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SRNAPharmacology I > DIURETICS > Flashcards

DIURETICS Flashcards

1
Q

Primary effects of diurectis

A

Primary effect of diuretics is to increase Na+ excretion (natriuresis), increase free water excretion, and increase the rate of urine flow

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2
Q

Thiazide vs thiazide like

A

The term thiazide-like diuretics refers to diuretic drugs that are pharmacologically similar (i.e.: same mechanism of action) to thiazide diuretics but are not thiazides chemically

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3
Q

Where is Na reabsorbed

A

The magnitude of effect for these agents is lower compared to
loop diuretics due to their site of action in the distal
convoluted tubule
• ~90-95% of the filtered Na+ load is reabsorbed BEFORE reaching
the distal convoluted tubule (this is the site of action of the
thiazide & thiazide-like diuretics)

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4
Q

• ALL thiazide & thiazide-like diuretics are ________ _________ Use cautiously in patient’s allergic to sulfonamides as cross
reaction can occur

A

sulfonamide derivatives

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5
Q

Thiazide diuretics:2 (the only IV is)

A

Chlorothiazide (Diuril®)
***** The only IV agent from this class
Hydrochlorothiazide
(HydroDIURIL®)

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6
Q

Thiazide-like Diuretics

A
  1. Chlorthalidone (Hygroton®)
  2. Indapamide (Lozol®)
  3. Metolazone (Zaroxolyn®,
    Mykrox®)
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7
Q 
Clinical	Uses	(cont.)	
•
A

Nephrolithiasis (kidney stones) due to idiopathic hypercalciuria
• Treatment of hypocalcemia
• Osteoporosis (very rarely done)

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8
Q

Thiazide diuretics can cause _____

A

hypercalcemia.

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9
Q

**Mechanism of Action: Thiazide Diuretics work

in

A

the Distal Convoluted Tubule

All target the Na/Cl- symport channel (moving Na and chloride in same direction)

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10
Q

Mechanism of action

A

After administration, thiazides are both freely filtered at the glomerulus AND actively
secreted into the proximal tubule by the organic acid secretory pathway
• Thus, these agents use both the
processes of glomerular filtration AND **active tubular secretion to gain access into the renal tubule

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11
Q

Urine

A

sodium, chloride and water comes out

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12
Q

• With exception of __________
thiazide diuretics are ineffective
in patients with severe renal
insufficiency

A

metolazone (use active tubular secretion)

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13
Q

*****The major differences between the thiazides is

A

their serum

t1/2 and duration of diuretic effect

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14
Q

These agents are _______preload

A

decreasing preload

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15
Q

Advese effects of thiazide diuretics

A

hypokalemia
Hypochloremia
Hyponatremia
HYPERCALCEMIA

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16
Q
  • The relative potencies vary between the agents

* Newer agents can be 2

A 
50-fold	more	potent	than	the	first	thiazide	
diuretic	Chlorothiazide	(Diuril®)
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17
Q

Initial antihypertensive response of thiazide diuretics

A
  • The thiazide diuretics decrease blood pressure initially by decreasing extracellular fluid volume (decreasing blood volume, decreasing preload) with a subsequent decrease in cardiac output
  • Long-term, cardiac output returns to baseline and extracellular volume returns almost to normal due to compensatory responses such as activation of renin-angiotensin-system
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18
Q

Sustained antihypertensive response of thiazide diuretics

A
  • The sustained antihypertensive effects is due to a decrease in vascular resistance (peripheral vasodilation)
  • The exact mechanism behind this is not known and it is unclear whether the resulting decrease in systemic vascular resistance after chronic thiazide therapy results from direct or indirect vasodilatory effect
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19
Q

****Diuretics adverse effects

A

Electrolyte abnormalities
• Hyponatremia, Hypokalemia, Hypochloremia, Hypomagnesemia,
Hypercalcemia

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20
Q

Any antihypertensive can cause

A

hypotension
headaches
Dizziness

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21
Q

INCREASE EFFECTS of those meds by thiazide

A

Thiazides can INCREASE the effects of:
• Nondepolarizing neuromuscular blocking agents
• Thiazides potentiate these agents by producing hypokalemia
• Skeletal muscle relaxants
• Digoxin due to thiazide causing hypokalemia, which increases risk of digoxin toxicity
• Lithium since thiazide decrease the excretion of lithium –increased risk of lithium toxicity
• Loop Diuretics

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22
Q

Decrease effects of thiazide

A

NSAIDS, NSAIDS

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23
Q

when combined with inhaled anesthetics

A

hypotension

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24
Q

LOOP diuretics o

A

inhibiotrs of Na-K-Cl symporter

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25
Q

Loop diuretics are

A

These agents cause greater diuresis than thiazide agents (because of where they work)

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26
Q

• The efficacy of loop diuretics is due to a combination of TWO factors:

A
  1. Approximately 25% of the filtered Na+ load normally is reabsorbed by the thick ascending limb of the loop of henle, and this is the region of the nephron where loop diuretics
    work
  2. Nephron segments past the thick ascending limb of the loop of henle DO NOT posses the reabsorptive capacity to rescue
    the flood of rejectate exiting the thick ascending limb
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27
Q

Often termed “high ceiling diuretics” due

A

to their high diuretic
potential
• As a class, loop diuretics have a rapid onset and short duration
of action

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28
Q

Loop Pharmacology.

Why does loop diuretics still work?

A

Loop diuretics enter the renal tubular lumen primarily by proximal tubular secretion by the organic acid transport system but glomerular filtration is also used to a MINOR degree
• This is the reason why loop diuretics still have a diuretic effect in
patients with severe renal insufficiency. The responses to loop
diuretics are maintained with GFR’s over a broad range, even in
the presence of impaired renal function. However, higher doses are required in renal failure patients to obtain adequate delivery
of the loop diuretic to its site of action
• Competitive inhibitors of the organic acid transport system (i.e.: probenacid or organic-by-products of uremia) can inhibit the
delivery of loop diuretics to their site of action and decrease their effectiveness

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29
Q

______ _____First loop diuretic introduced, used less frequently in the clinical
setting

A

Ethacrynic acid (Edecrin®)

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30
Q

(Only loop diuretic that can be given to a patient with a “true” sulfa or sulfonamide allergy)

A

Ethacrynic acid (Edecrin®)

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31
Q

• Most potent loop diuretic

A

• Bumetanide (Bumex®)

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32
Q

• Treatment of increased ICP

A

loop diuretics (they can decrease ICP)

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33
Q

Mechanism of Action: Loop Diuretics

•

A

Loop diuretics act by binding to
and blocking the Na+-K+-2Cl symport primarily in the thick ascending limb of the loop of
Henle, which inhibits the reabsorption of Na+
, K+ and Cl from the tubule lumen. These ions are then excreted along
with H2O
• Diuresis leads to loss of water
and salt with resulting decrease in intravascular volume thus lowering ventricular filling pressure and reducing pulmonary edema

34
Q

the symport bring

A

na , K and 2 Cl-

35
Q

Half life of loop diuretics vs. Thiazide

A

SHORT unlike thiazie

36
Q

Diuretics (D) improve symptoms of congestive heart failure by

A 
moving	patients	to	lower	cardiac	filling	pressures	along	the	same	ventricular	
function	curve.
37
Q

In addition to their diuretic action, loop diuretics also have a

A

direct veno dilating effect that increases venous capacitance
and will ⇓ preload, which also leads to ⇓ left ventricular filling
pressure
• Via this mechanism, the alleviation of pulmonary congestion/
edema can occur in patients who have fluid overload even BEFORE
appreciable diuresis can occur

38
Q

Venodilating effects:

A

• Venodilating effect occurs independently of diuresis and occurs
from increasing the synthesis of prostaglandins
• Loop diuretics increase the production of renal prostaglandins
and induce a prostaglandin mediated increase in renal blood
flow which also contributes to their natriuretic effect
• Giving NSAID’s such as indomethacin blocks this and decreases the
diuretic effect of loop diuretics

39
Q

Loops cause 5 hypos

A 
hyponatremia
hypoChloremia
hypokalemia
hypoMagnesemia
hypocalcemia
40
Q

**LOOP DIURETICS CAN CAUSE

A

OTOTOXICITY (acute or chronic) HUGE DOSES

41
Q

*****ETHACRYNIC ACID

A

OTOTOXICITY is the worst

42
Q

LOOPS

A

highly protein bounds

43
Q

ENhancement of Non depoleraizing nmB

A

due to hypoklaemia and a decease in the release of aCH

44
Q

Increased risk of _______ when loop diuretics with those agents

A

Nephrotocicity

Amionoglycoside
Amphotericin B
Cephalosporins
Vancomycin

45
Q

****Anesthesia and LOOD diuretics

A

Cardiac arrhythmias
• Patient’s with underlying cardiac conditions at increased risk
• Hypokalemia as a result of chronic diuretic use may potentiate non-depolarizing neuromuscular blocking agents such as cisatracurium and increases the dose of neostigmine
• However, acute hypokalemia does not affect dose requirements for
nondepolarizing neuromuscular blocking agents

46
Q

The presence of________ ________ is a sign that intravascular fluid volume is decreased. Increases in HCT and BUN are other signs of hypovolemia

A

orthostatic hypotension

47
Q

Loop diuretics can be used as a single drug or in combination with
mannitol for the treatment of increased ICP

A

• A combination of furosemide with mannitol is more efficacious in
decreasing ICP than either drug alone, however, there is an
increased risk of severe dehydration and electrolyte abnormalities with their combined use

48
Q

In addition to their diuretic action, loop diuretics also

A

have a direct venodilating effect that increases venous capacitance and will ⇓ preload, which also leads to ⇓ left ventricular filling
pressure

49
Q

Potassium Sparing Diuretics

A

Renal Epithelial Na+ Channel Inhibitors
• Amiloride (Midamor®)
• Triamterene (Dyrenium®)

Aldosterone receptor antagonists (aka: Mineralocorticoid receptor antagonists)
• Spironolactone (Aldactone®)
• Eplerenone (Insp

50
Q

Aldosterone receptor antagonists (aka:
Mineralocorticoid receptor
antagonists)

A

Spironolactone & eplerenone are competitive antagonists of aldosterone at the cytoplasmic mineralocorticoid receptor (MR) and block the actions of aldosterone on gene expression

RED: ****Antagonism of aldosterone by spironolactone and eplerenone results in a decrease in Na+ entry into the epithelial cells causing
decreased Na+ reabsorption (increased Na+ excretion) and decreased K+ excretion (increased K+ retention)

51
Q

MOA of aldosterone

A

INSIDE THE CELLS

52
Q

These agents ARE dependent upon

A

Circulating endogenous aldosterone levels for their effects (which includes diuresis)
• The higher the endogenous aldosterone level, the greater the diuretic effect of these agents
• These agents are ineffective in the absence of circulating aldosterone (i.e.: Addison’s disease)
• These agents “spare” K+ through their inhibitory effect on
aldosterone

53
Q

Aldosterone receptor antagonist won’ t work with people with

A

ADDISON’s Disease

54
Q

Spironolactone (Aldactone®)

A

• Is a synthetic steroid analog with a structure that closely
resembles aldosterone

Mechanism of action
• Competitive antagonist of aldosterone at cytoplasmic
mineralocorticoid receptors in the late distal tubule and collecting
duct
• Also has affinity toward progesterone and androgen receptors (anti-androgen agent) and antagonizes both these sex steroids receptors as well

55
Q

Spironolactone (Aldactone®):

Pharmacokinetics/Pharmacodynamics

A
  • Rapid and extensive hepatic first-pass metabolism

* Has several active metabolites with long half-lives

56
Q

Spironolactone (Aldactone®):

Pharmacokinetics/Pharmacodynamics active metabolite

A

Canrenone is the major active metabolite

57
Q

• Full pharmacologic effect

A

takes 2 to 4 days and effects on
aldosterone transport last for 48 to 72 hours after stopping
spironolactone

58
Q 
Spironolactone	(Aldactone®):	
*****Adverse	Effects	
• Principle	risk	for	spironolactone,	especially	in	the	presence	of	
renal	dysfunction	
****** Risk	for	hyperkalemia	is	increased	in	the	following:	
• Renal	failure	and	diabetic	patients	
• Pt’s	on	ACE-I’s	or	ARB’s	
• Pt’s	on	K+	supplements	
• Pt’s	on	NSAIDS	
• Elderly
A

• HYPERKALEMIA

59
Q

Spironolactone also antagonizes progesterone and androgen steroid receptors which can lead to:

A
  • Males – gynecomastia, impotence

* Females – breast tenderness, hirsutism

60
Q

Eplerenone (Inspra®)

• Eplerenone has for_____________ androgen and progesterone receptors and results in far less anti-androgen and antiprogesterone side effects compared to spironolactone

Metabolized by CYP 3A4 to inactive metabolites
• _________ is the most common adverse effect of concern

A

Is a selective, competitive aldosterone antagonist at mineralcorticoid receptors and is an analog of spironolactone

VERY LOW affinity
Hyperkalemia

61
Q

Renal Epithelial Na+ Channel Inhibitors

A

• Renal epithelial Na+ channel inhibitors BLOCK the epithelial Na+ channel in principle cells in the late distal tubule and collecting ducts decreasing the electrical chemical gradient
across the cell and enhance Na+ excretion and decrease K+excretion
• These agents “spare” K+ by interfering with this renal epithelial Na+ channel

62
Q

Renal epithelial Na channel inhibitors These agents ARE

A

NOT dependent on the presence of

circulating aldosterone levels to produce their diuretic effect

63
Q

Remember, only a small % of filtered Na+ (2-3%) is reabsorbed in the

A

LATE distal tubule & collecting ducts since these areas have a
limited capacity to reabsorb Na+, so the diuretic effect of these
agents is much less than thiazide and loop diuretics

64
Q

Carbonic Anhydrase Inhibitors

A

• Acetazolamide (Diamox®)
• Methazolamide (Glauctabs®, Neptazane®)
• Dorzolamide (Trusopt®)
only available in an eye drop dosage form
• Brinzolamide (Azopt®)
• only available in an eye drop dosage form

65
Q

CAI MOA

A

CAI’s potently inhibit, via noncompetitive inhibition, BOTH membrane-bound and cytoplasmic carbonic anhydrase in the proximal convoluted tubule. CAI’s also inhibit carbonic anhydrase that is located in the collecting duct system but this
is a secondary site of action of the CAI’s

66
Q

CAI MOA 2

A

• Carbonic anhydrase inhibition results in a decrease in the reabsorption of HCO3
-Na+ & water from the proximal
convoluted tubule lumen
• NaHCO3 is excreted, yielding a loss of HCO3 (the principle blood
buffer) and Na+. Much more HCO3
is lost compared with Na+
• The increased delivery of Na+ to the distal tubules leads to K+ loss
• H+ ions excretion is also decreased (more H+ is retained by the body)
• Acute increases in CO2 levels occur in tissues and the bloo

67
Q

Carbonic Anhydrase Inhibitors:

Mechanism of action (cont.)

A

In the eye, carbonic anhydrase inhibition decreases the production of aqueous humor which results in a decrease in intraocular pressure

CAI’s also inhibit carbonic anhydrase in the CNS to decrease abnormal and excessive discharge from CNS neurons (anticonvulsant activity).

Anti-convulsant activity from CAI’s is also
due in part to the drugs producing metabolic acidosis
• CAI’s also decrease the formation of cerebrospinal fluid by inhibiting carbonic anhydrase
• These agents can be used in the management of certain conditions that increase ICP

68
Q

Carbonic Anhydrase Inhibitors:

Effect on Urinary Excretion

A

• Increase in urinary excretion of HCO3
and a decrease in urinary excretion of H+ (body retains H+) in order to maintain electroneutrality, Cl- is retained by the
kidneys in the loop of Henle to offset the loss of HCO3
• Increase in urinary excretion of water, K+, and slight increase in
Na+ excretion

**The net effect of ALL these urinary changes is an alkaline urine (increase in urinary pH ~8) and development of metabolic acidosis (hyper-chloremic metabolic acidosis)

69
Q

Major indication of topical CAI (eye gtt)

A

Glaucoma

70
Q

ACute mountain sickness

A

CAIs

71
Q

*****Most adverse effects, contraindications, and drug interactions for acetazolamide

A

are secondary to urinary alkalinization or

metabolic acidosis adverse effect from the drug

72
Q

Acetazolamide has________bioavailability

A

100% bioavailability

73
Q

***Acetazolamide, by producing metabolic acidosis,

A

-can increase the respiratory drive in patients who have developed hypoxemia with resultant respiratory alkalosis, such as occurs with altitude sickness.
-Thus, acetazolamide-induced metabolic
acidosis can reverse the depressed ventilation seen in these patients (this is the basis for acetazolamide use in acute mountain sickness)
-In certain, not all, COPD patients, the loss of HCO3- necessary to buffer CO2 may result in the exacerbation of respiratory
acidosis since they may not be able to increase their ventilation adequately, leading to CNS depression

74
Q

OSMOTIC DIURETICS

A

MANNITOL

75
Q

All osmotic diuretics

A

inert substances
freely filtered at the glomerulus (SOLELY GLOMERULAR FILTRATION
CLASSIC- binds to ZERO RECEPTORS
Resist METABOLISM

76
Q

Resist metabolism

A

OSMOTIC DIURETICS

77
Q

OSMOTIC DIURESIS

A

Produce diuresis by causing through the osmotic property of the drug
depends on osmotic pressure exerted in renal tub

78
Q

Work in 3 areas

MAIN SITE:

A

Osmotic diuretics produce diuresis through the osmotic
property of the drug and ALL activity depends on the osmotic
pressure exerted in the tubule lumen
• Osmotic diuretics are administered to increase the osmolarity of plasma, glomerular filtrate, and renal tubular fluid resulting in osmotic diuresis
• Osmotic diuretics act in the proximal tubule, loop of Henle, & collecting duct; with

the primary site of action being the loop of Henle

79
Q

RENAL EFFECTS OF MANNITOL

A

• When administered IV, mannitol is completely filtered at the
glomerulus and increases the osmolarity of the glomerular filtrate
and prevents the reabsorption of water in the proximal
convoluted tubule, loop of Henle, and collecting duct
• The primary site of action for mannitol is in the loop of Henle
• As a result of this increased osmolarity in the renal tubular fluid,
there is an osmotic diuretic effect with enhanced urinary excretion
of water, Na+, Cl- and HCO3 ions. There is greater water loss
compared to electrolyte loss producing a “watery diuresis”

80
Q

RENAL EFFECTS OF MANNITOL

When administered IV, mannitol is completely ____________ and _________ the osmolarity of the glomerular filtrate
and prevents the reabsorption of water in the 3 spots in the renal tube (cite)
• The primary site of action for mannitol is in ____________
• As a result of this increased _________in the renal tubular fluid, there is an osmotic diuretic effect with enhanced urinary excretion of water, Na+, Cl- and HCO3 ions. There is greater ______ loss
compared to _______ loss producing a “________diuresis”
• Mannitol also extracts water from _________compartments
which expands __________ fluid volume, ________ blood viscosity, and ________ renin release. These effects increase renal blood flow which removes NaCl and urea from the renal medulla, thus reducing _________ -______ and hence reduce the ability to generate a ________urine

A

• When administered IV, mannitol is completely filtered at the glomerulus and increases the osmolarity of the glomerular filtrate
and prevents the reabsorption of water in the proximal convoluted tubule, loop of Henle, and collecting duct
• The primary site of action for mannitol is in the loop of Henle
• As a result of this increased osmolarity in the renal tubular fluid,
there is an osmotic diuretic effect with enhanced urinary excretion
of water, Na+, Cl- and HCO3 ions. There is greater water loss
compared to electrolyte loss producing a “watery diuresis”
• Mannitol also extracts water from intracellular compartments
which expands extracellular fluid volume, decreases blood
viscosity, and inhibits renin release. These effects increase renal
blood flow which removes NaCl and urea from the renal medulla,
thus reducing medullary tonicity and hence the ability to generate
a concentrated urine

81
Q

IN PLASMA: Induce movement of water? how?
Decreased intracranial pressure and intracranial edema effects
Mannitol given IV also ______ plasma osmolarity which will induce the movement of _______water to the extracellular and ________spaces along as osmotic gradient. Mannitol ________ blood viscosity which in turn ________(inc/dec)cerebral blood volume. This redistribution of fluid from intracellular spaces decreases brain bulk, reduces intracranial pressure and intracranial edema • The administration of _______of IV mannitol can pull _______ from the________ to the _______compartment
This _______ plasma osmolarity may result in an acute expansion of the________ fluid volume which could be poorly tolerated in patients with borderline cardiac function • Mannitol may facilitate decreases in ICP by also decreasing CSF volume

A

Decreased intracranial pressure and intracranial edema effects • Mannitol given IV also increases plasma osmolarity which will induce the movement of intracellular water to the extracellular and vascular spaces along as osmotic gradient. Mannitol reduces blood viscosity which in turn reduces cerebral blood volume. This redistribution of fluid from intracellular spaces decreases brain bulk, reduces intracranial pressure and intracranial edema • The administration of 50 grams of IV mannitol can pull 1 liter of fluid from the intracellular to the extracellular compartment • This increased plasma osmolarity may result in an acute expansion of the intravascular fluid volume which could be poorly tolerated in patients with borderline cardiac function • Mannitol may facilitate decreases in ICP by also decreasing CSF volume

82
Q

If larger doses of mannitol are given:

A

Volume expansion, hyponatremia, and metabolic acidosis caused by mannitol • If very large doses are infused too rapidly OR if mannitol is given to patient’s with pre-existing renal failure/impaired renal function, mannitol is retained in the circulation longer and will cause an increase in plasma osmolarity and result in a shift of intracellular water into the extracellular compartment resulting in cellular dehydration and overexpansion of the intravascular space with dilutional hyponatremia, reduction in hematocrit, metabolic acidosis, congestive heart failure, and pulmonary edema

SRNAPharmacology I (29 decks)

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