I.

CARBONIC ANHYDRASE INHIBITORS

II. LOOP DIURETICS
III. THIAZIDE
IV. POTASSIUM-SPARING DIURETICS
A. INHIBITORS OF RENAL EPITHELIAL NA+ CHANNELS
B. ANTAGONISTS OF MINERALOCORTICOID RECEPTORS
V. AGENTS THAT CONTROL WATER SECRETION
A. OSMOTIC DIURETICS
B. ADH ANTAGONISTS

CARBONIC ANHYDRASE INHIBITOR inhibits HCO3 reabsorption by blocking carbonic anhydrase

LOOP DIURETICS inhibits NaCl reabsorption in TAL by blocking NKCC2 transport
THIAZIDE inhibits NaCl reabsorption in DCT by blocking Na+/Cl- (NCC) transport
POTASSIUM-SPARING DIURETICS

INHIBITORS OF RENAL EPITHELIAL NA+ CHANNELS inhibits renal epithelial Na+ channels
ANTAGONISTS OF MINERALOCORTICOID RECEPTORS antagonizes the mineralocorticoid receptors
AGENTS THAT CONTROL WATER SECRETION

OSMOTIC DIURETICS prevents absorption of water countervailing osmotic force in PT and DTL
ADH ANTAGONIST antagonizes ADH
I. CARBONIC ANHYDRASE INHIBITORS Carbonic anhydrase
- forerunners of modern diuretics - zinc metalloenzyme
- discovered in 1937 when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic - 2 types:
 Type II – inside the cytoplasm “cy-TWO-plasm”
metabolic acidosis  Type IV – inside the luminal & basolateral membrane
- now rarely used as diuretics (With the development of newer agents), but they still have several specific applications - present in many nephron sites
- prototype: acetazolamide  predominant location: epithelial cells of the PCT, where it catalyzes the dehydration of H2CO3 to CO2 at the
luminal membrane and rehydration of CO2 to H2CO3 in the cytoplasm
- also involved in the secretion of titratable acid in CD system (2o site of action, intercalated cell?)

DRUG MOA Indications Contraindications PK PD Other Notes

GENERAL - inhibits HCO3 reabsorption  (Open Angle) Glaucoma - As a sulfonamide derivative: -  CA inhibition there will be a gradual 
by blocking carbonic - by decreasing formation of aqueous a) Bone marrow depletion   HCO3 reabsorption diuretic efficacy due to:
humor b) Skin toxicity (overall effect of 45% inhibition of
anhydrase - see the drugs for the dose & route c) Sulfonamide like renal lesion  HCO3 in the glomerular
the whole kidney reabsorption)
 Urinary Alkalinization d) Allergy filtrate
-
 Metabolic Acidosis - In large doses:  HCO3 depletion
a) Drowsiness
 Acute Mountain Sickness b) Paresthesia
- Above 3000m - Urinary alkalinization &
TOXICITY
- In RBCS:
metabolic acidosis  Hyperchloremic metabolic
  CO2 levels in peripheral tissues
 In cirrhosis: acidosis, due to
  CO2 level
z a) induce/worsen hepatic 
s in expired gas encephalopathy,
due to diversion of ammonia to
 Epilepsy systemic circulation
- as adjuvant therapy
- since metabolic acidosis controls (alkalinization of urine NH4+
seizures(?) excretion, resulting to
 (Familial) Hypokalemic hyperammonemia)
 In alkaline urine:
periodic paralysis b) calculus formation & ureteral colic
 Severe hyperphosphatenemia 2o to precipitation of Ca2+
- hyperchloremic acidosis &
COPD (worsening of acidosis)
-  urinary excretion ratio of
organic bases
Acetazolamide -  Glaucoma - - Well-absorbed orally
~100% oral bioavailability
- 
- 250 mg OD-QID -
- t ½ = 6-9 hours
- ROE: renal
Dichlorphenamide -  Glaucoma - - - -
- 50 mg OD-TID
Methazolamide -  Glaucoma - - Well-absorbed orally
- ~100% oral bioavailability
- -
- 50-100 mg BID-TID
- ROE: ~25%, ~75% M
Dorzolamide -  Glaucoma - - - -
- topical
Brinzolamide -  Glaucoma - - - -
- topical
II. LOOP DIURETICS

DRUG MOA Indications Contraindications PK PD Other Notes

GENERAL - inhibits NaCl reabsorption in  - -
TAL by blocking NKCC2 - a)
b)
transport
Furosemide -  - - - 
-
Bumetanide -  - - - 
Torsemide -  - - - 
Ethacrynic Acid -  - - - 
III. THIAZIDE

DRUG MOA Indications Contraindications PK PD Other Notes

GENERAL - inhibits NaCl reabsorption in  - -
DCT by blocking Na+/Cl- - c)
d)
(NCC) transport

Chlorthiazide -  - - - 
-
Indapamide -  - - - 
IV. POTASSIUM-SPARING DIURETICS

DRUG MOA Indications Contraindications PK PD Other Notes

A. INHIBITORS OF RENAL EPITHELIAL NA+ CHANNELS
GENERAL - inhibits renal epithelial Na+  - -
channels - e)
f)

Triamterene -  - - - 
-
Amiloride -  - - - 
B. ANTAGONISTS OF MINERALOCORTICOID RECEPTORS
GENERAL - antagonizes the  - -
mineralocorticoid receptors - g)
h)

Spironolactone -  - - - 
-
Eplerenone -  - - - 
Canrenone -  - - - 
V. AGENTS THAT CONTROL WATER SECRETION

DRUG MOA Indications Contraindications PK PD Other Notes

A. OSMOTIC DIURETICS
GENERAL - prevents absorption of water  - -
countervailing osmotic force - i)
j)
in PT and DTL
Mannitol -  - - - 
-
Glycerin -  - - - 
Isosorbide -  - - - 
Urea -  - - - 
B. ADH ANTAGONISTS
GENERAL - antagonizes ADH  - -
- k)
l)

Conivaptan -  - - - 
-
Lithium -  - - - 
Demeclocycline -  - - - 
 URINARY ELECTROLYTES
GROUP MECHANISM OF ACTION
NaCl NaHCO3 K+ Body pH
+ +++ + -
CARBONIC ANHYDRASE INHIBITOR inhibits HCO3 reabsorption by blocking carbonic anhydrase
++++ 0 + +
LOOP DIURETICS inhibits NaCl reabsorption in TAL by blocking NKCC2 transport
inhibits NaCl reabsorption in DCT by blocking Na+/Cl- (NCC) ++ + + +
THIAZIDE
transport
LOOP AGENTS + THIAZIDES ++++++ + ++ +

POTASSIUM-SPARING DIURETICS + (+) - -

+ (+) - -
INHIBITORS OF RENAL EPITHELIAL NA+ CHANNELS inhibits renal epithelial Na+ channels
+ (+) - -
ANTAGONISTS OF MINERALOCORTICOID RECEPTORS antagonizes the mineralocorticoid receptors

AGENTS THAT CONTROL WATER SECRETION

OSMOTIC DIURETICS increases the osmolality of the plasma and tubular fluid

ADH ANTAGONIST antagonizes ADH

Diuretic braking
- compensatory mechanism that is caused by continued administration of diuretics
1. Activation of SNS
2. Activation of RAS
3. Decrease pressure natriuresis by decrease BP
4. Hypertrophy of renal epithelial cells
5. Increased expression of renal epithelial transporters
6. Alteration of natriuretic hormones, ANP
DIURETICS IN CLINICAL PRACTICE
Mechanism of Edema Formation
1. Na+ excretion is a steep function of MABP such that small increases in MABP cause a marked increase in Na + secretion
2. Net (+) Na+ balance result into increase [Na+] in ECF
3. Stimulation of water intake (thirst) and urinary output (opposite occur in Na + balance)

 Changes in water intake & output adjust ECFV concentration toward normal thereby expanding contracted ECFV
 Total ECFV is distributed among many body compartments but it is the volume in the arterial tree that is sensed by the CV system and kidney

1. Shift to the right in the renal pressure-natriuresis relationship causes reduced Na+ excretion for any
level of MABP
2. Increase in total body Na+ and ECFV, decrease MABP
3. Additional ECFV would be distributed throughout various body compartment predisposing to EDEMA

1. Increase Na+ in expanded ECFV

2. Increase CO
3. Increase vascular resistance (autoregulation)
4. Increase MABP
5. Pressure natriuresis
6. Decrease ECFV
7. Decrease output and TPR

Mechanism for “entrapment” of ECFV at various sites leading to “missense” of ECFV in the arterial tree