Renal pharmacology

Renal Pharmacology
Physiology Review

Background:

 Body fluid and electrolyte composition are regulated by the kidney-- drugs that interfere
with renal transport may be useful in management of clinical disorders.
 Diuretics are drugs which block renal ionic transport, causing diuresis {an increase in
urine volume}, often associated with natriuresis {increase in sodium excretion}
 Diuretics often act at different sites of the tubule transport system, at specific membrane
transport proteins
 Diuretics that act on specific membrane transport proteins include:
o loop diuretics
o thiazides
o amiloride (Midamor)
o triamterene (Dyrenium)
 Diuretics may act through:
o osmotic effects (preventing water reabsorption)-- mannitol
o enzyme inhibition (carbonic anhydrase inhibitor)-- acetazolamide
o interaction with hormonal receptors: spironolactone
 Renal physiology and sites of diuretic action:

courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic
Institute, used with permission

 "The glomerular capillaries are very leaky about 400 times as high as most
other capillaries and produce a filtrate that is similar to blood plasma
except the it is devoid of proteins and cellular elements.
 The glomerular filtration rate (GFR) is effected by the same forces as
other capillaries:
o GFR = Kf X (Pc -Pb - PiG +PiB)
o where Kf = Filtration coefficient
o Pc = Glomerular hydrostatic pressure
o Pb = Bowman's capsule hydrostatic pressure
o PiG = Glomerular capillary colloidal osmotic pressure
o PiB = Bowman's capsule colloidal osmotic pressure "
 courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute,
used with permission

 Proximal tubule:
o Many solutes are reabsorbed in the early portions of the proximal tubule:
 85% of filtered sodium bicarbonate
 40% of sodium chloride
 60% of water

 nearly all of filtered organic solutes, including glucose and amino acids
 glucose, amino acids, and other organic solutes are reabsorbed by
specific transport systems

Sodium Bicarbonate and the Proximal Tubule

 Mechanism of Action: In the proximal tubule, sodium bicarbonate reabsorption can be
influenced by carbonic anhydrase inhibitors.
o Sodium bicarbonate reabsorbed in the proximal tubule depends on the action of
sodium/hydrogen exchanger which is found in the luminal membrane of the
proximal tubule epithelial cell.
1. proton secreted into lumen (urine) combine with bicarbonate to form
carbonic acid (H2CO3)
2. Carbonic acid is dehydrated by an enzyme carbonic anhydrase which is
localized (among other places) on the brush border membrane.
3. The dehydration products carbon dioxide and water easily move across
membranes. Carbon dioxide enters the proximal tubule by diffusion where
it is rehydrated back to carbonic acid.
4. Carbonic acid dissociates back to bicarbonate and the proton (step one)
5. This cycle depends on carbonic anhydrase
o Mechanism of Action: Inhibition of carbonic anhydrase decreases bicarbonate
reabsorption in proximal tubule, which in turn decreases water reabsorption
o Carbonic anhydrase inhibitor: acetazolamide (Diamox)
 In the proximal tubule, water is reabsorbed in direct proportion to salt.
 With a large concentration of impermeant solute, such as glucose or the diuretic
mannitol, water reabsorption would decrease for osmotic reasons. (Mechanism for
osmotic diuresis)

Organic Acid Secretory System

 Located in the middle third proximal tubule
o Organic acid secretory system secretes for example:
 uric acid

 antibiotics
 p-aminohippuric acid

Organic Base Secretory System

 Localized in both early and middle segments of the proximal tubule
o Organic base secretory system secretes, for example:
 creatinine
 procainamide {antiarrhythmic drug}
 choline
 Organic acid and base transport systems are important in delivery of diuretics to their site
of action: luminal side
 Drug interaction: diuretics and probenecid (secretory system inhibitor)

 Loop of Henle
o Thin limb
 water reabsorption
 driving force: osmotic -- due to hypertonic medullary fluid
 no active salt reabsorption, but impermeant solutes (mannitol, glucose)
will inhibit water reabsorption {a site of action for osmotic diuretics}
o Thick ascending limb of the loop of Henle: active sodium chloride reabsorption
{about 35% of filtered load}--
 impermeable to water
 since reabsorption of sodium chloride at this site dilutes the fluid in the
tubule, this segment may be referred to as "diluting segment."
 Reabsorption of sodium chloride in the thick ascending limb is dependent
upon the Na/K/2Cl co-transporter.
1. Loop diuretics block this transporter.
 furosemide (Lasix)
 bumetanide (Bumex)
 ethacrynic acid (Edecrin)
 torsemide (Demadex)

2. Normal activity of this transporter and Na/K ATPase results in an
increase in intracellular potassium, potassium efflux, and a lumen-
positive electrical potential:
3. This lumen-positive membrane potential provides the driving force
for reabsorption of magnesium and calcium cations.
4. Therefore loop diuretics which inhibit the action of the sodium
potassium chloride co-transporter, leading to increase sodium
excretion also leads to increased magnesium and calcium loss.
 Distal Convoluted Tubule
o Properties:
 impermeable to water
 sodium reabsorption (about 10% of filtered load) by sodium and chloride
co-transporter
 further dilution of tubular fluids
o Pharmacological blockade of sodium and chloride co-transporter:
 thiazide diuretics
 no potassium recycling; no lumen-positive membrane potential; -- no
calcium or magnesium loss by electrical forces
o Calcium is actively reabsorbed by:
 an apical calcium channel and
 Na/Ca exchanger
 regulated by parathyroid hormone
 Collecting Tubule
o Properties:
 About 2% to 5% of sodium chloride reabsorption
 Final site for sodium chloride reabsorption -- responsible for final sodium
concentration in the urine
 This site and late distal tubule -- where mineralocorticoids exert their
effect
 Major site of potassium secretion
 Major sites for sodium, potassium, and water transport

 principal cells
 Major site for proton secretion -- intercalated cells
 Separate sodium and potassium channels:
 Significant driving force for sodium entry
 Na after entering the principal cell is transported to the blood
{Na/K ATPase} with potassium translocated to the lumen urine
(lumen-negative electrical potential drives chloride back to the
blood)
 Accordingly, delivery of increased sodium to the collecting
tubule drives increased potassium efflux
 Diuretics (acting upstream) that increased delivery of
sodium to the collecting tubule will cause potassium loss
 Delivery of bicarbonate {not readily reabsorbed compared
chloride, increasing lumen-negative potentials}, will
increase further potassium loss.
 Diuretic-induced potassium loss, which is clinically
important, results from the above mechanisms coupled with
enhanced aldosterone secretion due to volume depletion.

 Major pharmacokinetic, pharmacodynamic and mechanism of action of Diuretic Classes:
o Carbonic Anhydrase Inhibitors
o Potassium Sparing
o Loop Diuretics
o Thiazides
o Osmotic Agents

Carbonic Anhydrase Inhibitors

 The enzyme, carbonic anhydrase exhibits the following characteristics:
o Its major location is the luminal proximal tubule membrane.
o Carbonic anhydrase catalyzes dehydration of carbonic acid, H2CO3 , required for
bicarbonate reabsorption

o Blockade of carbonic anhydrase activity induces a sodium bicarbonate diuresis,
which reduces body bicarbonate levels
 Carbonic anhydrase inhibitors are unsubstituted sulfonamides which are bacteriostatic.
These agents promote alkaline diuresis and a hyperchloremic metabolic acidosis.
o Prototype drug: acetazolamide (Diamox)
 Acetazolamide: (Diamox) is well absorbed orally and is excreted by tubular secretion, at
the proximal tubule.
o In renal insufficiency a dose reduction is appropriate.
o At maximal carbonic anhydrase inhibition, a 45% inhibition of bicarbonate
reabsorption is observed.
 This level of inhibition results in significant bicarbonate loss and a
hyperchloremic metabolic acidosis.
 Acetazolamide (Diamox) administration causes a reduction in aqueous
humor and cerebrospinal fluid production
o Clinical Application:
 Glaucoma:
 Because acetazolamide decreases the rate of aqueous humor
production, a decline in intraocular pressure occurs.
 Management of glaucoma is the most common indication for use
of carbonic anhydrase inhibitors.
 Dorzolamide (Trusopf), another carbonic anhydrase inhibitor
exhibits no diuretic or systemic metabolic effect; however,
administration of this agent causes a reduction in intraocular
pressure.
 Urinary Alkalinization:
 increased uric acid and cystine solubility by alkalinizing the urine
(by increasing bicarbonate excretion)
 for prophylaxis of uric acid renal stones, bicarbonate
administration (baking soda) may be required
 Metabolic Alkalosis:
 Results from:

o decreased total potassium with reduced vascular volume
o high mineralocorticoid levels
o These conditions are usually managed by treating the
underlying causes; however, in certain clinical settings
acetazolamide may assist in correcting alkalosis {e.g.
alkalosis due to excessive diuresis in CHF patients}
 Acute Mountain Sickness:
 Symptoms: weakness, insomnia, headache, nausea, dizziness
{rapid ascension of all of 3000 meters}; symptoms -- usually mild
 In serious cases: life-threatening cerebral or pulmonary edema
 Acetazolamide reduces the rate of CSF formation and decreases
cerebral spinal fluid pH.
 Prophylaxis against acute mountain sickness may be appropriate
 Other Uses:
 some role in management of epilepsy
 hypokalemia periodic paralysis
 increase urinary phosphate excretion during severe
hyperphosphatemia.
o Toxicity:
 hyperchloremic metabolic acidosis
 due to reduction of body bicarbonate stores
 renal stones:
 bicarbonate loss is associated with:
o phosphaturia
o hypercalciuria (calcium salts, relatively insoluble at
alkaline pH)
 renal potassium loss:
 increased sodium bicarbonate in the collecting tubule increases the
lumen-negative electrical potential -- enhances potassium excretion
o counteracted by potassium chloride administration
 Others:

 drowsiness, parathesias
 accumulation in renal failure (CNS toxicity)
 hypersensitivity reactions
 Contraindications:
 hepatic cirrhosis
o urinary alkalinization will decrease ammonium ion
trapping, increasing the likelihood of hepatic
encephalopathy.

Loop Diuretic Drugs

 Introduction
o Agents include:
 furosemide (Lasix)
 bumetanide (Bumex)
 torsemide (Demadex)
 ethycrinic acid --no longer in use because of toxicity.
 Mechanism of action:
o inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle
 inhibit the Na/K/2Cl transport system in the luminal membrane
1. reduction in sodium chloride reabsorption
2. decreases normal lumen-positive potential (secondary to potassium
recycling)
3. Positive lumen potential: drives divalent cationic reabsorption
(calcium magnesium)
4. Therefore, loop diuretics increase magnesium and calcium
excretion.
 hypomagnesemia may occur in some patients.
 hypocalcemia does not usually develop because calcium is
reabsorbed in the distal convoluted tubule.
 {in circumstances that result in hypercalcemia,
calcium excretion can be enhanced by

administration of loop diuretics with saline
infusion}
o Since a significant percentage of filtered NaCl is absorbed by the thick ascending
limb of loop of Henle, diuretics acting at this site are highly effective
 Loop diuretics--Properties: rapidly absorbed following oral administration (may be
administered by IV)
o acts rapidly
o eliminated by a renal secretion and glomerular filtration (half-life -- depend on
renal function)
o co-administration of drugs that inhibit weak acid secretion (e.g. probenecid or
indomethacin) may alter loop diuretic clearance.
o Other effects:
 Furosemide: increases renal blood flow; blood flow redistribution within
the renal cortex
 Furosemide decreases pulmonary congestion and the left ventricular filling
pressure in congestive heart failure (CHF) -- prior to an increase in urine
output.
 Clinical Uses:
o Major uses:
 acute pulmonary edema
 acute hypercalcemia
 management of edema
o Other uses:
 hyperkalemia:
 loop diuretics increase potassium excretion
 effect increased by concurrent administration of NaCl and water.
 acute renal failure:
 may increase rate of urine flow and increase potassium excretion.
 may convert oligouric to non-oligouric failure {easier clinical
management}
 renal failure duration -- not affected

 anion overload:
 bromide, chloride, iodide: all reabsorbed by the thick ascending
loop:
 systemic toxicity may be reduced by decreasing reabsorption
 concurrent administration of sodium chloride and fluid is
required to prevent volume depletion
 Toxicity:
o Hypokalemia metabolic alkalosis:
 increased delivery of NaCl and water to the collecting duct increases
potassium and proton secretion-- causing a hypokalemic metabolic
alkalosis
 in managed by potassium replacement and by ensuring adequate fluid
intake
o Ototoxicity:
 dose-related hearing loss (in usually reversible)
 ototoxicity more common:
 with decreased renal function
 with concurrent administration of other ototoxic drugs such as
aminoglycosides
o Hyperuricemia:
 may cause gout
 loop diuretics cause increased uric acid reabsorption in the proximal
tubule, secondary to hypovolemic states.
o Hypomagnesemia: loop diuretics cause:
recycling)
3. Positive lumen potential: drives divalent cationic reabsorption (calcium
magnesium)
4. Therefore, loop diuretics increase magnesium and calcium excretion.
 hypomagnesemia may occur in some patients.

 reversed by oral magnesium administration
o Allergic reactions:
 furosemide: skin rash, eosinophilia, interstitial nephritis(less often)
o Other toxicities:
 Dehydration (may be severe)
 hyponatremia (less common than with thiazides thought may occur in
patients who increased water intake in response to a hypovolemic thirst)
 Hypercalcemia may occur in severe dehydration and if a hypercalcemia
condition {e.g. oat cell long carcinoma} is also present.

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-
Lange, 1998, pp 242-259.

Thiazides

 Introduction:
o Thiazides inhibit NaCl transport at the distal convoluted tubule
o Prototypical thiazide: hydrochlorothiazide

Thiazides and Related Sulfonamide Diuretics
bendroflumethazide benzthiazide chlorothiazide chlorthalidone

hydrochlorothiazide hydroflumethiazide indapamide methyclothiazide

metolazone polythiazide quinethazone trichlomethiazide

 Properties:
o Oral administration
o Secreted by the organic acid secretory system
 compete with uric acid for secretion {uric acid secretory rates may
decline}

o Differences between thiazides:
 chlorothiazide (Diuril): less lipid soluble (requires relatively large doses)
 chlorthalidone (Hygroton): slowly absorbed -- longer duration of action
 indapamide (Lozol): mainly biliary secretion
o Mechanism of action:
 Diuretic action:Inhibition of NaCl reabsorption from the distal convoluted
tubule (luminal side)
 enhance calcium reabsorption in the distal convoluted tubule (unknown
mechanism)
 thiazides infrequently cause hypercalcemia but can unmask
hypercalcemia due to other causes such as carcinoma, sarcoidosis,
or hyperparathyroidism.
 Clinical Uses:
o Hypertension
o Congestive heart failure
o Nephrolithiasis (due to idiopathic hypercalciuria
o Nephrogenic diabetes insipidus
 Toxicity:
o Hypokalemic metabolic alkalosis and hyperuricemia
o Impaired carbohydrate tolerance
 may induce hyperglycemia
 impaired pancreatic insulin release
 decreased tissue glucose utilization
 hyperglycemia may be partially reversed by correcting a
hypokalemic state
o Hyperlipidemia
 5% to 15% increase in serum cholesterol and an increase in low-density
lipoproteins.
o Hyponatremia:
 Significant adverse effect, occasionally life-threatening
 Mechanism:

 hypovolemia-induced increase in ADH
 reduced renal diluting capacity
 increased thirst
 Prevention: decreasing the drug dose or limiting fluid intake
o Allergic reactions:
 Thiazides are sulfonamides: cross-reactivity within the group
 photosensitivity {rare}
 dermatitis {rare}
 Extremely rare reactions:
 hemolytic anemia
 thrombocytopenia
 acute necrotizing pancreatitis
o Other reactions:
 weakness
 fatigue
 paresthesias

Potassium-Sparing Diuretic Agents

 Introduction:
o These diuretics inhibit the effects of aldosterone at the cortical collecting tubule
and late distal tubule.
o Mechanisms of action:
 In the collecting tubule and duct, sodium reabsorption and potassium
excretion is regulated by aldosterone.
 Aldosterone increases potassium secretion by increasing Na/K
ATPase activity and sodium and potassium channel activity.
 Normally, sodium absorption in the collecting tubule results in a
lumen-negative electrical force that drives potassium excretion.
 Aldosterone antagonists interfere with this effect

 Aldosterone antagonists act similarly with respect to proton
movement, accounting for metabolic acidosis associated with
aldosterone antagonists.
 pharmacologic antagonism at mineralocorticoid receptors { spironolactone
(Aldactone)}
 inhibition of sodium transport through the luminal membrane {triamterene
(Dyrenium), amiloride (Midamor)}
 Some Potassium-Sparing effects occur with nonsteroidal anti-
inflammatory drugs, beta-blockers, converting enzyme-inhibitors, and
angiotensin receptor blockers.
 Spironolactone (Aldactone):
o Synthetic steroid: competitive aldosterone antagonist
 binds to cytoplasmic mineralocorticoid receptors -- preventing receptor
complex translocation to the nucleus
 also inhibits formation of active metabolite of aldosterone {by inhibiting
5-alpha reductase activity}
o hepatic inactivation
o slow onset of action
 Triamterene (Dyrenium):
o Renal excretion; hepatic metabolism-- extensive metabolism (short half life)
o Directly blocks Na entry through sodium-specific channels (apical collecting
tubule membrane) -- note that since potassium secretion is coupled to sodium
entry, potassium secretion {potassium-sparing} is reduced.
 Amiloride (Midamor):
o Excreted unchanged (urine)
o Directly blocks Na entry through sodium-specific channels (apical collecting
tubule membrane) -- note that since potassium secretion is coupled to sodium
entry, potassium secretion {potassium-sparing} is reduced.
 Clinical Uses:
o Mineralocorticoid excess:
 Conn's syndrome (primary hypersecretion)

 ectopic ACTH production (primary hypersecretion)
 secondary aldosteronism caused by:
 congestive heart failure
 hepatic cirrhosis
 nephrotic syndrome
 conditions that cause renal salt retention with reduced intravascular
volume
o other diuretics may further reduce intravascular volume
thus worsening secondary aldosteronism
 Toxicity:
o Hyperkalemia:
 Potassium-sparing diuretics can cause significant hyperkalemia
 Factors that increase the likelihood of hyperkalemia:
 renal disease
 presence of agents that reduce renin:
o beta-blockers
o nonsteroidal anti-inflammatory drugs (NSAIDs)
o ACE inhibitors
o angiotensin receptor blockers
 hyperkalemia more likely when potassium-sparing diuretics are used as
the only diuretic drug or in the presence of renal insufficiency.
 given in combination with thiazides, hypokalemia and metabolic
alkalosis associated with thiazide use may be balanced by
aldosterone antagonists
 Since thiazide adverse effects may predominate {hyponatremia,
metabolic alkalosis}, due to variations in bioavailability, individual
dose adjustment of the two drugs may be better.
o Hyperchloremic Metabolic Acidosis:
 Acidosis cause by inhibition of proton secretion along with potassium
secretion {similar to type IV renal tubular acidosis
o Gynecomastia:

 Endocrine abnormalities associated with synthetic steroids --
Spironolactone (Aldactone)
 gynecomastia (breast enlargement)
 impotence
 benign prostatic hyperplasia
o Acute Renal Failure:
 Triamterene (Dyrenium) plus indomethacin
o Kidney Stones:
 Triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing
renal stones:
 Contraindications:
o may cause severe (potentially fatal) hyperkalemia
o potassium supplements should be discontinued prior to administration of
o patients with chronic renal insufficiency are at particular risk
o hyperkalemia is also more likely to occur or it if beta-blockers or ACE inhibitors
are concurrently administered
o impairment of hepatic metabolism of triamterene spironolactone may require dose
adjustment

Osmotic Diuretics

 Introduction:
o Osmotic diuretics cause water to be retained within the proximal tubule and
descending limb of loop of Henle (freely permeable to water)
o Mannitol (Osmitrol) is an example of osmotic diuretic.
o Clinical Use: mainly used to reduce increased intracranial pressure;
 Osmotic diuretics: properties
o mannitol (Osmitrol) : not metabolized, freely filtered at the glomerular

o usually administered by IV; oral administration results in an osmotic diarrhea--
perhaps useful to promote elimination of toxic substances from the GI tract (in
conjunction with activated charcoal)
o urine volume increases with mannitol excretion due to direct osmotic effects
 sodium reabsorption is reduced because of increased urine flow rates
{decreased contact time between urine and tubular epithelial cells}
 Clinical Uses:
o To increase urine volume:
 may be used to prevent anuria if the kidney due to hemolysis or
rhabdomyolysis is presented with a large pigmented load.
 when renal hemodynamics are compromised
o To decrease intracranial or intraocular pressure:
 Mannitol (Osmitrol) extract water from intracellular compartments,
reducing total body water
 Following IV administration, intracranial pressure falls within 60-90
minutes.
 Toxicity:
o Volume expansion effects -- increased extra cellular fluid volume and
hyponatremia may cause pulmonary edema, complicating congestive heart failure
o Headache, nausea, vomiting -- commonly observed
o Dehydration and hypernatremia:
 fluid loss leads to significant dehydration and in the absence of adequate
fluid replacement leads to hypernatremia.

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-
Lange, 1998, pp 242-259.

Diuretics: antihypertensive properties

 Two main classes of diuretics are used in mangement
of hypertension: thiazides and potassium sparing
drugs.
 Objective: pharmacological alteration of sodium load
 A reduction in sodium leads to reduced intravascular
volume and a blood pressure reduction.
 Thiazide diuretics cause an inhibition of NaCl
transport in the Distal Convoluted Tubule (DCT)

Anatomy of the Nephron: From:
Guyton's Textbook of
Physiology, Ninth Edition

 Orally active thiazide drugs have historically been a mainstay of
antihypertensive treatment, although present therapy often involves other drugs.

Note the progression
of antihypertensive
medication;

 beginning
with a low
dosage of
either an
ACE
inhibitor,
calcium
channel
blocker or
beta blocker

 and
proceeding,
if needed to
add a diuretic

 and
ultimately
additional
more
powerful
drugs, such
as centrally
acting
sympatholyti
cs, peripheral
vasodilators

or
combination.

At each step dosages
are reviewed and if
the patient's
hypertension is
controlled then
therapy may be
continued with
review for possible
removal of
medication.

Figure adapted from
Harrison's
"Principles of
Internal Medicine,
Thirteenth Edition,
p. 1128

 Reduction in blood pressure is initially due to a reduction in extracellular
volume and cardiac output.
 Long-term antihypertensive effects of thiazides appear due to reduced vascular
resistance. The exact mechanism responsible for the reduction in vascular
resistance is not known.
 Thiazides, due to their inhibition of the Na+-Cl- symport system, increase
sodium and chloride excretion.(renal synport diagram)

Distal Convoluted Tubule:From: Goodman and Gilman's "The Pharmacological Basis
of Therapeutics, Ninth Edition

 Thiazide diuretics, when used in the management of hypertension, is
administered in combination with a potassium-sparing drug. Reduction in the
amount of potassium loss can be achieved by:
 using potassium sparing drugs block Na+ channels in the late distal
tubule and collecting duct (amiloride (Midamor) &triamterene
(Dyrenium))

 Note that
amiloride
(Midamor) and
probably
triamterene
(Dyrenium) blocks
sodium channels
in the luminal
membrane in the
late distal tubule
and collecting
duct.
 Such action
inhibits the normal
movement of Na+
into the cell.

 Normally, Na+
entry create the net
negative luminal
charge that results
in K+ efflux.
 By reducing the
net negative
luminal charge,
amiloride
(Midamor)/triamte
rene (Dyrenium)
administration
help conserve
potassium.
Therefore, they are
called "potassium
sparing".

Figure adapted from
"Goodman and Gillman's
The Pharmacological
Basis of Therapeutics"
Ninth Edition, p. 705

 Inhibition of aldosterone action (spironolactone (Aldactone))

 Spironolactone is
an antagonist of
mineralocorticoid
receptors
(aldosterone-
antagonist) .

 Normally,
aldosterone
interactions with
mineralocoricoid
receptors result in
synthesis of
aldosterone-
induced proteins
(AIPs).

 These proteins
appear to increase
the number or
activity of Na+
channels and
cause an increase
in Na+
conductance.

 Increased Na+
conductance (with
inward movement
of Na+) results in a
net negative

luminal charge
favoring K+ loss.

 Antagonism of the
interaction
between
aldosterone and its
receptor by
spironolactone
conserves K+
(potassium
sparing).

Figure from Goodman
and Gilman's "The
Pharmacological Basis of
Therapeutics" Ninth
Edition, p. 708

 inhibition of aldosterone release by ACE inhibitors or angiotensin-receptor
blockers

Clinical uses of diuretics

Carbonic Anhydrase Inhibitor

 Acetazolamide (Diamox)
 Glaucoma:
o decreases rate of aqueous humor production -- leads to a declining in intraocular
pressure
o most common indication for use of carbonic anhydrase inhibitors

o Dorzolamide (Trusopf): topical carbonic anhydrase inhibitor.
 no diuretic or systemic metabolic effects
 reduction in intraocular pressure comparable to oral agents
 Urinary Alkalinization:
o increased uric acid and cystine solubility by alkalinizing the urine (by increasing
bicarbonate excretion)
o for prophylaxis of uric acid renal stones, bicarbonate administration (baking soda)
may be required
 Metabolic Alkalosis:
o Results from:
 decreased total potassium with reduced vascular volume
 high mineralocorticoid levels
 These conditions are usually managed by treating the underlying causes;
however, in certain clinical settings acetazolamide may assist in correcting
alkalosis {e.g. alkalosis due to excessive diuresis in CHF patients}
 Acute Mountain Sickness:
o Symptoms: weakness, insomnia, headache, nausea, dizziness {rapid ascension of
all of 3000 meters}; symptoms -- usually mild
o In serious cases: life-threatening cerebral or pulmonary edema
o Acetazolamide (Diamox) reduces the rate of CSF formation and decreases
cerebral spinal fluid pH.
o Prophylaxis against acute mountain sickness may be appropriate
 Other Uses:
o some role in management of epilepsy
o hypokalemia periodic paralysis
o increase urinary phosphate excretion during severe hyperphosphatemia.

Loop Diuretics

 Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), ethacrynic acid
(Edecrin)
 Major Clinical uses:

o acute pulmonary edema
o acute hypercalcemia
o management of edema
 Other uses:
o hyperkalemia:
 loop diuretics increase potassium excretion
 effect increased by concurrent administration of NaCl and water.
o acute renal failure:
 may increase rate of urine flow and increase potassium excretion.
 may convert oligouric to non-oligouric failure {easier clinical
management}
 renal failure duration -- not affected
o anion overload:
 bromide, chloride, iodide: all reabsorbed by the thick ascending loop:
 systemic toxicity may be reduced by decreasing reabsorption
 concurrent administration of sodium chloride and fluid is required
to prevent volume depletion

Thiazides

chlorothiazide chlorthalidone
bendroflumethazide benzthiazide
(Diuril) (Hygroton)
hydrochlorothiazide
indapamide
(HCTZ, Esidrix, hydroflumethiazide methyclothiazide
(Lozol)
HydroDIURIL)
metolazone
(Zaroxolyn, polythiazide quinethazone trichlomethiazide
Mykrox)

 Hypertension
 Congestive heart failure
 Nephrolithiasis (due to idiopathic hypercalciuria
 Nephrogenic diabetes insipidus

Osmotic Diuretics

Mannitol (Osmitrol)

 To increase urine volume:
o may be used to prevent anuria if the kidney due to hemolysis or rhabdomyolysis is
presented with a large pigmented load.
o when renal hemodynamics are compromised
 To decrease intracranial or intraocular pressure:
o Mannitol extract water from intracellular compartments, reducing total body
water
o Following IV administration, intracranial pressure falls within 60-90 minutes.

Potassium Sparing Agents

 Amiloride (Midamor), triamterene (Dyrenium), spironolactone (Aldactone)
 Reduction of potassium loss associated with thiazide or loop diuretic administration
 Mineralocorticoid excess:
o Conn's syndrome (primary hypersecretion)
o ectopic ACTH production (primary hypersecretion)
o secondary aldosteronism caused by:
 congestive heart failure
 hepatic cirrhosis
 nephrotic syndrome
 conditions that cause renal salt retention with reduced intravascular
volume
 other diuretics may further reduce intravascular volume thus
worsening secondary aldosteronism

Diuretic-Other Drug Interactions
cardiac oral aminoglycoside
glycosides hypoglycemics antibiotics

non-steroidal
oral uricosuric anti-
anticoagulants drugs inflammatory
drugs

Adverse Diuretic effects and contraindications

Adverse Effects: Carbonic Anhydrase Inhibitors (Acetazolamide)

 Toxicity:
o hyperchloremic metabolic acidosis
 due to reduction in body bicarbonate stores
o renal stones:
 bicarbonate loss is associated with:
 phosphaturia
 hypercalciuria (calcium salts, relatively insoluble at alkaline pH)
o renal potassium loss:
 increased sodium bicarbonate in the collecting tubule increases the lumen-
negative and in inelectrical potential -- enhances potassium excretion
 counteracted by potassium chloride administration
o Others:
 drowsiness, parathesias
 accumulation in renal failure (CNS toxicity)
 hypersensitivity reactions
o Contraindications:
 hepatic cirrhosis
 urinary alkalinization will decrease ammonium ion trapping,
increasing the likelihood of hepatic encephalopathy.

Adverse Effects: Loop Diuretics

Toxicity:

 Hypokalemia metabolic alkalosis:
o increased delivery of NaCl and water to the collecting duct increases potassium
and proton secretion-- causing a hypokalemic metabolic alkalosis
o in managed by potassium replacement and by ensuring adequate fluid intake
 Ototoxicity:
o dose-related hearing loss (in usually reversible)
o more common:
 with decreased renal function
 with concurrent administration of other ototoxic drugs such as
aminoglycosides
 Hyperuricemia:
o may cause gout
o loop diuretics cause increased uric acid reabsorption in the proximal tubule,
secondary to hypovolemic states.
 Hypomagnesemia: loop diuretics cause:
2. decreases normal lumen-positive potential (secondary to potassium recycling)
3. Positive lumen potential: drives divalent cationic reabsorption (calcium
magnesium)
4. Therefore, loop diuretics increase magnesium and calcium excretion.
 reversed by oral magnesium administration
 Allergic reactions:
o furosemide: skin rash, eosinophilia, interstitial nephritis(less often)
 Other toxicities:
o Dehydration (may be severe)
o hyponatremia (less common than with thiazides thought may occur in patients
who increased water intake in response to a hypovolemic thirst)

o Hypercalcemia may occur in severe dehydration and if a hypercalcemia condition
{e.g. oat cell long carcinoma} is also present.

Adverse Effects: Thiazides

Toxicity:

 Hypokalemic metabolic alkalosis and hyperuricemia
 Impaired carbohydrate tolerance
o may induce hyperglycemia
 impaired pancreatic insulin release
 decreased tissue glucose utilization
 hyperglycemia may be partially reversed by correcting a hypokalemic
state
 Hyperlipidemia
o 5% to 15% increase in serum cholesterol and an increase in low-density
lipoproteins.
 Hyponatremia:
o Significant adverse effect, occasionally life-threatening
o Mechanism:
 hypovolemia-induced increase in ADH
 reduced renal diluting capacity
 increased thirst
 Prevention: decreasing the drug dose or limiting fluid intake
 Allergic reactions:
o Thiazides are sulfonamides: cross-reactivity within the group
o photosensitivity {rare}
o dermatitis {rare}
o Extremely rare reactions:
 hemolytic anemia
 thrombocytopenia
 acute necrotizing pancreatitis

 Other reactions:
o weakness
o fatigue
o paresthesias

Adverse Effects: Osmotic Diuretics

Toxicity:

 Volume expansion effects -- increased extra cellular fluid volume and hyponatremia may
cause:
o pulmonary edema, complicating congestive heart failure
 Headache, nausea, vomiting -- commonly observed
 Dehydration and hypernatremia:
o flow gloss leads to significant dehydration and in the absence of adequate fluid
replacement leads to hypernatremia.

Adverse Effects: Potassium-Sparing Diuretics

 Toxicity:
o Hyperkalemia:
 Potassium-sparing diuretics can cause significant hyperkalemia
 Factors that increase the likelihood of hyperkalemia:
 renal disease
 presence of agents that reduce renin:
 beta-blockers
 nonsteroidal anti-inflammatory drugs (NSAIDs)
 ACE inhibitors
 angiotensin receptor blockers
 hyperkalemia more likely when potassium-sparing diuretics are used as
the only diuretic drug or in the presence of renal insufficiency.

 Given in combination with thiazides, hypokalemia and metabolic
alkalosis associated with thiazide use may be balanced by
 Since thiazide adverse effects may predominate {hyponatremia,
metabolic alkalosis}, due to variations in bioavailability, individual
dose adjustment of the two drugs may be better.
o Hyperchloremic Metabolic Acidosis:
 Acidosis cause by inhibition of proton secretion along with potassium
secretion {similar to type IV renal tubular acidosis
o Gynecomastia:
 Endocrine abnormalities associated with synthetic steroids --
spironolactone:
 gynecomastia (breast enlargement)
 impotence
 benign prostatic hyperplasia
o Acute Renal Failure:
 triamterene (Dyrenium) plus indomethacin
o Kidney Stones:
 triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing
renal stones:
 Contraindications:
o may cause severe (potentially fatal) hyperkalemia
o potassium supplements should be discontinued prior to administration of
o patients with chronic renal insufficiency are at particular risk
o hyperkalemia is also more likely to occur or it if beta-blockers or ACE inhibitors
are concurrently administered
o impairment of hepatic metabolism of triamterene spironolactone may require dose
adjustment

Mechanisms whereby furosemide and thiazides are useful in calcium metabolism
disorders management

Role of Diuretics in Calcium Metabolism

 Loop Diuretics & Calcium Metabolism
o Furosemide (Lasix)
o Torsemide (Demadex)
o Bumetanide (Bumex)
o Inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle
 inhibit the Na/K/2Cl transport system in the luminal membrane
recycling)
3. Positive lumen potential: drives divalent cationic reabsorption
(calcium magnesium)
4. Therefore, loop diuretics increase magnesium and calcium
excretion.
 hypocalcemia does not usually develop because calcium is
reabsorbed in the distal convoluted tubule.
 {in circumstances that result in hypercalcemia,
calcium excretion can be enhanced by
administration of loop diuretics with saline
infusion}
 Clinical Uses:
 Major uses:
 acute pulmonary edema
 acute hypercalcemia
 management of edema

Thiazides & Calcium Metabolism

o Diuretic action:Inhibition of NaCl reabsorption from the distal convoluted tubule
(luminal side)
o enhanced calcium reabsorption in the distal convoluted tubule (unknown
mechanism)
 thiazides infrequently cause hypercalcemia but can unmask hypercalcemia
due to other causes such as carcinoma, sarcoidosis, or
hyperparathyroidism.

Thiazides: nephrogenic diabetes insipidus

 Diabetes insipidus: impaired renal water conservation, caused by:
o Inadequate vasopressin secretion (Central or cranial diabetes insipidus)
o Insufficient kidney response to vasopressin (nephrogenic diabetes insipidus)
o Induction of diabetes insipidus:
 hypercalcemia
 hypokalemia
 postobstructive renal failure
 lithium (incidence: as high as 33%)
 demeclocycline (Declomycin)
o Familial nephrogenic diabetes insipidus: X-linked, typically,recessive)
 Thiazides are central in treatment of nephrogenic diabetes insipidus, reducing urine
volume by up to 50%.
 Other drugs:
o Amiloride: by blocking lithium uptake by the sodium channel in the collecting
duct, amiloride is the drug of choice for lithium-induced nephrogenic diabetes
insipidus.
o Decrease in volume promotes increased proximal tubule reabsorption.

 Decreased extracellular fluid volume results in compensatory mechanisms
that increase NaCl reabsorption in the proximal tubule -- reducing the
volume delivered to the distal tubule.
 As a result, less free water is formed and polyuria is decreased
o Since the effectiveness of thiazide diuretics in treating nephrogenic diabetes
insipidus follows the extent of natriuresis, the effectiveness may be enhanced by
decreasing sodium intake.

Jackson, E.K. Diuretics In, Goodman and Gillman's The Pharmacologial Basis of
Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds)
TheMcGraw-Hill Companies, Inc.,1996, pp. 685- 713

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In,
Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird,
L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies,
Inc.,1996, pp.715-732

Chlorpropamide (Diabinese) and clofibrate (Abitrate, Atromid-S) : Central
(Cranial) Diabetes Insipidus

 Diabetes insipidus: impaired renal water conservation, caused by:
o inadequate vasopressin secretion (Central or cranial diabetes insipidus)
o inadequate kidney response to vasopressin (nephrogenic diabetes insipidus)
 Clinical Presentations:
o Large volumes of dilute (200 mOsm/kg) urine excreted
o With normal thirst, polydipsia is present
o By contrast with diabetes mellitus, the urine in diabetes insipidus is tasteless.
o Central or cranial diabetes insipidus can be discriminated from nephrogenic
diabetes insipidus by administration of desmopressin (DDAVP).
 Urine osmolality will
 increase following desmopressin administration in patients with
central diabetes insipidus

 have limited effect or no effect in patients with nephrogenic
diabetes insipidus.
 Causes of central diabetes insipidus:
o Head injury (near the pituitary and/or hypothalamus
o Hypothalamic or pituitary tumor
o Cerebral aneurysms
o CNS ischemia
o CNS infections
o Central diabetes insipidus: idiopathic or familial
 familial: autosomal dominant (chromosome 20)
 point mutations in the signal peptide and VP-neurophysin--
causing defects in synthesis, processing, and preprohoromone
transport.
 Treatment:
o Primary treatment: (antidiuretic peptides): desmopressin (DDAVP)
o Patients intolerant of desmopressin: chlorpropamide (Diabinese) (oral
sulfonylurea)
 Mechanism of action -- chlorpropramide
 potentiates effects of residual, circulating vasopressin (reduces
urine volume in more than 50% of patients)
 Antidiuretic mechanisms of carbamazepine (Tegretol), clofibrate,
chlorpropamide (Diabinese) have not been definitively determined.
o If polyuria is insufficiently reduced by chlorpropramide, a thiazide diuretic may
be added.
o For short-term management, the combination of carbamazepine (Tegretol) and
clofibrate (Abitrate, Atromid-S) will also decreased polyuria in central diabetes
insipidus:
 Serious, adverse effects associated with prolonged use of this combination
are limiting

Inc.,1996, pp.715-732.

Management of inappropriate secretion of antidiuretic hormone

 Disease of impaired water excretion caused by inappropriate vasopressin secretion,
resulting in:
o hyponatremia
o hypoosmolality
 Clinical effects:
o lethargy
o muscle cramps
o anorexia
o coma
o nausea
o convulsions
o vomiting
o death
 Clinical effects are seen only if excessive fluid intake (in oral or IV) occurs concurrently
with inappropriate vasopressin secretion.
 Causes:
o malignancies
o pulmonary disease
o CNS injury/diseases
 trauma
 infections
 tumors
o surgery

o drugs {cisplatin, Vinca alkaloids, cyclophosphamide (Cytoxan),chlorpropamide
(Diabinese), thiazide diuretics, phenothiazines, carbamazepine (Tegretol),
clofibrate, nicotine, narcotics, tricyclic antidepressants}
 Treatment
o water restriction
o IV hypertonic saline
o loop diuretics
o drugs that reduce the ability of vasopressin to increase water permeability in the
renal collecting ducts:demeclocycline (Declomycin)

Inc.,1996, pp.715-732.

Mechanism by which lithium compounds may cause a syndrome like diabetes
insipidus

Introduction

 Vasopressin: regulates water conservation

 Synonymous terms: vasopressin: arginine vasopressin (AVP): antidiuretic hormone
(ADH)

 Similar peptide: oxytocin-- common vasopressin and oxytocin receptor antagonists
o binds to myoepithelial cells in the mammary gland (milk ejection) and on uterine
smooth muscle cells (uterine contraction)

 The antidiuretic system consists of:
o CNS component (vasopressin synthesis, transport, storage, release)
 supraoptic nucleus (SON)
 paraventricular nucleus (PVN)

o Renal collecting duct system
 epithelial cells -- increased water permeability in response to vasopressin.

 Increased plasma osmolality: increased vasopressin release
 Factors affecting/modifying vasopressin release
o hypovolemia
o hypotension
o hypoxia
o drugs
o pain
o nausea
o certain endogenous hormones

Regulation of vasopressin secretion

 Osmotic Stimulation of Vasopressin Release
o CNS structures: osmoreceptive complex
1. Osmosensitive: magnocellular neurons (SON, PVN)
2. Subfornical organ (SFO) project to SON/PVN
3. Organum vasculosum of the lamina terminalis (OVLT) project during
clearing directly to SON/PVN
 Hypovolemic/hypotension stimulation of Vasopressin Release:
o Baroreceptors:
 Blood volume (filling pressures)--baroreceptors in:
 left atrium
 left ventricle
 pulmonary veins
 Arterial blood pressure: baroreceptors -- carotid sinus and aorta
 Nerve impulses from baroreceptors are carried:
 by the vagus and glossopharyngeal nerves to the nucleus of the
solitary tract
 to the A1-noradrenergic cells in the caudal ventrolateral medulla

 to the SON and PVN

Hormonal Effects

 Vasopressin release: stimulation
o acetylcholine (nicotinic)
o glutamine
o histamine (H1)
o dopamine (D1 & D1)
o neuropeptide Y
o prostaglandins
o aspartate
o cholecystokinin
o substance P
o vasoactive intestinal peptide
o angiotensin II

 Vasopressin release: inhibition:
o atrial natriuretic peptide
o gamma aminobutyric acid (gaba)
o opioids (dynorphin)

Drug Effects

 Vasopressin Release: Stimulation
o vincristine (Oncovin)
o nicotine
o morphine (high doses)
o cyclophosphamide
o tricyclic antidepressants
o epinephrine
o lithium (inhibits renal effects of vasopressin; enhances vasopressin release
 Vasopressin Release: Inhibition

o ethanol
o glucocorticoids
o haloperidol (Haldol)
o promethazine (Pherergan)
o phenytoin (Dilantin)
o morphine (low dose)
o fluphenazine (Prolixin)
o oxilorphan
o carbamazepine (Tegretol)(renal effects -- anti-diuresis; inhibits vasopressin
secretion (central effect)

Lithium Effects:

 Inhibits antidiuretic effect of vasopressin
o Lithium is used widely for management of bipolar disorder (manic- depressive).
o Lithium uptake by the sodium channel in the collecting duct, causes lithium-
induced nephrogenic diabetes insipidus.
o Lithium polyuria: normally reversible
o Mechanism of action:
 reduces V2 receptor-mediated adenyl cyclase stimulation
 Often, the antibiotic demeclocycline (Declomycin) reduces the antidiuretic effects of
vasopressin (possibly because of reduced cyclic AMP)

Inc.,1996, pp.715-732.

Diuretics

 Thiazides
o Hydrochlorothiazide (HCTZ, Esidrix, HydroDIURIL)

o chlorthalidone (Hygroton)
o Chlorothiazide (Diuril)
 The thiazides act in the distal tubule to decrease sodium reabsorption
(inhibits Na/Cl transporter).
 As a result of decreased sodium and chloride reabsorption, a
hyperosmolar diuresis ensues.
 Delivery of more sodium to the distal tubule results in potassium loss by
an exchange mechanism.
 Thiazides also promote calcium reabsorption, in contrast to loop diuretics.
 The initial decrease in blood volume followed by a longer-termed
reduction in vascular resistance appears to account for the hypotensive
effects of the thiazides.
 Adverse Effects
 Potassium depletion is a potentially serious side-effect that
may require potassium supplementation and/or concurrent
use of potassium-sparing diuretics.
 Hyperuricemia may occur precipitating gout.
 The increase in systemic uric acid is due to a
decrease in the effectiveness of the organic acid
secretory system.
 Diabetic patient may have difficulty in maintaining proper
blood sugar levels.
o Indapamide (Lozol)
o Metolazone (Zaroxolyn, Mykrox)
 Potassium Sparing
o Amiloride (Midamor)
o Spironolactone (Aldactone)
o Triamterene (Dyrenium)
 Loop Diuretics
o Furosemide (Lasix), Bumetaninde (Bumex), Ethacrynic Acid (Edecrin)

 Furosemide (Lasix),bumetanide (Bumex), and ethacrynic acid (Edecrin)
are "high-ceiling" loop diuretics acting primarily at the ascending limb of
the loop of Henle.
 The effectiveness of these agents is related to their site of action
because reabsorption of about 30 - 40% of the filtered sodium and
chloride load occurs at the ascending loop.
 Distal sites are not able to compensate completely for this
magnitude of reduction of NaCl reabsorption.
 Loop diuretics increase urinary Ca2+ in contrast to the action of thiazides.
 Loop diuretics also increase renal blood flow by decreasing renal vascular
resistance.
 These drugs are rarely used in the management of hypertension because of
their short duration of action and the availability of better drugs.
o Adverse Effects
 Ototoxicity
 Furosemide (Lasix) and ethacrynic acid (Edecrin) block renal excretion of
uric acid by competition with renal secretory and biliary secretory
systems.
 Therefore these agents can precipitate gout.
 Potassium depletion.
 Osmotic Diuretic: Mannitol (Osmitrol)

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