PHARMACOLOGY OF DIURETICS

CLASS PROTOTYPICAL MOA CLINICAL USE ADVERSE EFFECT CONTRAINDICATION

DRUGS

CARBONIC ANHYDRASE  Glaucoma

 Catalyzes the dehydration of (↓ intraocular pressure)  Hyperchloremic  Hepatic encephalopathy
H2CO3 at PCT (lumen)  Urinary alkalinization ( enhanced metabolic acoidosis in pt w/ cirrhosis (NH3 ↑ -
H+ produced by breakdown of renal excretion & solubility of cysteine -
(loss of HCO3 ) encephalopathy: CA-I

H2CO3, exchanged for Na+ & by ↑pH)  Renal stones ( calcium inhibits conversion of NH3
 Metabolic alkalosis ( correct phosphate stone form in to NH4+)
also combined w/ HCO3- at
CARBONIC PCT (lumen)
abnormalities if total body K+) alkaline urine)  Hyperammonemia (↑
ANHYDRA  Acute mountain sickness (forces  Renal potassium reabsorption of NH3 d/t
Acetazolamide -
kidney to excrete HCO3 , blood more wasting (NaHCO3 urinary alkalinization)
SE
acidic, fool body thinking have excess enhance K+ secretion)
INHIBITOR CARBONIC ANHYDRASE
CO2, thus excrete imaginary CO2 by
S INHIBITORS (CA-I) deeper & faster breathing, ↑ O2 in
-
(CA-I)  Inhibit HCO reabsorption blood)
+ +
 Reduces Na & H exchange  Other: treat patient with CSF
 NaHCO3 is excreted along w/ leakage (↓ICP)
H2O

CLASS PROTOTYPICAL MOA CLINICAL USE ADVERSE EFFECT CONTRAINDICATIO

 DRUGS
 Proximal tubule & LoH
(descending limb) are freely
permeable to water
 Osmotically active agent that
is filtered by the glomerulus
but x reabsorbed causes
water to be retained in these
segments & promotes water
diuresis
 Oppose ADH action in CD
 The ↑ in urine flow rate ↓ the
contact time between fluid &
OSMOTI Mannitol tubular epithelium, thus
C reducing Na+ & water
reabsorption
CLASS PROTOTYPICAL MOA
DRUGS
o Inhibit NaCl & KCl
 ↑ of urine volume
- ↑ water secretion in preference to
Na excretion. This effect can be
used when Na+ retention limits the
response to conventional agents
- To maintain urine volume
- In some pts w/ ARF caused by
ischemia, nephrotoxins,
hemoglobinuria & myoglobinuria
 ↓ of ICP
b4 & after neurosurgery & in
neurological conditions
 ↓ intraocular pressure
b4 ophthalmologic procedures & during
acute attack of glaucoma
CLINICAL USE
o Acute pulmonary edema
N
 Dehydration, hypernatremia
- Excessive loss of water & Na
 Hyperkalemia
- As water is extracted from
cells, intracellular [K+] ↑,
leads to cellular losses &
hyperkalemia
 Expansion of ECF volume
- May result in hyponatremia
causing CNS symptoms e.g. N,
V, headache
 Hyponatremia
- In pt w/ renal impairment,
mannitol parentally
administered & retained
intravenously. Causes osmotic
extraction of water from cells
→ hyponatremia
ADVERSE EFFECT CONTRAINDICATION
o Hypokalemic metabolic
 reabsorption by inhibiting
luminal Na+/K+/2Cl-
transporter (NKCC2) of
the TAL of LoH
- Action of NKCC2 contributes
to excess K+ accumulation
within cells. Back diffusion of
K+ into tubular lumen causes a
Frusemide lumen-positive potential that
+
drives the reabsorption of Ca2
+
& Mg : inhibition if NKCC2
LOOP lead to inhibition of Ca2 & +
+
Ethacrynic Mg reabsorption.
o Induce expression of
acids
COX2 → PGE2; inhibits
(non-
salt transport in the TAL
sulfonamide)
o ↑ RBF via prostaglandin
action on vasculature
CLASS PROTOTYPICAL MOA
DRUGS
 Inhibit NaCl reabsorption
from luminal side of DCT by
blocking Na+/Cl- transporter
o Other edematous condition alkalosis
o Acute hypercalcemia - By inhibiting salt reabsorption in
o Hyperkalemia TAL, it will ↑ Na+ delivery to CD,
thus ↑ secretion of K+ & H+
- Significantly enhances
o Ototoxicity
urinary excretion of K+. this
response is enhance by - Dose-related hearing loss
stimulation NaCl & water (reversible)
administration o Hyperuricemia
o Acute renal failure - Hypovolemia-associated
enhancement of uric acid
- ↑ urine flow rate → enhances
reabsorption in proximal tubule
K+ excretion. If a large
pigment load has precipitated o Hypomagnesemia
ARF, loop agents may help o Allergic reactions
flush out intratubular cast & Pts w/ hypersensitivity to
-
ameliorate intratubular sulfonamides (frusemides)
obstruction
o Anion overdose
- Treating toxic ingestion of
Br-, F-, I- which are
reabsorbed in the TAL (w/
simultaneous saline
administration)
CLINICAL USE ADVERSE EFFECT CONTRAINDICATION
 Hypertension  Water & electrolyte imbalance
 Edema associated w/  These effect same w/ that of
congestive heart LOOP DIURETICS Excessive use of any diuretic is
 (NCC)
 Enhance Ca2+ reabsorption
(in contrast to the situation in
TAL, loop diuretics inhibit
Ca2+ reabsorption):
- In proximal tubule:
THIAZID Hydrochlor
thiazide-induce volume
E othiazide depletion leads to enhanced
Na+ & passive Ca2+
reabsorption
- In the DCT: lowering
+
intracellular Na
=blockade of Na+ entry
failure, hepatic - Hypokalemic metabolic alkalosis dangerous in pts w/ hepatic
cirrhosis & renal d/s - Hyperuricemia cirrhosis, borderline renal
 Nephrolithiasis - ECF volume depletion failure, or heart failure
(process of forming - Hypotension
kidney stone) d/t - Hypochloremia
idiopathic - Hypomagnesemia
hypercalciuria
 Hypercalcemia
 Nephrogenic
 Hyponatremia (more common w/
diabetes insipidus THIAZIDE than LOOP)
 Impaired carbohydrate intolerance
- Thiazides may impair glucose
tolerance & hyperglycemia.
Hyperglycemia can be reduced when

enhances Na+/Ca2+ K+ is administered together w/

thiazides, suggesting that
exchange in the
hyperglycemia may related to
basolateral membrane, &
hypokalemia
↑ overall reabsorption of
 Hyperlipidemia (↑ plasma LDL, Ch
Ca2+
& TG)
 CNS symptoms & impotence can
be seen but x common
CLASS PROTOTYPICAL MOA CLINICAL USE ADVERSE EFFECT CONTRAINDICATION
DRUGS

Prevent K+ secretion by
antagonizing the effects of
aldosterone in CD  Cause severe, fatal,
Hyperkalemia
hyperkalemia in susceptible pts
Hyperchloremic
  Inhibition may occur by  Diuretic of choice in pts w/ metabolic acidosis (by  Pt w/ chronic renal
POTASSIU direct pharmacologic hepatic cirrhosis inhibiting H+ secretion insufficiency are esp.
M- antagonism of  Hyperaldosteronism: d/t 1°
I parallel w/ K+ vulnerable-should rarely be
mineralcorticoid receptor hypersecretion @ 2°
SPARING
secretion, it can cause
Spironolact hyperaldosteronism treated w/ potassium sparing
 Pseudo- hyperaldosteronism acidosis
one diuretics
(Liddle’s syndrome)
Gynecomastia (by
 Treatment of edema &  Pt with liver disease may have
actions on the steroid
hypertension: Na+ channel
impaired metabolism of
inhibitors are mainly used in receptors)
combination w/ LOOP & spironolactone
THIAZIDES in order to enhance
Na+ excretion & to counteract K+
wasting

 Inhibition of Na+ influx via  Treat Lithium-induced

epithelial sodium shannel nephrogenic diabetes insipidus
Amiloride (ENaC) by blocking Li+ transport into
- ENaC is critical for Na+ entry tubular epithelial cells
into cells down the  Inhibits Na+ channel in airway
electrochemical gradient epithelial cells, and is used to
+
created by Na pump in the improve mucociliary clearance
basolateral membrane, which
in pt w/ cystic fibrosis
pumps Na+ into interstitium
- This selective transepithelial
transport of Na+ establishes a
luminal negative
transepithelial potential which
in turn drives secretion of K+
 into tubule fluid
- The luminal negative
potential also facilitates H+
secretion via proton pump in
the intercalated epithelial
cells