Pro Cart Track Acetazolamide, Mannitol

2.1 – “Pro Cart Track”: Acet Acetazolamide, azolamide, ma mannitol nnitol Proximal con convoluted voluted tubule (PCT) pphysiology hysiology • Location of most renal resorption. (Pro cart Track; nephron map) • PCT is highly water permeable at PCT, maintaining a consistent concentration across epithelial cells and interstitium. • Na-K-ATPase pumps on the basolateral membrane (i.e. the intracellular compartment of the tubular epithelial cells) maintain a low intracellular sodium concentration to enable absorption (salty peanuts at the banana vending machine). • Na/H exchanger located on the apical membrane, transporting Na out of the lumen & H+ into the lumen (H+ helmeted kids walking in with peanuts; lumen = yellow track). Maintaining luminal H+ is critical for bicarb resorption. • H+ & HCO3 combine to form H2CO3 (bicarb cars). Luminal carbonic anhydrase catalyzes H2CO3 to H2O & CO2 (car battery = carbonic anhydrase). H2O & CO2 enter intracellular space via diffusion (water & fumes from cars entering epithelial tract. o Turned back into H+ & HCO3 via intracellular carbonic anhydrase (dude taking out car battery) o Intracellular HCO3 is transported into interstitium via basolateral transporter. Bicarb is taken out of the cell via a basolateral transporter and H is put back into the lumen by Na/H exchanger (car being taken to interstitium; helmet being reused). Diuretics • Acetazolamide (battery acid) o Reduces sodium resorption by inhibiting carbonic anhydrase, preventing bicarb resorption (leaking battery acid preventing bicarb car entering circulation). Bicarb stays in the proximal tubular lumen → urine alkalization. o Renal effects: ▪ Bicarb depletion causes increased NaCl resorption in the remainder of the nephron, such that diuretic efficacy falls within a few days. ▪ Also block sodium reabsorption →natriuresis (peanut wasting track lackey). ▪ Causes a normal anion gap metabolic acidosis with hypochloremia, as bicarb is not available to balance pH o Indications: Some of the first diuretics discovered. Not used as much for diuresis nowadays, but used in various other systems. ▪ Decreased production of aqueous humor, useful in the management of glaucoma (leaking eye-ball shaped cup). Most common clinical indication for carbonic anhydrase inhibitors ▪ Decrease rate of production of CSF. Useful in the management of idiopathic intracranial HTN (pseudotumor cerebri), although no indication of improved long-term prognosis (big head balloons) ▪ Useful in treatment & prevention of mountain sickness, which occurs with rapid ascension above 3000m (lackey on high wobbly guard tower). May be accompanied by life-threatening cerebral edema. Decreases CSF production and pH ▪ Urinary alkalization as with bicarb buildup, increases uric acid & cysteine buildup o Side effects/toxicities ▪ Like all potassium wasting diuretics, can cause hypokalemia d/t sodium resorption and potassium secretion in the collecting ducts (bananas on ground). Can avoid by combining with K-sparing diuretic. ▪ Can cause Type 2 renal tubular acidosis (two tubes on red cart). Can cause metabolic alkalotic hyperchloremia. • Can be seen in any defect in PCT bicarb reabsorption. May be useful in refractory metabolic acidosis ▪ Carbonic anhydrase inhibitors can enhance calcium phosphate stones d/t decreased solubility (rocks in front of dino car) ▪ Carbonic anhydrase inhibitors are sulfa drugs, so may cause hypersensitivity reactions including interstitial nephritis in patients who have a sulfa allergy (dino kid throwing rotten eggs) • Mannitol (tall man) o Osmotic diuretic acting at the PCT & descending limb of LOH (stream of water crossing into lumen) o Acts in other tissues by the same MOA: ▪ Draws free water out of brain tissue into circulation. Administered in urgent ICP. ▪ Draws free water out of other compartments, including eye. Useful in acute glaucoma (eyeball cup dousing fire) o Side effects/toxicities ▪ Extracellular volume induced by mannitol can case pulmonary edema (lung spots on wrecked driver) ▪ Rapidly distributed in extracellular compartment and cause hyponatremia d/t expanded extracellular volume. Can exacerbate HF (deflated balloon) ▪ Mannitol use without water replacement can cause water depletion dehydration, accompanied by hypernatremia (lots of spilled peanuts by wreck)