Flashcards in Diuretics Deck (36):
How is sodium reuptaken in the proximal tubule?
Na+/H+ antiporter swaps an Na+ from the urine for a H+ into the urine.
H+ is buffered by bicarbonate, and becomes CO2+ water. CO2 diffuses across the membrane, becomes H+ and bicarbonate again. Bicarbonate leaves on the basolateral side at the same time that sodium is actively pumped out the basolateral side by Na+/K+ ATPase
How do carbonic anhydrase in inhibitors work? What can they be used to treat?
Reduce the efficacy of the Na/H+ exchanger by reducing speed of proton buffering and CO2 diffusion by slowing down the carbonic anhydrase enzymes inside the cell and on the luminal surface
Can reduce aqueous humor production and thus be used in glaucoma (dorzolamide)
How does mannitol work and what is it used for?
Mannitol cannot be reabsorbed after filtration, so it is an osmotic diuretic (like glucose in diabetes)
It is given IV for brain edema or orally to purge the intestines of toxins
What happens in the thin loop of Henle?
Water is reabsorbed by the osmotic gradient created via the countercurrent multiplier. from the thick ascending limb (which is impermeable to water)
How are ions brought in in the thick ascending loop? How specifically do divalent cations get back in?
NKCC2 transporter: Na+/K+/2Cl- symporter
Na is pumped out via the Na/K+ ATPase, so K+ concentrates in the cell
K+ then leaks out into the lumen, increasing the potential (+) of the urine, driving divalent cations like Mg+2 and Ca+2 paracellularly back into the interstitium?
What class of drug inhibits NKCC2? Give an example.
Loop or "high ceiling" diuretics. Furosemide is most common
What are the three cell types of the juxtaglomerular apparatus? What are their functions?
1. Juxtaglomerular cells - located in afferent arterioles, act as intra-renal pressure sensors + secrete renin
2. Macula densa - read the NaCl environment inside the cell (located in distal tubule) and relay this to extraglomerular mesangial cells
3. Extraglomerular mesangial cells - communicate with macula densa via gap junctions, secrete prostaglandin E2 to stimulate juxtaglomerular renin release
What drug class is commonly given with loop diuretics and why?
ACE inhibitors, since NKCC2 will also be inhibited on macula densa cells, decreasing uptake of NaCl and stimulating renin release by JGA
ACE inhibitors can block the angiotensin system
What is the primary channel type of distal convoluted tubule?
NCC - sodium chloride symporter -> electrically neutral uptake of NaCl, with subsequent uptake of Na+
Why are divalent cations not passively reabsorbed in from the lumen of the convoluted tubule? How does calcium get in?
No K+ channel is present to leak out positive charge
Calcium gets in via Ca+2 pore on the apical membrane, and Na+/Ca+2 exchanger on basolateral membrane, both of which are under control of parathyroid hormone (will tend to increase blood calcium levels)
What class of drugs blocks NCC? Give two examples
Thiazide and thiazide-like diuretics
Chlorthalidone (longer half life)
Why can HCTZ be given for hypercalciuria?
Inhibition of NCC will prevent distal convoluted tubule Na+ uptake, which will cause low intracellular Na+ levels.
These low levels will further drive the Na+ / Ca+2 antiporter on basolateral surface which is stimulated via PTH
What two channel types exist on the apical surface of the principal cell of the kidney and how does this affect ion absorption?
ENaC - Epithelial sodium channel (brings sodium in)
ROMK - Renal outer medullary K+ channel (lets potassium out)
Both are driven by Na+/K+ ATPase on basal membrane.
Preference for Na+ reabsorption drives relative negative luminal potential, which facilitates the paracellular Cl- absorption
What does drug-induced diuresis do to the principal cells? What does this explain?
Increases the Na+ load, which stimulates further loss of K+
Explains the hypokalemia which can be caused by carbonic anhydrase inhibitors, loop, and thiazide diuretics
What controls the synthesis of ROMK / ENaC?
Aldosterone -> inserts more channels to facilitate Na+ retention and K+ excretion
What cell in the distal collecting tubule helps us secrete acid? What conditions favor this?
Alpha-intercalated cell -> uses H+ proton pump which is ATP dependent, and reabsorbs HCO3- on the basolateral surface from this (H+ was made from carbonic anhydrase)
H+ excretion is favored in negative intraluminal potential (basic environment filled with HCO3-)
What drug specifically inhibits ENaC to exert mild diuresis while sparing K+ (not as much sodium needed to be re-uptook by Na+/K+ ATPase)?
What is the mechanism of action of spironolactone? Is it K+ sparing?
Competitive antagonist of aldosterone -> mild diuretic, can actually cause hyperkalemia
What is meant by K+ sparing?
Diuretics which limit the loss of K+ in the late distal tubule / collecting duct.
How does lithium cause diabetes insipidus?
Reduces the expression of aquaporin 2 on apical membrane of principal cells, decreasing water reabsorption (normally stimulated by vasopressin)
What are the indications for furosemide?
1. Heart failure
2. Edema in liver cirrhosis
3. Pulmonary congestion
4. Renal syndromes including ACUTE RENAL FAILURE
5. Hypercalcemia, hyperkalemia
Why is furosemide good for hypercalcemia? What drug should be used for hypocalcemia?
Blockage of NKCC prevents K+ from making lumen most positive charged, inhibiting calcium reabsorption.
For hypocalcemia, blocking NCC via HCTZ will facilitate reabsorption of calcium
How might furosemide cause hypercalcemia?
The diuretic affect may cause it secondary to dehydration (Water lost more rapidly than calcium)
Why is furosemide good in acute renal failure and hyperkalemia?
Increases renal blood flow and hence urine flow, which can flush out K+ as well as intratubular casts
What are the major side effects of furosemide?
Hypokalemia (due to increased reabsorption of Na+ via ENaC)
Hypomagnesia (due to lack of Mg+2 reabsorption)
Hyperuricemia (uric acid reabsorption is increased in hypovolemia) -> gout
What drugs interfere with diuretics in general? How?
NSAIDs -> reduction of renal blood flow from loss of prostaglandin synthesis
What is HCTZ / chlorthalidone most often used to treat?
Primarily uncomplicated hypertension, often in combination with another long halflife drug like lisinopril (ACE inhibitor)
How does HCTZ exert its effect in the longrun?
Decrease in peripheral resistance due to unknown mechanism -> the diuretic effect is not long-lived
Give two other conditions HCTZ can be used to treat?
1. Idiopathic hypercalciuria with kidney stones -> previously explained. Can only cause hypercalcemia if there is an underlying condition (i.e. hyperparathyroidism)
2. Nephrogenic diabetes insipidius, even caused by lithium. Mechanism is paradoxical and unknown.
What are some of the possible ionic side effects of HCTZ?
1. Hypokalemic metabolic alkalosis (overaction of principle / intercalated cells)
2. Hyponatremia in predisposed individuals (loss of NCC transport)
3. Hyperuricemia - compete with uric acid for secretion by organic acid system
What are some of the metabolic side effects of HCTZ which might cause us to not used them?
1. Hyperglycemia (impaired insulin release) -> caution in diabetes / dyslipidemia
2. Altered lipid profile -> increase in total cholesterol / LDL
What is spironolactone used for and why?
1. severe CHF -> aldosterone mediates myocardial fibrosis, and spironolactone antagonizes this effect of cardiac remodelling
2. Primary and secondary aldosteronism
3. Hypertension with loop / thiazide diuretics to reduce K+ loss
4. **hepatic cirrhosis** -> reduces edema
What is the side effect of concern with spironolactone?
Gynecomastia due to androgen insensitivity
What is amiloride used for?
Prevention of diuretic induced hypokalemic acidosis
-> also prevents entry of lithium into principal cells (blocks ENaC), limiting aquaporin-2 interference in nephrogenic diabetes inspidus
Why is furosemide good in heart failure?
Reduces cardiac preload and consequently cardiac work