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Name 1 Carbonic Anhydrase Inhibitor
Where do Carbonic Anhydrase Inhibitors act?
They inhibit Carbonic Anhydrase in the Proximal Tubule (PT) of the Kidney
How does inhibition of Carbonic Anhydrase result in diuresis?
  • The H+ produced inside the cell (by Carbonic Anhydrase) are exchanged with Na+
  • Inhibition of Carbonic Anhydrase results in Na+ being left in the tubule 
Besides diuresis, what other important effect results from Carbonic Anhydrase Inhibitors (2)?
Bicarbonate (HCO3-) is created by carbonic anhydrase as well, and is absorbed into the blood.

Carbonic anydrase inhibitors thus have a net effect of:
  • Inhibiting bicarbonate (HCO3-) absorption
  • Inhibiting sodium (Na+) reabsorption
Is Acetazolamide toxic to the kidneys?
No, safe for use in renal impairment
What are the indications for Carbonic Anhydrase Inhibitors (3)?
  • Glaucoma
  • Metabolic alkalosis
  • Acute mountain sickness
What are 3 side effects of Carbonic Anhydrase Inhibitors?
  • Metabolic acidosis
  • Renal stones: Urine is alkaline (calcium salts become insoluble)
  • Hypokalemia: Due to Na+ reabsorption in distal nephron (due to K+ exchange)
Describe 3 important notes about Carbonic Anhydrase Inhibitors
  • Acts early in nephron (lots of downstream sites for Na+ reabsorption, not good)

  • Useful for glaucoma (as locally administered eye drops). Decreases rate of bicarbonate production leading to redued intraocular pressure

  • Mechanism for mountain sickness is not understood 
Name 2 Potassium-Sparing Diuretics

What membrane protein do K+-sparing diuretics act on?
ENaC (epithelial Na+ channel)
Where do K+-sparing diuretics act?
CCD (connecting segment of collecting duct)

and late distal tubule
Describe the physiology of K+-sparing diuretics and why they spare K+
They inhibit ENaC (directly or indirectly) which channels K+ out of the cell in the CCD.

Together, ENaC (Na+ channel), a K+ channel, and the Na+/K+ pump effectively exchange sodium and potassium through the cell, between the tubule and blood.
How does spironolactone work, specifically?
It inhibits ENaC indirectly, by acting as an aldosterone receptor antagonist.

This action also reduces the number of Na+/K+ ATPase pumps.

This causes natriuresis without causing loss of K+
Name 2 ENaC blockers (act by directly blocking ENaC as opposed to blocking the aldosterone receptor)
  • Triamterene
  • Amiloride
Describe in detail how ENaC blockers cause Natriuresis and spare Potassium
  • By blocking Na+ flow into cell, natriuresis effect is achieved
  • Because intracellular Na+ is low, the Na+/K+ ATPase pump cannot pump Na+ into blood
  • Therefore, ATPase pump is stalled and K+ stays in blood
Give 3 indications for Spironolactone
  • CHF, HTN (as adjunct)

  • Primary hyperaldosteronism 
Name 1 contraindication for Spironolactone
Describe 3 types of side effects of Spironolactone
  • Hyperkalemia (especially with use of ARBs)
  • Metabolic acidosis: Reduced reabsorption of Na+ leads to reduced H+ excretion
  • Spironolactone-specific:

    1. Gynecomastia
    2. Menstrual disorders
    3. Testicular atrophy
Describe 4 important notes on K+-sparing diuretics
  • All produce a fairly modest diuresis, typically given as an adjunct to a more powerful diuretic to avoid hypokalemia

  • Hydrochlorothiazide and K+-sparing can be found in combo pills

  • Only spironolactone has the anti-androgenic side effects (Eplerenone does not)

  • Aldosterone causes cardiovascular risk
Where in Nephron does Furosemide act?
Thick Ascending Limb (TAL)
What receptor is inhibited by Furosemide is in the Thick Ascending Limb (TAL)?
Na/K/2Cl co-transporter channel
What can be said about the Thick Ascending Limb as a site for a diuretic to act?
It is very ideal, because it is a key site for establishing the medullary concentration gradient.
What is the effect on electrolytes of Furosemide?
Causes Na+, K+, Cl-, Mg2+ and Ca2+ all to be lost in urine
Besides inhibiting Na+ reabsorption, what is an important secondary effect of inhibiting the Na/K/2Cl cotransporter regarding paracellular reabsorption? Explain.
Furosemide causes a more lumen-positive (+) gradient, because Na+ is left in the tubule.

As a result paracellular reabsorption of Mg2+ and Ca2+ is inhibited.
Besides inhibiting Na+ reabsorption, what is an another important secondary effect of inhibiting the Na/K/2Cl cotransporter regarding H+? Explain.
Because Furosemide causes a Na+ buildup in the lumen, the Na+/H+ antiporter in the Thick Ascending Limb (TAL) operates in overdrive.

This causes the tubule lumen to become more acidic. This can therefore cause metabolic alkalosis.
What is a side effect pertaining to serum K+ levels when using Furosemide?
Increased lumen Na+ at the TAL leads to much higher Na+ levels than normal in the distal nephron.

As a result, the Na+/K+ exchange in the CCD leads to K+ loss and potentially hypokalemia.
How long does Lasix (Furosemide) last for?
Peak effect: 30 mins
Length of action: 6 hours
List 2 main indications of Furosemide
  • Edema
  • Hypertension
List 2 contraindications to Furosemide
  • Severe electrolyte abnormalities
  • Hypovolemia
Describe and explain 5 main side effects of Furosemide
  • Hypovolemia: If too much Furosemide, more common if patient is predisposed
  • Electrolyte abnormalities: eg. Hypokalemia, hyponatremia
  • Metabolic alkalosis: Due to increased H+ excretion as a result of increased lumen Na+
  • Ototoxicity: Rare, reversible hearing loss. Most often in patient who are also taking aminoglycoside antibiotics (also ototoxic). The Na/K/2Cl transporter is also found in the ear.
  • Hyperuricemia: Two possible mechanisms: (1) Increase uric acid reabsorption in the PT (2) Compete for uric acid secretion in the PT
Describe 3 important notes regarding Furosemide
  • Response to loop diuretics reduced when lots of albumin in tubule (furosemide remains bound to albumin)

  • Loop diuretics more powerful than thiazides; therefore more useful in edema patients

  • Furosemide (and other loop diuretics) may result in allergic reaction in patients with sulfonamide allergy 
What kind of drug is Hydrochlorothiazide?
Where in Nephron do Thiazides act?
Distal convoluted tubule
What is the basic mechanism of Thiazides?
Inhibits the (NCC) Na/Cl symporter in the DCT.
What is a significant side effect of inhibiting the NCC with Thiazides?
Metabolic Acidosis

Mechanism: Inhibition of NCC symporter → Excess of Na+ and Cl- in the tubule → Puts the Na+/H+ cotransporter into overdrive → Leads to very acidic lumen of tubule (and metabolic acidosis)
What is the effect of Thiazides on serum K+?
Just like Furosemide, increased Na+ in lumen causes more than normal use of Na+/K+ exchange mechanism in CCD resulting in K+ loss (potential hypokalemia)
What is another important side effect of Thiazdes (this one is not well understood)...?
They cause increased Ca2+ reabsorption, which is actually maybe a good thing (prevents osteoporosis...)
Are Thiazides strong or weak diuretics?
Thiazides are Weak

Furosemide (Lasix) is a strong diuretic
What is an important secondary effect of Thiazides besides diuresis that is important in their use as anti-hypertensive drugs?
What is the net effect on plasma ion concentrations?
  • Decreased Na+, K+, Cl-
  • Increased Ca2+
Describe 4 important pharmacological points regarding Thiazides
  • Exert pharmacological effects from lumen of tubule

  • Thiazides enter renal tubule through secretion in the proximal tubule (PT). Thus, higher doses may be required in renal impairment to allow increased secretion of drug into tubule

  • Thiazides also compete with other drugs and endogenous substances (uric acid) for secretion in PT, so they can prolong residence of these other drugs/substances in the body

  • Chlorthalidone has a longer half-life than hydrochlorothiazide, leading to more consistent anti-HTN effect throughout the day
Name 3 indications for Thiazides
  • Hypertension
  • Edema
  • Nephrogenic diabetes insipidus
Name 6 side effects of Thiazides
  • Electrolyte abnormalities
  • Metabolic side effects

    Alkalosis: Due to loss of H+
    Hyperglycemia: Due to impaired insulin release and diminished utilization of glucose
    Hyperlipidemia: Increased cholesterol and LDL, mechanism not known
    Hyperuricemia: Thiazides compete with uric acid for secretion into proximal tubule 
  • Impotency: As a result of reduced volume 
What are 6 important notes regarding Thiazides?
  • Ineffective when creatinine clearance gets too low (kidneys required to exert effects)

  • Weaker than Loop Diuretics

  • Paradoxical effect in Diabetes Insipidus (mechanism unknown)

  • By enhancing Ca2+ reabsorption, can reduce formation of renal stones

  • Hydrochlorothiazide has a flat dose response curve, doses above 50mg are not efficacious (just increased side effects)

  • Thiazide and Loop Diuretics contain Sulfa drug (theoretical risk of allergic reaction) 
Name some features (3) that Thiazides and Loop Diuretics have in common, and (1) that feature that is opposite

  • Both can lead to metabolic acidosis
  • Both can cause hypokalemia (by same mechanism)
  • Both have allergy risk of Sulfa drugs

  • Thiazides reduce renal Ca2+ while Loop diuretics increase it
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