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128 Cards in this Set
- Front
- Back
What are diuretics used for?
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used to correct abnormal ECF volumes and treat edema
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What urine changes are needed to treat diuretics?
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↑ urine volume
↑ urine Na+ content |
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How does edema occur?
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Disease states → ↓blood flow to kidneys = sensed as insufficient arterial blood volume → salt & water retention = edema
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What disease states can lead to edema?
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CHF, cirrhosis, renal failure, etc
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What techniques are used to treat CHF? Types of drugs used to achieve this?
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treat the heart & use diuretics to ↓ afterload
thiazides, loop diuretics & aldosterone antagonists |
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How is ascites from hepatic cirrhosis treated? What do you have to watch out for?
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thiazide, loop and K+ sparing diuretics
monitor plasma protein levels and altered drug availability |
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What drugs are used in the treatment of pulmonary edema?
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Treat aggressively with loop diuretics
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What drugs are used in the treatment of cerebral edema?
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Osmotic diuretics for direct effects
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What drugs are used in the treatment of nephrotic syndrome?
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Treat with thiazide diuretics and ↓ salt intake
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What drugs are used in the treatment of acute renal failure?
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use osmotic or loop diuretics
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What's the primary goal in the treatment of renal edema?
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maintain kidney function
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What drugs are used in the treatment of chronic renal failure?
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treat aggressively with loop diuretics
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What diuretics are used in the treatment of hypertension?
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thiazides +/- K sparing
OR loop + thiazides (if refractory) AND ↓salt intake |
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What diuretics are used in the treatment of Nephrolithiasis?
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thiazides to ↑ calcium reabsorption
↓ salt intake |
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What diuretics are used in the treatment of Hypercalcemia?
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Loop diuretics to ↑ calcium excretion
Normal saline (to prevent contraction of extracellular space) +/- K+ as needed |
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What diuretics are used in the treatment of Nephrogenic Diabetes Insipidus?
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thiazide or loop diuretics to reduce plasma volume and contract the extracellular space
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What do all primary actions of diuretics involve?
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Changes in either secretion or reabsorption of solute in the nephron
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What drives/opposes filtration at the glomerulus?
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driven by hydrostatic pressure
opposed by oncotic pressure |
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What plasma contents aren't filtered at the glomerulus?
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Cells
Proteins (and drugs bound to proteins) Lipids |
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What's the site of action for all diuretics? What are the exceptions?
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within the lumen of the nephron
Exceptions = the K+ sparing aldosterone antagonists, spironolactone and eplerenone |
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Are diuretics filtered? What's the exception to this?
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No, they're bound to plasma proteins
Exception = aldosterone antagonists and the osmotic diuretics (mannitol) |
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How are the unfiltered diuretics transported into the nephron?
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by organic acid (anion) & base (cation) transporters located in the proximal tubule
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Which conditions decrease access of diuretics ot the tubule lumen?
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↓ renal blood flow
↑ levels of other drugs transported by OA/B transporters |
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What are some drugs that are also transported by the organic acid and base transporters?
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alpha-ketoglutarate
catecholamines uric acid choline histamine antibiotics cimetidine probenecid |
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How much is reabsorbed with an isotonic filtrate?
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about 80%
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What determines the osmoticity of the medullary interstitum?
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The countercurrent mechanism = hyperosmotic
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How much of the fitrated load is reabsorbed by the loop of Henle?
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About 15% (can increase to up to 80%)
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What's the osmotic state of the thick ascending limb filtrate?
What can change this? |
Hypotonic
Loop diuretics = hypertonic |
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How much of the fitrated load is reabsorbed by the DCT and cortical collecting duct?
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About 5%
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What drug affects the DCT and Cortical Collecting Duct? What's it's mechanism?
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Aldosterone acts at the nucleus of these cells to increase protein synthesis that increases Na permeability
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What affect does ADH have at the medulary collect duct?
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Causes aquaporins or H2O channels to fuse with the surface membrane, ultimately = concentrated, hypertonic urine
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Where does ADH work? What does it do?
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Medullary collecting duct.
Regulates H2O permiability |
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What influences K+ loss?
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Secretion is increased by increased K or Na load or increase in pH. It is decreased by decreased pH
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What's K exchanged for at the distal nephron?
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Na
(same with H+) |
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What can hypokalemia cause?
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ECG abnormalities
cardiac arrhythmias muscular weakness drowsiness confusion loss of sensation ↑ binding of cardiac glycosides |
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What are two factors influencing diuretic effectiveness?
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1. the transport mechanism affected
2. where the diuretic acts in the nephron |
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Why are proximally acting diuretics weak?
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even though 70-80% of the filtered load is handled, their actions are counteracted by more distal reabsorption mechanisms
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Why are distally acting diuretics weak?
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Because only 5-10% of the filtered load is involved
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Why are loop diuretics strong?
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1. An important transport mechanism (Na+,K+,2Cl- cotransporter) is inhibited
2. The affected site handles a large fraction of the filtered load (15-50%) 3. More distal mechanisms are not able to compensate |
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What is required to produce concentrated urine?
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A hypertonic medullary interstitium
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How is a hypertonic medullary interstitium created?
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The loss of H2O and gain of Na+ in the descending limb of Henle
Reabsorption of Na+ w/o H2O in the ascending limb of Henle |
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How is a hypotonic filtrate/dilute urine formed?
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Reabsorbing Na+ w/o H2O in the ascending limb of Henle and the distal convoluted tubule
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What's required to produce either a concentrated or dilute urine? What type of diuretics block this process?
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Reabsorption of Na+ w/o H2O in the ascending limb of Henle
Loop diuretics = impairs both concentration and dilution |
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Do diuretics acting at distal to the loop of Henle (thiazides) influence dilution or concentration of urine?
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Only dilution
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What are the diuretic agents? (6)
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1. CA Inhibitors
2. Osmotic diuretics 3. Thiazides 3a. Thiazide-related 4. K+ sparing 5. Loop or high ceiling 6. Antidiuretics and ADH antagonists |
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What's historically important about carbonic anhydrase inhibitors?
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Found by serendipity in 30's:
(1) led to discovery of carbonic anhydrase and its role in acid/base balance (2) CA inhibitors were 1st orally active, non-mercurial diuretics |
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Names of 2 Carbonic Anhydrase Inhibitors?
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acetozolamide, methazolamide
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Why do Carbonic Anhydrase Inhibitors have weak diuretic activity?
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1. Cause a self-limiting metabolic acidosis due to the loss of HCO3-
2. act at proximal tubule = effects reversed by more distal nephron |
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How are Carbonic Anhydrase Inhibitors used as diuretics?
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used to produce an alkaline urine to trap & increase the loss of weak acids in urine = to reverse metabolic alkalosis due to other diuretics
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How are Carbonic Anhydrase Inhibitors used clinically (non-diuretic usage)? (5)
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1. glaucoma (↓ vitreous humor)
2. ↑ CNS pressure or altitude sickness (↓ CSF) 3. Epilepsy (↓ pH?) 4. Some types of hypokalemic periodic paralysis 5. Hyperphosphatemia (↑ urinary PO4 secretion) |
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What are the adverse effects of Carbonic Anhydrase Inhibitors?
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drowsiness & dizziness
blood dyscrasias skin reactions |
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How do Carbonic Anhydrase Inhibitors reach their site of action?
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Organic acid transporter
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When are Carbonic Anhydrase Inhibitors contraindicated?
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Pts with liver cirrhosis can = hyperammonemia and hepatic encephalopathy
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Name 4 osmotic diuretics? Which is most often used?
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mannitol, urea, glycerin & isosorbide
mannitol |
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Route for mannitol? Why?
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IV, can't be absorbed from the gut
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How do osmotic diuretics work?
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Osmotically active particles in the lumen = retention of H2O = ↑ [H2O] = ↓ [Na+] in the tubule lumen, ↓ driving force for reabsorption of Na+, ↑ H2O & some Na+ excretion in the urine
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Where do osmotic diuretics work?
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Act primarily at the proximal tubule & to a less extent at the ascending limb of Henle
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How is water retention related to osmotic diuretic quantity?
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Directly related - large amounts may be needed.
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What must osmotic diuretics be able to do to achieve large quantities?
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- be freely filtered at the glomerulus
- undergo limited reabsorption - be pharmacologically and metabolically inert |
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What types of diuretics can maintain urine volume and kidney function?
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Osmotic diuretics
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When are osmotic diuretics not useful?
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If there is severe renal damage and loss of the selective permeability of the renal tubule membrane (i.e. caused by nephrotoxic agents or renal ischemia)
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How are osmotic diuretics used (non-diuretically)?
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Used to treat:
↑ intracranial pressure (↓CSF) ↑ intraocular pressure (↓ aqueous humor) |
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What are the adverse effects of osmotic diuretics?
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If given too rapidly IV, osmotic diuretics cause large shifts of fluid from cells to ECM = ↓ cell volume and impaired function
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When are osmotic diuretics contraindicated?
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CHF
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Name 3 Thiazides
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chlorothiazide, polythiazide, hydrochlorothiazide
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What type of medications are thiazides and how do they produce diuresis?
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Sulfonamide derivatives
Produce a diuresis with ↑ Cl- (not ↑ HCO3-) = effective in both acidic & alkaline conditions |
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What happens with high concentrations of some thiazides?
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Inhibit CA = ↑ HCO3- loss
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How do thiazides differ?
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duration of action
extent of CA inhibition maximally effective dose binding to serum proteins |
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How do thiazides enter the nephron? What effects can this have?
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Organic acid transporter
Interact with other compounds that use this transporter like penicillin and uric acid (competition can = ↑ serum uric acid) |
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What's the mechanism of action for thiazides?
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Inhibition of Na & Cl- co-transport and reabsorption of these ions in the distal tubule
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What does the action of thiazides partly depend on?
What drug can inhibit thiazides under certain conditions? |
Increasing kidney prostaglandins
May be inhibited by NSAIDS |
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What effects does thiazide-induced transporter inhibiton have on urine concentration?
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Increases Na, Cl, and, secondarily, K+.
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Are thiazides weak or strong diuretics? Why?
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Weak since only 5% of filtered Na is reabsorbed where they act.
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Why do thiazides produce less ECF distortion?
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Only cause modest diuresis and effect several ionic species
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What are the clinical uses of thiazides?
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Treat edema associated with: CHF, liver cirrhosis, premenstrual tension, and hormone therapy
Hypertension – actions involve direct effects on vascular smooth muscle |
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What effects do thiazides have on GFR and serum uric acid?
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Decreased GFR (not good if pt has decreased renal function)
Increased plasma uric acid (due to direct transporter competition and general increase in reabsorption due to decreased ECF volume) |
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What effects do thiazides have on Ca2+ and Cl excretion?
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↓ Ca2+ excretion – useful for hypercalciuria/osteoporosis
↑ Cl- excretion (and other halides, i.e. iodide(consider supplement) and Iodide/bromide/fluoride (treat toxicity) |
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What are the adverse effects of thiazides? (6)
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↑ cholesterol (5-15% - transient) & Triglycerides
Hypokalemia w/ prolonged use Arrhythmias in some settings Hyperglycemia (bad for diabetics) Metabolic alkalosis Hyperuricemia |
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How can thiazides cause hyponatremia?
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↑ ADH due to ↓ plasma volume
↓ diluting capacity of kidney ↑ thirst assoc with a ↓ plasma volume |
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Name 3 thiazide-related drugs
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metolazone, chlorthalidone, indapamide
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How are thiazide-related drugs the same/different than thiazides?
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Chemically similar but don't inhibit CA
Uses and adverse effects are similar |
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Efficacy, common combo med, and use of metolazone?
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Efficacious
Can be given in combination with a loop diuretic Can be effective with renal insufficiency |
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Special action and combo/use of indapamide?
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Has antihypertensive actions independent of diuretic activity
Used with loop diuretics in cases of renal failure |
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What are the two types of K+ sparing diuretics?
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Aldosterone antagonists
Nonaldosterone antagonists |
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What is spironolactone?
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An aldosterone antagonist that's a
structural analog of aldosterone |
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What's the active metabolite of spironolactone? How is it formed?
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canrenone
1st pass metabolism in the liver |
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What is the mechanism of action for spironolactone?
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It's active metabolite canrenone competes with aldosterone for binding to its cytoplasmic receptor & inhibits its actions
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When is spironolactone ineffective?
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Adrenalectomized pts (requires aldosterone to have effects)
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What type of inhibition is induced by spironolactone?
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competitive (effects reversed by increased aldosterone)
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What is eplerenone?
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an analog of spironolactone that is more selective for the aldosterone receptor
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What are the clinical uses of Aldosterone antagonists? (4) (why?)
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1. Primary and secondary hyperaldosteronism
2. Hypokalemia: given with other diuretics used to tx HTN/CHF 3. CHF: spironolactone found to have significant benefit independent of its diuretic effects 4. Liver cirrhosis & Nephrotic syndrome to avoid excessive loss of K+ |
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What are the adverse effects of Aldosterone antagonists? (6)
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1. hyperkalemia
2. ↑ serum Li+ 3. ↓ metabolism cardiac glycosides 4. gynecomastia (reversible) 5. tumorgenic in rats 6. hyperchloremic metabolic acidosis (due to ↓ H+ secretion) |
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Name 2 Nonaldosterone antagonists.
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triamterene
amiloride |
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Nonaldosterone antagonists mechanism of action?
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↓ Na+ reabsorption in the distal nephron by ↓ Na+ permeability = ↓ K+ loss.
Inhibition of Na+/H+ exchange = ↓ loss of NH4+ |
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Clinical uses of nonaldosterone antagonists?
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Used in combination with other diuretics to ↓ K+ loss when treating edemas associated with CHF, cirrhosis, etc.
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Clinical use of Amiloride?
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Has antihypertensive effects that are additive with those of the thiazides
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Adverse effects of nonaldosterone antagonists?
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Hyperkalemia (need to monitor serum K+ due to: electrical disturbances and ↓ effects of cardiac glycosides)
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Adverse effects of Triamterene? (3)
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- ↑ serum uric acid & ↑ chance of gout
- inhibits dihydrofolate reductase = megaloblastic anemia w/ cirrhotic pts - low solubility, can precipitate in urine and cause stones |
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Name four loop/high ceiling diuretics.
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ethacrynic acid
furosemide bumetamide torsemide |
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Effectiveness of loop/high ceiling diuretics? Percent Na+ excretion?
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Most effective
Can = 20%+ filtered Na+ excretion |
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Mechanism of action for loop/high ceiling diuretics?
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Primary is inhibition of the Na+/K+/2 Cl- transporter in the thick ascending limb of Henle
(20-50% of the filtered Na+ is handled at this site and the more distal nephron cannot compensate) |
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Concentration effects of loop/high ceiling diuretics?
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Transporter block = ↓ hyperosmolarity in the medullary interstitutium = impairs ability to produce dilute and concentrated urine.
Also, ↑ loss of K+ and H+ due to ↑ Na+ load at distal nephron and ↓ positive potential in lumen = ↑ excretion of Ca2+ and Mg2+ |
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What drug may decrease the actions of loop/high ceiling diuretics? Why?
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NSAIDS = decreased prostaglandin synthesis.
Loop diuretics may increase prostaglandins which may produce part of their effects. |
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What do loop/high ceiling diuretics change the excretion of?
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↑ plasma uric acid
↑ excretion of Ca2+ & Mg2+ (can treat hypercalcemia) ↑ excretion of titratable acid & NH4+ (= metabolic alkalosis) |
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What can high doses of furosemide & bumetamide cause?
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They can inhibit CA = ↑ excretion of HCO3-
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What other ions do loop/high ceiling diuretics increase the excretion of? Clinical use of this?
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Monovalent anions (Cl, Br, I, F)
Used to tx toxicities |
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Which diuretic increases renal blood flow?
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fuorsemide
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Which diuretics decrease pulmonary congestion in CHF?
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fuorsemide
ethacrynic acid |
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What actions can loop diuretics have that are independent of diuretic activity?
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can increase blood flow through vascular beds
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How do loop diuretics access the tubule lumen?
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Bind plasma proteins and enter via the organic acid transporter
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When should you consider using a higher dose of loop diuretics?
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OA competing compounds (NSAIDS, probenecid)
Renal disease |
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Clinical uses of loop diuretics? (7)
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1. Acute pulmonary edema ER
2. Edema: of cardiac, hepatic or renal origin (esp if refractory to less efficacious diuretics) 3. Mild to moderate HTN 4. Acute Hypercalcemia 5. Hyperkalemia (give w/ Na+ and H2O) 6. Acute renal failure (to ↑ urine flow and K+ excretion) 7. Anion overdose (bromide, fluoride and iodide toxicities, give with saline solution) |
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Which diuretic can decrease blood pressure w/o diuresis?
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Torsemide
(also indapamide and thiazides) |
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Adverse effects of loop diuretics? (3)
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1. Hypokalemia (must monitor K+ levels)
2. Metabolic Alkalosis 3. Extreme diuresis = volume depletion, hypotension & orthostatics, dizziness, h/a |
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What patients should be really concernted about the hypokalemic effects of loop diuretics?
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Patients on digitalis
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What adverse effects are caused from competition for binding to organic acid transporter while on loop diuretics? What meds are involved?
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↑ nephrotoxicity with cephalosporins
↑ ototoxicity with aminoglycoside antibiotics ↑ salicylate toxicity |
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What adverse effects do loop diuretics have on hearing and blood sugars?
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Ototoxicity & transient deafness
Diabetogenic (furosemide & bumetamide) |
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What adverse effects do loop diuretics have due to competitive binding of serum proteins?
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Messes up kinetics of warfarin and clofibrate
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What adverse effects do loop diuretics have on Li+?
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Decreased clearance
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What adverse effects do loop diuretics have on cholesterol?
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Increased LDL and TG levels
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What adverse effects do loop diuretics have on uric acid and magnesium? (why?)
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Hyperuricemia (due to increased reabsorption of uric acid in proximal tubule caused by decreased vascular volume)
Hypomagnesemia |
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What adverse effects do loop diuretics have on vascular volume? What can this cause?
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Severe decrease
Can = hyponatremia if patients increase H2O intake due to hypovolemia-induced thirst |
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What can you do when patients become refractory to normal doses of loop diuretics?
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Give in combo with thiazide/thiazide-related diuretcs to exhibit greater than additive effects (even when either drug alone only has min effects)
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What is the urinary issue in diabetes insiptidus? How can this be addressed?
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Polyuria due to ↓ADH
Can be treated (paradoxically) with thiazides/loop diuretics, which cause salt depletion and contraction of ECF = ↑ proximal tubule reabsorption of Na+ = ↓ volume of fluid reaching distal tubule |
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What's the cause of Central diabetes insipidus? How's it treated? (2 drugs besides diuretics)
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↓ ADH levels
1. Arginine vasopressin (AVP = ADH) and analogs desmopressin and lypressin (IM, SC or intranasally) 2. Chlorpropamide (a sulfonylurea, which ↑ actions of ADH) |
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What's the cause of nephrogenic diabetes insipidus? How's it treated? (2 drugs besides diuretics)
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↓ responsiveness to ADH
1. Amiloride to block Li+ uptake (if Li+ is involved in causing the decreased response) 2. NSAIDS, i.e. indomethacin (↓ prostaglandin synthesis = ↑ response to ADH) |
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What's SIADH?
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Syndrome of inappropriate secretion of ADH = too much ADH
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How's SIADH treated? (4 drugs - how do they work?)
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1. Loop diuretics (↓ ability to concentrate the urine)
2. Demeclocycline (a tetracycline ↓ actions of ADH, can’t use with liver dysfunction) 3. Vaptans (nonpeptide V2 receptor antagonists - have shown promise in clinical trials. Approved = conivaptan) 4. Lithium (↓ ADH actions - not used because it's often ineffective and can cause kidney damage) |