Exam 1: Lecture 2 & 3: Diuretics Flashcards
Diuretics that work in the PCT
Carbonic Anhydrase Inhibitors
SGLT2 Inhibitors
Osmotic diuretics (not main site)
Diuretics that work in the Thin Descending Limb
Osmotic Diuretics (Main site of action)
Diuretics that work in the Thick Ascending Limb
Loop Diuretics
Diuretics that work in the DCT
Thiazide Diuretics
Diuretics that work in the Collecting Duct
Vasopressin Receptor Antagonists
ENaC Inhibitors, K+ Sparing Diuretics
Aldosterone Antagonists, K+ Sparing Diuretics
Carbonic Anhydrase Inhibitors: Prototype
Acetazolamide
Carbonic Anhydrase Inhibitors: MOA
Inhibition of Carbonic Anhydrase, preventing Sodium Bicarbonate reabsorption, leading to increased Sodium and Water excretion
Sodium stays in the Lumen since less moves through NHE3 and water goes where Sodium goes
Occurs mostly PCT
Carbonic Anhydrase Inhibitors: Applications
Glaucoma Urinary alkalinization Metabolic alkalosis epilepsy CSF leakage Respiratory Stimulant Acute mountain sickness
Carbonic Anhydrase Inhibitors: Notables
Ineffective as a diuretic mono therapy due to effect on renal excretion are self limiting. Tolerance develops after 2-3 days
Risks associated are hyperchloremic & hypokalemic metabolic acidosis from Net lose of base in plasma and gain of CL-
Where does most potassium wasting occur?
Most occurs at the level of the collecting tubule
This is due to the ENaC, which when their is high Na+ in Lumen, will drive Na into cell causing K+ to be driven out. (causing hypokalemia)
Carbonic Anhydrase Inhibitors: Drugs
Acetazolamide = Prototype
Dorzolamide, Brinzolamide = eye drops
Dichlorophenamide, Methazolamide = oral
Carbonic Anhydrase Inhibitors: Glaucoma application
Block carbonic anhydrase, decreasing sodium and bicarbonate entry into cell. This reduces aqueous humor production which causes excess pressure causing glaucoma
Carbonic Anhydrase Inhibitors: Acute Mountain Sickness
Due to exposure to low oxygen lvls at high elevation
Preventing release of bicarbonate into CSF, which causes decrease in pH, and increase ventilation/oxygen delivery and decreasing the symptoms of acute mountain sickness
SLGT2 Inhibitors: Prototype
Dapagliflozin
SLGT2 Inhibitors: General MOA
Inhibition of SGLT2, preventing reabsorption of glucose in the PCT
SLGT2 Inhibitors: Applications
Diabetes mellitus, Type II Diabetes
SLGT2 Inhibitors: Notables
Side effects associated with non-specificity (bind to other SGLT), genetic and epigenetic variations
SLGT2 Inhibitors: Drugs
Dapagliflozin = Prototype (Farxiga)
Canagliflozin (Invokana)
Empagliflozin (Jardiance)
3rd line for type II Diabetes
SGLT2 Inhibitors: Steps
1st: SGLT2 inhibition, leading to increased conc of tubular fluid (more Glucose and Na excretion), reduction in extracellular fluid volume
Sensing of increased tubular Na leads to vasoconstriction (afferent)
Sensing increased tubular Na leads to inhibition of renin release, causing vasodilation (efferent)
This combo causes reduction in GFR, and intraglomerular hydrostatic pressure
What is the renal protective effect of SGLT2 inhibitors?
Reducing of GFR
SGLT2 Inhibitor: Clinical Application
Diabetes Mellitus, 3rd line therapy
Occurs when excess blood glucose, SGLT2 inhibitors will not allow excess glucose to be reabsorbed and thus excreted
Osmotic Diuretic: Prototype
Mannitol (Must be given IV, orally it will cause diarrhea)
Osmotic Diuretic: MOA
Prevents absorption of water through osmotic force mainly in Thin Descending Limb, also PCT
Osmotic Diuretics: Applications
Reduction of intracranial and intraocular pressure
Osmotic Diuretics: Risks
Hyperkalemia, Hypernatremia, and Hyponatremia (if any renal failure)
Osmotic Diuretics: Drugs
Mannitol (Prototype)
Glycerin isn’t really used much
Osmosis
Movement of water (solvent) from low to high solute concentration through semipermeable membrane
Osmotic Diuretics: MOA at PCT
Mannitol will reduce water reabsorption
Osmotic Diuretics: MOA in Thin Descending Limb in loop of Henle
Decreased sodium reuptake and decreased water reabsorption leading to an indirect effect in DCT and Collecting duct.
Will have increased delivery in lumen space, increasing the rate which also lowers Na reabsorption in DCT and Collecting duct, thanks to rate of flow.
increase urinary excretion of just about all electrolytes
Osmotic Diuretics: Clinical applications
Reduction of Intracranial pressure and
Reduction of Intraocular Pressure.
sometimes in drug OD, to make you pee more
Osmotic Diuretics Notables
Mannitol should be given IV
Key risks is dehydration
Hyperkalemia, Hyperatremia and Hyponatremia are all risks depending on dose and pathology
Osmotic Diuretic: Hypernatremia
Due to ENaC
Osmotic Diuretic: Hyponatremia
Can occur in patient with renal damage due to retaining mannitol in the blood
Osmotic Diuretic: Hyperkalemia
Can occur in high dose, patient dependent.
due to expansion of ECF volume, pulls K+ into plasma
Loop diuretics focus on which channel?
Inhibitors of NKCC2
Also known as “High Ceiling” diuretics
Where do loop diuretics work?
Thick ascending limb.
Loop Diuretic: Prototype
Furosemide
Loop Diuretic: MOA
Inhibition of NKCC2 in the Thick Ascending Limb
By inhibiting NKCC2, will reduce ROMK activity which drives Mg,Ca moving back into interstitial space.
Can also cause potassium wasting
Loop Diuretic: Applications
Mainly used for acute pulmonary edema and hypertension
Not first line of therapy for Hypertension,
Loop Diuretics: Notables
High Ceiling = most effective at producing diuresis
Risk: Hypokalemic metabolic alkalosis, hyperuricemia, hypomagnesemia, ototoxicity
Allergic Reaction
Potassium wasting
Happens at the level of the collecting duct
Increase in ions in lumen. The high conc of sodium taken up by principle cells (via ENaC) will cause potassium to move through the principle cell and back into the urine
Loop Diuretics: Drugs
Prototype: Furosemide
Torsemide, Bumetanide, Ethacrynic acid
Loop Diuretics: Acute Pulmonary edema
Very effective at removing water and treating edema
Cardiogenic
Cardiac component, related to cardiac dysfunction
Loop Diuretics: Hypertension and Hypercalcemia
Hypercalcemia = High plasma calcium levels
Works by reducing ROMK activity, reducing how much Ca it drives into cell
Loop Diuretics: Hypertension and Hypercalcemia
Hypercalcemia = High plasma calcium levels
Works by reducing ROMK activity, reducing how much Ca it drives into cell
Thiazides: Prototype
Hydrochlorothiazide
Thiazide: MOA
Inhibition of NCC in the DCT
Thiazide: Applications
Hypertension
Heart Failure
Nephrolithiasis due to idiopathic hypercalciuria (Kidney stone), and nephrogenic diabetes insidious (excessing urination)
Thiazide: Notables
Preferred over loops due to longer duration of action
Potassium wasting, lesser extent than loop diuretics though
Hypokalemic metabolic alkalosis, impaired carbohydrate tolerance, hyperlipidemia, hyponatremia, *impaired uric acid metabolism and gout , allergy
Thiazides: Drugs
HCTZ (prototype)
Metolazone
Chlorthiazide
Chlorthalidone
Thiazide Detailed MOA
Inhibition of NCC in DCT
Will cause modest increase in Na excretion
Some K+ wasting
Will enhance Ca reabsorption, opposite of loop diuretics which will decrease Ca in urine
Clinical Indications Thiazides
Hypertension
Edema in Heart failure
Kidney stones
Excessive peeing
Where is ADH produced
Produced in the Hypothalamus
Where is ADH stored
stored in the pituitary gland
What do Vasopression Receptor Antagonists target (Vaptans)
Vasopressin receptors
Quick facts about Aquaporins
6 Transmembrane regions
Create a pore, H2O moves in single file.
Selective binding for H2O
How many monomers is an aquaporin made of?
Four
Vaptans: Prototype
Canivaptan
Vaptans: MOA
Inhibition of V1 and V2 receptors (Nonselective)
or
Inhibition of V2 receptors (Selective)
Vaptans: Applications
Autosomal dominant polycystic kidney disease (try and slow progression)
Heartfailure
SIADH (Excessive release of ADH)
Vaptans: Notables
Nephrogenic diabetes insipidus (excessive water in urine)
Renal failure (Lithium and demeclocycline)
Dry mouth
Thirst
Hypotension (Tolvaptan)
Lithium = a lot of side effects
Vaptan: Drugs
Conivaptan (IV only, usually continuous)
Tolvaptan
- Lithium
- Demeclocylcine
Vaptan: MOA Steps
Vaptan prevent binding to V2 receptor and prevents the following from occuring
V2 work by….
Activating Adenylyl cyclase 6, which activates cAMP, which activates Protein Kinase A
PKA phosphorylates AQUA-2, which gets placed in lumen and causes water to move from Lumen through cell and into capillary
3 Main indications for vaptans
Polycystic Kidney Disease:(cAMP mediates cysts development, since cAMP is in cascade of V2 signaling….inhibiting V2 will slow cysts)
Heart failure:
Low blood volume triggers vasopressin release, so prevent cycle can help manage
SIADH: increase ADH leading to decreased plasma osmolality or increased arterial circulating volume
What do Potassium Sparing Diuretics target?
ENaC
Work via ENaC inhibitors and Aldosterone Antagonists (slower reaction, days to weeks for maximal effect)
Two kinds of K+ Sparing Diuretics?
ENac Inhibitors and Aldosterone Antagonists
K+ Sparing Diuretics: Prototype
ENaC inhibitor: amiloride
Aldosterone Antagonists: spironolactone
K+ Sparing Diuretics: MOA
Direct or indirect inhibition of ENaC
K+ Sparing Diuretics: Applications
Edema
Hypertension
*Hyperaldosteronism for AAs
K+ Sparing Diuretics: Notables
Weak diuretics but important for patients with hypokalemia
K+ Sparing Diuretics: Risks
Hyperkalemia, hyperchloremic metabolic acidosis, Gynecomastia (Man Boobies…AAs), Acute renal failure and Kidney stones
Direct ENaC inhibitors:
Amiloride (Prototype)
Triamterene
Indirect ENaC inhibitors
Spironolactone (Prototype)
Epierenone
K+ Sparing Diuretic MOA detailed
Direct: Blocking ENaC, preventing uptake of sodium so it stays in lumen (urine)
Indirect: Prevent signaling of aldosterone receptor, which is responsible for up regulating insertion of ENaC and Na/K+ ATPase
K+ Sparing Diuretics: Drivers for side effects
Reduction in Na uptake, will decrease electrogenic exchange of Na for K/H, which can cause hyperkalemia and acidosis.
Why are K+ Sparing Diuretics less effective?
Because the collecting duct only filters about 2-5% Na
Why are Thiazides preferred over loop diuretics?
Longer half life
