lect 2 diuretics april 2014
DESCRIPTION
diuretics:site 1 acting drugs with moa ans sarTRANSCRIPT
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Lecture 2
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Site 1: Proximal tubule
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Site 1: Proximal tubule
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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
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Site 1 Diuretics
Developed from sulfanilamide
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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
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SAR
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Site 1 Diuretics
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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).
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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.
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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
-
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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.
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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
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Mechanism of action:
Site 1 Diuretics
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Pharmacokinetics:Well absorbed from GIT, distributionLittle biotransformationExcretion: urineAttain high conc. in renal luminal fluid, proximal
tubule cells
Site 1 Diuretics
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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
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Exacerbate symptoms of cirrhosis of liverDevelopment of hepatic encephalopathy (due to
increased level of ammonia in systemic circulation)
Site 1 Diuretics
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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
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References
Wilson gisvold Foye