Clinical Pharmacology of Drugs Used To Affect Renal Function

Photo: Scanning electron micrograph of the glomerulus in a human kidney.
From: Widmaier EP. Vander’s Human Physiology: The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill Companies, Inc., 2014: 490
Learning Objectives:
1. List major types of diuretics and relate them to their sites of action.
2. List the major applications, toxicities, and the efficacy of thiazides, loop
diuretics and potassium-sparing diuretics.
3. Describe two drugs that reduce potassium loss during diuresis.
4. Describe a therapy that will reduce calcium excretion in patients who have
recurrent urinary stones.
5. Discuss the principle of force diuresis.
6. Describe drugs for reducing urine volume in nephrogenic diabetes insipidus.
7. Understand the usefulness of altering urine pH by drugs.
8. Discuss the mechanisms by which drugs and chemicals damage the kidney.
9. Understand how to select and prescribe drugs for patients with renal
impairment.
Companion: Renal Pharmacology eNotes
Marc Imhotep Cray, M.D. 2
Some Relevant Drugs:
A. Carbonic Anhydrase D. Thiazides F. ADH antagonists
Inhibitors chlorthalidone demeclocycline
Acetazolamide chlorothiazide lithium
dichlorphenamide hydrochlorothiazide lixivaptan
methazolamide metolazone tolvaptan
dorzolamide indapamide conivaptan
B. Osmotic Diuretics E. Potassium-sparing
mannitol diuretics
C. Loop Diuretics spironolactone
furosemide eplerenone
bumetanide triamterene
torsemide amiloride
ethacrynic acid

Topical Outline:
o Role of Renal System
 Volume Homeostasis
o Pharmacology Diuretic Drugs (Overview)
o Individual Agents/Classes
 High-efficacy (loop) diuretics
 Moderate-efficacy diuretics
 Low-efficacy diuretics
 Osmotic diuretics
 Carbonic Anhydrase Inhibitors
o Adverse effects of diuretics and Drug-Drug Interactions
o Alteration of Urine pH
o ADH Antagonists
 Clinical Cases and Discussions
 Practice
Marc Imhotep Questions & Answers/Explanations
Cray, M.D. 4
Key Abbreviations
 PCT, Proximal convoluted tubule
 DCT, Distal convoluted tubule
 TAL, thick ascending limb of the loop of Henle
 CCD, cortical collecting duct (including late DCT forming initial
collecting duct)
 MCD, medullary collecting duct
 GFR, glomerular filtration rate
 ENaC, epithelial sodium channel
 NCC, Na-Cl cotransporter (formerly NCCT or thiazide-sensitive
Na–Cl co-transporter)
 NKCC2, Na–K–2Cl co-transporter
 ROMK, rectifying outer medullary potassium channel
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 nephron that removes solute
without water; TAL and DCT are active salt-reabsorbing
segments that are not permeable by water
 Hyperchloremic metabolic acidosis A shift in body electrolyte
and pH balance involving elevated serum chloride, diminished
bicarbonate concentration, and a decrease in pH in the blood.
Typical result of bicarbonate diuresis
 Hypokalemic metabolic alkalosis A shift in body electrolyte
balance and pH involving a decrease in serum potassium and an
increase in blood pH. Typical result of loop and thiazide diuretic
actions
High-Yield Terms to Learn cont.
 Nephrogenic diabetes insipidus Loss of urine-concentrating
ability in kidney caused by lack of responsiveness to ADH (ADH
is normal or high)
 Pituitary diabetes insipidus Loss of urine-concentrating ability
in kidney caused by lack of ADH (ADH is low or absent)
 Potassium-sparing diuretic A diuretic that reduces exchange of
potassium for sodium in collecting tubule; a drug that 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
Key Concepts in Clinical Renal Pharmacology
 Diuretic drugs: their sites and modes of action, classification, adverse
effects and uses in cardiac, hepatic, renal and other conditions.
 Carbonic anhydrase inhibitors.
 Cation-exchange resins and their uses.
 Alteration of urine pH.
 Drugs and the kidney.
 Adverse effects.
 Drug-induced renal disease: by direct and indirect biochemical effects and
by immunological effects.
 Prescribing for renal disease: adjusting the dose according to the
characteristics of the drug and to the degree of renal impairment.
 Nephrolithiasis and its management.
 Pharmacological aspects of micturition.
 Benign prostatic hyperplasia.
 Erectile dysfunction.
Role of Renal System
 The kidneys comprise only 0.5% of body-weight, yet they
receive 25% of the cardiac output.
 Drugs that affect renal function have important roles in cardiac

failure and hypertension
 Disease of kidney must be taken into account when prescribing

drugs that are eliminated by it

Role of Renal System (2):
Volume Homeostasis
Kidneys are part of an integrated homeostatic mechanism for
maintaining volume of extracellular fluid (ECF) and thus
mean arterial pressure (MAP)
Other organs involved in this mechanism include:

 Heart (eg, cardiac output and heart rate),
 CNS (eg, sympathetic tone and ADH release),
 Lungs (eg, conversion of angiotensin I to angiotensin II), and
 Adrenal gland (eg, release of aldosterone)

Volume Homeostasis (2)
Several feedback control mechanisms operate among
components of this control mechanism ensure responses to
 volume expansion (increased extracellular fluid) and
 volume contraction (decreased extracellular fluid)
Design of drugs that selectively target components of this system

has led to major advances in therapy for cardiovascular diseases
such as hypertension and heart failure
 Discussed in Unit 4 Drugs Used In Disorders of the Cardiovascular System

Volume expansion
feedback control
Marc Imhotep Cray, M.D. Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 12
Volume contraction
feedback control
Marc Imhotep Cray, M.D. Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 13
Pharmacology Diuretic Drugs
 Definition: A diuretic is any substance that increases urine
and solute excretion
 This wide definition includes substances not commonly
thought of as diuretics, e.g. water
 To be therapeutically useful a diuretic should

 increase output of sodium as well as of water because
diuretics are normally required to remove edema fluid,
composed of water and solutes (of which sodium is most
important)

Diuretic Drugs (2)
Each day body produces 180 L of glomerular filtrate which is
modified in its passage down renal tubules to appear as 1.5 L of
urine
 Thus, if reabsorption of tubular fluid falls by 1%, urine output doubles
 Most clinically useful diuretics are organic anions

transported directly from blood into tubular fluid
 Following is a brief account of tubular function with particular

reference to sodium transport
 Intended to help to explain where and how diuretic drugs act
o it should be understood with reference to Figure following text
Diuretic Drugs (3)
Sites and modes of action
Proximal convoluted tubule (PCT)
 Some 65% of filtered sodium is actively transported from lumen of PCT by
sodium pump (Na+, K+-ATPase)
 Chloride is absorbed passively, accompanying sodium
 Bicarbonate is also absorbed through an action involving carbonic
anhydrase
 These solute shifts give rise to iso-osmotic reabsorption of water with

result that more than 70% of glomerular filtrate is returned to blood
from this section of nephron
 Epithelium of PCT is described as “leaky” because of its free permeability

to water and a number of solutes
Diuretic Drugs (4)
Proximal convoluted tubule cont.
 Osmotic diuretics such as mannitol are non-resorbable
solutes which retain water in tubular fluid (Site 1 in Figure)
 Their effect is to increase water rather than sodium loss

reflected in their special use acutely to reduce intracranial
or intraocular pressure and not states associated with
sodium overload

Diuretic Drugs (5)
Loop of Henle
 Tubular fluid now passes into loop of Henle where 25% of
filtered sodium is reabsorbed
 There are two populations of nephron:
 those with short loops confined to cortex, and
 juxtamedullary nephrons whose long loops penetrate
deep into medulla  are concerned principally with water
conservation
o following discussion refers to these long loops

Diuretic Drugs (6)
Loop of Henle cont.
 Physiologic changes best understood by first considering ascending limb
 In TAL (Site 2, Figure) sodium and chloride ions are transported from
tubular fluid into interstitial fluid by the three-ion co-transporter
system (i.e. Na+/K+/2Cl- called NKCC2) driven by sodium pump
o dependent on potassium returning to lumen through rectifying
outer medullary potassium (ROMK) channel otherwise K+ would
be rate limiting
 As tubule epithelium is “tight” here, i.e. impermeable to water tubular

fluid becomes dilute interstitium becomes hypertonic and
 fluid in adjacent descending limb, which is permeable to water
becomes more concentrated as it approaches tip of loop
o b/c hypertonic interstitial fluid sucks water out of this limb of tubule
Diuretic Drugs (7)
Sites and modes of action, Loop of Henle cont.
 High osmotic pressure in medullary interstitium is sustained by
descending and ascending vasa recta (long blood vessels of
capillary thickness that lie close to loops of Henle and act as
countercurrent exchangers) for incoming bld receives sodium
from outgoing bld
 Furosemide, bumetanide, torasemide and ethacrynic acid act
principally at Site 2 by inhibiting the three-ion transporter
(NKCC2) thus preventing sodium ion reabsorption and
lowering the osmotic gradient between cortex and medulla
results in formation of large volumes of dilute urine
 Hence, these drugs are called “loop” diuretics
Diuretic Drugs (8)
Distal convoluted tubule (DCT)
 Ascending limb of the loop then re-enters renal cortex where
its morphology changes into thin-walled DCT (Site 3, Figure)
 Here uptake is still driven by sodium pump but sodium and chloride
are taken up through a different transporter Na-Cl cotransporter,
called NCC (formerly NCCT)
 Both ions are rapidly removed from interstitium b/c cortical blood
flow is high and there are no vasa recta present
 Epithelium is also tight at Site 3 and consequently urine

becomes more dilute
 Thiazides act principally at this region of cortical diluting segment by
blocking NCC transporter
Diuretic Drugs (9)
Cortical collecting duct (CCD)
 In collecting duct (Site 4), Na ions are exchanged for K and H
ions
 Na ions enter through epithelial Na channel (called ENaC),

which is stimulated by aldosterone
 The aldosterone (mineralocorticoid) receptor is inhibited
by competitive receptor antagonist spironolactone
whereas
 sodium channel is inhibited by amiloride and triamterene
 All three of these diuretics are potassium sparing b/c K+ is normally
secreted through K+ channel, ROMK (see Figure), down potential
22
gradient
Marc Imhotep Cray, M.D. created by sodium reabsorption
Diuretic Drugs (10)
Cortical collecting duct (CCD) cont.
 All other diuretics, acting proximal to Site 4, cause potassium
Loss b/c they dump sodium into collecting duct
 Removal of this sodium through ENaC increases potential

gradient for potassium secretion through ROMK
 K+ sparing diuretics are weak diuretics b/c Site 4 is normally

responsible for “only” 2–3% of sodium reabsorption
 cause less sodium loss than thiazides or loop diuretics
 NB: Although ENaC does not have capacity to compensate for lg. Na
losses (e.g. loop diuretic usage) it is main site of physiologic control (via
aldosterone)
Marc Imhotep Cray, M.D. over sodium loss 23
Diuretic Drugs (11)
Cortical collecting duct (CCD) cont.
 Collecting ducts then travels back through medulla to reach
papilla in doing so it passes through a gradient of increasing
osmotic pressure which draws water out of tubular fluid
 This final conc. of urine is under influence of ADH =
increases water permeability by increasing expression of
specific water channels (or aquaporins)
o In ADH’s absence water remains in collecting duct
 Ethanol causes diuresis by inhibiting release of ADH from
posterior pituitary
NB: Diuresis may also be achieved by extrarenal
mechanisms, by raising cardiac output and increasing
renal blood flow, e.g. with dobutamine and dopamine.
Marc Imhotep Cray, M.D. Bennett PN, Brown MJ and Sharma P. Clinical Pharmacology 11th Ed. Edinburgh: Churchill Livingstone, 2012. 25
Diuretic Drugs (12)
Classification
 Maximum efficacy in removing salt and water that any
diuretic achieves is dependent on its site of action, thus it is
appropriate to rank diuretics according to their natriuretic
capacity (as set out in slides that follow)
 Classes:
1. High efficacy
2. Moderate efficacy
3. Low efficacy
NB: Percentages refer to highest fractional excretion of filtered
sodium under carefully controlled conditions and should not be taken
to represent average fractional sodium loss during clinical use.

Diuretic Drugs (13)
Classification
1. High efficacy
Furosemide and other “loop” diuretics can cause up to 25% of
filtered sodium to be excreted
 Their action impairs powerful urine-concentrating mechanism of loop
of Henle and confers higher efficacy compared with drugs that act in
relatively hypotonic cortex
Progressive increase in dose is matched by increasing diuresis,

 i.e. they have a “high ceiling” of effect
 they are so effective that over-treatment can readily dehydrate patient
Loop diuretics remain effective at a glomerular filtration rate

(GFR) below 10 mL/min (nml 120 mL/min) 27
Marc Imhotep Cray, M.D.
Diuretic Drugs (14)
Classification
2. Moderate efficacy
 The thiazide family, including chlorthalidone, chlorothiazide,
hydrochlorothiazide, metolazone and indapamide, cause 5-
10% of filtered sodium load to be excreted
 Increasing dose produces relatively little added diuresis

compared to loop diuretics
 i.e. they have a “low ceiling” of effect
 Cease to be effective once GFR has fallen below 20 mL/min

(except metolazone)
Diuretic Drugs (15)
Classification
3. Low efficacy
Triamterene, amiloride and spironolactone cause 2–3% of
filtered sodium to be excreted
 They are potassium sparing and combine with more
efficacious diuretics to prevent potassium loss, which other
diuretics cause
Osmotic diuretics, e.g. mannitol, also fall into this category

Diuretic Drugs (16)
Indications
 Edema states associated
 with sodium overload, e.g. cardiac, renal or hepatic disease, and
also
 without sodium overload, e.g. acute pulmonary edema following
myocardial infarction
NB: Edema may also be localized, e.g.
 angioedema over face and neck or around ankles with some
calcium channel blockers, or
 due to low plasma albumin, or immobility in elderly
 in none of these circumstances is a diuretic indicated
 Hypertension, by reducing intravascular volume and other mechanisms

too, e.g. reduction of sensitivity to noradrenergic vasoconstriction
Diuretic Drugs (17)
Indications cont.
 Hypercalcemia Furosemide reduces calcium reabsorption in ascending limb
of loop of Henle action may be utilised in emergency reduction of raised
plasma calcium levels, in addition to rehydration and other measures
 Idiopathic hypercalciuria, a common cause of renal stone disease, may be

reduced by thiazide diuretics
 Syndrome of inappropriate secretion of antidiuretic hormone secretion

(SIADH) may be treated with furosemide if there is a dangerous degree of
volume overload
 Nephrogenic diabetes insipidus, paradoxically, may respond to diuretics

which, by contracting vascular volume, increase salt and water reabsorption
Marcin PCT
Imhotep thus reduce urine volume
Cray, M.D. 31
Individual Agents/Classes
High-efficacy (loop) diuretics
Furosemide…
Moderate-efficacy diuretics
Thiazides…
Low-efficacy (K+ sparing) diuretics
Spironolactone…
Osmotic diuretics
Mannitol…
Carbonic Anhydrase Inhibitors
Acetazolamide…
Furosemide (Prototype)
Furosemide acts on thick portion of ascending limb of the loop
of Henle (Site 2 in slide 25) to produce effects described above
 b/c more sodium is delivered to DCT & CD (Site 4 in slide 25), exchange
with potassium leads to urinary potassium loss and hypokalemia
 Magnesium and calcium loss are increased by furosemide to same
extent as sodium effect on calcium is utilized in emergency
management of hypercalcemia
Pharmacokinetics
 Absorption from GIT is subject to considerable intra- and inter-
individual variation and it is highly bound to plasma proteins
 t½ is 2 hrs rises to over 10 h in renal failure

Furosemide cont.
Uses
 very successful for the relief of edema
 Urine production rises progressively with increasing dose
 Taken orally it acts within an hour and diuresis lasts up to 6 h
Caution
 Enormous urine volumes can result and over-treatment may lead to
hypovolemia and circulatory collapse
 Given intravenously it acts within 30 min and can relieve acute pulmonary
Edema partly by a venodilator action which precedes diuresis
 Important feature  retains efficacy even at a low GFR (10 mL/min or less)

Furosemide cont.
Adverse effects
uncommon, apart from excess of therapeutic effect (electrolyte
disturbance and hypotension due to low plasma volume) and
 Nausea
 Pancreatitis and,
 rarely, deafness, which is usually transient and associated
with rapid IV injection in renal failure
Non-steroidal anti-inflammatory drugs (NSAIDs), notably

indomethacin, reduce furosemide-induced diuresis by inhibiting
formation of vasodilator prostaglandins in kidney
High-efficacy (loop) diuretics cont.
Bumetanide, piretanide and ethacrynic acid are similar to
furosemide
Bumetanide may be preferred over furosemide
in heart failure b/c of its more predictable oral absorption
Ethacrynic acid is less widely used as it is more prone to cause

adverse effects, especially nausea and deafness
 Not a sulfonamide as are other loop diuretics, thus useful
option in sulfa-allergic pts.
Torasemide is an effective antihypertensive agent at lower
(non-natriuretic) doses (2.5–5 mg/day) than those used for
edema (5–40 mg/day)
Thiazides
Thiazides depress salt reabsorption in DCT (Site 3 in slide 25),
i.e. upstream of region of sodium–potassium exchange at CD
(Site 4 in slide 25)
 Hence , have important effect of raising potassium excretion
 Thiazides lower blood pressure, initially due to a reduction in
intravascular volume but chronically by a reduction in
peripheral vascular resistance
 accompanied by diminished responsiveness of vascular
smooth muscle to Epi/NE
 also have a direct action on vascular smooth muscle
membranes
Thiazides cont.
Uses
 given for mild cardiac failure and mild hypertension, or for more severe
degrees of HTN, in combination with other drugs
Pharmacokinetics
 Thiazides are well absorbed orally and most begin to act within an hour
 Differences among numerous derivatives lie in duration of action
Relatively water-soluble agents, e.g. chlorothiazide, hydrochlorothiazide
(HCTZ), are most rapidly eliminated, peak effect within 4–6 h and passing
off by 10–12 h
 excreted unchanged in urine and active secretion by PCT contributes to
high renal clearance and t½ of less than 4 h

Thiazides cont.
Pharmacokinetics
Relatively lipid-soluble members, e.g. polythiazide,
hydroflumethiazide, distribute more widely into body tissues
and act for >24 h
 can be problematic if used for diuresis, but there is no evidence this
property makes them more effective at controlling hypertension
With exception of metolazone, thiazides are not effective when

renal function is moderately impaired (GFR <20 mL/min), b/c
they are not filtered in sufficient concentration to inhibit NCC (Na-
Cl cotransporter)

Thiazides cont.
Adverse effects
 Adverse effects in general are discussed below
 Rashes (sometimes photosensitive)
 thrombocytopenia and
 agranulocytosis occur
 Thiazide-type drugs increase total plasma cholesterol concentration

 But in long-term use this is less than 5%, even at high doses
 Questions about appropriateness of thiazides for mild hypertension, of

which ischemic heart disease is a common complication, are laid to rest
by their proven success in randomized outcome comparisons

Diuretics related to thiazides
Several compounds, not strictly thiazides, share structural similarities and act
at same site on nephron (moderate therapeutic efficacy)
Overall, these substances have a longer duration of action, are used for
edema and hypertension, and their profile of adverse effects is similar to
thiazides
 Chlortalidone acts for 48–72 h after a single oral dose
 Indapamide is structurally related to chlortalidone but lowers blood
pressure at subdiuretic doses perhaps by altering calcium flux in
vascular smooth muscle
 Metolazone is effective when renal function is impaired
o It potentiates diuresis produced by furosemide and combination can
be effective in resistant edema although risk of hypokalemia is
Marc Imhotep Cray,very
M.D. high 41
Low-efficacy diuretics
 Spironolactone (Aldactone) is structurally similar to aldosterone and
competitively inhibits its action in distal tubule (exchange of potassium
for sodium, Site 4 in slide 25)
 Excessive secretion of aldosterone contributes to fluid retention in

 hepatic cirrhosis
 nephrotic syndrome
 congestive heart failure and
 primary hypersecretion (Conn’s syndrome)
 Spironolactone is also useful in treatment of resistant hypertension

 increased aldosterone sensitivity is increasingly recognized as a
contributory factor
Low-efficacy diuretics cont.
 Spironolactone has a short t½ (1.6 h), being extensively metabolized, and its
prolonged diuretic effect is due to most significant active metabolite,
canrenone (t½ 17 h)
 relatively ineffective when used alone
 more efficient when combined with a drug that reduces sodium It is
given orally in one or more doses totaling 100–200 mg/day
 Maximum diuresis may not occur for up to 4 days
 Spironolactone (and amiloride and triamterene) usefully reduces K+ loss
caused by loop diuretics
Warnings:
 combination with another K+ sparing diuretic must be avoided as
hyperkalemia will result
 Dangerous K+ retention is particularly likely if spironolactone is given to pts.
with impaired renal function
Adverse effects
 Estrogenic effects are major limitation to its long-term use
 the Randomized Aldactone Evaluation Study (RALES) even 25 mg/day caused breast
tenderness or enlargement in 10% of men
 Women may also report breast discomfort or menstrual irregularities, including
amenorrhea
 Minor gastrointestinal upset also occurs and there is increased risk of

gastroduodenal ulcer and bleeding
 reversible on stopping the drug
 Spironolactone is reported to be carcinogenic in rodents, but many years

of clinical experience suggest that it is safe in humans
 Nevertheless, UK license for its use in essential hypertension was withdrawn (i.e.
possible use long term in a patient group that includes the relatively young), but is
retained for other indications
 Eplerenone is a spironolactone analog licensed for use
in heart failure that appears to be free of estrogenic
effects; b/c of its lower affinity for estrogen receptor
 It is useful in patients who need an aldosterone-receptor

blocking agent, but are intolerant of endocrine effects of
spironolactone

Amiloride blocks ENaC sodium channels in distal tubule
 Action complements thiazides with which it is frequently combined to
increase sodium loss and limit potassium loss
 Example, coamilozide (amiloride 2.5–5 mg plus hydrochlorothiazide
25–50 mg) is used for hypertension or edema
 maximum effect of amiloride occurs about 6 h after an oral dose, with a

duration of action greater than 24 h (t½ 21 h)
 oral dose is 5–20 mg daily

 Triamterene (Dytac) is a potassium-sparing diuretic with
an action and use similar to amiloride (blocks ENaC sodium
channels in DCT)
 Diuretic effect extends over 10 h

Adverse effects
 Gastrointestinal upsets occur
Drug-drug interaction
 Reversible, non-oliguric renal failure may occur when
triamterene is used with indomethacin (and other NSAIDs)
 may also give urine a blue coloration
Osmotic diuretics
 Osmotic diuretics are small molecular weight substances that are
filtered by the glomerulus but not reabsorbed by renal tubule
and thus increase osmolarity of tubular fluid
 Thus they prevent reabsorption of water (and also, by more

complex mechanisms, of sodium) principally in PCT and also loop
of Henle
 Result is urine volume increases according to load of osmotic

diuretic
Osmotic diuretics cont.
 Mannitol, a polyhydric alcohol (mol. wt. 452), is used most commonly
given intravenously
 In addition to its effect on kidney, mannitol encourages movement of

water from inside cells to extracellular fluid which is thus transiently
expanded before diuresis occurs
 These properties define its uses, which are for rapid reduction of
intracranial or intraocular pressure, and to maintain urine flow to
prevent renal tubular necrosis
 b/c mannitol increases circulatory volume, it is contraindicated in

congestive cardiac failure and pulmonary edema

Carbonic Anhydrase Inhibitors
 The enzyme carbonic anhydrase facilitates reaction betw. CO2 and H2O to
form carbonic acid (H2CO3), which then breaks down to hydrogen (H+) and
bicarbonate (HCO3-) ions
 This process is fundamental to production of either acid or alkaline
secretions, and high concentrations of CA are present in gastric mucosa,
pancreas, eye and kidney
 MOA b/c number of H+ ions available to exchange with Na+ in PCT is
reduced, sodium loss and diuresis occur
 But HCO3- reabsorption from tubule is also reduced, and its loss in urine
leads within days to metabolic acidosis which attenuates diuretic
response to carbonic anhydrase inhibition
o Consequently, inhibitors of CA are obsolete as diuretics
• Still have specific uses
 Acetazolamide is most widely used CAI
Carbonic Anhydrase Inhibitors cont.
Reduction of intraocular pressure
 action is not due to diuresis  rather, formation of aqueous humor is
an active process requiring a supply of bicarbonate ions which depends
on carbonic anhydrase
 Inhibition of CA reduces formation of aqueous humor and lowers IOP
o this is a local action and is not affected by development of acid–base
changes elsewhere in body, i.e. tolerance does not develop
 In pts. w acute glaucoma, acetazolamide taken either PO or IV
 Acetazolamide is not recommended for long-term use b/c of risk of

hypokalemia and acidosis but brinzolamide or dorzolamide are effective
as eye drops, well tolerated, and thus suitable for chronic use in glaucoma

Carbonic Anhydrase Inhibitors cont.
Acetazolamide for High-altitude (mountain) sickness
 High-altitude (mountain) sickness may affect unacclimatized people at
altitudes over 3000 meters, especially after rapid ascent
 symptoms range from
 nausea
 lassitude and headache to
 pulmonary and cerebral edema
 Initiating cause is hypoxia:
 at high altitude, normal hyperventilatory response to falling oxygen
tension is inhibited b/c alkalosis is also induced
 Acetazolamide induces metabolic acidosis increases respiratory drive,

notably at night when apnetic attacks may occur, and thus helps to maintain
arterial
Marc Imhotep Cray, oxygen
M.D. tension 52
CAIs cont., acetazolamide for high-altitude
Dosage
 Usual dose is 125–250 mg twice daily, given orally on day
before ascent and continued for 2 days after reaching
intended altitude
 250 mg twice daily is used to treat established high-altitude

sickness, combined with a return to a lower altitude
(Note: this is an unlicensed indication in UK)
 As an alternative or in addition to acetazolamide

dexamethasone may be used:
 2 mg q6 hrs. for prevention, and
 4 mg q6 hrs. for treatment
CAIs cont., acetazolamide
Acetazolamide has two other uses
1. In periodic paralysis, where sudden falls in plasma K+ conc.
occur due to its exchange with Na+ in cells
 rise in plasma H+ caused by acetazolamide provides an
alternative cation to K+ for exchange with Na+
2. Acetazolamide may be used occasionally as a second-line

drug for tonic–clonic and partial epileptic seizures

CAIs cont., acetazolamide
Adverse effects
 High doses of acetazolamide may cause
 drowsiness and fever
 rashes (it is a sulfonamide-type drug) and
 paranesthesia may occur (from the acidosis)
 blood disorders have been reported
 Renal calculi may develop, b/c urine calcium is in less
soluble form, owing to low citrate content of urine a
consequence of metabolic acidosis
 Dichlorphenamide is a similar, but a more potent, inhibitor

of carbonic anhydrase
Adverse effects of diuretics
and
Drug-Drug Interactions

Potassium depletion
 Diuretics that act at Sites 1, 2 and 3 of slide 25 cause more sodium to reach
sodium–potassium exchange site in the distal tubule (Site 4) and so increase
potassium excretion
 This subject warrants discussion b/c hypokalemia may cause cardiac

arrhythmia in patients at risk (e.g. receiving digoxin)
 The safe lower limit for plasma potassium concentration is 3.5 mEq/L
 Whether or not diuretic therapy causes significant lowering of serum

potassium levels depends both on drug and on circumstances in which it is
used: The following slides explain more

Potassium depletion
 The loop diuretics produce a smaller fall in serum
K+ conc. than do thiazides, for equivalent diuretic effect,
but have a greater capacity for diuresis, i.e. higher efficacy
especially in large dose so are associated with greater
decline in potassium levels
 If diuresis is brisk and continuous, clinically important

potassium depletion is likely to occur

Potassium depletion cont.
 Low dietary intake of potassium predisposes to hypokalemia
risk is particularly notable in elderly, many of whom ingest less
than 50 mEq per day (dietary normal is 80 mEq).
 Hypokalemia may be aggravated by other drugs, e.g. β2-

agonists, theophylline, corticosteroids, amphotericin
 Hypokalemia during diuretic therapy is also more

likely in hyperaldosteronism
 whether primary or more commonly secondary to severe
liver disease, congestive heart failure or nephrotic
syndrome
 Potassium loss occurs with diarrhea, vomiting or small
bowel fistula and may be aggravated by diuretic therapy
 When a thiazide diuretic is used for hypertension no case

for routine prescription of a potassium supplement if no
predisposing factors are present

Potassium depletion can be minimized or corrected by:
 Maintaining a good dietary potassium intake (fruits, fruit juices,
vegetables)
 Combining a potassium-depleting with a potassium sparing agent
 Intermittent use of potassium-losing drugs, i.e. drug holidays
 Potassium supplements: KCl preferred b/c chloride is principal anion
excreted along with sodium when high-efficacy diuretics are used
 Potassium-sparing diuretics defend plasma potassium more effectively
than potassium supplements
NB: All forms of potassium are irritant to GIT, and in

esophagus may cause ulceration.
Elderly, in particular, should be warned never to take
such tablets dry but always with a large cupful of liquid
and sitting upright or standing.
Hyperkalemia
 Hyperkalemia may occur, esp. if a K+ sparing diuretic is given to a patient
with impaired renal function
 ACE inhibitors and ARBs can also cause a increase in plasma K+ levels
 They may cause dangerous hyperkalemia if combined with KCl
supplements or other potassium sparing drugs, in presence of
impaired renal function
 However, with suitable monitoring combination can be used
safely, as was well illustrated by the RALES trial
 Cyclosporine, tacrolimus, indomethacin and possibly other NSAIDs may

cause hyperkalemia with potassium-sparing diuretics

Hypovolemia
 Hypovolemia can result from over-treatment
 Acute loss of excessive fluid leads to postural hypotension
and dizziness
 A more insidious state of chronic hypovolemia can develop,
especially in elderly
 After initial benefit, pt. becomes sleepy and lethargic

 Blood urea concentration (BUN) rises and Na+ conc. may be
low
o Renal failure may result

Urinary retention
Urinary retention
 Sudden vigorous diuresis can cause acute retention of urine in
presence of bladder neck obstruction
 e.g. due to prostatic enlargement

Hyponatremia
 Hyponatremia may result if Na+ loss occurs in pts who drink a large quantity
of water when taking a diuretic
 Other mechanisms are involved, including enhancement of ADH release
 Such pts. have reduced total body Na+ and ECF vol. and are edema free
 Discontinuing diuretic and restricting water intake are effective
 The condition should be distinguished from hyponatremia with edema,

which develops in patients with CHF, cirrhosis or nephrotic syndrome
 Here salt and water intake should be restricted b/c ECF volume is expanded
 Combination of a potassium-sparing diuretic and ACE inhibitor can also

cause severe hyponatremia  more commonly than life-threatening
hyperkalemia

Urate retention
Urate retention with hyperuricemia and, sometimes, clinical gout occurs
with thiazides and loop diuretics
 Effect is unimportant or negligible with low-efficacy diuretics, e.g.
amiloride and spironolactone
 Two mechanisms responsible
 First, diuretics cause volume depletion, reduction in glomerular
filtration and increased absorption of almost all solutes in proximal
tubule, including urate
 Second, diuretics and uric acid are organic acids and compete for
transport mechanism that pumps such substances from blood into
tubular fluid
 Diuretic-induced hyperuricemia can be prevented by allopurinol or
probenecid (which also antagonizes diuretic efficacy by reducing their
transport into urine)
Magnesium deficiency
Magnesium deficiency: Loop and thiazide diuretics cause significant
urinary loss of magnesium
 potassium-sparing diuretics cause magnesium retention
 Magnesium deficiency brought about by diuretics is rarely severe enough

to induce classic picture of neuromuscular irritability and tetany  but
cardiac arrhythmias, mainly of ventricular origin, do occur
 respond to repletion of magnesium (2 g of Mg2+ is given as 4 mL 50%
magnesium sulfate infused i.v. over 10–15 min followed by up to 70
mmol infused over the next 24 h)

Carbohydrate intolerance
 Carbohydrate intolerance is caused by those diuretics that produce
prolonged hypokalemia, i.e. loop and thiazide type
Mechanism
 May affect depolarization and entry of calcium into islet cells which is
necessary to stimulate formation and release of insulin so glucose
intolerance is probably due to secondary insulin deficiency
 Insulin requirements thus increase in established diabetics and disease

may become manifest in latent diabetics
 effect is generally reversible over several months

Calcium homeostasis
 Renal calcium loss is increased by loop diuretics
 In short term this is not a serious disadvantage and furosemide may be
used in management of hypercalcemia after rehydration achieved
 In long term hypocalcaemia may be harmful, especially in elderly
patients, who tend in any case to be in negative calcium balance
 Thiazides, by contrast, decrease renal excretion of calcium

 this property may influence choice of diuretic in a potentially calcium-
deficient or osteoporotic individual as thiazide use is associated with
a reduced risk of hip fracture in elderly
 Hypocalciuric effect of thiazides has also been used effectively in
patients with idiopathic hypercalciuria commonest metabolic cause
of renal stones

Drug-Drug Interactions
 Loop diuretics (especially as intravenous boluses) potentiate ototoxicity of
aminoglycosides and nephrotoxicity of some cephalosporins
 NSAIDs tend to cause sodium retention, which counteracts the effect of

diuretics mechanism may involve inhibition of renal prostaglandin
formation
 Diuretic treatment of a patient taking lithium can precipitate toxicity from

this drug (increased sodium loss is accompanied by reduced lithium
excretion)
 Other drugs that may induce hyperkaliemia, hypokalemia, hyponatremia or

glucose intolerance with diuretics are described above
Alteration Of Urine pH
Alteration of urine pH by drugs is sometimes desirable  most
common reason is in treatment of poisoning
(a fuller account is given in poisoning and overdose)
A summary of main indications follows:

 Alkalinization of urine:
 increases elimination of salicylate, phenobarbital and
chlorophenoxy herbicides
 treats crystal nephropathy by increasing drug solubility, e.g.
of methotrexate, sulfonamides and triamterene
 reduces irritation of an inflamed urinary tract
 discourages growth of certain organisms, e.g. Escherichia coli
Alteration Of Urine pH cont.
 Urine can be made alkaline by sodium bicarbonate i.v., or by potassium citrate
by mouth
Caution: Sodium overload may exacerbate cardiac failure, and sodium or
potassium excess are dangerous when renal function is impaired
Acidification of urine:
 used as a test for renal tubular acidosis
 increases elimination of amphetamine, MDMA or “Ecstasy”, quinine and
phencyclidine (very rarely needed)
 Oral NH4Cl, taken w food to avoid vomiting, acidifies urine
o It should not be given to pts with impaired renal or hepatic
function
 Other means include arginine hydrochloride, ascorbic acid and
calcium
Marc Imhotep Cray, M.D. chloride by mouth 72
ADH Antagonists
 Demeclocycline
 Lithium
 Lixivaptan
 Satavaptan
 Conivaptan
 Tolvaptan

Antidiuretic Hormone Antagonists
 A variety of medical conditions, including
 Congestive heart failure (CHF) and
 Syndrome of inappropriate ADH secretion (SIADH) cause
water retention as a result of excessive ADH secretion
o Inability to form dilute urine in fully hydrated condition is
characteristic of SIADH
• Antagonists of ADH are needed to treat this condition
 Patients with CHF who are on diuretics frequently develop

hyponatremia secondary to excessive ADH secretion
Dangerous hyponatremia can result
Antidiuretic Hormone Antagonists (2)
Until recently, two nonselective agents
 lithium and
 demeclocycline (a tetracycline antimicrobial drug),
were used for their well-known interference with ADH activity
 Mechanism for this interference has not been completely
determined for either of these agents
 Demeclocycline is used more often than lithium because
of many adverse effects of lithium administration
 Demeclocycline is now being rapidly replaced by several
specific ADH receptor antagonists (vaptans), which have
yielded good clinical results

Vaptans
 There are 3 known vasopressin receptors, V1a , V1b , and V2
 V1 receptors are expressed in vasculature and CNS
 V2 receptors are expressed specifically in kidney
 Conivaptan (currently available only for intravenous use)
exhibits activity against both V1a and V2 receptors
 Oral agents tolvaptan, lixivaptan, and satavaptan are

selectively active against V2 receptor
 Tolvaptan, is very effective in treatment of hyponatremia,

SIADH and as an adjunct to standard diuretic therapy in
patients with CHF
Pharmacokinetics
 Half-life of conivaptan and demeclocycline is 5–10 hours,
while that of tolvaptan is 12–24 hours
Pharmacodynamics
 Antidiuretic hormone antagonists inhibit effects of ADH in
collecting tubule
 Conivaptan and tolvaptan are direct ADH receptor
antagonists
 both lithium and demeclocycline reduce ADH-induced
cAMP by mechanisms that are not completely yet clarified
Clinical Indications & Dosage
A. Syndrome of Inappropriate ADH Secretion
 For SIADH, water restriction is often treatment of choice
 ADH antagonists are used to manage SIADH when water restriction has
failed to correct abnormality
 Generally occurs in outpatient setting, where water restriction cannot
be enforced, but Can occur in hospital when large quantities of
intravenous fluid are needed for other purposes
o Demeclocycline (600–1200 mg/d) or tolvaptan (15–60 mg/d) can
be used for SIADH
• Appropriate plasma levels of demeclocycline (2 mcg/mL)
should be maintained by monitoring
• Tolvaptan levels are not routinely monitored

Clinical Indications cont.
B. Other Causes of Elevated Antidiuretic Hormone
 Antidiuretic hormone is also elevated in response to diminished effective
circulating blood volume, as often occurs in heart failure
 When Tx by volume replacement is not desirable, hyponatremia may
result
 As for SIADH, water restriction is often treatment of choice

o In patients with heart failure, this approach is often unsuccessful in
view of increased thirst and large number of oral medications being
used
 For patients with heart failure, intravenous conivaptan may be
particularly useful b/c it has been found that blockade of V1a receptors
leads to decreased peripheral vascular resistance and increased cardiac
output
Toxicity
A. Nephrogenic Diabetes Insipidus
If serum Na + is not monitored closely, any ADH antagonist can
cause severe hypernatremia and nephrogenic diabetes insipidus
 If lithium is being used for a psychiatric disorder, nephrogenic
diabetes insipidus can be treated with a thiazide diuretic or
amiloride
B. Renal Failure
Both lithium and demeclocycline have been reported to cause
acute renal failure
 Long-term lithium therapy may cause chronic interstitial nephritis
C. Other Adverse Effects
Dry mouth and thirst are common with many of these drugs
Tolvaptan may cause hypotension
Multiple adverse effects associated with lithium therapy have

been found and are discussed in CNS Drugs
Demeclocycline should be avoided in patients with liver

disease and in children younger than 12 years

Renal Drugs Summary Table
Rosenfeld GC and Loose DS. Board Review Series

Pharmacology 6th ed. Philadelphia, PA:
Marc Imhotep Cray, M.D.
Lippincott Williams & Wilkins, 2014.
Case-based Discussions

Case 7-Diuretics
A 64-year-old female with a past medical history of coronary artery disease,
hypertension, and congestive heart failure (CHF) presents with dyspnea at
rest and with exertion, orthopnea, and lower extremity pitting edema. Her
symptoms have worsened over the last 2 weeks and also include orthopnea,
worsening exercise tolerance, and tachypnea. On examination, she is
notably dyspneic and tachypneic, and also has jugular venous distension,
2+pitting edema, and rales on lung examination.
Patient is also found to have an audible S3. Her chest x-ray, pro-Brain
Natriuretic Peptide (BNP) level, and echocardiogram confirm the clinical
suspicion of CHF exacerbation with pulmonary edema. She is already on
maximal medical therapy with an ACE inhibitor, beta blocker, statin, and
aspirin. She is appropriately placed on oxygen and given intravenous
furosemide.
_ What is the mechanism of action of furosemide?
_ What electrolyte abnormalities can be caused by furosemide?
Summary:
A 64-year-old woman with pulmonary edema is prescribed
furosemide.
• Mechanism of action of furosemide: Inhibit active NaCl
reabsorption in the ascending limb of the loop of Henle,
increasing water and electrolyte excretion.
• Potential electrolyte abnormalities: Hypokalemia,
hypomagnesemia, and metabolic alkalosis because of enhanced
H + excretion.

Clinical Correlation
 Loop diuretics given intravenously promote diuresis within minutes,
making them ideal for the treatment of acute pulmonary edema.
 Furosemide is the prototype and most widely used drug in this class.
 Loop diuretics inhibit NaCl reabsorption in the ascending limb of the loop
of Henle. This causes a marked increase in the excretion of both water
and electrolytes.
 The excretion of potassium, magnesium, and calcium ions are all
increased, which may cause clinically significant adverse effects.
 A metabolic alkalosis may also occur as a result of the excretion of
hydrogen ions.
o However, the ability to cause excretion of these electrolytes may also
provide a clinical benefit in certain situations.
o Forced diuresis by giving IV saline and furosemide is a primary
method of treatment of hypercalcemia.
Case 8-Nondiuretic Inhibitors of Tubular Transport
Following his third episode of gouty arthritis, a 50-year-old man sees you in
the clinic. Each case was successfully treated acutely; however, your patient
is interested in trying to prevent future episodes. He is not on regular
medications and has a normal physical examination today. Blood work
reveals an elevated serum uric acid level and otherwise normal renal
function and electrolytes. A 24-hour urine collection for uric acid reveals
that he is under-excreting uric acid. Suspecting that this is the cause of his
recurrent gout, you place him on probenecid.
_ What is the mechanism of action of probenecid?
_ Which drugs could have their excretion inhibited by probenecid?

Summary:
A 50-year-old man with recurrent gout is prescribed probenecid.
• Mechanism of action of probenecid: Inhibits secretion of
organic acids and decreases reabsorption of uric acid, causing a
net increase in secretion.
• Other drugs whose secretion could be inhibited: Penicillin,
indomethacin, and methotrexate.

Clinical Correlation
 Gout is a disease in which uric acid crystals deposit in joints, causing an
extremely painful acute inflammatory arthritis.
 Persons with recurrent gout often have chronically elevated levels of uric
acid in their blood. This hyperuricemia is frequently caused by either
overproduction of uric acid or under-excretion of uric acid by the kidneys.
 Probenecid (and other uricosuric drugs) promotes the excretion of uric acid.
o It works by inhibiting the secretion of organic acids from the plasma into the tubular
lumen and blocking the reuptake of uric acid.
o The net result of this is an increase in the excretion of uric acid.
 The benefit of this is the prevention of recurrent gout attacks in chronic
under-excreters of uric acid.
 In those individuals who overproduce uric acid, allopurinol or febuxostat is
used.
o These drugs inhibit xanthine oxidase, a key enzyme in the production of uric acid.
o For patients with severe gout refractory to the above drugs, IV infusion of pegloticase
can quickly reduce serum urate and reduce deposits in joints.
Practice Questions &
Answers/Explanations

Question 1
A patient taking an oral diuretic for about 6 months presents with
elevated fasting and postprandial blood glucose levels. You check
the patient’s HbA1c and find it is elevated compared with normal
baseline values obtained 6 months ago. You suspect the glycemic
problems are diuretic-induced. What was the most likely cause?
a. Acetazolamide
b. Amiloride
c. Chlorothiazide
d. Spironolactone
e. Triamterene

Answer 1
The answer is c. Thiazides and thiazide-like diuretics (eg,
chlorthalidone, metolazone) tend to elevate blood glucose levels,
impair glucose tolerance, and cause frank hyperglycemia.
Several mechanisms have been proposed to explain the effect:
insulin resistance is the most likely mechanism.
Elevations of blood glucose levels, or other manifestations of
glycemic control, are rarely associated with treatment with
acetazolamide (a), amiloride (b), spironolactone (d), or triamterene (e).
Refs. G&G, pp 686-690; Katzung, pp 260-261.
NB: You may recall that diazoxide (mainly used as a parenteral

drug for prompt lowering of blood pressure) can be used in its oral
dosage form to raise blood glucose levels in some hypoglycemic
Marc Imhotep Cray, M.D. states. It is, chemically, a thiazide, but is not used as a diuretic.) 92
Question 2
A patient with essential hypertension is being treated with hydrochlorothiazide and a calcium
channel blocker, and is doing well. He also takes atorvastatin for hypercholesterolemia, and
aspirin to reduce his risk of an acute coronary syndrome. He is now diagnosed with a seizure
disorder. We begin therapy with one of the suitable anticonvulsants that, fortunately, does
not alter the metabolism of any of the medications prescribed for his cardiovascular
problems. We’ve also learn that systemic administration of acetazolamide may prove to be a
useful adjunct to the anticonvulsant therapy: the metabolic acidosis it causes may help
suppress seizure development or spread. So, we start acetazolamide therapy too. What is the
most likely outcome of adding the acetazolamide?
a. Excessive rises of plasma sodium concentration
b. Hypertensive crisis (antagonism of both antihypertensive drugs)
c. Hypokalemia via synergistic actions with the thiazide
d. Spontaneous bleeding (potentiation of aspirin’s actions)
e. Sudden circulating volume expansion, onset of heart failure 93
Answer 2
The answer is c. We seldom administer acetazolamide as a diuretic, because its
effects are “mild”; associated with significant changes of both urine pH (up) and
blood pH (down; metabolic acidosis); and self-limiting (once sufficient
bicarbonate has been lost from the blood, into the urine, refractoriness to
further diuresis occurs). More often we administer acetazolamide and other
carbonic anhydrase inhibitors for nonrenal/noncardiovascular problems, such
as to lower intraocular pressure in some cases of glaucoma (carbonic anhydrase
inhibitors inhibit aqueous humor formation) or as an adjunct to anticonvulsant
therapy as described here. As a result, we may forget that these systemically
administered drugs are diuretics, one common property of all the diuretics
being increased renal sodium loss (a natriuretic effect; thus, answer a is not
correct). We may even forget that carbonic anhydrase inhibitors, given
systemically, are potassium-wasting diuretics: they act proximally and deliver
extra sodium distally where, at the principal cells of the nephron, some extra
Na+ is taken up in exchange for additional K+ that gets eliminated in the urine.
Answer 2 cont.
In this scenario the patient is taking a thiazide, which is obviously potassium-wasting and
has potential in its own right to cause hypokalemia. Add a carbonic anhydrase to the regimen
and the risks of hypokalemia increase. Acetazolamide does not antagonize the
antihypertensive effects of thiazides or calcium channel blockers, nor provoke hypertension
or a hypertensive crisis (b). If there were any interactions between the acetazolamide and
the aspirin, it would be antagonism, not potentiation (d) of aspirin’s antiplatelet effects.
Aspirin undergoes renal tubular reabsorption, and that is a pH-dependent effect. Aspirin’s
reabsorption is reduced (that is, its excretion increases) in an alkaline urine, which is
precisely what occurs with acetazolamide. (You should recall that alkalinizing the urine is an
important adjunctive measure in treating severe salicylate poisoning, in part because it
reduces tubular reabsorption of salicylate.) There is no reason to suspect sudden rises of
blood volume, with or without concomitant heart failure from that (e). Indeed, the added
diuresis from the acetazolamide may, at least transiently, potentiate the effects of the
thiazide on urine volume, blood pressure, or both.
Refs. G&G, pp 677-681; Katzung, pp 256-257, 261-262, 265. 95
Question 3
An elderly patient with a history of heart disease is brought to the
emergency room with difficulty breathing.
Examination reveals that she has pulmonary edema.
Which treatment is indicated?
A. Acetazolamide.
B. Chlorthalidone.
C. Furosemide.
D. Hydrochlorothiazide.
E. Spironolactone.

Answer 3
Correct answer is C. This is a potentially fatal situation. It is
important to administer a diuretic that will reduce fluid
accumulation in the lungs and, thus, improve oxygenation
and heart function. The loop diuretics are most effective in
removing large fluid volumes from the body and are the
treatment of choice in this situation. In this situation, furosemide
should be administered intravenously. The other choices are
inappropriate.

Question 4
A group of college students is planning a mountain climbing trip
to the Andes. Which would be appropriate for them to take to
prevent mountain sickness?
A. A thiazide diuretic such as hydrochlorothiazide.
B. An anticholinergic such as atropine.
C. A carbonic anhydrase inhibitor such as acetazolamide.
D. A loop diuretic such as furosemide.
E. A β-blocker such as metoprolol.

Answer 4
Correct answer is C. Acetazolamide is used prophylactically

for several days before an ascent above 10,000 feet. This
treatment prevents the cerebral and pulmonary problems
associated with the syndrome as well as other difficulties,
such as nausea.

Question 5
An alcoholic male has developed hepatic cirrhosis. To control

the ascites and edema, which should be prescribed?
A. Acetazolamide.
B. Chlorthalidone.
C. Furosemide.
E. Spironolactone.

Answer 5
Correct answer is E. Spironolactone is very effective in the

treatment of hepatic edema. These patients are frequently
resistant to the diuretic action of loop diuretics, although
a combination with spironolactone may be beneficial. The other
agents are not indicated.

Question 6
A 55-year-old male with kidney stones has been placed on a
diuretic to decrease calcium excretion. However, after a few
weeks, he develops an attack of gout. Which diuretic was he
taking?
A. Furosemide.
B. Hydrochlorothiazide.
C. Spironolactone.
D. Triamterene.
E. Urea.

Answer 6
Correct answer is B. Hydrochlorothiazide is effective in
increasing calcium reabsorption, thus decreasing the amount
of calcium excreted, and decreasing the formation of kidney
stones that contain calcium phosphate or calcium oxalate.
However, hydrochlorothiazide can also inhibit the excretion of
uric acid and cause its accumulation, leading to an attack of
gout in some individuals. Furosemide increases the excretion
of calcium, whereas the K+-sparing osmotic diuretics,
spironolactone and triamterene, and urea do not have an effect.

Question 7
A 75-year-old woman with hypertension is being treated
with a thiazide. Her blood pressure responds well and
reads at 120/76 mm Hg. After several months on the
medication, she complains of being tired and weak. An
analysis of the blood indicates low values for which of
the following?
A. Calcium.
B. Glucose.
C. Potassium.
D. Sodium.
E. Uric acid.
Answer 7
Correct answer is C. Hypokalemia is a common adverse
effect of the thiazides and causes fatigue and lethargy in the
patient. Supplementation with potassium chloride or foods
high in K+ corrects the problem. Alternatively, a potassium
sparing diuretic, such as spironolactone, may be added.
Calcium, uric acid, and glucose are usually elevated by thiazide
diuretics. Sodium loss would not weaken the patient.

Question 8
Which is contraindicated in a patient with hyperkalemia?

A. Acetazolamide.
B. Chlorthalidone.
C. Chlorothiazide.
D. Ethacrynic acid.
E. Spironolactone.

Answer 8
Correct answer is E. Spironolactone acts in the collecting tubule to

inhibit Na+ reabsorption and K+ excretion. It is extremely important
that patients who are treated with any potassium-sparing diuretic
be closely monitored for potassium levels. Exogenous potassium
supplementation is usually discontinued when potassium-sparing
diuretic therapy is instituted and spironolactone is contraindicated
in patients with hyperkalemia. The other drugs promote the
excretion of potassium.

Question 9
Which of the following should be avoided in a patient with a

history of severe anaphylactic reaction to sulfa medications?
A. Amiloride.
B. Hydrochlorothiazide.
C. Mannitol.
D. Spironolactone.
E. Triamterene.

Answer 9
Correct answer is B. Hydrochlorothiazide, like many thiazide
and thiazide-like diuretics, contains a sulfa moiety within its
chemical structure. It is important to avoid use in those individuals
with severe hypersensitivity to sulfa medications. It
may be used with caution, however, in those with only minor
reaction to sulfa medications.

Question 10
A male patient is placed on a new medication and notes that his

breasts have become enlarged and tender to the touch. Which
medication is he most likely taking?
A. Chlorthalidone.
B. Furosemide.
C. Hydrochlorothiazide.
D. Spironolactone.
E. Triamterene.

Answer 10
Correct answer = D. An adverse drug reaction to spironolactone is
gynecomastia due to its effects on androgens and progesterone in
the body. Eplerenone may be a suitable alternative if the patient is
in need of an aldosterone antagonist but has a history of
gynecomastia.

Question 11
A patient presents to the emergency department with an extreme
headache. After a thorough workup, the attending physician
concludes that the pain is due to increased intracranial pressure.
Which diuretic would work best to reduce this pressure?
A. Acetazolamide.
B. Indapamide.
C. Furosemide.
E. Mannitol.

Answer 11
Correct answer = E. Osmotic diuretics, such as mannitol, are a

mainstay of treatment for patients with increased intracranial
pressure or acute renal failure due to shock, drug toxicities, and
trauma.

Question 12
Which diuretic has been shown to improve blood pressure in
resistant hypertension or those already treated with three blood
pressure medications including a thiazide or thiazide-like diuretic?
A. Chlorthalidone.
B. Indapamide.
C. Furosemide.
D. Mannitol.
E. Spironolactone.

Answer 12
Correct answer = E. Resistant hypertension, defined by

the use of three or more medications without reaching the
blood pressure goal, often responds well to aldosterone
antagonists. This effect can be seen in those with or without
elevated aldosterone levels.

See next slide for sources and links to additional study tools and resources.
Sources and further study:
eLearning
Renal cloud folder tools and resources
MedPharm Guidebook:
Unit 9 Drugs Used to Affect Renal Function
Renal Pharmacology eNotes
Clinical Pharmacology Cases 7, 8, & 55 (Learning Triggers)
Textbooks
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011
Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill,
2012
Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014
Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.

Clinical Pharmacology of Drugs Used To Affect Renal Function

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Photo: Scanning electron micrograph of the glomerulus in a human kidney.

Marc Imhotep Cray, M.D. 3

 Drugs that affect renal function have important roles in cardiac

 Disease of kidney must be taken into account when prescribing

Marc Imhotep Cray, M.D. 9

Other organs involved in this mechanism include:

Marc Imhotep Cray, M.D. 10

Design of drugs that selectively target components of this system

Marc Imhotep Cray, M.D. 11

 To be therapeutically useful a diuretic should

Marc Imhotep Cray, M.D. 14

 Most clinically useful diuretics are organic anions

 Following is a brief account of tubular function with particular

 These solute shifts give rise to iso-osmotic reabsorption of water with

 Epithelium of PCT is described as “leaky” because of its free permeability

 Their effect is to increase water rather than sodium loss

Marc Imhotep Cray, M.D. 17

Marc Imhotep Cray, M.D. 18

 As tubule epithelium is “tight” here, i.e. impermeable to water tubular

 Epithelium is also tight at Site 3 and consequently urine

 Na ions enter through epithelial Na channel (called ENaC),

 Removal of this sodium through ENaC increases potential

 K+ sparing diuretics are weak diuretics b/c Site 4 is normally

Marc Imhotep Cray, M.D. 26

Progressive increase in dose is matched by increasing diuresis,

Loop diuretics remain effective at a glomerular filtration rate

 Increasing dose produces relatively little added diuresis

 Cease to be effective once GFR has fallen below 20 mL/min

Osmotic diuretics, e.g. mannitol, also fall into this category

Marc Imhotep Cray, M.D. 29

 Hypertension, by reducing intravascular volume and other mechanisms

 Idiopathic hypercalciuria, a common cause of renal stone disease, may be

 Syndrome of inappropriate secretion of antidiuretic hormone secretion

 Nephrogenic diabetes insipidus, paradoxically, may respond to diuretics

Marc Imhotep Cray, M.D. 33

Marc Imhotep Cray, M.D. 34

Non-steroidal anti-inflammatory drugs (NSAIDs), notably

Ethacrynic acid is less widely used as it is more prone to cause

Marc Imhotep Cray, M.D. 38

With exception of metolazone, thiazides are not effective when

Marc Imhotep Cray, M.D. 39

 Thiazide-type drugs increase total plasma cholesterol concentration

 Questions about appropriateness of thiazides for mild hypertension, of

Marc Imhotep Cray, M.D. 40

 Excessive secretion of aldosterone contributes to fluid retention in

 Spironolactone is also useful in treatment of resistant hypertension

 Minor gastrointestinal upset also occurs and there is increased risk of

 Spironolactone is reported to be carcinogenic in rodents, but many years

 It is useful in patients who need an aldosterone-receptor

Marc Imhotep Cray, M.D. 45

 maximum effect of amiloride occurs about 6 h after an oral dose, with a

 oral dose is 5–20 mg daily

Marc Imhotep Cray, M.D. 46

 Diuretic effect extends over 10 h

 Thus they prevent reabsorption of water (and also, by more

 Result is urine volume increases according to load of osmotic

 In addition to its effect on kidney, mannitol encourages movement of

 b/c mannitol increases circulatory volume, it is contraindicated in

Marc Imhotep Cray, M.D. 49

 Acetazolamide is not recommended for long-term use b/c of risk of

Marc Imhotep Cray, M.D. 51

 Acetazolamide induces metabolic acidosis increases respiratory drive,

 250 mg twice daily is used to treat established high-altitude

 As an alternative or in addition to acetazolamide

2. Acetazolamide may be used occasionally as a second-line

Marc Imhotep Cray, M.D. 54