Duan: Diuretics I Flashcards
a compact cluster of convoluted capillaries, site of FILTRATION, functioning to remove certain substances from the blood before it flows into the convoluted tubule.
glomerulus
List the components of the nephron
glomerulus: site of filtration
tubule system: site of reabsorption, secretion, excretion
includes proximal convoluted tubule, Loop of Henle (descending, ascending), distal convoluted tubule, collecting tubule
What is the favoring force in glomerular filtration? What is the opposing force? How do you determine the net filtration pressure?
favoring force: capillary blood pressure
opposing force: blood colloid osmotic pressure
NFP = favoring force - opposing force
glomeruli in outer cortex & short loops of Henle that extend only short distance into medulla
blood flow through cortex is rapid
majority (70-80%) of nephrons
cortical nephron
- glomeruli in inner part of cortex & long loops of Henle which extend deeply into medulla.
– blood flow through vasa recta in medulla is slow
– medullary interstitial fluid is hyperosmotic
juxtamedullary nephron
A two-step process beginning with the active or passive extraction of substances from the tubular fluid into the renal interstitium (the connective tissue that surrounds the nephrons); then these substances are transported from the interstitium into the bloodstream . These transport processes are driven by Starling forces, passive diffusion, and active transport.
reabsorption
How does the descending limb of the loop of Henle differ from the ascending limb?
descending limb: highly permeable to H20
ascending limb: low permeability to H20 **responsible for 15-50% of reabsorption
This portion of the Loop of Henle allows for the passive and active transport of salts such as Na+ and Cl- to move out of the tubules and be reabsorbed. Also, most K+ in the tubules cycles back into the lumen.
thick ascending limb
What is the main function of the Loop of Henle?
create a concentration gradient in the medulla of the kidney by means of a countercurrent multiplier system; creates an area of high urea concentration deep in the medulla
Briefly explain the loop of Henle
Descending limb: progressively becomes more concentrated as it loses H20
Vasa recta: removes water leaving the loop
Ascending limb: pumps out Na+, K+, and Cl-, so that the filtrate becomes hypoosmotic
What happens to Na and Cl in the distal convoluted tubule? What happens to Ca++?
Na and Cl- are reabsorbed from the DCT, creating more dilute urine;
Ca++ is also reabsorbed due to PTH
Two cells of the collecting tubule? Which cells are the site of action of aldosterone? Which cells are involved in acid-base homeostasis?
principal cells and intercalated cells
- *aldosterone works on prinicipal cells to reabsorb Na+
- *intercalated cells participate in acid-base homeostasis
Increases the activity of both apical Na+ channels and the Na+/K+ ATPase in the collecting duct; increases Na+ reabsorption and K+ secretion
aldosterone
controls the water permeability of principal cells in this segment ;
regulates the insertion of aquaporin-2 (AQP2) into principal cells in the apical membrane
ADH (vasopressin)
If you have low ADH or absent ADH, what happens to your urine?
large volume of hypotonic and dilute urine, because there is low H20 permeability due to insertion of fewer aquaporins
If you increase ADH, what happens to your urine?
small volume of hypertonic and concentrated urine because there are more aquaporins and increased H20 permeability
How do you calculate the amount of solute excreted in the urine?
Amount filtered + amount secreted - total reabsorbed
This is a carbonic anhydrase inhibitor
Acetozolamide
**all end in -amide
How do carbonic anhydrase inhibitors work?
inhibit apical and cytosolic carbonic anydrase, thus increase HCO3- excretion
increase Na+, K+, and H20
**results in alkaline urine
causes metabolic acidosis as HCO3- levels drop
When are carbonic anhydrase inhibitors used as non-diuretics clinically?
A FAMILY GAME
Alkalinizing urine for excretion of weak acids
Familial hypokalemic periodic paralysis
Glaucoma (decrease aqueous humor formation)
Altitude (mountain) sickness (decrease CSF and pH)
Metabolic Alkalosis
Epilepsy (seldom used)
What are the adverse effects of carbonic anhydrase inhibitors?
A PACE acidosis (metabolic) potassium depletion allergic reactions (sulfonamide based) Ca+ nephrolithiasis encephalopathy
In what patient population are carbonic anyhdrase inhibitors contraindicated?
can cause hepatic encephalopathy in patients with cirrhosis of liver
**By producing an alkaline urine, CA inhibitors decrease excretion of NH4+ in the urine
This can lead to hyper-ammonemia and hepatic encephalopathy in patients with cirrhosis of the liver
These are the osmotic diuretics
mannitol
glycerin
isosorbide
urea
How do osmotic diuretics work?
freely filtered in the glomerulus
undergo limited reabsorption
quantity of water retained in proportional to the quantity administered
**act primarily in the proximal tubule and to a lesser extend in the ascending loop of Henle
When are osmotic diuretics used?
AAA ID
Acute tubular necrosis (increase urine volume in case of acute GFR decrease)
Anuria in hemolysis or rhabdomyolysis (prophylaxis use)
Angle-closed glaucoma (reduce intraocular pressure)
Increased intracranial pressure (used as the DOC)
Dialysis disequilibrium
When should osmotic diuretics not be used?
CHF
severe renal disease
What are the adverse effects of osmotic diuretics?
if administered too rapidly, can decrease cell volume and impair cell function
dehydration
hyperkalemia
hyponatremia
Name 3 adenosine A1 receptor antagonists
caffeine
Rolophylline
theophylline
How do adenosine A1 receptor antagonists work?
interfere with the Na+/H+ exchanger in the proximal convoluted tubule
adenosine-mediated enhancement of K+ secretion in the collecting tubule
Which 2 loop diuretics are sulfonamide derivatives?
Non-sulfonamide derivate?
Furosemide & torsemide
Ethacrynic acid
How do loop diuretics work? Where do they work in the kidney? What do they block?
Inhibit Na/K/Cl cotransporter in the ascending limb of Henle which decreases hyperosmolarity in the medullary interstitium
Clinical use of loop diuretics
Edema related:
emergency situations of acute pulmonary edema
edema of cardiac, hepatic or renal origin
Electrolyte or drug-related:
Acute hypercalcemia
Hyperkalemia - give with Na+ and water
Useful for anion overdose (Br-, Fl-, I-) in addition to saline
Torsemide: can decrease blood pressure without diuresis - useful for mild to moderate hypertension
Adverse effects of loop diuretics?
Ototoxicity & transient deafness
Diabetogenic (furosemide & bumetanide)
Compete for binding to serum proteins with drugs, such as warfarin and clofibrate
Reduced clearance of Li+
Hyperuricemia due to increased reabsorption of uric acid in proximal tubule caused by decreased vascular volume
Hypomagnesemia
Severe vascular volume decrease
Can lead to hyponatremia if patients increase H2O intake due to hypovolemia-induced thirst
Can decrease LDL and triglyceride levels
Contraindications to loop diuretic use?
severe Na+ and volume depletion
hypersensitivity to sulfonamides
Sulfonamide derivative found while trying to make a better CA inhibitor; produces a diuresis with increase Cl- (not HCO3-); effective in both acidic and alkaline conditions
thiazide diuretics
**hydrochlorothiazide
How do thiazide diuretics work?
inhibit Na+ and Cl- co-transport in the DISTAL tubule; increase Na+ and Cl- in the urine
**weak diuretic since only 5% of filtered Na+ in reabsorbed in the distal tubule
What do thiazide diuretics do to the reabsorption of Ca++?
increase overall reabsorption
Why are thiazide diuretics preferred?
cause less distortion of the ECF bc they cause a modest diuresis & effect the excretion of several ionic species
What are thiazide diuretics used for?
edema associated with CHF hypertension Ca++ nephrolithiasis bromide intoxication diabetes insipidus
Adverse effects of thiazide diuretics?
**Increased cholesterol (5-15% - transient) & LDL
Hypokalemia with prolonged therapy
Associated with arrhythmias in some settings
Hyperglycemia
Hypokalemic metabolic alkalosis
Hyperuricemia
Hyponatremia
the volume of fluid filtered from the glomerular capillaries into the Bowman’s capsule per unit time
Glomerular filtration rate (GFR)
[Urine conc * Urine flow]/plasma concentration
Which diuretics do not act on the luminal surface?
aldosterone antagonists
How are diuretics that are not filtered at the glomerulus transported into the nephron?
organic acid or base transporters in the proximal tubule
What decreases diuretic access to the tubule lumen?
decreased renal blood flow (decreased GFR)
Why are diuretics that act proximally weak?
Why are diuretics that act distally weak?
even though 70-80% of the filtered load is handles there, their actions are counteracted by more distal reabsorption
diuretics that act distally are weak bc only 5-10% of the filtered load is involved
Why are loop diuretics the most effective?
- they inhibit an important transport mechanism (Na/K/Cl transporter)
- the affected site handles a large fraction of the filtered load (15-50%)
- more distal mechanisms cannot compensate
How do loop and thiazide diuretics differ in how they affect concentration/dilution of urine?
loop diuretics act on the ascending limb of the loop of Henle, where Na+ is reabsorbed but water is trapped - so loop diuretics impair both the concentration and dilution of urine
thiazide diuretics act distal to the loop of Henle, so they can influence dilution, but not concentration
This loop diuretic can decrease blood pressure without diuresis
Torsemide
Thiazide-like diuretic, that has anti-hypertensive actions independent of its diuretic activity; used in cases of renal failure together with loop diuretics
Indapamide
This thiazide-like diuretic is efficacious and can be given in combo with a loop diuretic; can be effective in renal insufficiency
Metolazone
Why does hypokalemia occur with diuretics?
K+ is exchanged for Na+ in the distal nephron
This is an aldosterone agonist that is a K+ sparing diuretic
Spironolactone
What does aldosterone do?
essentially it increases Na+ reabsorption and K+ excretion
These are two non-aldosterone agonists that are K+ sparing diuretics
Triamterene
Amiloride
How do non-aldosterone antagonist, K+ sparing diuretics work?
decrease Na+ reabsorption in the distal nephron - with less Na+ uptake there is a decrease in K+ loss
What should you use to treat hepatic cirrhosis and ascites?
thiazide, loop, and K+ sparing diuretics
What should you use to treat pulmonary edema?
loop diuretics
What should you use to treat cerebral edema?
osmotic diuretics for direct effects
What do you use to treat nephrotic syndrome? Acute renal failure? Chronic renal failure?
thiazide diuretics, decrease Na+ intake
osmotic or loop diuretics
treat aggressively with loop diuretics
How to treat hypertension?
decrease salt intake
add thiazides, maybe a K+ sparing or loop diuretic
How to treat nephrolithiasis?
treat with thiazides to increase Ca++ reabsorption
decrease salt intake
How to treat hypercalcemia?
treat with loop diuretics to increase calcium excretion
+ normal saline to prevent contraction of extracellular space, +/- K+ sparing diuretics as needed
How to treat nephrogenic diabetes insipidus?
treat with thiazide or loop diuretics to reduce plasma volume and contract the extracellular space
What is diabetes insipidus?
increased urine output due to decreased ADH
What are the two types of diabetes insipidus? Which type will respond to desmopressin, an ADH analog?
central: decreased ADH due to injury, tumor or infection **will improve with desmopressin
nephrogenic: decreased ADH responsiveness **won’t respond to treatment with desmopressin
What is SIADH?
syndrome of inappropriate secretion of ADH –> too much ADH –> too much H20 reabsorption
