Diuretics

Fiona Parkinson, PhD

fparkinson@rossu.edu
Ross University School of Medicine

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 Practice questions available on Canvas
 e-mail me with questions or for an appointment

 Recommended reading
 Diuretic agents, Chapter 15. Basic & Clinical Pharmacology, 14th Edition,
by Katzung
 https://accessmedicine.mhmedical.com/content.aspx?bookid=2249&sectionid=17521
7531
 Drugs affecting renal excretory function, Chapter 25. Goodman &
Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition, by
Brunton, Hilal-Dandan and Knollmann
 https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=17027
0388

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Drug list
Drug Class
Carbonic anhydrase inhibitors Acetazolamide
Dorzolamide
Osmotic diuretics Mannitol
Loop diuretics Furosemide
Ethacrynic acid
Thiazides and congeners Hydrochlorothiazide
Indapamide
Potassium sparing diuretics Triamterene
Amiloride
Spironolactone
Vasopressin antagonists Conivaptan
Tolvaptan
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Learning Objectives
 List the diuretic drug classes: carbonic anhydrase inhibitors, osmotic diuretics, loop diuretics,
thiazides and congeners, potassium sparing diuretics, vasopressin (antidiuretic hormone
(ADH)) antagonists
 List the following drugs and assign them to the appropriate diuretic class: acetazolamide,
dorzolamide, mannitol, furosemide, ethacrynic acid, hydrochlorothiazide, indapamide,
triamterene, amiloride, spironolactone, conivaptan, tolvaptan
 Explain the molecular mechanism of action of each class of diuretics
 Describe the renal actions of diuretics, including urine composition
 Describe the main extra renal actions of diuretics
 Rank the different classes of diuretics according to their efficacies
 Describe the routes of administration and the elimination processes of diuretics
 Describe the main adverse effects, clinically important drug interactions and main
contraindications of diuretics
 Describe the therapeutic use of diuretics both in edematous and non-edematous states
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Definition of diuretics
 Diuretics are drugs that increase urine volume
 In many cases, the drugs increase Na+ excretion (i.e.
natriuretics), which indirectly increases urine volume
 Water follows Na+

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Classification of diuretics
 Diuretics as group of drugs can be classified in a variety of ways
 Different textbooks have different ways of classifying the drugs
 Chemical structure, e.g. thiazides
 Site of action, e.g. loop diuretics
 Mechanism of action, e.g. osmotic diuretics
 Efficacy, e.g. high ceiling diuretics
 It is more difficult to classify them according to therapeutic use because they
are used in multiple clinical conditions and have overlapping clinical uses.

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Site of action
Molecular target Location within the renal tubule
Carbonic anhydrase (CA) Proximal convoluted tubule
Na+-K+-2Cl- symporter (NKCC2) Thick ascending limb of Henle’s loop
(TAL)
Na+-Cl- symporter (NCC) Early distal convoluted tubule
Epithelial sodium channels (ENaC) Late distal convoluted tubule and
Aldosterone (mineralocorticoid) cortical collecting tubule (CCT)
receptor
Vasopressin (ADH) receptor Medullary collecting duct
*Note that osmotic diuretics (e.g. mannitol) do not have a molecular target, but primarily bring
about effects in the proximal convoluted tubule and the loop of Henle

ADH – antidiuretic hormone 7

Where do Carbonic
anhydrase
inhibitors Thiazides
diuretics act?
K+ sparing

Loop
diur-
Osmotic etics ADH
diuretics antagonists

8
Where do
diuretics act?

Figure 15.1, from Katzung 9

Relative efficacy
Diuretic class Site of action Mechanism of action Relative
efficacy
Carbonic anhydrase Proximal tubule Inhibit NaHCO3 reabsorption 2
inhibitors
Osmotic diuretics Proximal tubule and TDL Increase osmolarity of tubular 6
of Henle loop fluid
Loop diuretics TAL of Henle loop Inhibit Na+-K+-2Cl- symporters 15
Thiazides and congeners EDT Inhibit Na+-Cl- symporters 5
Potassium sparing LDT and CCT Inhibit epithelial Na+ channels 1
diuretics Inhibit aldosterone receptors 1
Vasopressin antagonists Medullary collecting duct Antagonize V2 receptors N/A
TAL – thick ascending limb; TDL – thin descending limb; EDT – early distal tubule; LDT – late distal tubule;
CCT – cortical collecting tubule

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Carbonic anhydrase
(CA) inhibitors
 Acetazolamide, dorzolamide
 Site of action
 Carbonic anhydrase
 Key role in acid secretion and
NaHCO3 resorption
 Proximal tubule epithelial cells
 Cytoplasmic (type II CA) and
 Luminal membrane-bound (type IV
CA)
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CA inhibitors: Mechanism of action
1. The basolateral Na+,K+-ATPase actively transports Na+ out of the cell into the interstitial
space.
2. This sets up a Na+ gradient as well as causing K+ to move into the cell.
3. The Na+ gradient drives the exchange of Na+ (inwards) and H+ (outwards) at the luminal
membrane. This exchange is mediated by Na+/H+ exchanger (NHE).
4. Luminal H+ reacts with filtered HCO3- to form H2CO3.
5. Membrane bound (apical membrane) CA catalyzes the H2CO3 to form CO2 and H2O.
6. CO2 rapidly diffuses across the cell membrane into the cell while water enters through
aquaporin channels.
7. Cytoplasmic CA catalyzes the combination of CO2 and H2O to form H2CO3 (remember that
enzyme reactions are bi-directional, with substrate/product concentrations normally determining
the direction of the reaction).
8. H2CO3 dissociates to form H+ and HCO3- in the cytoplasm, and the cycle begins again.
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CA inhibitors
 Carbonic anhydrase inhibitors, such as acetazolamide and
dorzolamide, reversibly inhibit both the membrane bound (type IV)
and cytoplasmic (type II) CA.
 This results in near total block of HCO3- reabsorption in the
proximal tubule, although CA-independent mechanisms are
present elsewhere in the nephron.

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CA inhibitors: renal effects
 Increased renal excretion of Na+, K+ and HCO3-
 Decreased renal excretion of NH4+ and H+
 Increase in urine pH (more alkaline for 2-3 days)
 Acid-base balance: metabolic acidosis
 Also hyperchloremia because the high blood H+ concentration drives Cl- movement from
the lumen to the blood, in order to maintain electroneutrality
 Diuretic efficacy: low
 Maximum increase in Na+ excretion is ~ 5% of the filtered Na+ load
 Moreover, as metabolic acidosis develops, the filtered load of HCO3- decreases, and
therefore the diuretic effect undergoes a complete tolerance in 2-3 days

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CA inhibitors: effects on other
organs/systems
 Inhibition of CA on the ciliary body epithelium decreases the
production of the aqueous humor, which is rich in HCO3-
 Inhibition of CA in the choroid plexus decreases the production of
cerebrospinal fluid

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CA inhibitors: pharmacokinetics
 Acetazolamide
 Administration:
PO, IV
 (IM not recommended because of pain secondary to the
alkaline pH)
 Dorzolamide
 Administration: topical (eye drops)
 No free drug or metabolites detected in plasma
 Therefore no systemic effects
 Not used as a diuretic
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CA inhibitors: adverse effects
 Sulfa-type allergic reactions (from protein-drug complex)
 Nephrolithiasis
 due to precipitation of calcium phosphate salts in alkaline urine
 Hyperchloremic metabolic acidosis (see “renal effects” slide)
 Hypokalemia
 Increased Na+ delivery to the CCT leads to increased secretion there of K+.
 Also, the increased delivery of HCO3- to the CCT increases the lumen negative potential
which favors K+ excretion.
 Ocular administration of dorzolamide can produce a bitter taste and also
localized reactions (burning, stinging or discomfort)

CCT-cortical collecting tubule 17

CA inhibitors: contraindications and
precautions
 Hepatic cirrhosis
 alkalinization of urine decreases urinary trapping of NH4+
 Chronic obstructive pulmonary disease
 the risk of metabolic acidosis is increased
 Hypersensitivity to sulfa drugs
 Hypokalemic states

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CA inhibitors: therapeutic uses
 Main uses
 Reduce intra-ocular pressure in open angle glaucoma
 Decrease CSF production
 Acute mountain sickness (mechanism uncertain, probably related to the
decreased pH of blood which in turn stimulates ventilation)
 Alkalosis, e.g. due to excessive use of thiazides or loop diuretics

 Rarely used for diuresis

 Edema from heart failure (together with distally acting diuretics)

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Osmotic diuretics
 Mannitol
 Sugar alcohol

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Osmotic: mechanism of action
 Pharmacologically inert
 Osmotic diuretics are freely filtered by the glomerulus.
 Reabsorption by the renal tubule is negligible
 Therefore, by an osmotic effect, they limit water reabsorption in
the segments of nephron that are freely permeable to water,
namely:
a) the thin descending limb (TDL) of loop of Henle (the main site of action)
b) the proximal tubule (main site of water reabsorption)
 It used to be thought that proximal tubule was the main site of action of osmotic diuretics
because it is the main site of water reabsorption. However, experimental evidence now
indicates that osmotic diuretics have relatively greater effect on the TDL than the proximal
tubule.
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Osmotic: renal effects
 Increased renal excretion of: Na+, K+, Ca2+, Mg2+, Cl-,
HCO3–, and PO43-
 Water diuresis increases more than salt diuresis
 Acid-base balance: not affected
 Efficacy of diuretic effect: usually good

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Osmotic: effects on other organs/systems
 By extracting water from intracellular compartments,
osmotic diuretics can cause an initial increase in
extracellular volume
 Later the diuretic effect can cause a decrease in
extracellular volume
 By extracting water from tissues into blood, osmotic
diuretics can reduce both intracranial and intraocular
pressure
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Osmotic: pharmacokinetics
 Administration: IV, as a bolus or over a defined period (up
to ~ 60 min)
 Remains in extracellular space and does not cross blood-
brain barrier
 T1/2: 0.25-1.7 h (can increase to 36 h in patients with renal
impairment)
 Biotransformation: negligible
 Excretion: in urine, as unchanged drug
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Osmotic: adverse effects
 Biphasic effect on extracellular volume
 Initial (transient) increase in extracellular volume, which
can cause hypervolemia, hyponatremia, pulmonary
edema (in patients with cardiac or renal disease)
 Decreased extracellular volume (with high doses, when
kidney function is normal), which can lead to
hypovolemia, dehydration and hypernatremia

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Osmotic: contraindications and precautions
 Severe renal failure
 Low glomerular filtration rate (GFR) cannot dissipate the initial
extracellular volume expansion
 Low GFR means that mannitol cannot be excreted, thus increasing
extracellular volume expansion
 Heart failure or pulmonary congestion
 Extracellular
volume expansion can cause circulatory overload and
exacerbate pulmonary edema
 Severe dehydration
 Osmotic diuretics increase dehydration because they extract water from
cells 26
Osmotic: therapeutic uses
 Cerebral edema (reduction of intracranial pressure)
 Acute angle-closure glaucoma (reduction of intraocular
pressure)
 To reduce intraocular pressure before and after iridotomy
 (Prevention and/or treatment of oliguria or anuria in acute renal
failure (promotion of diuresis), but no longer routinely
recommended)

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Loop diuretics
 Also called “high ceiling” diuretics
because they are the most
efficacious
 Furosemide
 A sulfonamide
 Ethacrinic acid
 Not a sulfonamide
 Site of action
 Na+-K+-2Cl- symporter (NKCC2)
 Thick ascending limb of Henle’s loop
(TAL)
 Luminal (apical) membrane

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Loop diuretics: mechanism of action
 Na+-K+-2Cl- symporter cotransports Na+, K+ and Cl- across a cell
membrane
 Ratio of 1:1:2 (therefore electroneutral)
 Driving force for this is the Na+ electrochemical gradient
 Generated by the basolateral Na+,K+-ATPase
 Actively transports Na+ out of the cell into the interstitial space
 Thisgradient allows K+ and Cl- to be cotransported against their
concentration gradients

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Loop diuretics
Loop diuretics inhibit the Na+-K+-2Cl- symporter leading to:
1. Decreased lumen-positive potential
 Causes a reduction in divalent cation (Ca2+ and Mg2+) reabsorption via paracellular
pathways
2. Decreased hypertonicity of the medulla
 Therefore a decreased ability of the kidney to concentrate the urine
3. Inhibition of macula densa sensitivity
 This occurs through inhibition of Na+ and Cl- transport by the Na+-K+-2Cl- symporter into
the macula densa, which can then no longer sense salt concentration in the tubular fluid
4. As a consequence of (3), there are two responses that can potentially
increase GFR:
 a) Inhibition of tubuloglomerular feedback
 b) Stimulation of renin release from the adjacent juxtaglomerular cells

Those loop diuretics that are sulfonamide compounds (e.g. furosemide) also
cause a slight inhibition of carbonic anhydrase 30
Loop diuretics
1. Decrease lumen-positive potential
 Lumen is normally more positive than
interstitial space
 Provides the driving force for the paracellular
flux of Ca2+ and Mg2+ into the interstitial space
 Loop diuretics
 Block Cl- transport from lumen
 Decrease lumen-positive potential
 Less drive for paracellular transport of Ca2+ and
Mg2+
 Increased excretion of Ca2+ and Mg2+
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Loop diuretics
2. Decrease hypertonicity of the medulla
 The kidney can concentrate urine:
 The Loop of Henle generates a gradient of osmotic pressure in the kidney
 This gradient allows for reabsorption of water in the collecting duct
 i.e. concentration of the urine (see Dr. Harrison’s lecture “Tubular Functions 1 & 2”)
 Loop diuretics:
 Block active Na+ and Cl- reabsorption in the thick ascending limb
 This suppresses the production of a hypertonic medullary interstitium
 Thus, loop diuretics block the kidney’s ability to concentrate urine

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Loop diuretics
3. Inhibit of macula densa sensitivity
 Macula densa relies on NKCC2 to detect NaCl
concentration
 Inhibition of NKCC2 at macula densa can lead to:
 Inhibition of tubuloglomerular feedback
 High tubular NaCl normally causes vasoconstriction of afferent
arteriole, leading to reduced GFR
 Loop diuretics block this and thus increase GFR

 Stimulation of renin release from adjacent juxtaglomerular cells

 Increased GFR 33
Loop diuretics
Tubuloglomerular Feedback
 Loop diuretics mimic the effect
of low GFR
 Prevent NaCl detection by
macula densa (mimic low GFR)
 Dilate afferent arteriole, activate
RAAS
 Cause GFR to increase
 [Review: adenosine mediates afferent
arteriolar constriction]

Dr. Harrison’s lecture “Renal Blood Flow and GFR”

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Loop diuretics: renal effects
 Increased renal excretion of: Na+, Cl-, K+, H+, Ca2+ (sulfonamides also
increase the excretion of HCO3-)
 Urine pH: acid
 Acid-base balance: metabolic alkalosis
 The diluting and concentrating capacities of the kidney are decreased
 Efficacy of diuretic effect: high
 the maximum increase in Na+ excretion is 20-25% of the filtered Na+ load
 the diuretic effect remains even when the GFR is less than 30 mL/min

 Duration of diuretic effect: 2-6 hours

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Loop diuretics: effects on other organs/systems

 Vasodilation, mainly in the venous bed

 Furosemide will have a rapid effect to reduce preload; diuresis
occurs later
 Redistribution of blood flow within the renal cortex
 Both of these effects are due in part to induction of
prostaglandin synthesis

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Loop diuretics: pharmacokinetics
 Administration: PO, IV (furosemide and ethacrynic acid),
IM (furosemide only)
 t1/2: short (furosemide, 0.5-2.5 h; ethacrynic acid, 2-4 h)

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Loop diuretics: adverse effects
 A number of metabolic effects as well as systemic effects
 The adverse effects NOT related to diuretic efficacy are rare
 Prolonged/inappropriate use of loop diuretics can lead to significant Na+
depletion
 Metabolic effects
 Hypokalemic metabolic alkalosis (same mechanism as thiazides)
 In part by increased Na+ delivery to the CCT, leading to increased
secretion there of K+ and H+
 In part by increased urine flow along the CCT (it sweeps K+
downstream so maintaining K+ gradient)
 Can be reversed by K+ replacement and correcting hypovolemia

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Loop diuretics: adverse effects
 Metabolic effects (con’t)
 Hyperuricemia
 Hypovolemia-induced increase of uric acid reabsorption in the proximal tubule
 Prevention is by lowering doses of loop diuretic to reduce hypovolemia

 Hypomagnesemia, hypocalcemia
 Results from the decrease in lumen positive potential in the thick ascending limb of
Henle
 Can be reversed by supplements

 Hypovolemia
 A direct consequence of diuretic action
 Prevention is by lowering dose Urea Uric acid

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Loop diuretics: other effects
 Cardiovascular
 Postural hypotension (if hypovolemia develops)
 Ototoxicity
 Tinnitus, hearing loss (dose-related, reversible and likely due to alteration in the
electrolyte composition of the endolymph)
 Most common with rapid infusion and in patients with poor renal function or taking other
ototoxic agents (e.g. aminoglycoside antibiotics)
 More common with ethacrynic acid

 Allergic reactions
 Sulfonamide loop diuretics (e.g. furosemide) may cause skin rash
 Rare, potentially lethal
 Exfoliative dermatitis, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia
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Loop diuretics: contraindications and precautions

 Serious hypovolemic or hyponatremic states

 Loop diuretics can cause hypovolemia and hyponatremia and
will therefore worsen such conditions
 Hypersensitivity to sulfa drugs
 Furosemide and other sulfonamide loop diuretics
 Not ethacrynic acid

 Drug-drug interactions with other ototoxic drugs

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Loop diuretics: therapeutic uses
 Acute pulmonary edema
 Heart failure
 Edema
 Associated with chronic renal failure or nephrotic syndrome
 Ascites
 Associated with hepatic cirrhosis or right-sided heart failure
 Hypertension
 When associated with renal insufficiency or heart failure
 Hypercalcemia
 (Addition of a thiazide can cause a dramatic synergistic effect when a patient
becomes refractory to a loop diuretic alone)
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Thiazides and congeners
 hydrochlorothiazide
 thiazide

 indapamide
 not a thiazide (but has same mechanism as thiazide, therefore a congener
or a thiazide-like diuretic)
 Classified as thiazides because of site of action/mechanism of
action

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Thiazides and congeners
 Site of action
 Na+-Cl- symporter (NCC)
 Early distal convoluted tubule (DCT)
 NCC is responsible for NaCl reabsorption from the lumen into
early DCT epithelial cells
 Driving force is from Na+ electrochemical gradient
 Basolateral Na+,K+-ATPase actively transports Na+ out of the cell into
the interstitial space

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Thiazides and congeners
 Mechanism of action
 Thiazide and thiazide-like diuretics
inhibit the Na+-Cl- symporter
 Results in reduced reabsorption of
NaCl
 Some thiazides (including
hydrochlorothiazide and
indapamide) are also weak
inhibitors of carbonic anhydrase

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Thiazides and congeners: renal effects
 Increased renal excretion of: Na+, K+, H+, Cl-, HCO3-
 Decreased renal excretion of: Ca2+, NH4+, uric acid
 Effect on Ca2+ is due to increased reabsorption via the Na+-Ca2+ exchanger on the
basolateral membrane
 Urine pH: slightly alkaline (in part due to weak inhibition of carbonic
anhydrase), if any change at all
 Acid-base balance: metabolic alkalosis
 Kidney diluting capacity: decreased
 Efficacy of diuretic effect: moderate
 The maximum increase in Na+ excretion is 5-10% of the filtered Na+ load
 Moreover the diuretic effect disappears if the glomerular filtration rate is less than 30
mL/min)
 Duration of diuretic effect: variable (6-48 hours) 46
Thiazides and congeners: effects on other
organs/systems

 Arteriolar vasodilation (after chronic administration)

 Thiazideshyperpolarize vascular smooth muscle;
 Lower doses than are required for diuresis

 Open K-ATP channels (e.g. pancreatic beta cells)

 Hyperpolarization; decrease insulin release

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Thiazides and congeners:
pharmacokinetics
 Administration: PO
 Excretion: hydrochlorothiazide - 100% urine as free drug;
indapamide - virtually completely metabolized
 Allare secreted by the organic acid secretory system in the
proximal tubule and compete with the secretion of uric acid
(potential for hyperuricemia)

48
Thiazides and congeners: metabolic adverse effects
 Hypokalemic metabolic alkalosis (same mechanism as loop diuretics)
 In part by increased Na+ delivery to the CCT, leading to increased secretion there of K+
and H+
 In part by increased urine flow along the CCT (it sweeps K+ downstream so maintaining
K+ gradient)
 Can be reversed by K+ replacement and correcting hypovolemia
 Hyperglycemia
 Impairment in insulin release and in cellular glucose utilization
 Can unmask latent diabetes mellitus

 Hyperlipidemia
 Unknown mechanism, but often resolves on long-term administration
 Hypovolemia
 Due to diuretic effect, therefore dose dependent

49
Thiazides and congeners: metabolic adverse effects (con’t)

 Hyperuricemia
 Increased uric acid reabsorption
 Hypovolemia-induced; prevention is by lowering doses of thiazide diuretic to reduce
hypovolemia
 Decreased uric acid secretion

 Hypercalcemia
 Inhibition of NCC leads to increased Ca2+ reabsorption in DCT
 Increased intracellular Ca2+ increases activity of basolateral Na+-Ca2+ exchanger

 Hyponatremia (rare, but can be fatal)

 Water and Na+ are lost from the body, but Na+ loss is greater
 ADH secretion limits water loss
 [compare to loop diuretics – reduced interstitial gradient, reduced effect of ADH on water
reabsorption]
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Thiazides and congeners: other adverse effects

 Cardiovascular
 Postural hypotension (if hypovolemia develops)
 Palpitations (likely related to hypokalemia)

 Genitourinary
 Sexual dysfunction (dose-related, up to 30% of patients after chronic treatment)
 Allergic reactions
 Thiazides are sulfonamides and may cause skin rash
 Rare, potentially lethal
 Exfoliative dermatitis, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia

51
Thiazides and congeners: contraindications
and precautions

 Hypersensitivity to thiazides, or sulfonamide-derived drugs

 Serious hypovolemic, hyponatremic, hypokalemic or hypercalcemic states
 Diabetes mellitus
 Gout
 Anuria
 Renal impairment

52
Thiazides and congeners: therapeutic uses
 Hypertension (a first line treatment and the first choice of diuretics)
 Edema associated with diseases of:
 a) the heart (i.e. heart failure)
 b) the kidney (i.e. nephrotic syndrome)

 Calcium nephrolithiasis, idiopathic hypercalciuria.

 Nephrogenic diabetes insipidus
 (Seems paradoxical - likely related to the effect of thiazides to reduce diluting activity of
the kidney)
 (compare to loop diuretics that reduce concentrating activity)

53
Potassium sparing diuretics
 Two groups of drugs acting through different mechanisms
 triamterene,amiloride
 organic bases

 spironolactone
 steroid

 Sites of action
 Epithelial
sodium channels (ENaC) - triamterene, amiloride
 Aldosterone (mineralocorticoid) receptor - spironolactone

 Late distal convoluted tubule (DCT) and cortical collecting tubule

(CCT)
54
Potassium sparing
diuretics
 Mechanisms of action
 1. Epithelial Na+ channel (ENaC)
inhibition
 2. Aldosterone (mineralocorticoid)
receptor antagonism

 Intercalated cell has carbonic K+

anhydrase and produces HCO3- and H+

55
Potassium sparing diuretics – CCT
 Na+ reabsorption in the late distal tubule and the cortical collecting tubule is
mediated by apical membrane sodium channels (ENaC) in the principal cells
 Entry of Na+ into these cells again occurs because of the Na+ electrochemical
gradient generated by the basolateral Na+,K+-ATPase
 Na+ entry depolarizes the cell providing a driving force for K+ to exit the cell
via specific K+ channels
 Thus, the luminal trans-membrane movement of Na+ and K+ are coupled
 The increased K+ in lumen increases H+ in lumen, so both are excreted
 Inhibition of ENaC channels by amiloride or triamterene prevents Na+
reabsorption
 The consequent reduction in K+ excretion gives rise to the term
“potassium-sparing diuretics”
56
Potassium sparing diuretics – ENaC inhibition

 Inhibition of ENaC channels by amiloride or triamterene prevents Na+

reabsorption
 Reduced Na+ reabsorption leads to reduced K+ and H+ secretion
 The decrease in K+ excretion gives rise to the term “potassium-sparing
diuretics”

57
Potassium sparing diuretics - aldosterone
(mineralocorticoid) receptor antagonists
 Aldosterone is a natural agonist of aldosterone receptors
 Nuclear/steroid receptor
 Receptor activation causes gene transcription and the synthesis of
aldosterone-induced proteins
 Increases ENaC channel and Na+,K+-ATPase expression
 Causes Na+ and water retention and increases K+ and H+ excretion

 Spironolactone is an aldosterone receptor antagonist

 Blocks the effects of aldosterone
 This results in reduced ENaC channel and Na+,K+-ATPase expression and reduced K+
and H+ excretion

58
Potassium sparing diuretics: renal effects
 Increased renal excretion of: Na+, Cl-.
 Decreased renal excretion of: K+, Ca2+, H+
 Urine pH: alkaline
 Acid-base balance: potential for hyperchloremic metabolic
acidosis
 H+ excretion is reduced, production of new HCO3- is reduced
 Kidney diluting and concentrating capacity: unaffected

59
 Potassium sparing diuretics:
pharmacokinetics
 Administration: PO
 Spironolactone has a slow onset of action (due to MoA)

MoA – mechanism of action 60

Potassium sparing diuretics: adverse effects

 All drugs
 Hyperkalemia (up to 20% of patients). It can lead to asthenia, muscular
weakness, paresthesias, diarrhea, bradycardia, AV block (in serious
cases asystole or ventricular fibrillation may ensue)
 Metabolic acidosis (by inhibiting H+ secretion, only with high doses)
 Potential for hyperchloremia, because of reduced plasma HCO3-

 Spironolactone
 Sexualdysfunction (> 40%)
 Gynecomastia, menstrual irregularities (by effects on steroid receptors)

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Potassium sparing diuretics: contraindications
and precautions
 Chronic renal insufficiency (the risk of hyperkalemia is increased)
 Hyperkalemic states
 Severe hepatic disease (drug-induced fluctuations in serum
electrolyte concentration can occur rapidly and precipitate coma)
 Patient treated with drugs that blunt the renin angiotensin system
(β-blockers, ACE inhibitors) - increases risk of hyperkalemia
 Patients receiving high doses of NSAIDs
 NSAIDs can ↓GFR, ↓renin, ↓Ang II, ↓aldosterone, ↓K+ excretion,
potentially causing hyperkalemia
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Potassium sparing diuretics: therapeutic uses
 All drugs
 Treatment and prevention of hypokalemic states (i.e. in response to
therapy with loop or thiazide diuretics)
 Amiloride
nephrogenic diabetes insipidus (it blocks the uptake of Li+
 Lithium-induced
by the ENaC Na+ channels in the collecting tubule)
 Spironolactone
 Systolic heart failure
 Primary hyperaldosteronism (adrenal adenoma, adrenal hyperplasia)
 Secondary hyperaldosteronism (due to hepatic cirrhosis, congestive heart
failure, nephrotic syndrome, renal artery stenosis)
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Vasopressin antagonists
 conivaptan, tolvaptan
 “….vaptans”
 Non-peptide

 Site of action
 Vasopressin (ADH; AVP) receptors
 Medullary collecting duct
 [SIADH (elevated ADH)]
 [diabetes insipidis (reduced ADH action)]

ADH – antidiuretic hormone; AVP – arginine vasopressin

SIADH – syndrome of inappropriate ADH
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Vasopressin antagonists: mechanism of action
 Vasopressin (ADH) is released by the posterior pituitary in response to an
increase in plasma osmolality or a decrease in blood pressure
 Vasopressin acts at three different receptors (V1a, V1b and V2)
 All of which are G-protein-coupled but show distinct patterns of expression in a range of
tissues in the body
 Depending on its site of action, vasopressin demonstrates antidiuretic or
vasopressor properties
 V2 receptors are on the basolateral membrane of principal cells of the
medullary collecting duct

65
Vasopressin antagonists: mechanism of action
(con’t)
 Activation of V2 receptors promotes insertion of aquaporin channels into
the apical membrane thereby increasing water movement from the lumen
across the apical membrane into the principal cell
 Conivaptan and tolvaptan are non-peptide competitive antagonists of V2
receptors
 Inhibition of V2 receptor function in the principal cells of the medullary
collecting duct reduces water reabsorption
 Conivaptan is also an antagonist at V1a receptors which does have effects on renal
blood flow, but this is a minor contributor to its diuretic properties
 Tolvaptan is essentially V2 receptor-specific

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Vasopressin antagonists: renal effects
 Increased water diuresis
 Water diuresis increases more than salt diuresis
 This can alleviate hyponatremia
 Increased renal excretion of: Na+, K+, Ca2+
 Urine osmolality: decreased
 Acid-base balance: not affected

67
Vasopressin antagonists:
pharmacokinetics
 Administration: conivaptan, IV; tolvaptan, PO
 Excretion: primarily feces

 Strong inhibitors of CYP3A4

68
Vasopressin antagonists: adverse effects
 Infusion-site reactions (with conivaptan)
 GI: nausea, xerostomia (with tolvaptan)
 Postural hypotension (if hypovolemia develops)
 Hypokalemia

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Vasopressin antagonists: contraindications and
precautions

 Hypovolemic hyponatremia
 Will make condition worse
 Concurrent use with strong CYP3A4 inhibitors (e.g.
clarithromycin, a macrolide antibiotic)

70
Vasopressin antagonists: therapeutic uses
 Syndrome of inappropriate ADH secretion (SIADH)
 SIADH leads to water retention
 Water restriction is first strategy; vasopressin antagonists are
used when this fails to correct the disorder
 Chronic hypoosmolar hyponatremia
 In hypoosmolar hyponatremia there is near normal total body Na+ but
increased total body water
 Low serum osmolality, urine osmolality greater than serum osmolality

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Effects of diuretics on urinary electrolyte composition

Carbonic Osmotic Loop Thiazide Potassium Vasopressin

anhydrase diuretics diuretics diuretics sparing antagonists
inhibitors diuretics
Na+ + ++ +++ ++ + 0
K+ + + ++ ++ - 0
H+ - + + + - 0
Ca2+ 0 + ++ - 0,- 0
Cl- 0,- + ++ + + 0
HCO3- ++ 0,+ 0,+ + 0 0
Urates - 0 - - 0 0
pH ↑ ↓ ↓ ↑/↓ ↑ 0
+ increased; - decreased; 0 negligible change

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Hypokalemia
 Definition
 Total serum potassium < 3.5 mEq/L (normal range 3.5-5.0 mEq/L)
 Etiology
 Excess renal K+ loss (e.g. hyperaldosteronism)
 Gastrointestinal losses (e.g. vomiting, secretory diarrheas)
 Transcellular shift (from extracellular to intracellular; e.g. insulin therapy)
 Insufficient intake (malnutrition)
 Drugs (e.g. carbonic anhydrase inhibitors, thiazide, osmotic and loop diuretics, β-
agonists, cisplatin, amphotericin B, gentamicin)

73
Major causes of hypokalemia
Hypokalemia (con’t)
 Symptoms and signs
 Skeletal muscle weakness, flaccid muscle paralysis, rhabdomyolysis, respiratory failure
 Disturbances in cardiac repolarization (can precipitate serious arrhythmias in patients
receiving digitalis)
 Constipation, paralytic ileus
 Polyuria, polydipsia

 Treatment
 Correction of the underlying cause may suffice when hypokalemia is mild
 KCl, oral or IV, when potassium supplementation is needed

75
Hyperkalemia
 Definition
 Total serum potassium > 5.3 mEq/L (normal range 3.5-5.0 mEq/L)
 Etiology
 Diminished renal excretion (e.g.chronic advanced renal failure)
 Transcellular shift (from intracellular to extracellular; e.g. acidosis, cell destruction,
diabetic hyperglycemia)
 Sudden increase in intake
 Drugs (e.g. potassium-sparing diuretics, β-blockers, heparin, digoxin (high doses),
NSAIDs, ACE inhibitors, angiotensin II antagonists)

76
Major causes of hyperkalemia
Hyperkalemia (con’t)
 Symptoms and signs
 Disturbances in cardiac excitability and conduction (slowing of AV conduction, AV block
and cardiac standstill)
 Flaccid paralysis (in case of severe hyperkalemia)

 Treatment
 Insulin and glucose
 Calcium gluconate (to combat the deleterious effect of hyperkalemia upon the heart)
 β2 agonists
 Hemodialysis

78
Urine acidification
 Goals
 To increase the renal excretion of ionizable organic bases.
 To provide conditions appropriate for the activity of urinary tract antiseptics.

 Drugs used
 Ammonium chloride (NH4Cl) is converted by the liver to urea and H+. Hydrogen ions are
then excreted by the kidney. It is given PO or IV. It is contraindicated in hepatic
insufficiency.

79
Urine alkalinization
 Goals
 To increase the renal excretion of ionizable organic acids.
 To increase the solubility of certain weak acids that are more soluble as salt than as non-
ionized acids (uric acid, cysteine, methotrexate, sulfonamides).
 Drugs used
 Sodium bicarbonate, lactate, acetate, citrate.
 Carbonic anhydrase inhibitors such as acetazolamide (since these drugs deplete the
body stores of bicarbonate it is wise to administer both the drug and sodium bicarbonate)

80
Summary
 6 classes of diuretics
 Sites of action in kidney tubule; mechanisms of action; diuretic efficacy
 Effects on Na+, K+, Ca2+, HCO3- excretion
 Therapeutic use – e.g. hypertension, heart failure, edema, glaucoma
 Adverse effects, precautions, contraindications
 Effects on acid-base balance
 Hyper-, hypo-kalemia
 Urine acidification, alkalinization

81
Where do
diuretics act?

Figure 15.1, from Katzung 82

Learning Objectives
 List the diuretic drug classes: carbonic anhydrase inhibitors, osmotic diuretics, loop diuretics,
thiazides and congeners, potassium sparing diuretics, vasopressin (antidiuretic hormone
(ADH)) antagonists
 List the following drugs and assign them to the appropriate diuretic class: acetazolamide,
dorzolamide, mannitol, furosemide, ethacrynic acid, hydrochlorothiazide, indapamide,
triamterene, amiloride, spironolactone, conivaptan, tolvaptan
 Explain the molecular mechanism of action of each class of diuretics
 Describe the renal actions of diuretics, including urine composition
 Describe the main extra renal actions of diuretics
 Rank the different classes of diuretics according to their efficacies
 Describe the routes of administration and the elimination processes of diuretics
 Describe the main adverse effects, clinically important drug interactions and main
contraindications of diuretics
 Describe the therapeutic use of diuretics both in edematous and non-edematous states
83