- In patients who have not responded to loop diuretic b/c of prox reabsorp of Na, the addition of metolazone will cause massive Na (and K) loss
-- Combo requires close monitoring of patient since fraction excretion of Na can reach 50% of filtered load