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From: Widmaier EP. Vander’s Human Physiology: The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill Companies, Inc., 2014: 490
Learning Objectives:
1. List major types of diuretics and relate them to their sites of action.
2. List the major applications, toxicities, and the efficacy of thiazides, loop
diuretics and potassium-sparing diuretics.
3. Describe two drugs that reduce potassium loss during diuresis.
4. Describe a therapy that will reduce calcium excretion in patients who have
recurrent urinary stones.
5. Discuss the principle of force diuresis.
6. Describe drugs for reducing urine volume in nephrogenic diabetes insipidus.
7. Understand the usefulness of altering urine pH by drugs.
8. Discuss the mechanisms by which drugs and chemicals damage the kidney.
9. Understand how to select and prescribe drugs for patients with renal
impairment.
Companion: Renal Pharmacology eNotes
Marc Imhotep Cray, M.D. 2
Some Relevant Drugs:
A. Carbonic Anhydrase D. Thiazides F. ADH antagonists
Inhibitors chlorthalidone demeclocycline
Acetazolamide chlorothiazide lithium
dichlorphenamide hydrochlorothiazide lixivaptan
methazolamide metolazone tolvaptan
dorzolamide indapamide conivaptan
B. Osmotic Diuretics E. Potassium-sparing
mannitol diuretics
C. Loop Diuretics spironolactone
furosemide eplerenone
bumetanide triamterene
torsemide amiloride
ethacrynic acid
Marc Imhotep Cray, M.D. Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 12
Volume contraction
feedback control
Marc Imhotep Cray, M.D. Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 13
Pharmacology Diuretic Drugs
Definition: A diuretic is any substance that increases urine
and solute excretion
This wide definition includes substances not commonly
thought of as diuretics, e.g. water
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)
Pharmacokinetics
Thiazides are well absorbed orally and most begin to act within an hour
Differences among numerous derivatives lie in duration of action
Relatively water-soluble agents, e.g. chlorothiazide, hydrochlorothiazide
(HCTZ), are most rapidly eliminated, peak effect within 4–6 h and passing
off by 10–12 h
excreted unchanged in urine and active secretion by PCT contributes to
high renal clearance and t½ of less than 4 h
Overall, these substances have a longer duration of action, are used for
edema and hypertension, and their profile of adverse effects is similar to
thiazides
Chlortalidone acts for 48–72 h after a single oral dose
Indapamide is structurally related to chlortalidone but lowers blood
pressure at subdiuretic doses perhaps by altering calcium flux in
vascular smooth muscle
Metolazone is effective when renal function is impaired
o It potentiates diuresis produced by furosemide and combination can
be effective in resistant edema although risk of hypokalemia is
Marc Imhotep Cray,very
M.D. high 41
Low-efficacy diuretics
Spironolactone (Aldactone) is structurally similar to aldosterone and
competitively inhibits its action in distal tubule (exchange of potassium
for sodium, Site 4 in slide 25)
These properties define its uses, which are for rapid reduction of
intracranial or intraocular pressure, and to maintain urine flow to
prevent renal tubular necrosis
The safe lower limit for plasma potassium concentration is 3.5 mEq/L
ACE inhibitors and ARBs can also cause a increase in plasma K+ levels
They may cause dangerous hyperkalemia if combined with KCl
supplements or other potassium sparing drugs, in presence of
impaired renal function
However, with suitable monitoring combination can be used
safely, as was well illustrated by the RALES trial
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
Acidification of urine:
used as a test for renal tubular acidosis
increases elimination of amphetamine, MDMA or “Ecstasy”, quinine and
phencyclidine (very rarely needed)
Oral NH4Cl, taken w food to avoid vomiting, acidifies urine
o It should not be given to pts with impaired renal or hepatic
function
Other means include arginine hydrochloride, ascorbic acid and
calcium
Marc Imhotep Cray, M.D. chloride by mouth 72
ADH Antagonists
Demeclocycline
Lithium
Lixivaptan
Satavaptan
Conivaptan
Tolvaptan
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
Marc Imhotep Cray, M.D. 77
Antidiuretic Hormone Antagonists (5)
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
B. Renal Failure
Both lithium and demeclocycline have been reported to cause
acute renal failure
Long-term lithium therapy may cause chronic interstitial nephritis
Marc Imhotep Cray, M.D. 80
Antidiuretic Hormone Antagonists (8)
C. Other Adverse Effects
Dry mouth and thirst are common with many of these drugs
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.
Marc Imhotep Cray, M.D. 117