diuretics

plasma proteins,lipids –> filtrate –> 99% reabsorbed [diuretics block by 1% -->twice incr filtrate] –>urine N=1.5l/day.

ICF rich in [K+] & reabsobed proximally,secreted distally.

PCT -max [Na+] reabsorption  –> but diuretic action is weak & ADRs: compensatory mech incr salt reabsorption distally, CAi disturb acid base balance.

medullaryAscLH –>FUROSEMIDE high efficacy since less compensation distally.

corticalAscLH –>THIAZIDE medium efficacy.

DT,CD –>K+ SPARING mild diuresis.

PCT -reabsorption of

• Na+, Na+Glu by elecchgrad
• K+, Glu, AA, PO4-3, OrgAn- by symporter
• NaHCO3 by NaH+antiporter, CA, Na+HCO3-symporter
• Cl- by paracellular passively w/ other anion
• Na+ H2O to maintain isotonicity balance.

thickAscLH – reabsorb maxNa+Cl- by Na+K+2Cl- cotransporter & elecchgrad  [high at papilla tip from passive countercurrentmech(hairpin loop) & vasarecti shunts decr blood flow]  –> luminal hypotomic but hypertonic hypertonic /w absorbs H2O form descLH making that lumen hypertonic.

corticalDT – reabsorb some more NaCl by a symporter.

terminalDT,CD - reabsorb of

• Na+ by aldosterone w/ passsive Cl- reabsorption & secretion of K+,H+.
• H2O by ADH & medulla elecchgrad causing luminal hypertonicity.

free water clearance [vol/unit time to excrete solute isoosmotically] -

• 0 if urine isotonic
• + if hypertonic
• - if hypotonic

GFR depends on:

• co
• renal blood flow
• aff  & eff arterioles diff
• elecchgrad in juxtamed nephrons(20%) altered by redistr of blood
• RAS
• Adr, PG, ANP

high ceiling  -loop diuretics -FUROSEMIDE, BUMETANIDE (more potent lowADR:myopathy),  mercurials,EA

• med oral absorp, rapid short action, max diuresis [10l], dose dependent response, chr use nephron hypertrophy resistance.
• inh  AscLH Na+K+2Cl-cotransporter [incr distal K+excr -hypokalaemia (low since short action allows compensatory repletion)] & abolish medulla high elecchgrad [urine stays isotonic]  –> both strong diuresis –> initial Rx for all edema [cardiac,renal,liver,lung], alt to mannitol in intracranial edema & poison forced diuresis, complicated HTN [renal failure, cirrhosis, CHF, vasodil complication, thiazide resistance, emergency HTN w/ vol overload, blood transfusion overload].
• GFR unaltered [compensatory mech to the incr renal flow & medulla redistribution] –> use in renal insufficiency & resistant nephrotic edema.
• iv inj incr venodil –> decr preload –> quick relief to LVF & pulm edema before natriuretic effect.
• incr Ca+2, Mg+2 excr –> use in hypercalcaemia & renal stones.
• decr urea,Glu excr –> ppt gout,DM.

mod efficacy -thiazides & thiazide like -

• good oral , 1hr onset, long action, flat dose response.
• only inh cortical DT Na+Cl-symporter [but prominent hypokalaemia since long acting] [hypertonic urine +free water clearance] –> maintenance therapy of mild mod edema esp cardiac, 1st choice in uncomplicated mild(10mm)HTN esp elders, diabetes insipidus.
• decr renal blood flow & GFR  [causing resistance] –> CI: renal failure, cirrohsis.
• incr Mg+2, Glu excr.
• decr Ca+2 [use in hypercalcaemia of recurrent renal stones], urea excr –> ppt gout.

chronic use of high dose loop & thiakide diuretics complications -

• hypokalaemia (fatigue, ms cramps, arrhyth, alkalosis).  Rx -high K+ diet/supplements, K+ sparing diuretics in cirrohsis, post MI, digitalis, quinidine, sulfonylurea, TCA, elders.

• dehydration, low BP from isotonic natriuresis esp furosemide.  Rx-saline.
• dilutional hyponatremia, edema -incr thirst. Rx-glucocorticoids, stop water intake & diuretic use.
• ototoxicity from incr Na+ in endolymph.
• CI- PIH, gout, Dnephropathy, dyslipedemia, DM.
• allergy, git, cns symptoms.

interactions-

• potentiate antiHTNsives
• hypokalaemia w/ digitalis, quinidine, sulfnylurea, TCA
• rise Li+ levels
• nephrotoxicity w/ aminoglcosides, 1st cephalosporins, amphotericinB.
• inh by NSAIDs, probenecid.

CAi -acetazolamide -

• decr NaHCO3 reabsorp in PCT & incr K+ excr distally[hypokalaemia] –>mild alk diuresis [but self limiting & decr NH3 absorp(cirrhosis -->hepatic coma)]- use in UTI, incr acidic drug excr
• decr IOP by inh aqh form -use adj in glaucoma
• incr CO2(sedation) –>decr siezure threshold in brain – use adj in abscence siezures.
• ADR- BMdepr, allergy, git, cns symptoms.

K+sparing diuretics acting on CD —> mild natriuresis w/out K+loss –> use to prevent hypokalaemia w/ other diuretics, break thiazide resistance from hyperaldostr esp in cirrhosis & nephrotic syndrome

SPIRANOLACTONE – steroid antagonizing aldosterone by binding its ICF receptor –> decr AIP[NaKATPase,Nachannel].  [ADR- hirusitism, gynaecomastia, impotence, menstrual irregularities]

TRIAMPTERENE, AMILORIDE -nonsteroids directly inh Na+channel.  [ADR- git] add uses- prevents Dinsepidus ADR from Li+reabsorp, incr fluidity of cystic fibrosis secretions.

CI- renal insufficiency[-->hyperkalaemia], cirrhosis[-->acidosis], PUD, ACEi/AT1antagonists.

interactions- incr digoxin, inh by aspirin.

osmotic diuresis- iv MANNITOL

• inert low molwt nonelectrolyte –> decr ICP in head inj stroke, decr IOP in glaucoma, low plasma osmolarity of rapid dialysis.
• incr blood vol , GFR, ion excr, urine vol –> use in impending renal failure , poison forced diuresis.

DESMOPRESSIN -selective V2 agonist in CD incr ADH action –> neurogenic Dinsepidus [pituitary ADHdef], nocuria.  ADR-fluid retention, hyponatrimea.