Lecture 2

Site 1: Proximal tubule

Site 1: Proximal tubule
Carbonic anhydrase inhibitors
Sulphamoyl containing compounds
2 groups heterocyclic sulphonamide
derivatives
SAR:
Simple heterocyclic sulphonamide:
acetazolamide Sulphamoyl group required
for activity
Sulphamoyl nitrogen unsubstituted
Substitution of methyl group on acetazolamide
ring nitrogen - methazolamide
Site 1 Diuretics
Site 1 Diuretics
Developed from
sulfanilamide
Moiety to which Sulphamoyl group is attached
aromatic
Derivative with high lipid/water partition
coefficient and low pKa greatest CA inhibitory
activity and diuretic activity

m-disulfamoylbenzene compounds: 1,3-
disulamoyl benzene lacked diuretic Activity
Substituents diuretic activity
Dichlorphenamide CA inhibition, chlouretic
activity
Chloraminophenamide: less CA inhibition, poor
diuretic
Site 1 Diuretics
SAR
Site 1 Diuretics
Mechanism of Action
CA is located both intra-cellularly (type II
CA) and in the luminal brush border
membrane (type IV CA) of proximal
convoluted tubule cells.
Both of these site I locations are major
targets of the CA inhibitors.
These diuretics also inhibit intracellular CA
in the intercalated cells of the connecting
and cortical collecting tubules (i.e. site 4).
Mechanism of Action
During the first 4 to 7 days of continuous therapy
with CA inhibitor - an increase in Na
+
and HC0
3
-

excretion:
(a) Inhibition of intracellular CA in proximal tubule
cells - decreases the available H
+
normally
exchanged for luminal fluid Na - decreased
proximal tubule reabsorption of Na
(b) Inhibition of CA on the luminal brush border
membrane of proximal tubule cells -causes a
decrease in the production of carbon dioxide
within the luminal fluid and a decrease in the
proximal tubule uptake of carbon dioxide.
Mechanism of Action
Net result - decrease in the reabsorption of HCO
3
-
.
No massive diuresis on inhibition of the portion of
proximal tubule Na
+
reabsorption under the control
of CA
Other Na
+
reabsorption sites downstream
(especially site 2) compensate for action by
reabsorbing much of the additional Na
+
presented
to them.
Some of the luminal fluid is reabsorbed
downstream by a non CA mediated system
The actions of the CA inhibitors ultimately result in
the urinary loss of only 2 to 5% of the filtered load
of Na and up to 30 % of the filtered load of HCO
3
-


Mechanism of Action
Secondarily, the CA inhibitors enhance the urinary
excretion of a substantial amount of K
+
Urinary loss of K
+
increases because the proximal
tubule actions of CA inhibitors
present a greater percentage of the filtered load of
Na to site 4,
increase the flow rate of luminal fluid through the
distal convoluted tubule and collecting tubule and
decrease the availability of intracellular H
+
at site 4
All three changes favor enhanced exchange of
luminal fluid Na
+
for intracellular K at site 4.
Mechanism of Action
The urinary concentration of Cl
-
decreases
after CA inhibitors administration
CA inhibitors are primarily Natriuretic,
bicarbonaturetic, and kaliuretic agents.
Resistance to diuretic action
Mechanism of action:

Site 1 Diuretics
Pharmacokinetics:
Well absorbed from GIT, distribution
Little biotransformation
Excretion: urine
Attain high conc. in renal luminal fluid, proximal
tubule cells
Site 1 Diuretics
Adverse effects:
Development of metabolic acidosis due to loss
bicarbonate
Hypokalemia due to renal loss of K
+
20% reduction in GFR due to increase in flow
rate of luminal fluid , increase in reabsorption of
additional solute
Hypersensitivity reactions: urticaria, drug fever,
interstitial nephritis, etc.
Parasthesia (tingling sensation), drowsiness,
fatigue, anorexia, GI disturbances, urinary
calculi
Site 1 Diuretics
Exacerbate symptoms of cirrhosis of liver
Development of hepatic encephalopathy (due to
increased level of ammonia in systemic
circulation)
Site 1 Diuretics
Uses:
Glaucoma (CA enzyme in eye)
Inhibition of CA reduce rate of formation of
aqueous humor reduce intraocular pressure
Acute mountain sickness
Adjuvant for epilepsy
To create alkaline urine to hasten renal
excretion of noxious weak acids, to maintain
urinary solubility of poor water soluble
endogenous weak acids

Site 1 Diuretics
References
Wilson gisvold
Foye