Diuretics Flashcards
What is the definition of a diuretic?
Chemical substance which promotes increased urine flow rate and result in a net loss of sodium, chloride, and/or water
What is the relative potency of diuretics affecting the proximal tubule, loop of Henle, distal convoluted tubule, and collecting duct? Why?
Loop > proximal > distal > collecting duct
Based on the amount of sodium resorption that happens at all of these segments. The only inconsistency here is that proximal tubule diuretics (i.e. acetazolamide) are less potent than loop of Henle because the sodium and water reabsorption which is blocked there will be compensated for increased activity of sodium transport in the distal nephron.
Why is acetazolamide not the most effective diuretic, other than the distal sodium reabsorption issue?
Only 30% of filtered Na is reabsorbed by bicarbonate, most is reabsorbed as NaCl
Fall in serum HCO3 also results in decreased filtered load and thus decreased diuresis
What are the metabolic effects of acetazolamide and what type of urine / osmolyte imbalances will it cause?
Normal anion gap hyperchloremic metabolic acidosis -> by blocking bicarbonate reabsorption, NaCl reabsorption is favored, and base is lost.
Urine - becomes alkalinized, due to high concentration of bicarbonate
Electrolytes: causes hypokalemia due to increased distal convoluted tubule ENaC absorption to compensate (think of banana on ground next to red #2 car)
What is methazolamide and its clinical indication?
Derivative of acetazolamide with fewer renal side effects
-> better lipid solubiity and aqueous humor penetration
Used for glaucoma to block carbonic anhydrase in ciliary body, decreasing IOP
Other than rare use in glaucoma, what are the primary clinical indications of acetazolamide? What will be made worse by this?
Cystinuria and hyperuricemia -> cystine and uric acid are more soluble in alkaline urine
Calcium phosphate stones will be made worse by this -> less soluble in higher pH
Treatment of metabolic alkalosis in edematous states (fluid overload, good to correct this)
Altitude sickness -> corrects respiratory alkalosis caused by hyperventilation
What are the important loop diuretics and which one is special / what side effect can it not induce?
Furosemide, Bumetanide, Torsemide
Special: Ethacrynic acid - think Ethics in sketchy -> not a sulfa drug. Can be used in patients with sulfa allergy
Sulfa drugs risk causing acute interstitial nephritis (link of blue kidney bag in sketchy)
How do the loop diuretics get to the TALH and what is their potency dependent on?
Secreted into proximal tubule by organic acid pathway. Potency is determined by urinary concentration of diuretic, not plasma concentration
What are the ionic disturbances induced by loop diuretics?
Inhibit NKCC - increased sodium, chloride, and potassium excretion
Hypomagnesia, hypocalcemia - loss of K+ positive intraluminal potential
What effect do loop diuretics have on gout?
Acutely - increased uric acid excretion due to increased flow rate
Chronically - volume contraction results in increased uric acid reabsorption in proximal tubule -> worsens gout
What effect do loop diuretics have on urinary concentration and dilution and why?
Decrease free water clearance -> impaired urinary dilution -> too much solute left in urine for DCT to deal with
Decreased free water absorption -> impaired urinary concentration -> unable to make medullary gradient for concentration of urine in the distal collecting duct
What are the edematous states which loop diuretics are useful in treating?
Pulmonary edema, edema in patients with renal failure (also induce increased RBF by inducing COX), nephrotic syndrome, heart failure
What are some nonedematous states which loop diuretics are used for?
Hypertension
Hypercalcemia or hyperuricemia -> must give with saline to prevent volume contraction
Acute renal failure -> improves urine production
What metabolic acid state do loop diuretics induce?
Metabolic alkalosis - probably due to contraction alkalosis (think of guy squeezing out water from tube in sketchy) -> increased angiotensin II (stimulates Na/H exchanger) and aldosterone (stimulates H+ secretion for K+ reuptake in alpha intercalated cell).
What is one scary and possibly irreversible side effect of loop diuretics?
Ototoxicity - deafness. Think of gong in sketchy
-> NKCC2 is present in cochlear stria vascularis, results in edema of ear if blocked
What part of the nephron does mannitol affect? How? How does it get into the nephron?
Affects all segments of the nephron. It is freely filtered at the glomerulus and decreases water and solute absorption at various segments, including sodium at the proximal tubule and urea reabsorption in the collecting duct
Ma
What is the relative potency of mannitol vs loop diuretics?
Lower sodium excretion, but highest peak urine flow of all diuretics -> greatest risk for dehydration
It increases free water clearance
This relates to its indication
What are the three most important indications of mannitol?
- Cerebral edema
- Prevention of dialysis disequilibrium syndrome (rapid removal of osmolytes from plasma causes cerebral edema)
- Intoxications - enhances urinary excretion of toxins / drugs
What are the acute and chronic effects of mannitol on plasma osmolality? ECF volume?
Acutely - hyponatremia - pulls water into ECF, diluting sodum
Chronically - Hypernatremia - dehydration due to decreased free water clearance
ECF volume - diuresis of sodium and water leads to hypovolemia (drop in total body Na)
What accounts for the majority of the diuretic effect of mannitol?
Increases vasa recta blood flow -> medullary washout, destruction of concentration gradient (lack of countercurrent exchange)
What are the clinically relevant distal convoluted tubule diuretics and their mechanism of action?
Hydrochlorothiazide, chlorthalidone, metolazone
Inhibit Na/Cl cotransporter
What effect do thiazides have on uric acid and why?
Volume contraction -> stimulates urate absorption
Thiazides also compete with proximal tubule organic acid transporter -> decrease excretion
Can cause hyperuricemia / gout
What effect do thiazides have on urinary concentration and dilution?
Concentration - no effect, gradient made in TALH
Dilution - impaired
What patients are at greatest risk of having hypokalemia from thiazide diuretic use?
Those also using a loop diuretic -> lots of sodium will reach collecting duct
What type of kidney stone do thiazides treat and why?
Calcium stones -> usually calcium phosphate (opposite of acetazolamide usage)
-> increase calcium reabsorption from the DCT
What are rarer but important possible side effect of thiazide diuretics?
Hypercalcemia - never give if hypercalcemic, as can worsen problem via volume contraction and increased reabsorption as well
Acute interstitial nephritis (they are sulfa drugs)
Hyperlipidemia and hyperglycemia (think of candy and butter on high platform in sketchy)
What transporters does aldosterone normally increase the speed or number of?
Principle cell: Na/K ATPase, ENaC, ROMK
Alpha-intercalated cell: H+ ATPase
Think of all the things with keys in them on the right side of the K+ sparing diuretics sketchy
What drugs work as competitive inhibitors of aldosterone?
Think of the lady going to stop the mineral court food services man, while holding an apple in her hand and observed by the inspector with a spiral notebook
Eplerenone (apple)
Spironolactone (spiral notebook)
What are the effects of aldosterone antagonists on plasma urine and electrolytes? Why?
Increased Na excretion (block ENaC) Decreased K+ excretion (Less Na moves out of lumen, intraluminal charge is more positive, less driving force of K+ out thru ROMK) Metabolic acidosis (less H+ excretion due to more positive intraluminal potential preventing H+ release by alpha interacalated cells)
What are the clinical uses of aldosterone antagonists which aren’t OB/GYN?
Prevent diuretic induced urine K losses
Adjunct with other diuretics
Treatment of hyperaldosteronism
What are the adverse effects of aldosterone antagonists?
Hyperkalemia and gynecomastia (particularly spironolactone, which antagonizes androgen receptor as well)
What are aldosterone independent potassium sparing diuretics and what is their mechanism of action?
Think of almond guy and tangerine woman toppling the cart of peanuts into the collecting duct
Amiloride (almond) and Triamterene (tangerine)
-> block ENaC an in aldosterone independent mechanism, would be additive to spironolactone or eplerenone
What is a unique indication for aldosterone independent K+ sparing diuretics (unlike aldosterone antagonists)?
Treatment of Liddle’s syndrome - autosomal dominant constitutively active ENaC -> blocks this activity
Think of the liddle gnome falling into the collecting duct
What is the diuretic braking effect and how can this be prevented?
Prolonged diuretic use results in a plateau in weight loss and return to previous value, due to increased stimulus for Na retention and less natriuretic response to drug.
Prevented by dietary sodium restriction in conjunction with diuretic use, as well as more frequent / prolonged dosing.
What are some other causes of diuretic resistance?
Decreased GFR: volume contraction, reduced renal blood flow (i.e. HF, NSAID use, hypoalbuminemia)
Increased reabsorption: Hypertrophy of proximal tubule cells, volume contraction
Inadequate GI absorption: especially in edematous states
What type of renal tubular acidosis can K+ sparing diuretics cause and why?
Type IV renal tubular acidosis -> associated with hyperkalemia
- > hypoaldosteronism causes hyperkalemia which decreases NH4 excretion and hence acidosis
- > Aldosterone also directly stimulates H+ secretion by alpha-intercalated cells, blocked in the presence of these drugs
- > lastly, H+ not secreted into lumen by H+-ATPase because of lack of negative charge from hypoaldosteronism
