2

3
 Na+ (65%) Na+ (5%)
& H2O actively
aldosterone Na+

ADH H2O
Na+ (25%)
actively

H2O
Na+ & Urea

4
 Proximal convoluted tubule

6
Thick ascending limb
Distal convoluted tubule
Collecting tubule
 Principles of diuretic action
 Increase rate of urine flow
 Increase rate of excretion of Na+
(natriuresis) and of accompanying
anion, usually Cl-
 NaCl is the major determinant of
extracellular fluid (ECF) volume
 Diuretics reduce the ECF volume by
decreasing total-body NaCl content

10
 Continued use Net deficit in
of diuretics total-body Na+

Bring Na+
excretion in line Renal
with Na+ intake compensation

“Diuretic braking”

11
 BP = CO x TPR

CO = HR x SV

TPR = vascular resistance

 Diuretics
1. Carbonic anhydrase inhibitors
2. Osmotic diuretics
3. Loop diuretics
(High-ceiling diuretics, Inhibitors of Na+-K+-2Cl-)

4. Thiazide and Thiazidelike diuretics

(Inhibitors of Na+-Cl- symport)

5. K+-sparing diuretics
 Carbonic anhydrase inhibitors

Acetazolamide

 Inhibits HCO3-
reabsorption

Numbers in parentheses indicate stoichiometry.

14
 CA inhibitors

Inhibits CA in proximal tubule

(major site)

Other actions
 CA is present in extrarenal tissues:
eye, gastric mucosa, pancreas,
CNS and erythrocyte

15
 CA inhibitors

EYE
 In ciliary body: CA mediates formation
of HCO3- in aqueous humor

 Inhibition of CA reduces rate of aqueous

humor formation and then reduces
intraocular pressure (IOP)

16
 CA inhibitors

Toxicity
Acetazolamide
Sulfonamide-like toxicity e.g.
ƒ Bone marrow depression
ƒ Skin toxicity
ƒ Sulfonamide-like renal lesion
ƒ Allergic reaction in patients
hypersensitive to sulfonamides
17
 CA inhibitors

Adverse effects
 Hyperchloremic metabolic acidosis
 Renal stones
 Hypokalemia (reversed by K+ supplement)
 Drowsiness and paresthesias (for large
dose of acetazolamide)
 Hypersensitivity reactions (fever, rashes,
bone marrow suppression, and interstitial
nephritis) may also occur
18
 CA inhibitors

Contraindications

CA inhibitors induce Decrease urinary

alkalinization of urine excretion of NH4+

Patient with Hyperammonemia

Hepatic cirrhosis and hepatic
encephalopathy

19
 CA inhibitors

Indications

Glaucoma (reduce IOP)

Urinary alkalinization
Metabolic alkalosis
Acute mountain sickness
(decrease in serum pH lowers hemoglobin's
affinity for oxygen, thereby increasing
oxygen delivery to the tissues)

20
 Osmotic diuretics
 Mannitol (iv. route only)
 Glycerin, Isosorbide (Oral)
 Freely filtered at glomerulus
 Undergo limited reabsorption by renal tubule
 Pharmacologically inert
 Increase osmolarity of plasma and tubular
fluid

21
 Osmotic diuretic

Site of action
Proximal tubule and descending
limb of Henle’s loop (freely
permeable to water)

22
 Osmotic diuretic

Toxicity
 Prior to diuresis: extracellular volume
expansion and hyponatremia
 Excessive use of mannitol without
adequate water replacement: severe
dehydration, hyperkalemia, and
hypernatremia

24
 Osmotic diuretic

Indications
Acute renal failure
Reduction of intracranial and
intraocular pressure
Reduction of cerebral edema
and brain mass before and
after neurosurgery

25
 Loop diuretics
(High-ceiling diuretics)
(Inhibitors of Na+-K+-2Cl- symport)
(TAL)
• TAL has large
absorptive capacity

• Inhibit Na+-K+-2Cl-
symporter in TAL of
Henle’s loop
• Furosemide
• Ethacrynic acid
• Bumetanide
26
• Torsemide
 Loop diuretics

Pharmacokinetics
 Loop diuretics bound to plasma proteins
therefore delivery of drugs to tubules
by filtration is limited
 They are secreted by organic acid
transport system in proximal tubule
then gain access to their binding sites
on Na+-K+-2Cl- symport in luminal
membrane of thick ascending limb
27
 Loop diuretics

Postdiuretic Na+ retention

“nephrons begin to avidly reabsorb Na+
when concentration of loop diuretics
in tubular lumen is decreased”

Overcome by
ƒ Restricting dietary Na+ intake
ƒ More frequent administration
of loop diuretic
28
Thick ascending limb
Collecting tubule
 Loop diuretics

Adverse effects
 Hypokalemic metabolic alkalosis
(reversed by K+ replacement)

 Ototoxicity
 Hyperuricemia
 Hyperglycemia
 Hypomagnesemia
 Hypocalcemia (may not occur since Ca2+ is actively
reabsorbed at DCT)

 GI disturbance
31
 Loop diuretics
Adverse effects (cont.)
 Allergic reaction (sulfonamide-like
A/E): skin rash, eosinophilia, and,
less often, interstitial nephritis
 Hyperlipidemia
 Decrease HDL
 Photosensitivity
Furosemide
 Paresthesias
 Bone marrow depression
32
 Loop diuretics

Contraindications

Severe Na+ and volume depletion

Hypersensitivity to sulfonamides
(for sulfonamide-based loop
diuretics)
Anuria

33
 Loop diuretics

Drug interactions
Aminoglycosides
(synergism of ototoxicity of both drugs)
Anticoagulants (Å anticoagulant activity)
Digitalis glycosides
(Å digitalis-induced arrhythmias)
Lithium (Å plasma level of lithium)
Propranolol (Å plasma level of propranolol)

34
 Loop diuretics

Drug interactions (cont.)

 Sulfonylureas (hyperglycemia)

 Cisplatin (Å risk of diuretic-induced

ototoxicity)

 NSAIDs (blunted diuretic response and

salicylic toxicity when given with high
doses of salicylates)

35
 Loop diuretics

Drug interactions (cont.)

 Probenecid (competitively inhibits furosemide
secretion by organic acid transport system Î
blunted diuretic response)

 Thiazide diuretics (synergism of diuretic activity of

both drugs leading to profound diuresis)

 Amphotericin B (Å potential for nephrotoxicity and

intensification of electrolyte imbalance)

36
 Loop diuretics

Indications
 Acute pulmonary edema
 Chronic congestive heart failure (CHF)
 Hypertension
 Edema of nephrotic syndrome
 Edema and ascites of liver cirrhosis
 Drug over dose (through forced diuresis)
 Chronic renal insufficiency

37
 Thiazide and Thiazide-like diuretics
(Inhibitors of Na+-Cl- symport)
Inhibit Na+-Cl-
symporter at distal
convoluted tubule

•Hydrochlorothiazide
•Indapamide
•Metolazone
•etc.

38
 Thiazides

Pharmacokinetics
Thiazides are secreted into
proximal tubule by organic acid
secretory pathway
Probenecid compete with
thiazides for transport into
proximal tubule

39
 Thiazides

Adverse effects
 Metabolic alkalosis Hypomagnesemia
 Hypokalemia Hypercalcemia
 Hyponatremia Hyperuricemia
 Hypochloremia Hyperglycemia

Hyperlipidemia
Allergic reaction:sulfonamide-like reaction

40
 Thiazides

Contraindications
 Hypersensitivity to sulfonamides

41
 Thiazides

Drug interactions
Decrease effects of: Increase effects of:
ƒAnticoagulant ƒ Anesthetics
ƒUricosuric agents ƒ Diazoxide
used to treat gout ƒ Digitalis glycosides
ƒSulfonylureas ƒ Lithium
ƒInsulin ƒ Loop diuretics
ƒ Vitamin D

42
 Thiazides

Drug interactions (cont.)

Effect of thiazides may be decreased by
• NSAIDS (both nonselective and selective COX-2
inhibitor)
• Bile acid sequestrants (reduced absorption of
thiazides)

Hypokalemia induced by thiazides may

be increased by
• Amphotericin B
• Corticosteroids

43
 Thiazides

Lethal drug interaction

Thiazides and quinidine

Prolongation of QT ⊕
Hypokalemia
interval by quinidine

Polymorphic ventricular tachycardia

(torsades de pointes)
44
 Thiazides

Indications
Hypertension
Heart failure
Nephrolithiasis due to
idiopathic calciuria
Nephrogenic diabetes insipidus

45
 Thiazides

Use of thiazides in hypertension

 Inexpensive
 Administered once daily
 Do not require dose titration
 Have few contraindications
 Used alone or combined with other
antihypertensive drugs
 Safe
 Reduce cardiovascular morbidity and
mortality in hypertensive patients
 Best initial therapy
46
 K -sparing
+ diuretics
2 groups
1.Mineralocorticoid receptor antagonist
(aldosterone antagonist):
spironolactone, canrenone, etc.
2.Inhibitors of renal epithelial Na+ channel:
triamterene and amiloride

47
 Mineralocorticoid receptor antagonist
(aldosterone antagonist): spironolactone
AIP=aldosterone-induced proteins
1= activation of membrane-bound Na+
channels
2= redistribution of Na+ channels from
cytosol to membrane
3= de novo synthesis of Na+ channel
4= activation of membrane-bound
Na+,K+-ATPase
5= redistribution of Na+,K+-ATPase from
cytosol to membrane
6= de novo synthesis of Na+,K+-ATPase
7= changes in permeability of tight
junctions
8= increased mitochondrial production of
ATP

Net effect of AIP is to increase Na+ conductant of luminal

membrane and Na+ pump activity of basolateral membrane
48
 K+- sparing diuretic

Competitively inhibits binding of

aldosterone to mineralocorticoid

receptor (MR)

Do not require access to

tubular lumen to induce diuresis

49
 K+- sparing diuretic

Other actions
Spironolactone has some affinity
toward progesterone and
androgen receptors

Induce gynecomastia, impotent,

menstrual irregularities

50
 K+- sparing diuretic

Pharmacokinetics
Spironolactone
 is metabolised extensively
 Undergoes enterohepatic circulation
 Has short half-life (1.6 hr)
 Active metabolite (canrenone) has
long half-life (16.5 hr) – prolongation
of spironolactone effect
51
 K+- sparing diuretic

Adverse effects
Spironolactone
Hyperkalemia
Gynecomastia Effect on
steroid
Impotent
receptors
Decreased libido
Hirsutism
Deepening of voice
Menstrual irregularities
52
 K+- sparing diuretic

Adverse effects (cont.)

Spironolactone

GI. A/E CNS A/E

ƒ Gastritis ƒ Drowsiness
ƒ Lethargy
ƒ Gastric bleeding
ƒ Ataxia
ƒ Peptic ulcer ƒ Confusion
ƒ Headache
Skin rashes
Blood dyscrasias
53
 Inhibitors of renal epithelial Na+ channel:

• Triamterene
• Amiloride

Inhibit epithelial
Na+ channel in
late distal tubule
and collecting
duct

54
 K+- sparing diuretic

Adverse effects
Amiloride Triamterene

Hyperkalemia Hyperkalemia
Nausea Nausea
Vomiting Vomiting
Diarrhea Leg cramps
Headache Dizziness

55
 K+- sparing diuretic

Drug interactions

Salicylates: Æ tubular secretion of

canrenone
Æ diuretic efficacy of
spironolactone
Spironolactone alters clearance of
digitalis glycosides

56
 K+- sparing diuretic

Pharmacokinetics
 Amiloride is eliminated as unchanged
by urinary excretion
 Triamterene
ƒ is metabolised extensively to active metabolite:
4-hydroxytriamterene sulfate
ƒ Active metabolite is as effective as
triamterene
ƒ Toxicity of triamterene may be enhanced in
both hepatic disease and renal failure
ƒ Hepatic diseases decrease metabolism of
triamterene
ƒ Renal failure decrease urinary excretion of
active metabolite
57
 K+- sparing diuretic

Indications
 Coadministered with thiazide or loop
diuretics in treatment of edema and
hypertension
(Moduretic = amiloride 5 mg + hydrochlorothiazide 50 mg)

 Primary hyperaldosteronism
 Secondary aldosteronism (evoked by
heart failure, hepatic cirrhosis,
nephrotic syndrome, severe ascites)
58
Reference
 Hardman TG, Limbird LE, eds. Goodman &
Gilman’ s The pharmacological basis of
therapeutics. 11th ed. New York: McGraw-Hill,
Health Profession Division. 2006.
 Katzung BG, Masters SB, Trevor AJ, eds. Basic
and clinical pharmacology. 11th ed. Access
Medicine E-Books from McGraw-Hill
(http://www.accessmedicine.com/resourceTOC.
aspx?resourceID=16). 2009.