Last edited: 11/22/2022

DIURETICS
Diuretics Medical Editors: May, Sarah and Camille

OUTLINE
I) OVERVIEW OF RENAL PHYSIOLOGY III) DIURETICS CLASSES V) ASCITES DIURESIS VII) APPENDIX
(A) PROXIMAL CONVOLUTED TUBULE (PCT) (A) OSMOTIC DIURETICS CIRRHOSIS VIII) REVIEW QUESTIONS
(B) DESCENDING LIMB OF LOOP OF HENLE (B) CARBONIC ANHYDRASE CONGESTION DUE TO CIRRHOSIS IX) REFERENCES
(DLOH) (C) LOOP DIURETICS REGIMEN
(C) ASCENDING LIMB OF LOOP OF HENLE (D) THIAZIDE DIURETICS OTHER THERAPIES
(ALOH) (E) POTASSIUM-SPARING DIRETICS VI) ADVERSE DRUG REACTIONS
(D) DISTAL CONVOLUTED TUBULE (DCT) IV) FLUID DIURESIS LOOP DIURETICS
II) DIURETICS (A) SIGNS & SYMPTOMS OF CONGESTION THIAZIDE DIURETICS
(A) DIURETICS (B) CAUSES OF CONGESTION (A) POTASSIUM SPARING DIURETICS
(B) SITES OF DIURETIC ACTION (C) REGIMEN (B) CARBONIC ANHYDRASE INHIBITORS
(C) OSMOTIC DIURETICS
(D) MECHANISM OF ACTION
I) OVERVIEW OF RENAL PHYSIOLOGY

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Figure 1. Overview of Nephron Physiology

(A) PROXIMAL CONVOLUTED TUBULE (PCT)

Where most sodium reabsorption (65%) occurs
o Hence, decent amount of water is also reabsorbed
 Recall: Since water follows the salt
Where many other nutrients are also reabsorbed, such as glucose, amino acids, bicarbonate
(1) Normal Physiology

Bicarbonate (HCO3–) is excreted into the PCT CO2 passively enters the cell
from the glomerulus o It can be reabsorbed through the tubular cell
o Primary molecule of interest in the PCT membrane because it is lipid-soluble
o Too charged; and hence, can’t be reabsorbed
Inside the cell, carbonic anhydrase catalyzes
In the lumen, HCO3– is catalyzed through a CO2 into HCO3–
series of steps into Carbon Dioxide (CO2) o Via the following reaction:
o Different proteins and molecules play a role in this  CO2 + H2O  H2CO3  HCO3– + H+
conversion • Water can be found inside the cell
 Na+/H+ Transporter
• Transport protein on the tubular membrane HCO3– in the cell is pumped out to the
that allows sodium (Na+) to enter the cell, bloodstream
while pumping a proton (H+) out of the cell in
o Through the Cl⁻/HCO₃⁻ exchangers on the
return
basolateral membrane which moves a Cl– ion from
• The proton (H+) is vital the bloodstream into the cell
 Carbonic anhydrase
• Enzyme found on the tubular membrane that Na+/K+ ATPase keeps the osmotic gradient
catalyzes the following reaction in the lumen:
o HCO3– + H+  H2CO3  CO2 + H2O inside the cell
• Catalyzes the following reaction in the cell: o Pumps Na+ out of the cell and into the bloodstream,
and moves K+ inside
o Against concentration gradient: needs energy (ATP)

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(B) DESCENDING LIMB OF LOOP OF HENLE (DLOH)
Has a primarily role in water reabsorption
No specific diuretics
o Mannitol and urea work on both PCT and D-Limb of LOH

(C) ASCENDING LIMB OF LOOP OF HENLE (ALOH)

Reabsorbs sodium (25%) and water
(1) Normal Physiology
Na+/K+/2Cl- Co-Transporter Cl- in the cell is reabsorbed into the blood
o Na+, K+, and Cl- from the lumen enter the cell
together

Na+ in the cell is reabsorbed into the blood Mg2+ and Ca2+ move from the lumen into
via the Na+/K+ ATPase the bloodstream via the paracellular route
o The tubular lumen is positively-charged; hence, calcium
 Which subsequently pumps K+ into the cell
and magnesium can’t stay in the tubular lumen

(D) DISTAL CONVOLUTED TUBULE (DCT)

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Reabsorbs Na+ (10%) and water

o Amount of molecules reabsorbed is considerably less as compared to the other sites

o Sodium reabsorption, especially in the Late DCT, is dependent on Anti-Diuretic Hormone (ADH)
(1) Normal Physiology of Early DCT
Na+ and Cl- enter the cell from the lumen Ca2+ in the lumen moves into the cell
 Via the Na+/Cl- cotransporter
 Parathyroid Hormone (PTH)
Na+ in the cell is reabsorbed into the blood
via the Na+/K+ ATPase Ca2+ in the cell moves out into the blood,
 Which subsequently pumps K+ into the cell while the Na+ in the blood goes back into
H2O is also reabsorbed into the blood the cell
 Because it gets reabsorbed with the Na+ and Cl–  Via the Ca2+/Na+ exchanger
via the osmotic gradient

(2) Normal Physiology of Late DCT

Principal Cells
Na+ moves from the tubular lumen into the
 Aldosterone
cell
 via the ENaC (Epithelial Na+ Channel)

Na+ in the cell moves into the blood via the

Na+/K+ ATPase
 While moving K+ from the blood into the cell
 Which will reabsorb H2O with it into the blood

K+ in the cell will move down its

concentration gradient from the cell into
Intercalated Cells
the lumen
 The K+ will be excreted into the urine

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II) DIURETICS

(A) DIURETICS
Main function is to eliminate molecules (e.g., sodium, chloride, water, other electrolytes into the urine) by targeting particular
parts of the Nephron
o Hence, it’s important to review the tubular reabsorption processes occurring in the kidney

(B) SITES OF DIURETIC ACTION (C) OSMOTIC DIURETICS

(1) Sites of Action:
Proximal Convoluted Tubule (PCT)
Descending Limb of Loop of Henle (DLOH)
(2) Drug
E.g., Mannitol
(3) Mechanism of Action
When it moves through the afferent arteriole 
glomerulus  gets filtered out of the glomerulus
It’s a large solute molecule
o Hence, when it moves through the afferent arteriole
AfraTafreeh.comFigure 2. Primary Sites of Diuretic Action and through the glomerulus, it gets filtered out
 Its large size prevents it from being reabsorbed
o When it gets filtered out, it creates a powerful osmotic
(1) Proximal Convoluted Tubule (PCT) gradient that pulls water into the PCT and continues
There is NO diuretic that specifically and directly targets to move down into the DLOH
sodium in the PCT; but if there is, it can cause a massive Causes massive degree of diuresis of primarily large
loss of sodium and water in the urine amounts of water molecules
Not primarily used as a diuretic
(i) Carbonic Anhydrase Inhibitor Used for reducing intracranial pressure

(2) Ascending Limb of Loop of Henle (ALOH)

(i) Loop Diuretics

(3) Early DCT

(i) Thiazide Diuretics

(4) Late DCT

Sodium reabsorption, especially in the Late DCT, is
dependent on Anti-Diuretic Hormone (ADH)

(i) Potassium-Sparing Diuretics

 Has two types:
Figure 3. Osmotic Diuretics

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(D) MECHANISM OF ACTION

(1) Proximal Convoluted Tubule (PCT) (2) Ascending Limb of Loop of Henle (ALOH)
(i) Carbonic Anhydrase Inhibitor (i) Loop Diuretics
 Primarily inhibits carbonic anhydrase  Inhibits Na+/K+/2Cl- Co-Transporter
• Recall: it catalyzes the following reaction:
o HCO3– + H+  H2CO3  CO2 + H2O
o CO2 + H2O  H2CO3  HCO3– + H+
 With carbonic anhydrase inhibited, the following
occurs:
• Inhibits the catalysis of CO2 + H2O into HCO3–
+ H+ inside the cell
o Lessens the amount of H+ that can be
pumped out of the cell and into the lumen
 Does not allow Na+ to come into the
cell via the Na+/H+ Transporter
 Does not allow the conversion of
HCO3– into H2CO3
o Also lessens the HCO3– that can be
reabsorbed into the bloodstream
• Overall, Na+ and HCO3– remains high in the
lumen
o Since water follows the salt, it also takes
water with it into the urine
• Increased HCO3– and Na+, and
subsequently, H2O excreted into the urine

Figure 5. Mechanism of Action: ALOH

Figure 4. Mechanism of Action: PCT

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(3) Early DCT (4) Late DCT

(i) Thiazide Diuretics (i) Aldosterone Antagonist

 Inhibits Na / Cl CoTransporter
+ -

(ii) ENaC Blockers

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Figure 6. Mechanism of Action: Early DCT

Figure 7. Mechanism of Action: Late DCT

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III) DIURETICS CLASSES

(A) OSMOTIC DIURETICS

(i) Drugs
 Mannitol
 Urea
Mechanism of Action
Mannitol is a large molecule, which (↑) osmolarity
o This creates a gradient that pulls water from
extravascular spaces (tissue cells, interstitial spaces),
such as brain tissue, and the vitreous humor (in eye)
o This water is pulled into the bloodstream
Indications
Cerebral Edema → (↑) ICP (Intracranial Pressure)
o May be caused by:
 Large strokes (Ischemic or Hemorrhagic; SAH)
 Diabetic Ketoacidosis

(↑) IOP (Intraocular Pressure)

o May be caused by:
 Acute Glaucoma

(i) Effects on the Kidney

Complications
This massive loss of water, with the assumption of
functional kidneys, will be filtered with mannitol and be
excreted. This leads to:
o Hypovolemia; significant volume (↓) → (↓) BP
o Hypernatremia in the blood; since aquaresis spares
electrolytes and it’s only the excretion of water
Figure 1. Osmotic Diuretics are indicated for Cerebral Edema
In case of non-functional kidneys (such as in AKI or and Acute Glaucoma where there is an increase in pressure.
ESRD), water cannot be excreted through the kidneys, and However, depending on the functionality of the kidneys, it can
therefore remains in the vascular space, this keeps the produce different effects or side effects.
blood volume very high (↑↑↑)
o Pulmonary Edema; this fluid leaks out into particular
tissue spaces; most commonly into the lung
o Hyponatremia; since there is too much water in
relation to the electrolytes (Na+)

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 (B) CARBONIC ANHYDRASE
(i) Drugs:
 Acetazolamide
Mechanism of Action Indications
These drugs specifically work at the proximal convoluted This drug has a diuretic effect as well as other effects that
tubules (PCT) by inhibiting the carbonic anhydrase reduce particular fluids.
enzyme.
o This prevents the reabsorption of bicarbonate (HCO3) High Altitude/ HAPE
 Therefore, there is (↑) excretion of HCO3 into the o This is useful for patients with increased risk of
urine. altitude sickness/ High Altitude Pulmonary Edema
o (↓) HCO3 level in the blood → (↓) pH (HAPE).
 This is called Metabolic Acidosis  At high altitudes there is (↓↓) O2 → hypoxemia,
(non-anion gap) pulmonary edema, etc.
• Acetazolamide can be taken before going to
high altitudes,
REMEMBER: Acid-Base Equation o It can (↓) pH of blood which (↑) tidal
volume by (↑) rate and depth of respiration
 (↓) CO2 to make pH higher to
compensate and (↑↑) O2 to improve
ventilation and oxygenation.
Fluid Diuresis
o Used as an adjunct therapy.
Source: https://www.timeofcare.com/acid-base-
disturbances/
Prevention/Reduction of particular fluids
o In the eye: (↓) aqueous humor production → (↓)
If there is (↓) HCO3 there will consequently be (↑) H+ intraocular pressure (especially in glaucoma)
leading to (↓) pH o In CNS: (↓) CSF production → (↓) Intracranial
pressure

o With (↓) pH, it acts on central chemoreceptors →

this stimulated chemoreceptors will (↑) rate and depth
of respiration. • These are used in patients that do not have
 This would (↑) tidal volume, to bring in (↑↑) O2 underlying lesions or disease that causes ICP
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• But (↑↑) CO2 that is exhaled, this (↓) CO2 level to build up.
in the blood.

o This also leads to (↓) proton excretion, therefore (↓)

Na reabsorption.
 With loss of sodium, there is loss of water as well.

Figure 2. Mechanism of action and indication of carbonic

anhydrases

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(C) LOOP DIURETICS

(i) Drugs: Mechanism of Action:
 Furosemide (LASIXs)
These drugs are very effective in causing massive
 Torsemide
amounts of sodium and water loss, they are one of the
 Bumetenide
most powerful diuretics.
 Ethacranic acid
o They act on the ascending limb of the loop of
Henle and directly block the Na/K Co-transporter that
causes massive loss of sodium, chloride and water
into the urine.
 It is useful in patients with CHF, CKD, AKI, or
volume overloaded due to IV fluid, etc.

Pharmacodynamic/ Pharmacokinetic aspect:

(i) Dose-Response Curve
(ii) Potency
Threshold dose: the dose that allows the kidneys to
Diuretics have different points of potency, while efficacy
produce a decent amount of urine.
stays roughly the same.
o As you (↑) the dose, the response (urine produced)
o As you (↑) the dose, the potency (↓) but they all have
will (↑) quickly but at a certain dosage point it will
the same e-max (efficacy).
plateau, this is the maximum amount of urine that can
be produced. The most potent diuretic is one that produces maximum
efficacy at the lowest dose; Bumetanide.
o The next ones are Torsemide and Furosemide,
respectively.

The equivalent diuretic doses:

Figure 3. Dose-Response Curve

So if you start with a low dose and the patient produces

only a small amount of urine, it might mean that the Figure 4. Loop Diuretics have different potencies
threshold dose has not been reached yet.
o If the dose is (↑), this might (↑) the urine but at a
certain dose, the same amount of urine will be Bumetanide is 40 times more powerful than furosemide,
produced no matter how much you (↑) the dose. and Torsemide is 2 times more powerful than furosemide.
o Therefore, lower doses of Butemanide can be used to
produce maximum efficacy or higher doses of
furosemide to produce the maximum efficacy.

Figure 5. The difference between the potencies of loop diuretics

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Bioavailability (F) Indications:
Furosemide = 50% Excretion of potassium
o If given by PO, give double the dose (e.g. if 40 mg is o For example in hyperkalemia (↑ K+), when a loop
given IV, 80 mg is given PO) diuretic is given, this will inhibit the Na-K-2Cl
Torsemide = >80% cotransporter
o PO and IV form is almost equal
• (↑↑) Na and (↑↑) Cl that reaches the distal
Bumetanide = >80% convoluted tubule (DCT)
o PO and IV form is almost equal o Positive ions are moving out of the tubular
lumen into the tubular cell, there is a loss
of positive ions in the tubular lumen
 Potassium moves into the lumen to
compensate for that, this (↑) K+
excretion called kaliuresis

o Excretion of calcium
 In patients with hypercalcemia (↑ Ca2+), due to
the drug blocking the Na-K-2Cl co-transporter, (↓)
reabsorption of Na and Cl
• The inside of the tubular lumen becomes (↑)
negative
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due to the negative charge of the lumen,
this prevents the Ca2+ from being
reabsorbed back into the cell.
 (↑) excretion of Ca2+

Figure 6. Indications: loop diuretics are used to decrease potassium and calcium

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 (D) THIAZIDE DIURETICS
(i) Drugs
 Hydrochlorothiazide (HCTZ)
 Chlorothiazide
 Metolazone
 Chlorthalidone
Mechanism of Action
Thiazide diuretics block the Na -Cl co-transporter (in the early DCT)
+ -

→ This leads to water, sodium and chloride loss in the urine + retention of calcium (causing hypercalcemia)

Indications (additional)
Essential Hypertension Calciuria and Risk of Kidney Stones
o In the arterioles: causes smooth muscle relaxation
and in turn vasodilation (Nephrolithiasis)
o Since thiazides block the Na+-Cl- co-transporter and
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o In the venule: (↓) Na+ and Water reabsorption the reabsorption of Na , Cl , and Water
+ -

 Blocking (mainly) the sodium reabsorption → (↓)

Na+ in the cell and this gradient pulls more Na+ in
the cell and more Ca+2 out (to be reabsorbed)
• (↑) Ca+2 reabsorption (and less in the urine)

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Figure 8. Thiazide Diuretics promotes the reabsorption of

calcium, thereby decreasing its level in the urine and
decreasing Calciuria.

Figure 7. Mechanism of Action of Thiazide Diuretics in the

treatment of Essential Hypertension
Osteoporosis
o (↑) Ca+2 reabsorption → more calcium for the
osteoblast to deposit into the bone tissue, which may
be beneficial for patients with osteoporosis

Figure 9: Due to Thiazide Diuretics actions in increasing

Calcium Reabsorption, they are indicated in patients with
Osteoporosis as well as patients with the risk of Nephrolithiasis.

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(E) POTASSIUM-SPARING DIRETICS

(i) Drugs
Aldosterone Blockers:
o Spironolactone
o Eplerenone
ENaC Blockers:
o Amiloride
o Triamterene
Mechanism of Action
Exert their effects on the later parts of the DCT
o Aldosterone blockers: block aldosterone

o ENaC blockers: block the ENaC channels directly

Indications (additional)
Conn’s Syndrome Hypertension + Chronic Hypokalemia
(Hyperaldosteronism) + CHF (Congestive Heart Failure)
o Hyperaldosteronism causes:
 Hypernatremia; due to (↑) Na+ reabsorption
 (↑) Blood volume (and ↑ BP); due to (↑) Water
reabsorption
 Hypokalemia; due to (↑) K+ excretion Nephrogenic Diabetes Insipidus (DI)
 Metabolic alkalosis

Figure 11: ENaC Blockers are indicated in Nephrogenic

Diabetes Insipidus

Figure 10: Aldosterone Blockers are indicated in Conn's

Syndrome

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 IV) FLUID DIURESIS
A patient presenting with generalized edema may have fluid buildup in their chest and/or abdomen. This can lead to
pain/discomfort and reduced urinary output. This scenario would be an indication for fluid diuresis.

(A) SIGNS & SYMPTOMS OF CONGESTION (B) CAUSES OF CONGESTION

Pulmonary edema (1) Congestive Heart Failure
Pleural effusion
Pitting edema The most common cause of congestion of fluid buildup
Distended abdomen (i) Left-Sided Heart Failure
Ascites
Hepatomegaly  Systolic Dysfunction – Heart cannot contract
Weight gain blood out of the heart
 Diastolic Dysfunction – The heart has thick
ventricle and high filling pressures; thus, there is
difficulty filling the heart with blood
 Due to left-sided heart failure, fluid backs up in the
pulmonary circulation, leading to pulmonary
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(ii) Right-Sided Heart Failure
 Fluid backs up through the superior/inferior vena
cava (peripheral systemic circulation), leading to
ascites, hepatomegaly, and bipedal edema
(2) Acute Kidney Injury / Chronic Kidney Disease
When there is acute kidney injury or chronic kidney
disease, there is decreased urine output and hence,
decreased fluid elimination
Decreased fluid elimination leads to increased blood
volumes, which in turn increases congestion
(3) Fluid Overload
Hospitalized patients may receive massive amounts of
intravenous fluids (iatrogenic), which increases blood
volume and congestion
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(C) REGIMEN
Patients presenting with signs of congestion may need diuretics to decrease fluid buildup
Mechanism of Action of Diuretics
o Diuretics block the reabsorption of sodium and water, thereby decreasing blood volume, preload, and congestion

(1) Loop Diuretics (4) Potassium-sparing Diuretics

Loop diuretics are the first-line drugs given since it is the Mechanism of Action: blocks sodium reabsorption and
most effective at decreasing sodium and water potassium excretion in late DCT
reabsorption (strongest diuretic effect) o Diuretic effect
Mechanism of Action: inhibits Na+/K+/2Cl- transporters o increase potassium retention
along the thick ascending limb of the loop of Henle These drugs combat the hypokalemia caused by loop and
o Reduces sodium and water reabsorption thiazide diuretics
(2) Thiazide Diuretic
Mechanism of Action: inhibits Na+/K+/2Cl- transporters
along the early part of distal convoluted tubule
Indications for Use:
o Increase diuresis / Augment the effect of loop
diuretic
 If target fluid diuresis has not been achieved with
loop diuretics alone, a thiazide diuretic may be
added
o Hypernatremia
 Loop diuretics cause more water loss than sodium
loss  hypernatremia
 Thiazide diuretics cause more sodium loss than
water loss; thus, this drug may be used to
address loop diuretic-induced hypernatremia
(3) Carbonic Anhydrase Inhibitors
Mechanism of Action: Inhibits sodium and bicarbonate
reabsorption
o Diuretic effect
o Decreases serum pH (due to decreased bicarbonate
levels); counteracts metabolic alkalosis
Indications for Use: hypokalemia and metabolic
alkalosis due to concurrent use of loop and thiazide
diuretics
o When using both loop and thiazide diuretics, sodium
reabsorption is blocked at multiple points except the
late part of the distal convoluted tubule
o The high concentration of sodium at that point
increases sodium reabsorption in the DCT
o When sodium is reabsorbed in the distal convoluted
tubule, protons and potassium are pulled out,
increasing their secretion  hypokalemia and
metabolic alkalosis

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V) ASCITES DIURESIS

CIRRHOSIS REGIMEN
Cirrhosis refers to scarring or fibrosis of the liver due to (1) Aldosterone Blockers
chronic liver disease; it can cause signs of congestion or
fluid buildup The first-line and primary drug for treating patients with
o Fibrotic liver increases the pressure of the portal ascites and edema secondary to cirrhosis are
circulation aldosterone blockers
o This stimulates the liver to release peptides (nitric Mechanism of Action: Blocks the effect of aldosterone on
oxide) which cause vasodilation of the splanchnic the distal convoluted tubule
vessels o Decreases sodium and water reabsorption
o Blood flow is redirected to the splanchnic vessels and o Decreases potassium excretion
organs, thereby reducing renal perfusion and High doses of these drugs are given to patients
activating the renin-angiotensin-aldosterone system presenting with signs of congestion secondary to
o The RAAS will increase the secretion of aldosterone, cirrhosis
which acts on the DCT to facilitate sodium and water
reabsorption and potassium excretion (2) Loop Diuretics
o This propagates worsening ascites and pitting May be given as add-on therapy
edema Given in lower doses to augment diuresis
CONGESTION DUE TO CIRRHOSIS OTHER THERAPIES
Hepatomegaly
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Ascites Albumin supplementation
Pitting edema

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VI) ADVERSE DRUG REACTIONS

LOOP DIURETICS THIAZIDE DIURETICS
Hypernatremia Hyponatremia
o Recall: Loop diuretics cause greater water loss than o Recall: Thiazide diuretics cause greater sodium loss
sodium loss than water loss
Hypovolemia Hypercalcemia
Hypocalcemia Hypomagnesemia
Hypomagnesemia Hypokalemia
Hypokalemia Metabolic alkalosis
o Due to potassium excretion Hyperuricemia
Metabolic alkalosis Hyperglycemia
o Due to proton and bicarbonate loss Hyperlipidemia

Hyperuricemia
o Due to furosemide competing with uric acid on the
organic acid transporter
Hyperglycemia
o Due to decreased insulin sensitivity of tissues
Ototoxicity
o More common with ethacrynic acid and high doses of
loop diuretics

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(A) POTASSIUM SPARING DIURETICS (B) CARBONIC ANHYDRASE INHIBITORS

Hyperkalemia Metabolic acidosis
Metabolic acidosis o Due to decreased bicarbonate reabsorption
o Due to decreased proton excretion Increased risk of kidney stones
Gynecomastia o Decreased bicarbonate reabsorption causes urine to
o Aldosterone blockers may also displace androgen be more alkalotic
from androgen receptors Increased serum ammonia
o When ammonia binds with a proton, it forms
ammonium, which is electrically charged and more
difficult to reabsorb
o In the absence of protons, ammonia is not converted
to ammonium, thereby increasing ammonia
reabsorption
Hypokalemia

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VII) APPENDIX

Group Drugs Mechanism of Action Indications

Mannitol Mannitol is a large molecule, which (↑) osmolarity Cerebral Edema → (↑) ICP (Intracranial Pressure)
Urea o This creates a gradient that pulls water from extravascular o May be caused by:
Osmotic Diuretics

spaces (tissue cells, interstitial spaces), such as brain tissue,  Large strokes (Ischemic or Hemorrhagic; SAH)
and the vitreous humor (in eye)  Diabetic Ketoacidosis
o This water is pulled into the bloodstream

(↑) IOP (Intraocular Pressure)

o May be caused by:
 Acute Glaucoma

Acetazolamide These drugs specifically work at the proximal convoluted tubules High Altitude/ HAPE
(PCT) by inhibiting the carbonic anhydrase enzyme. It can (↓) pH of blood which (↑) tidal volume by (↑) rate and depth of respiration
- This prevents the reabsorption of bicarbonate (HCO3) o (↓) CO2 to make pH higher to compensate and (↑↑) O2 to improve ventilation and
- Therefore, there is (↑) excretion of HCO3 into the urine. oxygenation.
Carbonic Anhydrase

- (↓) HCO3 level in the blood → (↓) pH

- This is called Metabolic Acidosis (non- Fluid Diuresis
anion gap) o Used as an adjunct therapy.

With (↓) pH, it acts on central chemoreceptors → this stimulated

chemoreceptors will (↑) rate and depth of respiration. Prevention/Reduction of particular fluids
o This would (↑) tidal volume, to bring in (↑↑) O2 In the eye: (↓) intraocular pressure (especially in glaucoma)
 But (↑↑) CO2 that is exhaled, this (↓) CO2 level in the blood. In CNS: (↓) CSF → (↓) Intracranial pressure
o These are used in patients that do not have underlying lesions or disease that causes
ICP to build up.

This also leads to (↓) proton excretion, therefore (↓) Na reabsorption.

o With loss of sodium, there is loss of water as well.

Furosemide (LASIXs) These drugs are very effective in causing massive amounts of Excretion of potassium in hyperkalemia (↑ K+)
Torsemide sodium and water loss, they are one of the most powerful diuretics. Drug inhibits the Na-K-2Cl cotransporter
Bumetanide o They act on the ascending limb of the loop of Henle and
Ethacrynic acid directly block the Na/K Co-transporter that causes massive loss o (↑↑) Na and (↑↑) Cl that reaches the distal convoluted tubule (DCT)
of sodium, chloride and water into the urine.  Positive ions are moving out of the tubular lumen into the tubular cell, there is a
Loop Diuretics

 It is useful in patients with CHF, CKD, AKI, or volume loss of positive ions in the tubular lumen
overloaded due to IV fluid, etc. • K+ moves into the lumen to compensate for that, this (↑) K+ excretion called
kaliuresis

Excretion of calcium in hypercalcemia (↑ Ca2+)

Drug blocks the Na-K-2Cl cotransporter, (↓) reabsorption of Na and Cl
o The inside of the tubular lumen becomes (↑) negative
 When Ca2+ reaches the ascending limb, due to the negative charge of the lumen,
this prevents the Ca2+ from being reabsorbed back into the cell.
• (↑) excretion of Ca2+

Diuretics PHARMACOLOGY: NOTE #18. 17 of 19

 Hydrochlorothiazide Thiazide diuretics block the Na+-Cl- co-transporter (in the early Essential Hypertension
(HCTZ) DCT) → this leads to water, sodium and chloride loss in the urine + o In the arterioles: causes smooth muscle relaxation and in turn vasodilation
Chlorothiazide retainment of calcium (causing hypercalcemia)
o In the venule: (↓) Na+ and Water reabsorption
Metolazone
Chlorthalidone
Thiazide Diuretics

Calciuria and Risk of Kidney Stones (Nephrolithiasis)

o Since thiazides block the Na+-Cl- co-transporter and the reabsorption of Na+, Cl-, and
Water
 Blocking (mainly) the sodium reabsorption → (↓) Na+ in the cell and this gradient
pulls more Na+ in the cell and more Ca+2 out (to be reabsorbed)
• (↑) Ca+2 reabsorption (and less in the urine)

Osteoporosis
o (↑) Ca+2 reabsorption → more calcium for the osteoblast to deposit into the bone tissue,
which may be beneficial for patients with osteoporosis

Aldosterone Blockers: Exert their effects on the later parts of the DCT Conn’s Syndrome (Hyperaldosteronism)
o Spirono-lactone o Aldosterone blockers: block aldosterone o Hyperaldosteronism causes:
Potassium-Sparing Diuretics

o Eplerenone  Hypernatremia; due to (↑) Na+ reabsorption

ENaC Blockers:  (↑) Blood volume (and ↑ BP); due to (↑) Water reabsorption
o Amiloride  Hypokalemia; due to (↑) K+ excretion
o ENaC blockers: block the ENaC channels directly  Metabolic alkalosis
o Triamterene

Hypertension + Chronic Hypokalemia + CHF (Congestive Heart Failure)

Nephrogenic Diabetes Insipidus (DI)

18 of 19 PHARMACOLOGY: NOTE #18. Diuretics

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VIII) REVIEW QUESTIONS IX) REFERENCES

1) Which of the following drugs increase calcium
reabsorption and therefore decrease the risk of
nephrolithiasis and may help to treat osteoporosis?
a) Spironolactone
b) Triamterene
c) Hydrochlorothiazide
d) Mannitol
2) Which of the following is NOT an indication of
thiazide diuretics?
a) Essential Hypertension
b) Diabetes Mellitus
c) Diabetes Insipidus
d) Congestive Heart Failure
3) What is NOT one of the possible complications of
osmotic diuretics?
a) Hyponatremia
b) Hypernatremia
c) Cerebral Edema
d) Pulmonary Edema
4) Which of the following drugs may be used in the
treatment of Conn’s syndrome?
a) Triamterene
b) Chlorothiazide
c) Spironolactone
d) Mannitol
5) In a patient with congestive heart failure and chronic
hypokalemia, which of the following drug classes
may reduce the mortality risk?
a) Aldosterone blockers
b) Loop diuretics
c) Beta blockers
d) Thiazide diuretics
6) Which of the following statements about diuretics is
FALSE?
a. Thiazide diuretics inhibit sodium reabsorption along
the distal convoluted tubule
b. Ethacrynic acid is a carbonic anhydrase inhibitor
c. Carbonic anhydrase inhibitors may be used to
counteract metabolic alkalosis
d. Loop diuretics cause greater water loss than sodium
loss
7) Which is the first-line drug used to relieve
congestion secondary to a cirrhotic liver?
e. Furosemide
f. Ethacrynic acid
g. Acetazolamide
h. Eplerenone
8) Which diuretic may cause ototoxicity?
i. Acetazolamide
j. Hydrochlorothiazide
k. Spironolactone
l. Furosemide
9) Potassium sparing diuretics may cause the following
EXCEPT?
m. Decreased sodium reabsorption
n. Metabolic alkalosis
o. Hyperkalemia
p. Gynecomastia
10) Which drug increases the risk for kidney stone
formation?
a) Acetazolamide
b) Hydrochlorothiazide
c) Spironolactone
d) Furosemide

Diuretics PHARMACOLOGY: NOTE #18. 19 of 19

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