Pharmacology of Diuretics Diuretics increase urinary sodium chloride (saliuresis).

Diuretics are used for HTN and edematous states such as CHF, cirrhosis, nephrotic syndrome. (Raymond remo ed ima!es of effect of salt inta"e#e$cretion on %ei!ht and effect of CHF &#' diuretic on sodium e$cretion and (CF olume.) )f salt input * output, you %ill retain %ater %ei!ht (see a+o e) and +e!in to e$crete more sodium. Therefore, steady state (CF depends on sodium inta"e. ,imilarly, incremental increases in (CF cause proportionate increases in sodium e$cretion (a+o e). Role of diuretics (dema occurs if sodium is not properly excreted and (CF e$pands. This occurs in CHF, cirrhosis, and nephrotic syndrome. )n addition to reduced e$cretion, the threshold ECF is elevated, so that sodium e$cretion doesn-t start until hi!her'than'normal (CF (see a+o e). Chronic Adaptation to Diuretics Diuretics increase NaCl e$cretion, %hich lo%ers (CF. .ut +ody senses this natriuresis and hypol olemia, and adapts %ith renin'an!iotensin'aldosterone system. This is the diuretic braking effect. Loop Diuretics Furosemide, .umetanide, (thacrynic acid. These +loc" Na#/#Cl co'transporter in the T01. These are hi!h ceilin! diuretics +ecause of potency (234 of sodium is normally rea+sor+ed here). There is also a strong braking mechanism, +ecause loop diuretics allo% hi!h Na& at the distal tu+ule, %here sodium rea+sorption is upre!ulated. This rebound sodium retention can +e countered +y concurrent use of a thiazide diuretic to +loc" distal rea+sorption. 5ther effects include increased calcium excretion, and increasin! enous capacitance (pulls edema fluid into the (C6). Side effects: 77hypokalemic metabolic alkalosis due to lots of distal /& and H& %astin!. ,ince there is olume contraction, renin and aldosterone increase, compoundin! this %astin!. ''hyperuricemia due to reduced uric acid e$cretion may lead to !out. ''hypercalciuria ''(thacrynic acid & amino!lycoside 8 ototo$icity999 Thiazide Diuretics Hydrochlorothia:ide (HCT;), Chlorthalidone, <etola:one. These are lo% ceilin! diuretics %ith no re+ound sodium retention +ecause they act at the DCT. Thia:ides act +y +loc"in! the Na#Cl co'transporter. 5ther effects include antihypertensive effect independent of diuretic effect. 0lso, decreased calcium excretion (opposite of loop diuretics) can help treat kidney stones and osteoporosis.

Side effects: ''hypokalemic metabolic alkalosis for the same reasons as loop diuretics. ''hyperuricemia due to reduced uric acid e$cretion may lead to !out.

Potassium-sparing Diuretics ,pironolactone= aldosterone anta!onist, inhi+its +asolateral Na#/ antiporter in the principal cell. 0miloride, Triamterene= (naC +loc"ers. These are lo% efficacy diuretics. 5ther effects include= 77Spironolactone reduces C F mortality. !t has potent antihypertensive effects +ecause myocardium also has aldosterone receptors. ''0miloride reduces "idney to$icity from lithium, %hich enters ia the amiloride'sensiti e (naC channel. Side effect: yperkalemia " potentially fatal9

Carbonic Anhydrase nhibitors C0 cataly:es the hydration of HC5>, %hich !enerates H& for secretion into pro$imal tu+ule in e$chan!e for Na&. C0 inhi+itors pre ent this H& !eneration, pre entin! Na& and HC5> rea+sorption. 5 erall, the +ody %astes NaHC5>. This simulates #$% type &. ?nli"e other diuretics, the acidosis +y C0 inhi+itors is accompanied +y hypokalemia. Side effects: ''0cidosis due to +icar+onate loss. ($actly li"e renal tu+ule acidosis (RT0) type 2. ''Hypo"alemia. ''Terato!enic.

Classification of diuretics based on predominant site of action Type of Diuretic Carbonic Anhydrase Inhibitor Acetazolamide Loop #urosemide $thacr nic acid Thiazide H drochlorothiazide (etal ozone Potassium Sparing Triamterene Amiloride *!ironolactone Collecting )uct + Na+absor!tion K+ loss H+ secretion H !er"alemic acidosis )istal Tubule ++ Site of Action Potency Primary Effect Secondary effect Complications H !o"alemic h !erchloremic acidosis H !o"alemic al"alosis H !o"alemic al"alosis

Proximal Tubule

Na /H exchange
+ +

K+ loss HCO3- loss K+ loss H secretion

+

%oo! o& Henle

+++

Na+/K+/'Cl absor!tion

Na absor!tion
+

K+ loss H secretion
+

(Raymond remo ed ima!e sho%in! site of action of arious diuretics.)