ACTI TH

NAL SYSTE
 Drugs used in renal disorders

Drugs that modify Drugs that modify

salt excretion water excretion

PCT TAL DCT CCT | OsmotiC diuretics

(mannitol)
op K+-sparing ADH
diuretics diuretics agonists
(furosemide) (spironolactone) (desmopressin)
Carbonic
anhydrase

(aceh tamide)) t(hydrThlor th azide)

 Urinary System
Hepatic veins
(cut)
Esophagus (cut)
Inferior vena
cava
Adrenal gland Renal artery Renal
hilum Renal vein
Aorta
Kidney

lliac crest Ure€er

Rectum (cut)
Uterus
Urinary
bladder
Urethra

0 2011 Peaeon Education, Inc.

 Kidney Anatomy
Cortical
blood Arcuate
vessels blood vessels
Interlobar
blood Minor calyx
vessels
Major calyx
Renal vein
Renal pelvis
Rena Renal
l nerve Pyramid
hilum
Renal
artery Papilla
Medulla
Ureter Renal column

Cortex
Capsul
e
Nephron
Disfał corivołuted tubuie
Nephron loog

Renal c¢irpu9cle
CQ D URET
A. Introduction
1. Function. Diureücs increaøø urine production by acting on Łe Õdney (Fig. 3.1). Most agents
aflect water balance indirectly by altering elecœolyte reabsorption or secreûon. Osmoôc agents
affect water balance directly.
ż. fPsrN. Natriuretic diurełiCc produce diuresis, associated with increoced codium țHa•)
excretion, which results in a concomitant l0ss 0ł Wałer and a reduction in extracellular volume.
3. lndicøtionø. Diuretic agents are generally used for the management of edema, hypertension,
congestive heart failure (CHF), and abnormalities in body fluid distribution.
4. ddrsføs affect. Diuretics can cause eleCtr0lpe imbuiøncec, such as hypokalemia, hyponatre-
mia, and hypochloremia, and disturbances in acid-base balance.
 Proximal Ca2+
convoluted NaHCO NaCI Distal convoluted
NaCI (PTH)
tubule tubule

Proximal
straight
tubule
K*
H”
Glomerulus
Ca2• Cortical collect
Mg2 duct
Nya NaCI
+* (+aIdosterone)

2Cl-

Thick H”
ascending
limb
Carbonic anhydrase 2’
Thin
inhibitors
descending +ADH
Medullary
limb
O Osmotic collecting
duct
agents O Loop Thin
diuretics Henle ascending

O Thiazide diuretics
sparing
O Potassium diuretics limb

O Antidiuretic hormone agonisVantagonis

FIGURE 3.1. Sites of action of the nephron and diuretic agents.
B. Carbonic anhydrase inhibitors
1. S$acilic sgeffts include aCetaz0laMide and methaz0laMide.
2. ă#ncheniam eI actian
a. Carbonic anhydrase (CA) is an enzyme predominately found in the proximal con›oluted
tubule ofthe nephron. It catalyzes le dehydration of H2CO, to CO2atle luminal membrane
and the rehydration of CO2to H,CO, in the cpoplasm (Fig. 3.2).
b. CA inhibitors cause reYersible inhibition ol the ca4oniC anhydrase enzyme leading to
reduced sodium and bicarbonate reabsorption and, therefore, inCre&sed excretion oI
sodium, bicarbonate, and water(Fig. 3.2).
3. lndicetittn8. CA inhibitors are rarely used as diureacs.
8. These drugs are most useful in the treatment of glauCom8. They reduce aqueous
humor production and, consequently, reduce ocular pressure.
b. They may be used to produce alkalinization oC urine to enhance renal secretion oI uric aciä
and cyHeine.
C. They maybe used for prophylaxis and œeatment of acute mounRin sickness.
d. CA inhibitors are someêmes used as an adjuvant œeatment for epilepsy, but the develop-
ment of tolerance limits their use.

a. MetaboliC 0Ciäosis may occur due to a reduction in bicarbonate stores. Urine aRalinity
decreases the solubility of calcium (Ca2•)salu and increases the risk for renal calculi forma-
êon (kidney stones). Pota88ium {Ñ•} w8sting maybe severe.
b. Drowsiness and parestheslas are common following large doses.
C. Thèse agents are 8ullonamide derivatiYe8; therefore, precauêon must be used in paêents
with a sulfa allergy.
d. The use of thèse drugs is contraindicated in the presence of hepatic Cirrhosis.
 Apical Basolateral
membrane membrane

Lumen of
proximal tubule

3HCO3—

NHE3

H+ + HCO3—
H”
H2CO3
CAll
2K”

Acetazolamide
Acetazolamide CO2 + H2O

CO2 + H2O

FIGURE 3.2. Proximal tubule cell: site of action for carbonic anhydrase inhibitors. (Reprinted with permission from
Golan D. Principles of Pharmacology. 4th ed. Philadelphia, PA: Wolters Kluwer Health, 2016, Fig. 21.6.)
C. Loop diuretics
1. Spnailia sgsflfs include furosemide, bumetanide, torsemide, and ethacrynic acid.
2. äfech8ni8m ötactiön. Loop diureëcs inhibit active sodium chloride (NaCl) reabsorption in Ñe
thick a8cenäing limb of the l0op oC Henle by inhibiêng the activity of the N8•/E•J2CI‘8yMpoñer
(NKCC2) (Fig. 3.3). Diuresis occurs within 5 minutes of inuavenous (N) adminisoaêon
and within 30 minutes of oral adminisuaêon.
a. Because of the high capacity for NaCl reabsorpûon in Öis segment, agents acüve at
this site markedy increase water and elecuolyte excreêon and are referred to as high-
ceilin¢ diuretics.
b. They also reduce the lumen-posiGve potential (Fig. 3.3); therefore, magnesium (Mg'•) and
calcium (Ca2•)excretion is increased.
c. They block the kidney¥ abili9 to concentrate urine by interfering with an impouant step in
the production of a hypertonic meduPary intersti?um.
d. Loop diuretics cause increased renal prostaQandin production, which accounts for some of
their activi@. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the
efîectiveness ofloop diuretics.
3. indications
a. Loop diuretics are used in the treatment of congestive heañ lailure by reducing acute pulmo-
nag edema and edema refractory to other agents. When administered with thiazide diuretics,
they have a synergistic effect.
b. These agents are used to treat hypeñension, especially in individuals with diminished
renal lunction. They reduce plasma volume and total peripheral resistance.
b. They may be used to treat acute hypercalcemi8 due to hyperparathyroidism or malignancy.
d. These drugs are often effective in producing diuresis in patients responding maximally to
other types of diuretics.
4. Adverse eYects end contleindications
8. Loop diuretics produce hypotension and volume depletion.
b. They can cause hypokalemia due to enhanced secretion of K*. They may also produce 81k8l0-
sis due to enhanced H* secretion. Mg2*wasting can occur with chronic use.
{1) The risk of cardiac glycoside (digoxin) toxicity increases in the presence of hypokalemia.
C. Loop diuretics can cause dose-related 0t0toxicity, more often in individuals with
renal impairment.
{1} These effects are the most pronounced with ethacrynic acid.
}2} These agents should be administered cautiously in the presence of renal disease or wi%
the use of other ototoxic agents, such as aminoglycosides.
d. All loop diuretics, except ethacqnic acid, are sullonamides; therefore, precaution must
be used in patients with a sulfa allergy.
 Apical Basolateral
membrane membrane

Lumen of
medullary thick
ascending limb

Na*

2CI" NKCC2
2K“

K’

K” CI"

ROMK CLC-K2

FIGURE 3.3. Thick ascending limb of loop of

Henle: site of action for loop diuretics. (Reprinted
with permission from Golan D. Principles of Na” 10
Pharmacology. 4th ed. Philadelphia, PA: mV
Wolters Kluwer Health, 2016, Fig. 21.7.) +
D. Thiazide and thiazide-like diuretics
1. S$scilic age»M
a. True liazides include chlorothiazide and hydr0chlorothiazida. Chloroliazide is Ie only
liazide avafiable for parenteral use.
b. Thiazide-like drugs lcludemetolazone, chlofihalidone, and indapamida.
(I) They have properties similar to thiazide diuretics but may be elective in the
presence of renal impairment.
2. Uecheniam ct actien. Thiazide diuretics inhibit acCve reabsorption of NaCl in the
dicBl coñYoluted Rbule by blocking the Na•-GI- cotranspoñer(NCC)(Fig. 3.4). This results in
the net excretion of sodium and an accompanying volume of water. Diuresis occurs within 1 to
2 hours.
a. They deCreaae the diluting capaci9 oI the nephron.
b. These agents increase excredon of Na•, Cl , K•, and, at high doses, bicarbonate (HCO, ). They
also fo tlC0 0ECfi0li0n 01 g°’*.
3. Indications
8. Thiazide diuretics are the preferred class of diuretic for the treatment of essential hypeñen-
sion when renal function is normal.
{I J They are often used in combination with other antihypertensive agents to enhance their
blood pressure-lowering eflects.
{2) They reduce plasma volume and total peripheral resistance.
b. These agents reduce the formation of new calcium stones in idiopathic hypercalciuria.
Thiazide diuretics may be useful in patients with oephrogeniG diabetes insipidus that is not
responsive to antidiuretic hormone (ADH).
C. They are often used in combination with a potassium-sparing diuretic to manage edema
associated with renal dysfunction, hepatic cirrhosis, heart failure, and hormonal imbalances.
ñ. Adverse eEecN and contraindications
8. Thiazide diuretics produce electrolyte imbalances such as hypokalemia, hyponatremia, and
hypercalcemia. Potassium supplementation may be required.
b. The risk of cardiac glycoside (digoxin) toxicity increases in the presence of hypokalemia.
C. These agents often elevate serum urate, presumably as a result of competition for the organic
anion carriers (which also eliminate uric acid). Gout-like symptoms may appear.
d. Thiazide diuretics can cause hyperglycemia (especially in patients wit diabetes), hypertri-
glyceridemia, and hypercholesterolemia.
e. These agents are sullonamide derivatives; therefore, precaution must be used in patients
with a sulfa allergy.
 Apical
Basolateral
membrane
membrane

Lumen of distal
convoluted tubule

Thiazides
NCX1
Na"
3Na”
NCC
3Na”
’Na‘/K* ATPase

2K*
ca2+

TRPVS Kir 4.1/5.1

CF
2
gci-
Mg ’
2
Mg +
TRPM6/
TRPM7
FIGURE 3.4. Distal convoluted tubule: site of
action for thiazide and thiazide-like diuret-
ics. (Reprinted with permission from Golan
D. Principles of Pharmacology. 4th ed.
Philadelphia, PA: Wolters Kluwer Health, 2016,
Fig. 21.8.)
E. Potassium-sparing diuretics
!. Specilin speiif5 include spironolactone, eplerenone, amiloride, and triamterene.
2. Mechanism of attion
a. Potassium-sparing diuretics reduce Na reabsorption and X' secretion by antagonizing the
effects of aldosterone in the collecting tubule.
b. Spironolactone and eplerenone inhibit the action ol aldosterone by competitively
binding to the mineralocoñicoid receptor and preventing subsequent cellular events that
regulate K’ and H’ secretion and Na’ reabsorption. An important action is a reduction

0.
in the synthesis of epithelial Na‘ channel (ENaC) in the principal cells of the
collecCng duct (Fig. 3.5).
|1) These agents are active only when endogenous mineralocorticoid is present; the effects
are enhanced when hormone levels are elevated.
|2} Eplerenone is hi9hly selective for the mineralocorticoid receptor.
{3} Spironolactone binds to other nuclear receptors such as the flndr0gen receptor or
pro9esterone receptor. This may lead to additional side effects.
{4} Therapeutic effects are achieved only after several days.
c. Amiloride and triamterene bind to and block the EHaC and thereby decrease absorption of
Na+ and excretion of K+ in the cortical collecting tubule, independent of the presence of
min- eralocorticoids (Fig. 3.5).
{1} These drugs produce diuretic effects 2-4 hours after oral administration.
 Apical
membrane Basolateral
membrane

lntercalated cell
Type B, Non-A Non-B + vH•
H — ATR
Cr*
Na’
Na*—‹’SLC4A0
SLC4A9
HCO/"
(HCO3

HCO3"

,’ Pendrin
CI"

CF

A milor ide, Principal cell

Triamterene
†ENaC expression 3Na*
T Na*/K* ATPase expression' Na*/K*
ATPaea
Na*
ENaC

FIGURE 3.5. Cortical collecting duct: site of

action for potassium -sparing diuretics. (Re
printed with permission from G olan D.
Principles of Pharmacology. 4th ed.
Philadelphia, PA: Wolters Kluwer Health,
2016, Fig 21.9.)
3. Indications
a. Spironolactone and eplerenone are not potent diuretics when used alone.
{1} They are primarily used in Combination with thiazide or loop diuretics to treat hyperten-
sion, CHF, and reIraCtoq edem8.
{2J They are also used to induce diuresis in clinical situations associated with hyperaldoste-
ronism, such as in 8drenal hyperplasia.
b. Amiloride and triamterene are used to manage GHF, Cirrhosis, and edem8 caused by second-
ary hyperaldosteronism. They are available in combination products containing thiazide or
loop diuretics to treat hypeñension.
C. Oflen times, %ey are used as an adjunct to other diuretic agents to prevent X• loss.
ñ. Adverse eYects and contraindicetions
a. All potassium-sparing diuretics can cause hyperkalemia.
{1} Precaution must be taken since this can lead to cardiac arrhythmias.
{2) The risk is increased in patients with chronic renal insufficiency and in those who
take medications that inhibit renin (NSAIDs) or angiotensin II (angiotensin-
converting enzyme inhibitors).
b. Hyperchloremic metabolic acid0Sis may occur due to inhibition of H* and K' secretion.
c. Spironolactone is associated with gynecomastia in men and can also cause menstrual abnor-
malities in women.
F. Osmotic diuretics
1. S$ecitic agent. Mannitol.
2. Vssùsaism ot dütien. Mannitol is eacily liltered at the glomerulus but po0rly reabcorbeä. It
increases the osmotic pressure of the Qomerular Htrate, which inhibits roabcorption oI wator
and oloctrol9es and increases urine output.
3. lnëicatiens
a. Mannitol is commonly used to reduce inaacranial pressure due to aauma and to reduce
intraoCular pressure püor to a surgical procedure.
b. It is used in pr0phylaxi8 oI acute renal 4ailure resulêng from physical trauma or
surgery. Even when filœaêon is reduced, suTicient mannitol usuaûy enters the tubule to
promote urine output.
ñ. Advoæn oEocN enë contiainëicatiens
a. The osmotic forces that reduce intraceûular volume ulëmately expand eHracellular
volumo, therefore, proeauCiofi must be taken in paêentswith üHF or pulmoaaq
coagesCioa.
b. The volume expansion may cause adverse eäects such as headache and nausea.
II. ANTIDIURETIC DRUGS
A. Agents that influence the action of antidiuretic hormone (ADH) (vasopressin)
1. Agents that influence the action of ADH will influence the permeability of the luminal surface of
the medullary collecting duct to water by causing water-specific water channels (aquaporin II)
to be inserted into the plasma membrane (Fig. 3.6).
a. Under conditions of dehydration, ADH levels increase to conserve body water.
b. Agents that elevate or mimic ADH have an antidiuretic eHect.
c. Agents that lower or antagonize ADH have a diuretic e£ect.
d. Vasopressin binds to three receptors: V„ in the vasculature, V„ in the brain, and V, in
renal collecting ducts.
Vasopressin and vasopressin analogs
a. Specific agenfs include vasopressin and desmopressin (DDAVP).
b. indications
{1) These agents are useful in the management of central diabetes insipidus.
{2J Desmopressin is also used to treat nocturnal enuresis.
{3) Studies have suggested that vasopressin and its analogs are useful to
maintain pressure in patients with septic shoCk and to increase Clofiing

Ü
O
w

m
laCtor VIII in patients with type I Willebrand disease.
c. Adverse eEects and nonttaindic8tions. These drugs can produce serious cardiac-
related adverse e0ects, and they should be used with caution in individuals with coronary
artery disease. Hyponatremia occurs in about 5% of patients.
 Lumen= Collecting tubule
urine Interstitium-
blood

AQP2

HCO

HCO

cAMP ADH

HCO

AQP2 AQP3,4
FIGURE 3.6. Medullary collecting duct: site of HCO HCO
action for ADH agonists and antagonists.
3. ADH antagonists
a. Spenilia spsnG include conivaptan (a mixed Vlaand Ve antagonist) and tol¥aptan (a V2
selective antagonist).
b. indications. Conivaptan is approved for the treatment of hypeN0lemic hyponatremia
and syndrome ol inappropriate ADH {SIADH}. Tol›aptao is approved for heating
hyponatremia associated with CHF, cirrhosis, and SIADH. These agents may be more
effective in treating hypervolemia in heart failure than diuretics.
c. Adverse eYezts may include nausea and xerostomia. Rapid correction of
hyponatremia (>l2 mEq/L/24 h) may cause Osmotic demyefination.
{1) Symptoms of osmotic demyelination may include lethargy, confusion, behavioral
disturbances, movement disorders, paresis, or seizures.
d. Nonreceptor anta9onisR of ADH action include demeclocycline and lithium carbonate.
They may be useful in the treatment of SIADH.
{1} Adverse effects of demeclocycline
{a) It may cause photosensitivity.
{b) Dose-dependent nephrogenic diabetes insipidus is common wi% use (reversible
on discontinuation).
{c) It may lead to tooth discoloration or tissue hyperpigmentation in children.
 No Yes

Potassium
sparing HCOt-
diuretic loss
No Yes

Carbonic
anhydrase
inhibitor
No Yes

Thiazide
diuretic Loop FIGURE 3.7. Identification of drug class
diuretic based on plasma electrolyte changes.
 High-Yield Terms to Learn
Bicarbonate diuretic A diuretic that selectively increases sodium bicarbonate excretion. Example: a carbonic anhydrase
inhibitor
Diluting segment A segment of the nephron that removes solute without water, the thick ascending limb and the dis-
tal convoluted tubule are active salt-reabsorbing segments that are not permeable by water
Hyperchloremic metabolic A shift in body electrolyte and pH balance involving elevated serum chloride, diminished
acidosis bicarbonate concentration, and a decrease in pH in the blood. Typical result of bicarbonate diuresis
Hypokalemia metabolic A shift in body electrolyte balance and pH involving a decrease in serum potassium and an increase
alkalosis in blood pH. Typical result of loop and thiazide diuretic actions
Nephrogenic diabetes Loss of urine-concentrating ability in the kidney caused by lack of responsiveness to antidiuretic
insipidus hormone (ADH is normal or high)
Pituitary diabetes Loss of urine-concentrating ability in the kidney caused by lack of antidiuretic hormone (ADH is low
insipidus or absent)
Potassium-sparing A diuretic that reduces the exchange of potassium for sodium in the collecting tubule; a drug that
diuretic increases sodium and reduces potassium excretion. Example: aldosterone antagonists
Uricosuric diuretic A diuretic that increases uric acid excretion, usually by inhibiting uric acid reabsorption in the
proximal tubule. Example: ethacrynic acid
 DRUG SUMMARY TABLE
See Figure 3.?
Hydrochlorothiazide Osmotic Diuætias
Carbonic Anhydrase Inhibitors (Microzidel Mannitol I0smitrol)
Acetazolamide (Diamoxl Methyclothiazide Urea CUre-Na)
Dichlorphenamîde (Keveyisl (Enduronl
Methazolamide (Neptazane) Antidiuretic Hormone Ay¥nisk
Thiazide-Like Diuretics DezmoprezWn(DDAVPl
Loop Diuretics Chlorthalidone IThalitone) Vasopressin (Pitressin Synthetic,
Bumetanide (Bumex) Indapamide (Lozidel Vêsostrictl
Ethacrynic acid (Edecrin) Metolazone (Zaroxolyn)
Furosemide (Lasix) Vasoyressin Antagonists
Torsemide (Demadex) Potassium-Sparing Diuretics ¢onivaptan (Vaprisol)
Amiloride (Midamor) Demeclocycline (Declomycin)
Thiazides Diuratics Eplerenone (Inspral Lithium carbonate țLithobïdl
Chlorothiazide (Diuril) Spironolactone (Aldactone, Caro3pirl Tolvaptan (Samsca)
Triamterene (Dyrenium)
DRUG SUMMARY TABLE: Diuretic Agents
Carbonic
Su bclassanhydrase inhibitors
Mechanism of Action Clin ica I Applications Pharmacokinetics Toxicities, Interaction s
Acetazolamide Inhibits carbonic anhydrase. In Glaucoma, mountain Oral, parenteral Metabolic acidosis; sedation,
proximal tubule, bicarbonate sickness • edema with Diuresis is self-limiting paresthesias.
reabsorption is blocked and alkalosis but effects in Hyperammonemia in
glaucoma cirrhosis
Na* is excreted with HCO3".In and mountain sickness
glaucoma, secretion of aqueous persist
humor is reduced, and in moun-
tain sickness, metabolic acidosis
increases respiration
Dorzolamide, brinzolamide: topical carbonic anhydrase inhibitors for glaucoma only

Loop diuretics
Metabolic hypokalemia
Furosemide, Inhibit Na*/W/2CF transporter in Heart failure, pulmonary Oral, parenteral alkalosis •
also thick ascending limb of loop of edema, severe hyper- ototoxicity
bumetanide, Henle. Cause powerful diuresis tension; other forms • hypovolemia • efficacy
of torsemide and increased Ca * excretion edema; hypercalcemia reduced by nonsteroidal
anti-inflammatory drugs.
Sulfonamide allergy (rare).
Ethacrynic acid: like furosemide but not a suPonamide and has some uricosuric effect

Thiazide diuretics
Hydrochloro- Inhibit Na*/CI" transporter in Hypertension, mild heart Oral Metabolic hypokalemia alka-
thiazide, distal convoluted tubule. Cause failure, hypercalciuria with losis • early hyponatremia
chlorthalidone moderate diuresis and reduced stones • nephrogenic dia- • increased serum glucose,
tthiazide-like); excretion of calcium betes insipidus lipids, uric acid •
many other efficacy reduced by
thiazides nonsteroidal anti-
inflammatory drugs.
Sulfonamide allergy (rare)
K'-sparing diuretics
Spironolactone, Steroid inhibitors of cytoplasmic Excessive K* loss when Oral
eplerenone aldosterone receptor in corti- using other diuretics Hyperkalemia • gynecomas-
cal collecting ducts • reduce V • heart failure tia (spironolactone only)
excretion • aldosteronism
Amiloride Inhibitor of ENaC epithelial Excessive K* loss when Oral
sodium channels in cortical col- using other diuretics Hyperkalemia
lecting duct, reduces Na’ reab- • usually in combination
sorption and K* excretion with thiazides
Triamterene: like amiloride but much less potent
SGLT2 inhibitors
Canagliflozin, Inhibitors of sodium-glucose Diabetes Oral Urinary tract infections
dapagliflozin cotransporter in the proximal
tubule, markedly increase glucose
excretion

Osmotic diuretics
Mannitol Osmotically retains water in Solute overload in rhab- Intravenous; short Hyponatremia followed by
tubule by reducing reabsorption domyolysis, hemolysis, duration hypematremia • headache,
in proximal tubule, descending tumor lysis syndrome nausea, vomiting
limb of Henle's loop, and collect- • brain edema with coma
ing ducts • in the periphery, man- • acute glaucoma
nitol extracts water from cells
ADH agonise

Desmopressin, Subcutaneous, nasal Hyponatremia

vasopressin Agonists at V and V2ADH recep- Pituitary diabetes
tors, activate insertion ofaquapo- insipidus • hypertension
rin water channels in collecting
tubule, reduce water excretion
• vasoconstriction
ADH antagonists
Conivaptan Antagonist at V V2receptors SIADH, hyponatremia Parenteral Infusion site reactions

ToIv•R•on:like conivaptan, more selective forV2•eceptors

Demeclocycline: used in SIADH, mechanism unclear
End