Diuretics & ADH - Full PPT Flashcards
Where do Carbonic Anhydrase Inhibitors act?
Proximal tubule
ex. Acetazolamide
Is acetazolamide used as a kidney diuretic?
No, not a clinical use
Where do loop diuretics act?
Ascending loop of Henle
How useful are loop diuretics?
Extremely!
What do Loop diuretics do (mech.)?
Inhibit Na, K, 2 Cl transporter
Where do Thiazide diuretics act?
DCT (distal convoluted tubule)
What are Thiazide diuretics extremely useful for?
Hypertension
What do thiazide diuretics do?
Inhibit NaCl symporter
Where do Potassium sparing diuretics work?
In Cortical collecting tubule
What are K+ sparing diuretics useful for? What are their mechanisms?
-Useful for prevention of K+ loss
-Either:
1. Inhibit aldosterone receptors
OR
2. Block Na exchange for K and H
Where does AHD work? What does it do?
Works in medullary collecting duct.
Acts to recruit aquaporin channels.
Where do osmotic diuretics work?
Proximal tubule and/or descending limb of the loop of Henle
What two Loop Diuretics must you know?!
Furosemide (Lasix)
Bumetanide
What is the mechanisms of Loop Diuretics?
Inhibit Na, K, 2 Cl transporter in the ascending loop of Henle
Normally the ascending loop of Henle accounts for how much of the Na+ reabsorption?
25%
How do loop diuretics influence ions?
-Tubular fluid becomes hypo-osmolar as Na, K and Cl are pumped out but water remains inside (no aquaporins here!)
What od loop diuretics prevent?
Decrease in osmolarity –> results in greater retention of ions and water in later segments of nephron
What effect do loop diuretics have on urine composition?
- Inc. NaCl excretion
- Inc. K excretion
- -> Some increased nephron Na is exchanged for K in the collection tubule
What side effect can loop diuretics cause by altering K+ concentration?
They decrease K+ concentration in body (inc. in urine) which can cause K+ to be too low in the cochlea and inhibit hearing.
What are the therapeutic uses of Loop Diuretics?
- Pulmonary edema
- Other edematous conditions
- Hyperkalemia
- Acute renal failure
- Anion overdose (Bromide, Fluoride, and Iodide)
How do loop diuretics compare in terms of effect to thiazides?
Loop diuretics work earlier in the tubule than thiazide diuretics so more Na+ and Cl- gets absorbed here and these drugs have larger effect!
What are the three thiazide diuretics?
Chlorathalidone
Hydrochlorothiazide
Metalazone
What is the mechanism of thiazide diuretics and where do they work?
Block NaCl transporter in the DCT
What does blocking the NaCl transporter cause?
- NaCl transporter normally accounts for 8% of NaCl reabsorption
- Block of this transport mechanism results in excretion of water, Na, Cl and K in urine
- K gets excreted because some of the increased Na is exchanged for K in the cortical collecting tubule
What are thiazide diuretics used for therapeutically?
- HTN
- Heart failure
- Nephrolithiasis caused by hypercalcemia
- Nephrogenic diabetes insipidus
What are major side effects of thiazide diuretics?
- Hyperglycemia
- Hyperuricemia –> kidney stones!
- Hypokalemia
- Hyperlipidemia
- Hyponatremia
- Allergic reactions
How are thiazide diuretics like Type 1 diabetes?
Thiazides are sulfonylureas
- They bind to SUR (sulfonyl urea receptor) on K+ channel controlling insulin release, opening the channel and hyper polarizing the beta cell
- Thus, they suppress insulin release!
What happens after thiazide diuretics bind to SUR on beta cells?
- SUR is on the K+ channel and controls insulin release, opening the channel
- Opening the K+ channel causes hyper polarization
- This suppress Ca2+ channels from allowing Ca2+ to flow in
- Thus, supressing insulin release from secretory granules
What part of the blood pressure equation do thiazides affect?
Major effect on resistance (R) –> hyper polarizes smooth muscle –> vasodilators
Why are thiazides used in HTN?
- They hyper polarize smooth muscle –> vasodilation
- They also dec. blood volume –> dec. BP
What do thiazides do to uric acid levels?
They raise uric acid levels/ prevent secretion/ precipitate gout
What are the three main potassium sparing diuretics?
- Spironolactone
- Triamterene
- Amiloride
What is the mechanism of action fro Spironolactone?
Inhibits aldosterone receptors
What is the mechanism for Triamterene and Amiloride?
Inhibit Na+ exchange for K+ and H+ in the cortical collecting duct.
-Inhibit Enac channels!!
What does blocking the exchange of intraluminal Na+ for extraluminal K+ cause?
- Less K+ to be excreted
- this exchange occurs on the abluminal (away from lumen) side - Na+/K+ exchange
What is the major use of K+ sparing diuretics?
- Hyperaldosteronism
- Prevent K+ wasting caused by other diuretics
What is special about Eplerenone and the heart?
Prevents fibrotic changes in kidneys and hearts caused by aldosterone, and has been shown to improve survival in heart failure
What is special about Eplerenone and the kidney & heart?
Prevents fibrotic changes in kidneys and hearts caused by aldosterone, and has been shown to improve survival in heart failure
What are side effects of K+ sparing diuretics?
- Hyperkalemia
- Hyperchloremic metabolic acidosis (normal anion gap, dec. plasma bicarbonate, inc. plasma chloride)
- Gynecomastia (spironolactone)
- Acute renal failure (specific to triamterene and indomethacin)
- Kidney stones
Where is aldosterone synthesized?
Adrenal cortex in the adrenal gland
What does aldosterone do?
Increases resorption of ions and water in the kidney (stimulated by angiotensin II)
Where does aldosterone act?
On nuclear mineralcorticoid receptors (MR)
What are the ADH-like diuretics?
ADH = Vasopressin
Desmopressin (synthetic congener)
What are Vasopressin and Desmopressin used to treat?
- Diabetes insipidus
- Bedwetting
What is the MOA for Vasopressin (ADH) and Desmopressin?
Stimulation of G-protein coupled receptors in the collecting duct to recruit aquaporin channels
–> Water moves by osmosis through the aquaporin channels to the hyperosmolar medullary region of the kidney
How can Vasopressin or Desmopressin be administered?
Parenterally (intravenously), Intranasally or orally
What is Demecocycline?
An antibiotic with some activity as an ADH antagonist
What is the major osmotic diuretic?
Mannitol
How does mannitol work?
It is not reabsorbed in the nephron!
-Thus, it exerts an osmotic effect to retain water
What is mannitol used for?
It’s used to reduce body water or to reduce intracranial or intraocular pressure
What are some toxicities of mannitol?
- Extracellular volume expansion
- Dehydration, hyperkalemia, hypernatremia
- Hyponatremia when renal function is impaired
What are SGLT-2 (sodium glucose transporters)?
- Symporters for sodium and glucose into the cells.
- Typically reabsorb 90% of filtered glucose
- Transport maximum of about 240 mg/dL (above this glucose spills in urine)
- Present in PROXIMAL TUBULE
What is the mechanism of SGLT-2 inhibitors?
Reduce reabsorption of glucose
-Cause loss of glucose in urine
What are SGLT-2 inhibitors used for?
Helps reduce blood sugar levels in diabetes mellitus
-Causes weight loss (loss of energy)
What types of side effects are SGLT-2 inhibitors associated with?
MANY side effects:
-Ketoacidosis, UTI, yeast infections, hypoglycemia
What are three examples of sodium-glucose transport inhibitors?
- Canigliflozin
- Dapagliflozin
- Gliflozin
What is the ending of SGLT-2 inhibitors?
-Flozin’
Inhibiting flo of glucose
What is the major carbonic anhydrase inhibitor?
Acetazolamide
Why aren’t carbonic anhydrase inhibitors useful as diuretics?
Carbonic anhydrase is too important of an enzyme.
-When you block it, there are an incredible number of side effects
What are carbonic anhydrase inhibitors used for?
- Treat glaucoma
- Produce urinary alkalinization
- Treat metabolic alkalosis (usually treated with restoration of volume and chloride)
- Treat acute mountain sickness
What side effects are associated with carbonic anhydrase inhibitors?
- Hyperchloremic metabolic acidosis
- Renal stones
- Renal K+ wasting
What proximal tubule process is carbonic anhydrase directly related to?
Conversion of H2O + CO2 to H2CO3
What is the function of Organic Anion Transporters?
Transport small hydrophilic organic molecules into (secretion) or out of (reabsorption) the nephron lumen
What drives the transport of small hydrophilic organic molecules in OATs?
Driven by decarboxylate simport or antiport
–> Dicarboxylate is typically alpha keto glutarate
What is the important of OATs?
They have a role in gout!
What does OAT1, OAT3 and OAT4 do?
Tranport Uric acid from the proximal tubule lumen (ureter) into the epithelial cell and then to the circulation (blood)
What are three ways to treat gout?
- Reduce inflammation
- Reduce uric acid
- Inhibit renal OATs
How do you reduce inflammation in gout?
NSAIDs
-> don’t use salicylates!
How do you reduce uric acid in gout?
Allopurinol!
How does Allopurinol reduce uric acid?
It blocks the formation of gout by blocking xanthine oxidase and inhibiting the formation of uric acid
What can be used to inhibit renal OATs?
Probenicid or Sulfinpyrazone
What is the mechanism of Probenicid/Sulfinpyrazone?
Inhibits renal organic acid transporters of urate to facilitate excretion (normally 90% of urate is reabsorbed in proximal tubule)
How do Thiazide diuretics relate to OATs?
Thiazide diuretics are substrates for OATs
- They inhibit secretion of uric acid by OAT1 on the basolateral (blood) side of the nephron
- They also serve as substrates for the URAT antiporter to increase urate reabsorption on the luminal side of the nephron
- –> Net effect is that they increase blood uric acid
Where does Aldosterone bind/act?
Nuclear mineralcorticoid receptors (MR) within the principle cells of the distal convoluted table and collecting duct.
What does Aldosterone do in the principle cells?
- Activates Na+/K+ pumps
- Upregulates Enac channels!
What is Convaptan?
An ADH antagonist that can be used to treat syndromes involving inappropriate ADH secretion
Where is ADH created?
Hypothalamus
Where is ADH stored?
Posterior pituitary
How does ADH lead to the insertion of aquaporin channels?
- ADH binds V2 receptors - G protein coupled receptors on basolateral plasma membrane of the epithelial cells
- This G protein receptor couples to the heterotrimetic G protein Gs
- This activates adenylyl cyclases III and VI to convert ATP to cAMP + 2Pi
- Rise in cAMP triggers insertion of Aquaporin-2 water channels by exocytosis of intracellular vesicles containing the channels
