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 – unsubstitutedSubstitution 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 activityDichlorphenamide – 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 HC03-

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 HCO3

-. 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 HCO3

-

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 inhibitorspresent 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 anddecrease 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, distributionLittle biotransformationExcretion: urineAttain high conc. in renal luminal fluid, proximal

tubule cells

Site 1 Diuretics

Adverse effects:Development of metabolic acidosis due to loss

bicarbonateHypokalemia 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 liverDevelopment 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 sicknessAdjuvant for epilepsyTo 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