8/25/09 Kuma Diuretics (Ios)

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Edema is caused by

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fluid retention --> high BV --> high BP

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Left heqrt failure

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SOB caused by high pressure in lungs

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Right Heart failure

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High pressure in capillaries causes edema mainly in the feet

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Flow through kidney

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Renal afferent--> glomerulus--> efferetn artery --> PCT--> LH--> DCT-->CD

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Vesa recta

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maintians the concentration gradient in the medulla

has selective water and sodium re-absorption

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Total ECF volume

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12.5 L

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GFR

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125 mL/min

Total ECV is filtered every 100 min per

100 mL of urine is produced every 100 min

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PCT

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Important site of glucose, bicarb, amino acids, organic solutes regulation (67% Na re-absorbed here)

Cl and water follow passively to maintain electrical and osmolar neutrality

Site of organic acid secretion (uric acid, some diuretics, some antibiotcs (pen))

organic base secretin occurs in early/middle PCT (creatinine, procainamide)

almost all glucose and 99% filtered electroytes re-absorbed

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Descending loop of henle

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descends it to the medullla of kidney

is permeable to water impermeable to Na and Cl

tubular osmolartiy increases--> increases salt concentration

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Ascending loop of henle

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cells impermeable to water

cells activley reabsorb Na, Cl and K= Na/Cl/K cotransport system

a major site of Na reabsorption in nephron (besides PCT)

K back diffusion into lumen=driving force for Ca and Mg reabsorption

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DCT

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Na actively reabsorbed, Cl co-transported and water follows passively

at terminal end, have Na/K exchange sites--> fine-tuning K content in urine

Na reabsorption and K secretion stimulated by aldosterone

Ca reabsorption occurs by apical Ca channel and Na/Ca exchanger

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Percentage of blood plasma entering kidneys

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16-20%

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CD

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Primary site K secretion
ADH (vassopressin) --> increase premeability of duct to water--> increase water channels-->increase water reabsorption

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Main site for diuretics

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ascending loop of henle

DCT

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Diuretics ususlally act at lumin surface to:

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prevent water reabsorption

influence specfic transporter mechanisms

act on enzymes or hormone receptors in renal epithelial cells

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Generalizations about diuretic agents

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Must be secreted into the renal tubule to act on transporters

changes in Na reabsorption affect water and K reabsorption

most water and Na reabsorption occurs in the PCT

most effective diuretic agents act more in the distal tubule regions

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When Na delivery to the CD increases what happens to K?

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stimulates K secretion

increase in Na reabsorption causes an increase in K loss

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Osmotic Diuretic Drug names

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mannitol
urea
glycerin

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Osmotic diuretic solutes are:

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freely-filterable by the glomerulus so it easily goes from the blood into the tubule

undergo limited renal tubular reabsorption (want inside the tubular so act as a solute)

relatively inert

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MOA of osmotic diuretics

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Limit water reabsorption from segments that are water permeable (PCT and the descending loop of henle)

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intra-luminal osmotic diuretics

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non- reabsorbable solute--> contervailing osmotic force

as fluid passes along the tubules, the solute becomes more concentration

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countervailing osmotic force of intra-luminal osmotic diuretics cause...

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decrease water reabsorption
decrease Na concentration in tubular lumen

decrease Na reabsorption

decrease concentration gradient driving force into tubular cell

increase Na flux from peritubular fluid into lumen due to change in concentration gradient

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Extra-luminal osmotic diuretics

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non-reabsorbable solute in blood

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Extra-luminal osmotic diuretics cause...

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increase in ECF volume (because of the increase of solutes in the blood)

decrease renin release

increase renal blood flow

increase renal medullary blood flow (distrubs concentration gradients)--> increases removal of NaCl and urea from the renal medulla--> decreases renal medullary tonicity-->decreases the driving force for water reabsorption into the medulla
-->increase rate of urine flow-->diuresis

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In severe hyperglycemia, what would happen to diureses?

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Glucose reabsorption exceeds capacity of PCT--> unreabsorbed glucose becomes an osmotic diuretic

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Uses of Osmotic diuretics

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Extract water from the eye or brain

agents extract water from intracellular compartments--> decreases cerebral edema or decreases intraocular pressure

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Side Effects of osmotic diuretics in regards to ECF volume

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acute expansion of ECF volume
- osmotic agent administration --> increases ECF osmolarity--> increases ECF volume
- problem in patients with CHF or PE (they already have expanded blood volume)

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Side Effects of osmotic diuretics

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increase ECF volume
HA, N/V (common)
hyponatremia (decrease Na concentraions)
hypersensitivity reactions
dehydration/hypernatremia (if treated for extended periods of time, need fluid replacement)

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How are osmotic diuretics usulaly administered?

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parenterally

isosorbide can be given orally

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What side effect would you anticipate with orally administered mannitol?

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Osmotic diarrhea

there is an increase in solute concentration in the GI tract--> decrease water reabsoption

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Carbonic anhyrase inhibitiors
Drug

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Acetazolamide

dorzolamide

brinzolamide

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Is CO2 lipid soluble?

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Yes, very

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What diuretic causes the most K loss

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carbonic anhydrase inhibitors

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what is acetazloamide used for

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acute mountain sickness

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Na reabsorption is denpendent on exchange with...

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H in the PCT

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H is regenerated by concerted action of:

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carbonic anhydrase IV (luminal membrane)

carbonic anhydrase II (cytoplasmic)

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HCO3 reabsorption is dependent on:

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carbonic anhydrase IV and II

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carbonic anhydrase reaction

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CO2 + H2O<--> carbonic anhydrase<--> HCO3 + H

the forward reaction is Carbonic anhydrase IV and the reverse is II

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MOA of carbonic anhydrase inhibitors

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blockade of carbonic anhydrase --> decrease intracellar H --> decrease Na reabsorption --> increase Na excretion

decrease H secretion --> decrease HCO3 reabsorption --> increase Na excretion --> alkaline urine pH (metabolic acidosis)

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What are Carbonic anhydrase effects on K?

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increases secretion of K in distal nephron in CD

promoted by alkaline urine--> increase HCO3 + increase of delevery of Na to late DCT/CD --> increase lumen negative potential--> increase K secretion

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Uses of carbonic anhydrase

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limited usefullness as a diuretic because Na not absorbed in the PCT is reabsorbed in the more distal areas of the tubule

metabolic alkalosis (desired outcome sometimes such as for acute mountain sickness to increase RR)

glaucoma

Ca present in ciliary processes

Ca inhibition

Prevention of acute mountain sickness

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What carbonic anhydrase inhibitors are used for glaucoma

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dorzolamide

brinzolamide

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carbonic anhydrase inhibitors MOA to decrease aqueouse humor production

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decrease HCO3 synthesis by ciliary cells--> decrease aqueous humor formation--> decrease intraocular pressure

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MOA of carbonic anhydrase inhibitors to prevent acute mountain sickness

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HCO3 excretion--> decrease ECF [HCO3]--> metabolic acidosis--> increase ventilation

decrease CSF fromation, decrease CSF pH --> decrease cerebral edema and AMS symptoms

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CNS side effects of carbonic anhydrase

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paresthesias (tingling in fingers and toes because of a local increase in CO2)
drowsiness

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Contraindications of carbonic anhydrase in patients with hepatic cirrhosis because

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increase in urine pH--> decrease trappin of NH4 in urine

ammonia accumulates in systemic circulation

hepatic encephalopathy

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Side effects of carbonic anhydrase

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CNS

metabolic acidosis: induced by chronic reduction of HCO3 stores

Kidney stones

K depletion --> increase HCO3 + Na in distal nephron --> increase K secretion

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Process of how kidney stones are formed from carbonic anhydrase

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bicarbonaturia --> phosphaturia + hypercalciuria (Ca phosphate crystals are formed)

alkaline urine --> decrease solubility of Ca salt--> precipitaion --> kidney stone formation