Diuretics

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Diuretics

• Steven Cheng, MD
• Assistant Professor
• Division of Nephrology
• Washington University School of Medicine

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Five Reasons to Stay Awake

• You get to see how all the lectures on tubular
  physiology are clinically
• relelvant

4. This will all be on the test. No, seriously.
It will be
3. I may or may not spontaneously produce Dr.
Mislers dog Kukla

• Youll have a solution when your girlfriend
  complains about
• swollen ankles

• You may just learn something that will save
  someones life
• someday

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Diuretics

• Agents that promote natriuresis (salt loss) and
  diuresis (water loss)
• One of the most commonly prescribed medications
  in the United States
• Used to treat hypertension and fluid retention

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Salt Water Balance
What causes edema?
1. Edema is a manifestation of an increase in
the interstitial fluid compartment of the body
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Salt Water Balance
What causes edema?
1. Edema is a manifestation of an increase in
the interstitial fluid compartment of the body
¼ Plasma
¾ Interstitium
1/3 ECF
2/3 ICF
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Salt Water Balance
What causes edema?
1. Edema is a manifestation of an increase in
the interstitial fluid compartment of the body
¼ Plasma
¾ Interstitium
1/3 ECF
2/3 ICF
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Salt Water Balance
What causes edema?
1. Edema is a manifestation of an increase in
the interstitial fluid compartment of the body
When water is added to the system, it distributes
evenly 2/3 to the ICF, 1/3 to the ECF
¼ Plasma
¾ Interstitium
Isotonic fluid, however, stays in the ECF
1/3 ECF
2/3 ICF
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Salt Water Balance
What causes edema?
1. Edema is a manifestation of an increase in
the interstitial fluid compartment of the body
I S O T O N I C
BP
¼ Plasma
¾ Interstitium
Edema
1/3 ECF
2/3 ICF
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Salt Water Balance
What causes edema?
1. Edema is a manifestation of an increase in
the interstitial fluid compartment of the body
I S O T O N I C
¼ Plasma
¾ Interstitium
1/3 ECF
2/3 ICF
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Salt Water Balance
What causes edema?
1. There is a change in capillary hemodynamics
favoring the movement of fluid from the vascular
to interstitial space
Increased Hydrostatic Pressure
Decreased Oncotic Pressure
Increased Capillary Permeability
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Salt Water Balance
What causes edema?
2. There is retention of salt and water by the
kidney
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Salt Water Balance
Where can we find edema?
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Salt Water Balance
Pulmonary Edema
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Salt Water Balance
Cerebral Edema
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Diuretics

• Diuretics have profound clinical implications
• They allow physicians to manipulate salt and
  water excretion in impaired states of
  volume/solute regulation
• Like all great therapeutic interventions, they
  have the potential to make patients better, and,
  when not considered carefully, the potential to
  make patients worse

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Diuretics

• Act primarily by inhibiting Na channels in the
  renal tubular system
• To reach the tubular lumen, these drugs must be
• Ingested and absorbed
• Effectively circulated
• Secreted into the renal tubular lumen
• Bound to the target transporter

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Question 1

• All of the following are potential obstacles in
  the diuretics migration from pill bottle to
  apical transporter EXCEPT
• A. Low Albumin States
• B. Pt non compliance
• C. Renal Failure
• D. All of these are obstacles to effective
  diuresis

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Question 2

• In patients with nephrotic syndrome, oral
  diuretics
• A. Are not effective, since these patients have
  volume retention due to low albumin states and
  not salt retention
• B. Are absorbed more efficiently in the gut
• C. May bind albumin in the urine instead of
  their targeted apical transporters
• D. Are unable to reach the apical transporters
  due to impaired glomerular permeability

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Regulation of Urine Content
ADH
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Diuretics
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Diuretics

• Are all diuretics pretty much the same?
• Well, they all cause people to pee
• But recognize the difference based on the
  channels being blocked
• Favorite test questions focus on Why is one
  diuretic better than another in a particular
  context?

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Diuretics
Loop
Thiazides
K Sparing
Other
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Diuretics
LOOP DIURETICS
Representative Example Furosemide (Lasix)
Onset of action roughly 30 minutes with PO, 5
minutes with IV Duration 6 hours
Factoid pee like a racehorse originates from
the use of lasix to improve speed in racehorses
decreased body weight by roughly 3
LASIX Lasts Six Hours
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Diuretics
LOOP DIURETICS
Representative Example Furosemide (Lasix)
Site of Action NaK2Cl transporter in the Thick
Ascending Limb
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Loop Diuretics

• Decrease sodium reabsorption
• Impairs the generation of a medullary gradient
• Thus
• Impairs urine dilution
• Impairs urine concentration

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Hunh?
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Regulation of Urine Content
ADH

• NaK2Cl is necessary for
• Dilution of Tubular Filtrate
• Establishing the Hypertonic Medullary
  Interstitium
• Providing the concentration gradient by which
  water is reabosrbed from the collecting duct
  (urinary concentration)

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Effect of Lasix
ADH
LAS I X

• Blocking NaK2Cl causes
• Impaired dilution
• No concentration gradient
• Increased free water excretion

Impaired dilution
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Lasix Lets see that one more time
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Diluting and Concentrating
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Diluting and Concentrating
Distal Tubule
TAL
Collecting Duct
TAL
Medullary Interstitium
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Diluting and Concentrating
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The Lasix Effect
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Loop Diuretics

• Decrease sodium reabsorption
• Impairs the generation of a medullary gradient
• Thus
• Impairs urine dilution
• Impairs urine concentration

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Loop Diuretics
Na
Na
K
K
Cl
Calcium
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Loop Diuretics
Loop Diuretics Increase excretion of Calcium
Na
Na
K
K
Cl
Calcium
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Loop Diuretics
The increase in Na delivery to the Collecting
Duct causes an increase in the exchange of Na for
secretion of K/H
Collecting Duct
Na
Na
Na
Na
K
H
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Diuretics

• LASIX
• Quick onset of diuresis
• Good for acute volume overload
• Increases urinary calcium excretion
• Used to treat hypercalcemia (Malignancy,
  Hyperparathyroidism)
• Increases urinary excretion of potassium and
  hydrogen ions
• Used to treat acute hyperkalemia

3 Reasons to love your loop diuretic
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Diuretics

• LASIX
• Excessive diuresis can lead to volume depletion
  and ARF/hypotension/CV collapse

3 Reasons to think twice
Diuresis
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Diuretics

• LASIX
• Excessive diuresis can lead to volume depletion
  and ARF/hypotension/CV collapse

3 Reasons to think twice
Diuresis
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Diuretics

• LASIX
• Excessive diuresis can lead to volume depletion
  and ARF/hypotension/CV collapse
• Can exacerbate calcium based kidney stones
• Can cause hypokalemia, metabolic alkalosis

3 Reasons to think twice
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Diuretics
Impairs dilution and concentration
Acute overload, edema, ?Ca/K
?serum K, Met Alkalosis, Volume Depletion, ?U Ca
TAL NaK2Cl
Loop
Thiazides
K Sparing
Other
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Diuretics
THIAZIDE DIURETICS
Representative Example Hydrochlorothiazide (HCTZ)
Onset of action roughly 2 hours Duration 6-12
hours
Factoid In April of 2005, Hydrochlorothiazide
was nominated as one of the most intimidating
medication names.
Less effective at GFR lt 40
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Diuretics
THIAZIDE DIURETICS
Representative Example Hydrochlorothiazide (HCTZ)
Factoid In April of 2005, Hydrochlorothiazide
was nominated as one of the most intimidating
medication names.
Site of Action Distal Convoluted Tubule
Effect HCTZ impairs urinary dilution, increases
Na excretion in the urine
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Regulation of Urine Content
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Regulation of Urine Content
HCZT
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Regulation of Urine Content
HCZT
ADH

• Thiazide Diuretics
• Impair Dilution, leading to excretion of salt and
  water
• Do not disrupt the concentrating mechanism

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HCTZ Effect
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Question 3

• Why are patients on thiazides more prone to
  hyponatremia than those on loop diuretics?
• A. Thiazides provide greater natriuretic effect
  than loop diuretics
• B. Trick question They both equally predispose
  patients to hyponatremia
• C. Loop diuretics impair renal urine
  concentration and dilution, whereas thiazides
  impair only urine dilution
• D. By increasing delivery of salt to the
  collecting duct, thiazide diuretics increase the
  drive for free water absorption, leading to
  hyponatremia

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Diuretics
How do I choose between a loop diuretic and a
thiazide diuretic?
Similarities
Both will make you pee
Both can be used for edema and HTN
Both can result in hypokalemia and metabolic
alkalosis
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Diuretics
How do I choose between a loop diuretic and a
thiazide diuretic?
Differences
Impairs both greater free water excretion
Impairs dilution only more prone to ?Na
Concentration/Dilution
Greater kaliuretic effect better for Tx of ?K
Less kaliuresis
Potassium
Increases Ca excretion better for Tx of ?Ca
?Ca reabsorption better for folks with Ca stones
Calcium
Better in renal failure Relieves resp distress
Inexpensive First line agent for HTN
Unique Superpowers
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Diuretics
Impaired dilution and concentration
Acute overload, edema, ?Ca/K
?serum K, Met Alkalosis, Volume Depletion, ?U Ca
TAL NaK2Cl
Loop
Impaired dilution
Hyponatremia, ?serum K, Met Alkalosis, Volume
Depletion
DCT Na/Cl cotrnsprt
Edema, HTN, Ca stones
Thiazides
K Sparing
Other
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Diuretics
What do you do for patients with persistent
hypokalemia?
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K-Sparing Diuretics
1. Aldosterone Antagonists
Factoid If Peter Griffin (Family Guy) was on a
diuretic it would probably be spironolactone,
which would account for his gynecomastia
Representative Example Spironolactone Site of
Action Cortical Collecting Duct Mechanism
Competes with aldosterone receptor Pharmacokinetic
s Can take between 10-48 hours to reach maximal
efficacy
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K-Sparing Diuretics
Collecting Duct
Na
Aldosterone is the mineralocorticoid which
promotes Na reabsorption by increasing the number
of Na channels (ENaC) on the luminal surface and
the number of Na-K pumps on the basolateral
surface
Na
Aldo
Na
Na
K
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K-Sparing Diuretics
Collecting Duct
Na
Aldosterone is the mineralocorticoid which
promotes Na reabsorption by increasing the number
of Na channels (ENaC) on the luminal surface and
the number of Na-K pumps on the basolateral
surface
Na
Aldo
Na
Na
Spironolactone is an aldosterone antagonist, thus
preventing sodium reabsorption and K excretion
K
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K Sparing Diuretics

• Theres more to aldosterone than meets the eye

There are mineralocorticoid receptors in the
heart as well Local production of aldosterone in
the heart is proportional to degree of heart
failure Aldosterone may stimulate cardiac
fibrosis and hypertrophy (Bad)
Aldosterone Antagonists may be particularly
beneficial in the long term management of certain
patients with heart failure
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K Sparing Diuretics

• Despite being a weaker diuretic, aldosterone
  antagonists have a greater effect in cirrhotics
  than lasix!
• Cirrhotic patients have a poor response to lasix
  due to their low albumin state and reduced
  tubular secretion.
• Aldosterone antagonists do not require secretion
  into the tubular lumen, and thus may remain
  effective despite marginal renal perfusion in the
  context of cirrhosis

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K-sparing Diuretics
2. ENaC Blockers
Factoid Amiloride was first approved for use in
1967, the same year that Thurgood Marshall was
sworn in as the first African American justice of
the Supreme Court
Spares potassium by decreasing the lumen-negative
gradient that drives the exulsion of K/H into the
lumen
Representative Example Amiloride,
triamterene Site of action Corical collecting
duct Mechanism Blocks ENaC channels Pharmacokinet
ics Half-life 3-5 hours
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K-Sparing Diuretics
Collecting Duct
Na
Amiloride and triamterene directly block the ENaC
channel
Na
Aldo
Na
Na
This makes amiloride an ideal agent for the
treatment of patients with Liddles Syndrome, in
which there is an abundance of active ENaC
channels expressed in the CCD
K
K
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K-Sparing Diuretics
Collecting Duct
Li
Li
Li
Factoid Certain drugs (trimethoprim,
pentamidine) may have mild diuretic effects due
to their ability to block reduce the number of
open ENaC channels
Li
Li
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Question 4

• A young bipolar patient with AIDS is seen in
  clinic. He was recently hospitalized and treated
  for PCP pneumonia with high doses of Bactrim
  (trimethoprim sulfamethoxazole). He also takes
  lithium and a cocktail of antiretroviral drugs.
  Since the completion of his antibiotic, the
  patient states that his breathing has improved
  dramatically, but he notes that he is always
  thirsty and has urine output of Gaussian
  proportions.

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Question 4 (cont)

• The intern blows this off, but since youve read
  this syllabus you hypothesize that
• A. Accumulation of TMX has led to nephrogenic DI
• B. The patient may have lithium-induced
  nephrogenic DI because Bactrim increases the open
  Na channels available for Li entry into cells
• C. The patient may have psychogenic polydipsia
  and worsening mania due to decreased absorption
  of lithium during treatment with Bactrim
• D. Amiloride my alleviate his symptoms.

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Diuretics
Impaired dilution and concentration
Acute overload, edema, ?Ca/K
?serum K, Met Alkalosis, Volume Depletion, ?U Ca
TAL NaK2Cl
Loop
Impaired dilution
Hyponatremia, ?serum K, Met Alkalosis, Volume
Depletion
DCT Na/Cl cotrnsprt
Edema, HTN, Ca stones
Thiazides
?K, CHF, ESLD Li tox, Liddles
K Sparing
CCD
Decreased distal Na reabsorption
? serum K, gynecomastia
Other
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Other Diuretics

• CAI
• Ex Acetazolamide
• Blocks carbonic anhydrase
• Causes alkaline diuresis

Applications Glaucoma Prophylaxis of Mountain
Sickness
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Other Diuretics

• Osmotic Diuretics
• Ex Mannitol
• Non-reabsorbable polysaccharide
• Preferential water diuresis

The net effect is akin to putting SpongeBob
Squarepants in the lumen of the renal tubule.
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Final thoughts

• Rebound
• The kidney is a master at compensation
• In the absence of salt restriction, the kidney
  will adapt to the effect of the diuretic
• After an initial diuresis, further natriuresis
  will be blunted by post-diuretic salt retention
• Salt restriction is, thus, crucial to continued
  diuresis

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Downstream Compensation
Fortune Cookie To fool the kidney, you must
think like the kidney
ADH
The addition of a downstream diuretic (in this
case, something that blocks the distal tubule)
will prevent the kidney from reclaiming Na and
water
LAS I X
As the kidney is an awfully smart fellow, it may
try to restore steady-state Na status by
increasing reabsorption distal to the site of
diuretic action
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Clinical Scenarios

• For each of the following clinical scenarios,
  pick the appropriate diuretic
• A. Loop
• B. Thiazide
• C. Aldosterone Antagonist
• D. ENaC Inhibitor
• E. The square root of Misler/(1.73x Kukla)

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Clinical Scenarios
60 year old with history of myocardial infarction
presents to ER with sudden onset shortness of
breath after participating in regional pickle
eating contest Too winded to speak in full
sentences Crackles/Rales on exam, 2 LE edema,
Oxygen Saturation 74 on 5L O2
LASIX Why? Rapid onset of diuresis, Pulmonary
edema Result? Symptomatic relief, avoidance of
intubation and mechanical ventilation
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Clinical Scenarios
48 year old man seen in clinic after experiencing
exquisite pain in groin last week. Passed the
following Ca-based stone with urination. Noted to
have BP 153/80
Thiazide Why? HTN, Ca-based stone Result?
Decrease risk for future stone formation, reduce
BP, decrease risk of cardiovascular
complications/death due to HTN
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Clinical Scenarios
12 year old with a strong family history of HTN,
noted to have a BP of 188/60. Has been treated
with thiazides, beta-blockers, ACE-inhibitors
without BP control. Labs show a serum K of 3.1,
bicarb of 32.
ENaC Inhibitor Why? Suspicion of Liddles (family
history, HTN, low K, metabolic alkalosis) Result?
Reduced blood pressure, decrease in
cardiovascular risk from HTN
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Clinical Scenarios
63 year old with a history of CHF. Edema is
managed with dietary restriction of Na and a loop
diuretic, but patient still occasionally short of
breath with minimal exertion. Is in clinic for
follow up and management of his heart failure.
Aldosterone Antagonist Why? Class III-IV
HF Result? Decreased mortality at 16-24 months
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Clinical Scenarios
62 year old woman with CKD complaining of
generalized weakness, intermittent palpitations.
Serum K level is 6.8 (normal 3.5-4.5)
Lasix Why? Kaliuretic effect Result? Reduction of
serum K, prevention of cardiac arrhythmia and
death
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Clinical Scenarios
69 year old man presents with back pain and
anemia. Is found to have Ca 11.6 mg/dL. In
addition to hydration with NS and the diagnosis
of Multiple Myeloma, what diuretic should be
given?
Lasix Why? Increase Ca excretion Result? Reduce
serum Ca, prevent cardiac, renal, neurologic,
musculoskeletal complications of hypercalcemia.

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Clinical Scenarios
Iron Chef Morimoto shows up in your clinic for a
routine check up. He has no significant past
medical history. His renal function in intact.
Electrolytes are stable. BP is 153/87
Thiazide Why? Essential HTN Result? Reduction of
future cardiovascular risk, many more years of
dominance on The Iron Chef.
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Clinical Scenarios
47 year old with chronic hepatitis and cirrhosis.
Has noted increasing abdominal girth over the
last several days despite treatment with Lasix.
Serum K is 3.2 (normal 3.5-4.5)
Aldosterone Antagonist Why? Hypokalemia, improved
volume removal in a cirrhotic patient Result?
Mild alleviation of volume retention, improvement
in serum K.
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Clinical Scenarios
The previous patient has a slight improvement in
edema and ascites. However, after three days she
develops worsening renal function. What could
have happened?