The document discusses various classes of diuretic drugs, including their mechanisms of action, therapeutic uses, and adverse effects. It focuses on loop diuretics, which act on the thick ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption, resulting in increased urinary excretion of sodium, chloride, potassium, magnesium, and calcium. Loop diuretics are potent and commonly used to treat edema associated with congestive heart failure or liver/kidney disease but can cause electrolyte imbalances and other adverse effects if not carefully monitored.
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Basic Pharmacology of Diuretics
1. 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
2. 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.
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Companion: Renal Pharmacology eNotes
3. Marc Imhotep Cray, M.D.
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
chlorthalidone
chlorothiazide
hydrochlorothiazide
metolazone
indapamide
E. Potassium-sparing
diuretics
spironolactone
eplerenone
triamterene
amiloride
F. ADH antagonists
demeclocycline
lithium
lixivaptan
tolvaptan
conivaptan
5. Marc Imhotep Cray, M.D.
Mercurial Diuretics
5
Organomercurial agents inhibit active Cl− transport, especially in
ascending limb of the Henle loop
In acidic conditions, Hg2+ dissociates, binds to, and inhibits sulfhydryl
enzymes Na+ reabsorption is thus decreased; more Na+ and Cl− are
excreted
Because more Na+ is delivered to distal nephron during diuresis, K+ and
H+ excretion (sum of urinary NH4 + plus titratable acid − urinary
HCO3−) may increase
In alkaline conditions, Hg2+ does not dissociate, and patients become
refractory to mercurials
6. Marc Imhotep Cray, M.D.
Mercurial Diuretics (2)
6
Mercurial diuretics (eg, mercaptomerin) are poorly absorbed
when taken orally, so an intramuscular route is required
Because of this difficulty and their toxicity (eg, systemic
poisoning, cardiac toxicity, hypersensitivity, worsening of
renal insufficiency), mercurials are largely obsolete
They are sometimes used for CHF, cirrhosis, and portal
obstruction because they do not deplete K+
8. Marc Imhotep Cray, M.D.
Carbonic Anhydrase Inhibitors (CAIs) Capsule
8
Diuretic drugs such as acetazolamide (prototype),
dichlorphenamide, methazolamide and dorzolamide
inhibit carbonic anhydrase, particularly at proximal
convoluted tubule
Carbonic anhydrase normally catalyzes dehydration of
carbonic acid (H2CO3)
o As a result of CAIs, H+ needed for Na+-H+ exchange
is reduced, HCO3− and Na+ reabsorption in
proximal tubules is suppressed, and diuresis is
promoted
9. Marc Imhotep Cray, M.D.
Carbonic Anhydrase Inhibitors:
Mechanism of Action
9
The enzyme carbonic anhydrase normally helps to make H+
ions available for exchange with sodium and water in proximal
tubules
CAIs block action of carbonic anhydrase, thus preventing
exchange of H+ ions with sodium and water
these agents block formation of H+ and HCO3- from CO2 and
H2O end result is that bicarbonate is excreted in urine
10. Marc Imhotep Cray, M.D.
Carbonic Anhydrase Inhibitors:
Mechanism of Action
10
Inhibition of carbonic anhydrase reduces H+ ion concentration in
renal tubules
As a result, there is increased excretion of bicarbonate, sodium,
water, and potassium
Reabsorption of water is decreased and urine volume is increased
11. Marc Imhotep Cray, M.D.
CAIs: Therapeutic Uses
11
Adjunct agents in long-term management of open-angle
glaucoma
Used with miotics to lower intraocular pressure before ocular
surgery in certain cases
Also useful in treatment of:
Glaucoma
Edema
Epilepsy
High-altitude sickness
12. Marc Imhotep Cray, M.D.
CAIs: Therapeutic Uses cont.
12
Acetazolamide is sometimes used in management of edema
secondary to CHF when other diuretics are not effective
CAIs are less potent diuretics than loop diuretics or thiazides
metabolic acidosis they induce reduces their diuretic effect in
2 to 4 days
16. Marc Imhotep Cray, M.D.
Thiazide Diuretics Capsule
16
Thiazide (benzothiadiazide) diuretics inhibit Cl− reabsorption, especially in
distal portion of ascending limb of Henle loop and proximal portion of
distal convoluted tubule
Excretion of Na+, K+, Cl−, and HCO3 − is increased
refractoriness does not develop to diuretic effect
Often used to treat chronic edema and essential hypertension and, less
often, nephrosis some forms of diabetes insipidus, and hypercalciuria
Common adverse effects are hypokalemia (K+ supplements are
recommended) may lead to alkalosis, and hyperglycemia
Extra caution is needed when these agents are used with digitalis for CHF
because of greater digitalis toxicity in conditions of low K+
Because thiazides are excreted via glomerular filtration and tubular
secretion they compete with uric acid for tubular secretion result in
increase bld uric acid can precipitate gout in at risk persons
17. Marc Imhotep Cray, M.D.
Thiazide and Thiazide-Like Diuretics:
Mechanism of Action
17
Inhibit tubular reabsorption of sodium and chloride ions
Action primarily in ascending loop of Henle and early distal tubule
Result: water, sodium, and chloride are excreted
Potassium is also excreted to a lesser extent
Dilate arterioles by direct relaxation
Lowered peripheral vascular resistance
Depletion of sodium and water
Drug Effects
18. Marc Imhotep Cray, M.D.
Thiazide Diuretics:
Therapeutic Uses
18
Hypertension (one of most prescribed group of agents)
Edematous states
Idiopathic hypercalciuria
Diabetes insipidus
Adjunct agents in treatment of CHF and hepatic cirrhosis
19. Marc Imhotep Cray, M.D.
Thiazide Diuretics:
Adverse Effects
19
Body System Effect
CNS Dizziness, headache,
blurred vision, paresthesias,
decreased libido
GI Anorexia, nausea, vomiting, diarrhea
20. Marc Imhotep Cray, M.D.
Thiazide Diuretics:
Adverse Effects
20
Body System Effect
GU Impotence
Integumentary Urticaria, photosensitivity
Metabolic Hypokalemia, glycosuria,
Hyperglycemia, Hyperuricemia (gout)
22. Marc Imhotep Cray, M.D.
Potassium-Sparing Diuretics
22
Those in clinical use include:
Epithelial sodium channel blockers:
Amiloride
Triamterene
Aldosterone antagonists:
Spironolactone
Eplerenone
23. Marc Imhotep Cray, M.D.
Potassium-Sparing Agents Capsule
23
Two major categories of K+-sparing diuretic drugs are
1. Na+ channel antagonists (eg, amiloride, triamterene) and
2. Aldosterone receptor antagonists (eg, spironolactone)
Amiloride and triamterene inhibit active Na+ reuptake
Enhanced Na+ and Cl− excretion disrupts Na+ transport and
reduces K+ secretion
They moderately increase Na+, Cl−, and HCO3− excretion
when they are used with other diuretics, Na+ excretion
increases and K+ is retained
Reversible azotemia can occur
24. Marc Imhotep Cray, M.D.
K+-Sparing Agents Capsule cont.
24
Triamterene can increase serum uric acid levels, so caution is
needed for its use in patients with gout
Spironolactone reduces aldosterone-mediated Na+-K+
exchange at distal convoluted tubule which increases Na+
loss while reducing K+ excretion
Adverse effects of both types of drugs include hyperkalemia
(especially when impaired renal function exists)
Combination therapy with K+-sparing drugs is not advised, but
they are often used with other diuretics (eg, thiazides) that
increase K+ excretion to prevent hypoklemia
25. Marc Imhotep Cray, M.D.
Potassium-Sparing Diuretics:
Mechanism of Action
25
Work in collecting ducts and distal convoluted tubules
Interfere with sodium-potassium exchange
Competitively bind to aldosterone receptors
Block reabsorption of sodium and water usually induced by
aldosterone
26. Marc Imhotep Cray, M.D.
Potassium-Sparing Diuretics:
Drug Effects
26
Prevent potassium from being pumped into tubule, thus
preventing its secretion
Competitively block aldosterone receptors and inhibit its action
Excretion of sodium and water is promoted
27. Marc Imhotep Cray, M.D.
Potassium-Sparing Diuretics:
Therapeutic Uses
27
spironolactone and triamterene
Hyperaldosteronism
Hypertension
Reversing potassium loss caused by potassium-depleting
drugs (diuretics)
amiloride
Treatment of CHF
28. Marc Imhotep Cray, M.D.
Potassium-Sparing Diuretics:
Adverse Effects
28
Body System Effect
CNS Dizziness, headache
GI Cramps, nausea,
vomiting, diarrhea
Other Urinary frequency,
weakness, hyperkalemia
Spironolactone (also blocks androgenic receptors)
gynecomastia, amenorrhea, irregular menses
30. Marc Imhotep Cray, M.D.
Loop (High-Ceiling) Diuretics Capsule
30
Bumetanide, ethacrynic acid, furosemide, torsemide acts
mainly on thick ascending limb of the Henle loop
Because they elicit greatest diuresis possible, they are also
termed high-ceiling diuretics
They act at luminal nephron surface and inhibit electrolyte
reabsorption, with resultant greater Na+, Cl−, K+, Mg2+, and
Ca2+ excretion
Inhibition of NaCl reabsorption in Henle loop decreases strength
of countercurrent concentrating mechanism and causes greatly
increased urine output
31. Marc Imhotep Cray, M.D.
Loop Diuretics Capsule cont.
31
Pharmacologic Effects
Bumetanide, furosemide, and torsemide are weak inhibitors of carbonic
anhydrase
Ethacrynic acid, which is not a sulfonamide, does not inhibit this
enzyme
Refractoriness does not occur
Clinical Use
Loop diuretics are used for acute pulmonary edema, edema associated
with CHF, cirrhosis, and renal disease
Adverse effects
Fluid and electrolyte imbalances are most common adverse effects
All increase Cl− more than Na+ excretion, which can lead to
hypochloremic alkalosis
32. Marc Imhotep Cray, M.D.
Loop Diuretics:
Mechanism of Action
32
Act directly on ascending limb of loop of Henle to inhibit
sodium and chloride reabsorption
Increase renal prostaglandins, resulting in dilation of blood
vessels and reduced peripheral vascular resistance
33. Marc Imhotep Cray, M.D.
Loop Diuretics:
Drug Effects
33
Potent diuresis and subsequent loss of fluid
Decreased fluid volume causes:
Reduced BP
Reduced pulmonary vascular resistance
Reduced systemic vascular resistance
Reduced central venous pressure
Reduced left ventricular end-diastolic pressure
Potassium depletion
34. Marc Imhotep Cray, M.D.
Loop Diuretics:
Therapeutic Uses
34
Edema associated with CHF or hepatic or renal disease
Less commonly than thiazides, control of hypertension
35. Marc Imhotep Cray, M.D.
Loop Diuretics:
Adverse Effects
35
Body System Effect
Nervous Dizziness
Headache
Ototoxicity (tinnitus)
Blurred vision
GI Nausea/vomiting, diarrhea
36. Marc Imhotep Cray, M.D.
Loop Diuretics:
Adverse Effects
36
Body System Effect
Hematologic agranulocytosis,
neutropenia,
thrombocytopenia
Metabolic hypokalemia,
hyperglycemia,
hyperuricemia,
hypomagnesemia,
metabolic alkalosis
38. Marc Imhotep Cray, M.D.
Osmotic Diuretics Capsule
38
Osmotic diuretics (mannitol, glycerol, urea) enter nephron
through glomerulus but are poorly reabsorbed along nephron
because of their relatively large molecular size
Presence of unabsorbed molecules in tubule lumen creates a
concentration (osmotic) gradient across tubular membrane
In proximal convoluted tubule, reabsorption of Na+ and water
decreases, which produces diuresis without marked changes in
Na+ or Cl− excretion
Mannitol, agent used most often, is a hexacarbon sugar alcohol
that is given intravenously it is not metabolized
39. Marc Imhotep Cray, M.D.
Osmotic Diuretics Capsule cont.
39
Osmotic diuretics are used to treat
cerebral edema and glaucoma (by reducing cerebrospinal
or intraocular fluid pressure)
oliguria and anuria, and
certain phases of acute renal failure (as prophylaxis)
Because osmotic diuretics increase blood volume adverse
effects include decompensation in patients with CHF
Hyperosmolarity or hyponatremia can occur during therapy
of renal failure or cirrhosis
40. Marc Imhotep Cray, M.D.
Osmotic Diuretics: Mannitol
Mechanism of Action
40
Work in proximal tubule
Nonabsorbable producing an osmotic effect
Pull water into blood vessels and nephrons from
surrounding tissues
41. Marc Imhotep Cray, M.D.
Osmotic Diuretics:
Drug Effects
41
Reduced cellular edema
Increased urine production, causing diuresis
Rapid excretion of water, sodium, and other electrolytes, as well
as excretion of toxic substances from kidney
Reduces excessive intraocular pressure
42. Marc Imhotep Cray, M.D.
Osmotic Diuretics:
Therapeutic Uses
42
Used in treatment of patients in early, oliguric phase of ARF
To promote excretion of toxic substances
Reduction of intracranial pressure
Treatment of cerebral edema
44. Marc Imhotep Cray, M.D.
Illust. of where of diuretics act, and how
44
Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012
45. Marc Imhotep Cray, M.D.
See next slide for sources and links to additional study tools and resources.
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46. Marc Imhotep Cray, M.D.
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.
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