Diuretic Drugs pharmacological class

SITES OF ACTION thiazides

K+-sparing

osmotic
diuretics

carbonic
anhydrase
inhibitors

structural class
loop diuretics
Methylxanthenes CA Inhibitors, Loop Diuretics, Thiazides
Glomerulus Osmotic diuretics Osmotic diuretics Distal tubule
Proximal tubule Loop of Henle
5%
Antikaliuretics

Thick
70% Ascending
Limb 4.5%
Collecting
duct

20%
100%
GFR 180 L/day
Plasma Na 145 mEq/L
Filtered Load 26,100
mEq/day 0.5%
Volume 1.5 L/day
Urine Na 100 mEq/L
Na Excretion 155 mEq/day
 CA inhibitors

Acetazolamide
Dorzolamide
Bumetanide
 Carbonic anhydrase Inhibitors
Carbonic anhydrase:
Location: PCT
Function:
catalyzes the dehydration of H2CO3, a
critical step in the proximal reabsorption of
H2CO3.
CARBONIC ANHYDRASE INHIBITORS

Acetazolamide, dichlorphenamide, methazolamide

Developed from
sulfanilamide,
after it was
noticed that
sulfanilamide
caused metabolic
acidosis and
alkaline urine
 MOA
Inhibition of carbonic anhydrase activity
profoundly depresses bicarbonate
reabsorption in the proximal tubule.

------ sodium bicarbonate diuresis

----- decrease in total bicarbonate stores
 CARBONIC ANHYDRASE INHIBITORS

CA
CO2 + H2O H2CO3 H+ + HCO3-

mild diuretics
decrease acidity of urine
action limited by hyperchloremic
metabolic acidosis
 Pharmacokinetics
Well absorbed after oral administration
Increase in urine pH in 30 m9in: due to

Bicarbonate diuresis

Excretion is by tubular secretion in

proximal tubule.
 Pharmacodynamics
Inhibition of carbonic anhydrase--------------
---- decrease bicarbonate reabsorption in
proximal tubule.

Maximal acetazolamide administration -----

----- 45 % inhibition of whole kidney
bicarbonate reabsorption.
 Therapeutic Uses
Glaucoma (dorzalamide, brinzolamide)
Urinary alkalinization
Metabolic Alkalosis
Acute mountain Sickness
Epilepsy
 Urinary alkalinization
Uric acid and cystine
Renal excretion of weak acid Aspirin is
enhanced by acetazolamide
 Metabolic Alkalosis
When the alkalosis is due to excessive use of
diuretics in patients with severe heart failure

Metabolic alkalosis secondary to Respiratory

acidosis
 Acute mountain sickness
Symptoms
Weakness, dizziness, insomnia,
headache, nausea
Progressive pulmonary and cerebral
edema ------ life threatening.

What is the role of acetazolamide?

 Decrease cerebrospinal fluid formation

Decrease pH of the cerebrospinal fluid

and Brain

Can be used for prophylaxis 24 hour

before ascent.
 Toxicity
Hyperchloremic metabolic acidosis
Renal stones
Renal potassium wasting
Hypersensitivity reactions --- fever, rashes,
bone marrow supression
 Contra indications

Hepatic cirrhosis
 THIAZIDE DIURETICS

variable effects on CA inhibition

block Na+-Cl- co-transport
relax vascular smooth muscle

General Structure of Thiazide Diuretics

 Thiazide Diuretics

Chlorothiazide
Hydrochlorothiazide
Indapamide
Metolazone
 Pharmacokinetics
Chlorothiazide is less lipid soluble ---- must
be given in relatively large doses
Chlorothalidone: slowly absorbed longer
duration of action
Idapamide: excreted primarily by biliary
system
All thiazides compete with uric acid
secretion
Pharmacodynamics
 CLINICAL USES Of THIAZIDES

1) HYPERTENSION

2) EDEMA (cardiac, liver, renal)

3) NEPHROLITHIASIS (IDIOPATHIC
HYPERCALCIURIA)

4) NEPHROGENIC DIABETES INSIPIDUS

 Toxicity

Hypokalemic metabolic alkalosis

Hyperuricemia
Impaired carbohydrate tolerance
Hyperglycemia
Hyperlipidemia
Hyponatremia
Allergic reactions
 LOOP DIURETICS

Furosemide,
Bumetanide,
Ethacrynic acid
 Pharmacokinetics
Rapidly absorbed
Eliminated by renal secretion as well as
glomerular filtration
Rapid diuresis after IV administration

DOA: 2-3 hours

Pharmacodynamics
 strong diuretics

block Na+-K+-2Cl- co-transport

increase K+, Mg++ and Ca++ excretion

 Actions

Induce renal prostaglandin synthesis

These prostaglandins participate in the renal
actions of these drugs.
Direct effect on blood flow
Increases renal blkood flow
Redistribution of blood flow within the renal
cortex.
Relieve pulmonary congestion
Reduce let ventricular filling pressures in CHF
Therapeutic uses
 CLINICAL USES OF LOOP DIURETICS
EDEMA due to CHF, nephrotic syndrome or
cirrhosis
Acute heart failure with PULMONARY
EDEMA
Acute renal failure ---- enhance K+
excretion, increase rate of urine flow
HYPERCALCEMIA
Anion overdose: bromide, fluoride and
iodide are reabsorbed in thick ascending
limb
 Adverse Effects of Loop Diuretics

Hypokalemic metabolic alkalosis,

Hyperuricemia
Hyperglycemia
Hyponatremia
Hypocalcemia (in contrast to thiazides)
Hypomagnesemia
Hypersensitivity
Dehydration and postural hypotension
Ototoxicity (especially if given by rapid IV
bolus)
 POTASSIUM-SPARING DIURETICS

Spironolactone
Triamterene,
Amiloride
 Antagonize the effects of aldosterone

at cortical collecting tubule and late distal

tubule
 Mechanisms of inhibition
Direct pharmacological antagonism of
mineralocorticoid receptors ---
spironolactone

Inhibition of Na+ flux through ion channels

in the luminal membrane --- triamterene,
amiloride
POTASSIUM-SPARING DIURETICS

spironolactone is an aldosterone
antagonist
triamterene and amiloride directly
inhibit electrogenic Na+ transport
useful adjuncts with K+-depleting
diuretics
 Therapeutic uses

Mineralocorticoid excess -----

Primary hypersecretion:
Conns syndrome,
Ectopic ACTH production

Secondary aldosteronism:
CHF, Hepatic cirrhosis,
Nephrotic syndrome,
 Toxicity
Hyperkalemia
Hyperchloremic metabolic
acidosis
Gynecomastia
Acute renal failure
Kidney stones
 Agents that
enhance water
excretion
Osmotic diuretics
OSMOTIC DIURETICS
HO
CH2OH

-
H H O
HO-C-H
-
HO-C-H
-
H-C-OH
-

H-C-OH
-

CH2OH O H OH
Mannitol H

Isosorbide
H2COH

H2COH O

=
H2N-C-NH2
H2COH

Glycerol Urea
 Proximal tubule and descending limb of
loop of henle are freely permeable to
water.

Osmotic agent causes water to be

retained in these segments and promote a
water diuresis
 Mannitol
Not metabolized
Handled by glomerular filtration
Poorly absorbed
 Pharmacodynamics
Limits water reabsorption in those segments of
nephron that are freely permeable to water ----
- the proximal tubule and descending limb of
loop of henle by exerting an osmotic force------
- increase urine volume with mannitol
excretion.
Hypernatremia.

 Therapeutic Uses
To increase urine volume

Reduction of intracranial and intraocualr

pressure
 Toxicity

Extra cellular volume Expansion

Dehydration and Hypernatremia

 OSMOTIC DIURETICS
relatively inert pharmacologically
freely filtered at the glomerulus
limited reabsorption by renal tubules
 OSMOTIC DIURETICS: Therapeutic
Uses
Prophylaxis of renal failure
Mechanism:
Drastic reductions in GFR cause dramatically
increased proximal tubular water reabsorption
and a large drop in urinary excretion
Osmotic diuretics are still filtered under these
conditions and retain an equivalent amount of
water, maintaining urine flow

Reduction of CSF pressure and volume

Reduction of intraocular pressure
 Adverse Effects of Osmotic Diuretics

Increased extracellular fluid volume

Hypersensitivity reactions
Glycerol metabolism can lead to hyperglycemia
and glycosuria
Headache, nausea and vomiting
 ADH antagonists

Lithium
Demeclocycline
THANKS