Jackson 8 Flashcards
Diuresis =
excessive urine ouput
Reasons for use of diuretics
congestive heart failure
heart weakens → ↓ cardiac output → ↓ GFR → ↑ aldosterone → ↑ Na+ and H2O reabsorption → ↑ ECV and edema
hypertension
↑ ECV → ↑ plasma volume → ↑ blood pressure
Different diuretics act on different segments of the nephron. They gain access to tubules either by
filtration or secretion.
Osmotic diuretics - retain water by
increasing osmotic pressure; act in water-permeable segments of the nephron (PT & descending loop of Henle)
CA inhibitors – reduce
Na+ reabsorption; proximal tubule is major site of action
Loop diuretics – act in
thick ascending limb to inhibit Na+ reabsorption via the Na+ K+ 2Cl- symporter
Thiazides – block
Na+Cl- symporter in early distal tubule
K+ - sparing – two classes that both act in
late distal tubule and cortical collecting duct to inhibit sodium reabsorption AND potassium secretion
- aldosterone antagonists
- ENaC blockers
Aquaretics –
ADH receptor antagonists
Osmotic diuretics increase the osmotic pressure in the
tubular fluid, and, thus, impair Na+ reabsorption.
Osmotic diuretics
Examples include
mannitol and pathologically elevated glucose.
Osmotic diuretics
gain access to tubule by glomerular filtration
are poorly reabsorbed
will have an effect where tubule is freely permeable to water
some of what’s not reabsorbed in PT and DL can be reabsorbed downstream, but typically results in excretion of 10% of filtered Na+
note: ↓ water reabsorption → ↓ Ca2+ reabsorption by solvent drag
Carbonic anhydrase inhibitors reduce
Na+ reabsorption by inhibiting CA, thus reducing the H+ available for the Na+/H+ antiporter.
Acetazolamide is an example of a
CA inhibitor.
CA inhibitors gain access to the
proximal tubule via secretion
CA inhibitors
Most of the diuretic effect is in the
proximal tubule where ~1/3 of Na+ reabsorption relies on the Na+/H+ antiporter
CA inhibitors
Diuretic effect is
not large
downstream segments will increase Na+ reabsorption when tubular Na+ increases
typically increases Na+ excretion to 5-10% of filtered load
Loop diuretics are the most
powerful of all diuretics; they inhibit Na+ reabsorption in the ascending limb of the loop of Henle.
Furosemide (lasix) is an example of a
loop diuretic.
Loop diuretics are secreted into the
proximal tubule (not filtered)
LOOP DIURETICS:
Inhibit
Na+K+2Cl- symporter in the thick ascending limb which inhibits Na+ reabsorption
Loop diuretics
urine leaving loop is not
dilute
Loop diuretics
no osmotic gradient established in the
medulla interstitium so water is not reabsorbed along collecting duct → urine is dilute (500 mOsm instead of 1400 mOsm)
Loop diuretics
Can increase
Na+ excretion to as much as 25% of filtered load, because Na+ reabsorption capacities downstream of their site of action are limited.
Thiazide diuretics
Thiazide diuretics like
chlorothiazide are secreted into the proximal tubules, and they act in the early distal tubule to block the Na+Cl- transporter
Thiazide diuretics
kidney’s ability to dilute urine is
diminished
Thiazide diuretics
reabsorption of water in the collecting duct still occurs, but
5-20% of the filtered Na+ is excreted
K+-sparing diuretics
K+ - sparing diuretics act where
K+ is normally secreted into the tubular fluid by the principal cells. There are two types of K+- sparing diuretics
K+-sparing diuretics
1. aldosterone antagonists, e.g. spironolactone
block
aldosterone’s ability to increase Na+ transporters in principal cells
must get inside tubular cells to block aldosterone receptors
K+-sparing diuretics
2. ENaC blockers, e.g. amiloride
block
Na+ reabsorption across the apical membrane
these act on a membrane protein so can gain access by secretion into the proximal tubule
Aquaretics
Aquaretics, e.g. tolvaptan, increase excretion of water by blocking the action of
ADH in the late distal tubules and collecting duct. Water is eliminated without the loss of solutes.
Secondary effects of diuretics
Diuretic braking phenomenon
Continued use of diuretics becomes
less effective because volume contraction counteracts the effects of the diuretic, i.e. diuretics decrease ECV so compensatory mechanisms activated
diuretic braking
1. increased sympathetic activity in response to reduced BP —>
decrease GFR à increase PT reabsorption & increase renin
diuretic braking
2. decrease
natriuretic peptides
diuretic braking
3. secrete renin from
juxtaglomerular apparatus à increase angiotensin II and aldosterone à decrease Na+ excretion
diuretic braking
4. stimulate ADH release —->
decrease water excretion
Side effects of Procrit ® treatment include
flu-like symptoms, headaches, high BP, and cardiovascular problems
Using EPO to treat anemia in dialysis patients
Treatment of anemia typically uses
Procrit ® to stimulate erythropoiesis (rather than rely on transfusions).
Increased excretion of K+
Diuretics increase Na+ reabsorption, so they secondarily influence
renal processing of other solutes (and water)
K+ excretion increases because……
diurectics increase the flow of tubular fluid which stimulates K+ secretion
diuretics reduce ECV à increase aldosterone à stimulate K+ secretion
K+ -sparing diuretics are used to prevent an increase in K+ secretion
Disruption of acid-base balance
Acid-base balance is affected by all diuretics
CA inhibitors —>
metabolic acidosis
Loop and thiazide diuretics —>
reduced ECV à metabolic alkalosis
potassium-sparing diuretics —->
metabolic acidosis because H+ secretion in distal tubule and cortical collecting duct is inhibited
Except for the K+ sparing diuretics, all other diuretics
alter calcium excretion.
Osmotic and CA inhibitors both act in
proximal tubule and reduce reabsorption of calcium in this segment (so excretion is increased).
Loop diuretics increase calcium excretion by affecting the
transepithelial voltage that normally provides the driving force for paracellular transport of calcium.
Thiazide diuretics stimulate calcium reabsorption in the distal tubule and thus reduce
excretion.
Normally, distal tubule reabsorbs 9% of filtered calcium via active transport.
The concentration of NaCl in the dialysis fluid is similar to that in
plasma.
Urea, potassium, phosphate diffuse from blood into dialysis fluid.
Bicarbonate is high in the dialysis fluid so it
diffuses into blood to correct blood acidity
Methods of accessing the blood for dialysis: pros & cons
catheter –
used to access venous blood for short-term treatment; scarring, vessel narrowing or occlusion can occur
Methods of accessing the blood for dialysis: pros & cons
AV fistula –
preferred for long-term treatment; creates an anastomosis between artery and vein. Arterial blood is withdrawn, and blood is returned to the vein after dialysis.
Methods of accessing the blood for dialysis: pros & cons
AV graft –
uses an artificial/synthetic vessel to join an artery and vein when vascular problems do not permit using a fistula; can become narrowed which can lead to clotting and/or infections.
Dialysis treatment requires a prescription and can vary based on
type of solution, frequency, and size of dialyzer – typically 3-4 hours per treatment, three times per week
Side effects and complications of hemodialysis
Short-term side effects:
fatigue, chest pains, cramps, nausea, headaches
often called “dialysis hangover”
due to acute, dramatic changes in blood chemistry.
Long-term consequences of hemodialysis
sepsis, endocarditis & osteomyelitis (secondary infections)
amyloid deposits in joints (like amyloid plaques that form in neural tissue) can result from the
build-up of trace minerals (e.g. copper, zinc, and aluminum) that might be in the dialysis fluid.
Patients with chronic renal failure are almost always diagnosed with anemia due
inadequate secretion of erythropoietin (EPO) and loss of erythrocytes.
EPO is produced by
interstitial fibroblasts in the renal cortex, and its production is controlled at the transcriptional level.
EPO production is stimulated when
PO2 is low due to activity of transcription factors that regulate EPO synthesis (hypoxia-inducible factors 1 and 2 or HIF-1 and HIF-2)
HIFs are continually produced, but are targeted for degradation when
O2 is normal.
When O2 is low, they function as
transcription factors to increase EPO synthesis and secretion.
EPO stimulates differentiation of
erythrocyte progenitor cells in the bone marrow
