DIURETICS
SUMOLLY ANAK DAVID
DEFINITION
Anything that promotes the formation of urine
by the kidney.
Diureticsare drugs that
increase the excretion of
solutes (mainly NaCl) and water.
The primary goal of diuretic therapy is to
reduce ECF volume in order to lower
blood pressure or rid the body of
excess interstitial fluid (edema).
FUNCTION OF THE NEPHRONS
1. Proximal Tubules
Reabsorption of :
Almost all filtered organic
Glucose, amino acid
Sodium chloride
NaHco3 (carbonic anhydrase dependent)
Highly permeable to H20
Secretion of:
H+ (via Na+/H+ exchanger)
2. Thin Descending Limb of Loop Of Henle
Highlypermeable to H20
Not permeable to NaCl, urea
3. Thin ascending Limb of Loop Of Henle
Permeableto NaCl: passive reabsorption of NaCl
Impermeable to H20
4. Thick Ascending Limb of Loop Of Henle
permeable to NaCl, K+,Mg2+, Ca2+
Not permeable to H20, urea
5. Distal Convuluted Tubule
Actively
transport NaCl
Impermeable to H20
6. Collecting Duct
Reabsorption of:
Na+ (aldosterone dependent)
H2o (ADH dependent)
Secretion of:
H+
K+
REGULATION OF RENAL FUNCTION BY SELECTED HORMONES
MAJOR DIURETIC CLASSES
♠ thiazide diuretics:
♪ hydrochlorothiazide, chlorothiazide
♠ loop diuretics:
♪ furosemide, torsemide, indapamide
♠ K+ sparing diuretics:
♪ amiloride, triamterene,
♪ spironolactone,eplerenone
♠ osmotic diuretics:
♪ mannitol, urea
♠ carbonic anhydrase inhibitors:
♪ acetazolamide
SITE OF ACTION OF DIURETICS
LOOP DIURETIC
BUMETANIDE, INDAPAMIDE, FRUSEMIDE,
TOLBUTAMIDE
Mechanism of action:
♣ inhibit the Na+/ K+/ 2Cl- cotransport system in
the thick ascending limb of Henle's loop .
♣ Inhibiting the kidney's ability to reabsorb
sodium, thus enhancing the loss of sodium in
the urine. And when sodium is lost in the
urine, water goes with it.
♣ This type of diuretic is called a high-ceiling
diuretic or a loop diuretic.
THERAPEUTIC EFFECT
Hypertension, CHF (in the presence of
renal insufficiency or for immediate effect).
ARF, CRF, ascites, and nephrotic syndrome
Acute Pulmonary Edema, other edema
conditions
To enhance urinary excretion of chemical
toxins
Hypercalcemia (loop diuretic cause increase
in Mg2+ & Ca2+ excretion)
ADVERSE
EFFECT
PHARMACOKINETIC/ DYNAMIC
Bumetanide Furosemide Torsemide
(Bumex®) (Lasix®) (Demadex®)
Equivalent Dose, mg 1 40 20
Bioavailability 85% 60% 85%
(po/iv dose ratio) (1) (1.5 ) (1)
Elimination Route Met.; Renal Mainly Renal Hepatic Met.
(half-life) (60 - 90 min) (1 hr; 9 hrs in ESRD) (3 hrs; 7 hrs in cirrhosis)
Onset of action, min
40 / 5 40 / 5 40 / 10
(po / iv)
Duration (po) (hrs) 4 6 6
0.5 - 2.0 mg 20 - 80 mg 10 - 40 mg
Usual Adult Oral Dosage
qd -bid qd - bid qd - bid
THIAZIDE DIURETIC
HYDROCHLOROTHIAZIDE,
CHLORTALIDONE, CHLOROTHIAZIDE
Mechanism of action:
♣ Thiazide diuretics are secreted into the tubular fluid by
proximal tubule cells. These agents act in the distal
convoluted tubule and block a Na+, Cl- symporter that is
associated with the luminal membrane.
♣ ↑ plasma urate concentration:
-compete with the urate for secretion by the organic acid
secretory system at the proximal tubules
♣ ↓ GFR ( direct effetc on renal vasculature)
♣ ↓ ca2+ secretion due to direct effect at the early portion of the
distal tubules hypercalcemia
THERAPEUTIC EFFECTS
treat edema associated with a variety of
pathophysiologic conditions including
congestive heart failure, cirrhosis, renal
insufficiency and the nephrotic syndrome,
therapy of hypertension
Decrease ca2+ excretion
PHARMACOKINETIC
Only 10% of chlorothiazide is absorbed
Efficacies of thiazides are the same but
potencies are different
Agent Dose (mg/day)
CTZ 500-2000
HCTZ 25-200
Not metabolised
Eliminated by secretion at proximal tubules
ADVERSE EFFECTS
POTASIUM SPARING DIURETICS
ALDOSTERONE VS, NA+ CHANNEL
VS
Blocking the exchange of sodium for potassium,
resulting in excretion of sodium and
potassium but relatively little loss of
potassium…
♣ Aldosterone antagonist:
◙ eg: spironolactone, eplerenone
◙ competitive inhibitor of aldosterone at the
mineralocorticoid receptors
◙ act at the distal portion of distal tubule &
the collecting duct
♣ Aldosterone effect:
↑ Na+, H2o reabsorption,
↑ K+ secretion & Ca2+ excretion
ADVERSE EFFECT
POTASSIUM SPARING DIURETIC
ADVERSE EFFECT
THERAPEUTIC USES
Use in combination with loop & thiazide
diuretic
Enhances natriuresis caused by other diuretics
Prevents hypokalemia
Block aldosterone
Tx of primary hyperaldosteronism
Tx of edema of liver cirrhosis
Tx of hypertension
Tx for heart failure
CONTRAINDICATION/ DRUG
INTERACTION
Hypersensitivity
Anuria
Hyperkalemia
Pregnancy (spironolactone)
Increased risk of hyperkalemia
Other K sparing diuretic
Potassium supplements/ diets (bananas, nuts, salt)
ACEis/ ARBs
OSMOTIC DIURETICS
MANNITOL, UREA
Mechanism of action:
Freely filterable but non reabsorbable solutes
↑ tubular osmolarity, causes water to be retained in the segment &
promotes water diuresis
Act mainly at the proximal tubule to reduce the
reabsorption of H20 & solutes including NaCl
Marked increased in delivery of Na+ & H2o out of the
loop of Henle
↑ osmolarity of extracellular fluid-extraction of
H20 from intracellular compartments
Expansion of extracellular fluid volume
↓ blood viscocity
Inhibition of renin release
↑ in urinary excretion of all elctrolytes ( Na+, K+,
Ca2+, Mg2+, Cl-, HCO3, PO4)
Toxicity and Adverse Effects :
Expansion of extracellular volume
Lead to pulmonary edema in pt with
heart failure or pulmonary congestion
Extraction of H2o from cell
Increased ECFV & hyponatremia
(Headache , nausea , vomiting)
Loss of H2o in excess of electrolytes
dehydration
THERAPEUTIC USES
Osmotic diuretics maintain renal blood flow in
patients with acute renal failure.
These agents can also be used to treat increases
in intraocular pressure in glaucoma as well as
reduce cerebral edema
↑ elimination of toxic agents via the urine
CARBONIC ANHYDRASE
INHIBITORS
ACETAZOLAMIDE
Mechanism of action: interfere with the reabsorption of
HCO3 which is reabsorbed in the proximal tubule and
requires the activity of carbonic anhydrase
Toxicity and Adverse Effects: Metabolic acidosis as a
result of HCO3- loss, sedation and paresthesia. Also,
because of the structural similarity to sulfonamides,
carbonic anhydrase inhibitors can cause bone marrow
depression and allergic reactions
Therapeutic uses: Carbonic anhydrase inhibitors are not
used for their diuretic properties. Rather these agents
are used to reduce intraocular pressure in the treatment
of glaucoma. This is because these agents inhibit
intraocular carbonic anhydrase and thus the formation
of aqueous humor. Also used to treat epilepsy & motion
sickness.
DOSAGE OF DIURETICS (ADULTS)
Diuretics Route Dose
Furosemide p.o, iv, im 20-80 mg/day divided q 6-12H
HCTZ p.o 25-100mg/day in 1 or 2 doses
CTZ (deleted) p.o 500mg-2gm in 1 or 2 doses
iv 100-500mg/day
Spironolactone p.o 25-400mg/day in 1-2 divided doses
Acetazolamide p.o 250mg od-qid
INTERACTIONS
Interacting drugs Potential interactions
ACEIs / K+ ↑ hyperkalemia => cardiac problem
sparing diuretics (monitor serum potassium closely)
Aminoglycosides/ Ototoxicity & nephrotoxicity
Loop diuretics (monitor serum creatinine)
Digoxin/ thiazide Hypokalemia=> increased digoxin binding
& loop diuretics and toxicity
(monitor K+ and cardiac function)
B-blockers/ Hyperglycemia, hyperlipidemia,
thiazide diuretics hyperuricemia
Steroids/ thiazide ↑ risk of hypokalemia
& loop diuretics (monitor serum potassium closely)
CBZ/ thiazide Increased risk of hyponatremia
diuretics (monitor Na+)
REFERENCE
Michael T. Piascik. 2002. The Pharmacodynamics of
Diuretic Drugs.
Anderson et al. Handbook of Clinical Drug Data. 10th
edition.
British National Formulary. 50th edition. 2005.
Lance et al. Drug information Handbook. 17th Edition.
2008-2009.
www. [Link]
Nasr Anaizi. 1997-2002 the Drug Monitor
Brater, D. C. DIURETIC THERAPY. 339 (6) 387-395.
Katzung, B.G. 2004. basic & clinical pharmacology. 9th
ed. Diuretic Agents.
