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

Marc Imhotep Cray, M.D.
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.
2
Companion: Renal Pharmacology eNotes

Some Relevant Drugs:
3
A. Carbonic Anhydrase
Inhibitors
Acetazolamide
dichlorphenamide
methazolamide
dorzolamide
B. Osmotic Diuretics
mannitol
C. Loop Diuretics
furosemide
bumetanide
torsemide
ethacrynic acid
D. Thiazides & Thiazides-like
chlorthalidone
chlorothiazide
hydrochlorothiazide
metolazone
indapamide
E. Potassium-sparing
diuretics
spironolactone
eplerenone
triamterene
amiloride
F. ADH antagonists
demeclocycline
lithium
lixivaptan
tolvaptan
conivaptan

Topical Outline:
4
o Role of Renal System
 Volume Homeostasis
o General Principles of Diuretic Action
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 Alkalinization
o Acidification
o Drugs and the Kidney and Prescribing in Renal Disease
o ADH Antagonists
 Clinical Cases and Discussions
 Practice MCQs

Key Abbreviations
5
 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
6
 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.
7
 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
8
 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
9
 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
 drugs can damage kidney and disease of kidney affects
responses to drugs (will be covered elsewhere)

Role of Renal System (2):
Volume Homeostasis
10
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)
11
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

Marc Imhotep Cray, M.D. 12
Volume expansion
feedback control
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Volume contraction
feedback control
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

General Principles of Diuretic Action
14
 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)

GP of Diuretic Action (2)
15
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

16
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

17
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

18
 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
Loop of Henle

19
 Physiologic changes best understood by first considering ascending limb
 In TAL (Site 2, slide 25) 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
Loop of Henle cont.

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 TAL (Site 2, slide 25) by inhibiting the three-ion
transporter (NKCC2) thus preventing sodium ion reabsorption
and lowering osmotic gradient betw. cortex and medulla
results in formation of large volumes of dilute urine
 Hence, called “loop” diuretics

Distal convoluted tubule (DCT)
 Ascending limb of the loop then re-enters renal cortex where its
morphology changes into thin-walled DCT (Site 3, slide 25)
 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 at this region of cortical diluting segment by blocking NCC
transporter

 In collecting duct (Site 4, slide 25), 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
gradient created by sodium reabsorption
Cortical collecting duct (CCD)

 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) over sodium loss
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
Cortical collecting duct (CCD) cont.
NB: Diuresis may also be achieved by extrarenal
mechanisms, by raising cardiac output and increasing
renal blood flow, e.g. with dobutamine and dopamine.

25Bennett PN, Brown MJ and Sharma P. Clinical Pharmacology 11th Ed. Edinburgh: Churchill Livingstone, 2012.
Sites of action of diuretic drugs
Inset show transporters and ion
channels targeted in tubular
cells at these sites
• ENaC, epithelial sodium
channel;
• NCCT, thiazide-sensitive
Na–Cl co-transporter;
• NKCC2, Na–K–2Cl co-
transporter;
• ROMK, rectifying outer
medullary potassium channel

Classification
26
 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.

Classification
27
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)

Classification
28
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)

Classification
29
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

Indications
30
 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

 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
in PCT thus reduce urine volume
Indications cont.

Individual Agents/Classes
32
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
33

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)
34

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
35

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 more predictable oral absorption
Ethacrynic acid is less widely used as it is more prone to cause
adverse effects, especially nausea and deafness (ototoxicity)
 Not sulfa containing 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)
36

NB Sidebar: Sulfa drugs and sulfa allergies
 Sulfa containing drugs:
Sulfonamides antibiotics, Sulfasalazine, Probenecid, Furosemide,
Acetazolamide, Celecoxib, Thiazides, Sulfonylureas
(Scary Sulfa Pharm FACTS)
 Clinical manifestations of sulfa allergies= Pts. w sulfa allergies
may develop:
 Fever
 Urinary tract infection
 Stevens-Johnson syndrome (SJS)
 Hemolytic anemia, thrombocytopenia agranulocytosis, and
 Urticaria (hives)
 Symptoms range from mild to life threatening

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
37

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
o excreted unchanged in urine and active secretion by PCT
contributes to high renal clearance and t½ of less than 4 h
38

Thiazides cont.
Pharmacokinetics
 Relatively lipid-soluble members, e.g. polythiazide,
hydroflumethiazide, distribute more widely into body tissues
and act for >24 h
o can be problematic if used for diuresis, but no evidence this property
makes them more effective at controlling hypertension
With exception of metolazone, thiazides are not effective when
renal function is impaired (GFR <20 mL/min), b/c they are not
filtered in sufficient conc. to inhibit NCC (Na-Cl cotransporter)
39

Thiazides cont.
Adverse effects
(Adverse effects in general discussed in a section to follow)
 Rashes (sometimes photosensitive)
 thrombocytopenia and
 agranulocytosis occur
 Thiazide-type drugs can 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
40

Diuretics related to thiazides
Several compounds, not strictly thiazides, share structural similarities and
act at same site on nephron
Overall, these agents have a longer duration of action, are used for
edema and hypertension, and their profile of adverse effects similar to
thiazides
 Chlorthalidone 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
very 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 of 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
42

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 w a drug that reduces sodium
 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 43

Adverse effects
 Estrogenic effects are major limitation to its long-term use
 Randomized Aldactone Evaluation Study (RALES) even 25 mg/day caused breast
tenderness or enlargement in 10% of men (N Engl J Med. 1999 Sep 2;341(10):709-17)
 Women may also report breast discomfort or menstrual irregularities, including
amenorrhea
 Minor gastrointestinal upset and increased risk of gastroduodenal ulcer
and bleeding
 Usually reversible on stopping drug
 Spironolactone is reported to be carcinogenic in rodents, but clinical
experience suggest tit is safe in humans
 Nevertheless, UK license for its use in essential hypertension was withdrawn (i.e.
possible use long term in a pt. group including relatively young), but is retained for
other indications 44

 Eplerenone is a spironolactone analog licensed for use
in heart failure
 free of estrogenic effects; b/c of its lower affinity for
estrogen receptor
 It is useful in pts who need an aldosterone-receptor blocking
agent, but are intolerant of endocrine effects of spironolactone
45

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
46

 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
47

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
48

Osmotic diuretics cont.
 Mannitol, a polyhydric alcohol (mol. wt. 452), is used most commonly
given intravenously
 In addition to effect on kidney, mannitol encourages movement of water
from inside cells to extracellular fluid ECF (including circulatory volume)
thus transiently expanded before diuresis occurs
Uses:
Rapid reduction of intracranial or intraocular pressure, and to maintain urine
flow to prevent renal tubular necrosis
Contraindications:
 b/c mannitol increases circulatory volume, it is contraindicated in
congestive cardiac failure (CHF) and pulmonary edema (PE)
49

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
 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 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 50

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
51

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 oxygen 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 53

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
54

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
55

Adverse effects of diuretics
and
Drug-Drug Interactions
57

Potassium depletion
57
Diuretics that act at Sites 1, 2 and 3 of slide 25 cause more
sodium to reach sodium–potassium exchange site in 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)
Safe lower limit for plasma potassium conc. 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 following slides explain more

Potassium depletion
58
 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
 NB: Hypokalemia predisposes pts Tx with cardiac glycosides
(digoxin) to toxicity (permissive for digoxin binding at K+ binding
site on Na+/K+ ATPase)

Potassium depletion cont.
59
 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 and 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
60

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 K 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. 61

Hyperkalemia
Hyperkalemia may occur, esp. if a K+ sparing diuretic is given to
a patient with impaired renal function
 ACE inhibitors and ARBs can 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
o However, w suitable monitoring combination can be used safely,
as was well illustrated by RALES trial
 Cyclosporine, tacrolimus, indomethacin and possibly other
NSAIDs may cause hyperkalemia w potassium-sparing diuretics
62

Treatment of hyperkalemia
Tx of ↑K+ depends on severity and following measures are
appropriate:
 Any potassium-sparing diuretic should be discontinued
 A cation-exchange resin, e.g. Polystyrene sulfonate resin can
be used orally (more effective than rectally), to remove body
potassium by gut
 K+ may be moved rapidly from plasma into cells by giving:
o sodium bicarbonate, 50 mL 8.4% solution through a central line, and
repeated in a few minutes if characteristic ECG changes persist
o glucose, 50 mL 50% solution, plus 10 units regular insulin by i.v.
infusion
o nebulized β2-agonist, salbutamol 5–10 mg, is effective in stimulating
pumping of potassium into skeletal muscle

Tx of hyperkalemia cont.
 In presence of ECG changes, calcium gluconate, 10 mL of 10%
solution, given i.v. and repeated if necessary in a few minutes
o it has no effect on serum potassium but opposes
myocardial effect of a raised serum potassium level
o Caution
• Calcium may potentiate digoxin and should be used cautiously, if
at all, in a patient taking this drug
• NB: Sodium bicarbonate and calcium salt must not be mixed in a
syringe or reservoir b/c calcium precipitates
 Dialysis may be needed in refractory cases & is highly effective

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
63

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
64

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
65

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)
66

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)
67

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
68

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
69

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
70

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
71

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 chloride by mouth 72

Drugs and the Kidney
and
Prescribing in Renal Disease

Drugs and the Kidney
Drug-induced renal disease
Drugs and other chemicals damage kidney by 3 major mechanisms:
1. Direct biochemical effect Substances that cause such toxicity include:
 heavy metals, e.g. mercury, gold, iron, lead
 antimicrobials, e.g. aminoglycosides, amphotericin, cephalosporins
 iodinated radiological contrast media, e.g. agents for visualizing GIT
 analgesics, e.g. NSAID combinations
 solvents, e.g. carbon tetrachloride, ethylene glycol
2. Indirect biochemical effect:
 cytotoxic drugs and uricosurics may cause urate to be precipitated in
tubule
 calciferol may cause renal calcification by inducing hypercalcemia
 diuretic and laxative abuse can cause tubular damage secondary to K+
and Na+ depletion
 anticoagulants may cause hemorrhage into kidney

Drugs and the Kidney (2)
Drug-induced renal disease cont.
3. Immunological effect
 A wide range of drugs produces a wide range of injuries:
 including phenytoin, gold, penicillins, hydralazine, isoniazid, rifampin,
penicillamine, probenecid, sulfonamides
 drugs may cause damage by more than one of above mechanisms, e.g. gold
 Sites and pathological types of injury are:
o Glomerular damage, eg. Penicillamine= damage from circulating
immune complexes
o Tubule damage, eg. acids, e.g. salicylate (aspirin), cephalosporins &
bases, e.g. aminoglycosides, Heavy metals and contrast media
o Tubule obstruction, eg. Methotrexate is relatively insoluble at low
urine pH and can precipitate in distal nephron

Drugs and the Kidney (3)
 Other drug-induced lesions of kidney include:
 Vasculitis, caused by allopurinol, isoniazid, sulfonamides
 Allergic interstitial nephritis, caused by penicillins (especially), thiazides, allopurinol,
phenytoin, sulfonamides
 Drug-induced lupus erythematosus, caused by hydralazine, procainamide,
sulfasalazine
 Drugs may thus induce any of common clinical syndromes of renal injury, namely:
 Acute renal failure, e.g. aminoglycosides, cisplatin
 Nephrotic syndrome, e.g. penicillamine, gold, captopril (only at higher doses than
now recommended)
 Chronic renal failure, e.g. NSAIDs.
 Functional impairment, i.e. reduced ability to dilute and concentrate urine (lithium),
potassium loss in urine (loop diuretics), acid–base imbalance (acetazolamide)

Prescribing In Renal Disease
 Drugs may:
 exacerbate renal disease (see previous section)
 be ineffective, e.g. thiazide diuretics in moderate or severe renal failure;
uricosurics
 be potentiated by accumulation due to failure of renal excretion
 First option is to seek an alternative drug that does not depend on renal
elimination
 NB: Problems of safety arise for pts. w impaired renal function who must
be treated w a drug that is potentially toxic and that is wholly or largely
eliminated by kidney
 A knowledge of, or at least access to, sources of pharmacokinetic data
is essential for safe therapy for such patients,
o e.g. manufacturers’ data, formularies and specialist journals

Prescribing In Renal Disease (2)
Drug t½ (h) in normal and severely impaired renal function
Glomerular filtration rate <5 mL/min (normal value is 120 mL/min).
These values illustrate major effect of impaired renal function on
elimination of certain drugs. Depending on circumstances, alternative
drugs must be found or special care exercised when prescribing drugs
that depend significantly on kidney for elimination.
Modifiedafter:BennettPN,BrownMJandSharmaP.Clinical
Pharmacology11thEd.Edinburgh:ChurchillLivingstone,2012.

t½ of other drugs, where activity is terminated by metabolism,
is unaltered by renal impairment
  but many such drugs produce pharmacologically active metabolites
that are more water soluble than parent drug rely on kidney for their
elimination, and accumulate in renal failure, e.g.
o acebutolol,
o diazepam,
o warfarin,
o meperidine
Majority of drugs fall into an intermediate class =
 partly metabolized and
 partly eliminated unchanged by kidney

 Administering correct dose to a patient with renal disease
must take into account both
1. extent drug normally relies on renal elimination and
2. degree of renal impairment
 Best guide to renal impairment is creatinine clearance and not
serum creatinine level itself as serum Cr can be notoriously
misleading in elderly and at extremes of body mass
 CrCl can be predicted from serum creatinine concentration, sex, age
and weight using Cockcroft–Gault formula
o A number of free online calculators are available, e.g. http://www.medical-
calculator.nl/calculator/GFR/
To learn more see: Tutorial_3 Renal Drug Elimination and Dosing in Renal Impairment

Dose adjustment for patients with renal impairment
 Adjustment of initial dose (or where necessary priming or loading dose) is
generally unnecessary, as volume into which drug has to distribute should be
same in uremic and healthy subject
 There are exceptions to this rule of thumb for example, volume of distribution of
digoxin is contracted in urinemic patients due to altered tissue binding of drug
 Adjustment of maintenance dose involves either reducing each dose given
or lengthening time between doses
 Special caution is needed when patient is hypoproteinemia and drug is
usually extensively plasma protein bound, or in advanced renal disease
when accumulated metabolic products may compete for protein binding
sites
 Careful observation is required in early stages of dosing until response to
drug can be gauged

General rules
1. Drugs that are completely or largely excreted by kidney, or drugs that produce active,
renally eliminated metabolites:
 give a normal or, if there is special cause for caution (as discussed above), a slightly
reduced initial dose, and lower maintenance dose or lengthen dose interval in
proportion to reduction in creatinine clearance
2. Drugs that are completely or largely metabolized to inactive products:
 Give normal doses
 When note of special caution (as above) applies, a modest reduction of initial dose
and maintenance dose rate are justified while drug effects are assessed
3. Drugs that are partly eliminated by kidney and partly metabolized:
 give a normal initial dose and modify maintenance dose or dose interval in light of what
is known about patient’s renal function and drug its dependence on renal elimination
and its inherent toxicity

Recall that time to reach steady-state blood concentration is
dependent only on drug t½, and a drug reaches 97% of its
ultimate steady-state concentration in 4-5 x t½
 Thus, if t½ is prolonged by renal impairment, so also will be the time to
reach steady state.
Schemes for modifying drug dosage for patients with renal
disease diminish but do not remove their increased risk of
adverse effects
 patients should be observed carefully throughout a course of drug TX
 Where service is available, dosing should be monitored by drug plasma
concentration measurements

ADH Antagonists
87
 Demeclocycline
 Lithium
 Lixivaptan
 Satavaptan
 Conivaptan
 Tolvaptan

Antidiuretic Hormone Antagonists
88
 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)
89
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

90
 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
Vaptans

91
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

92
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

93
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

94
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

95
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:
Lippincott Williams & Wilkins, 2014.

Case-based Discussions
97

Case 7-Diuretics
98
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:
99
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
100
 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
101
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:
102
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
103
 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
104

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
91

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
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.
94

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.
96

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.
97

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.
98

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.
99

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.
100

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.
101

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.
102

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.
103

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.
104

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.
105

Question 8
Which is contraindicated in a patient with hyperkalemia?
A. Acetazolamide.
B. Chlorthalidone.
C. Chlorothiazide.
D. Ethacrynic acid.
E. Spironolactone.
106

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.
107

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.
108

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.
109

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.
110

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.
111

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.
112

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.
113

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.
114

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.
115

See next slide for sources and links to additional study tools and resources.
130

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.
131

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