Diuretic Drugs pharmacological class

SITES OF ACTION thiazides

distal
tubule
K+-sparing

osmotic
diuretics

collecting
duct
carbonic glomerulus
proximal
anhydrase tubule
inhibitors urine
blood
(artery)

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

 Excretionis 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
 Uricacid 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

 Inhibitionof 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
-
HO-C-H O
-
HO-C-H
-
H-C-OH
-

H-C-OH
-

CH2OH O H OH

Mannitol H

H2COH
Isosorbide
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
 Notmetabolized
 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