Diuretics Pharmacology Flashcards
What part of the nephron do CA inhibitors act on?
PT
CA inhibitors MOA
Inhibition of CA causes bicarbonate excretion to go up. Being alkaline, makes urine basic.
Enhanced Cl- reabsorption that results in acidosis
What are the major clinical uses for CA inhibitors?
To alkalinize urine in cysteinuria
To reduce intraocular pressure
Manage seizures
Give prohpx for mountain sickness
What is the one CA inhibitor named?
Acetazolamide
What are the side effects of acetazolamide?
Metabolic acidosis
K+ loss in urine acutely that goes away
MOA of osmotic diuretics
PCT: isoosmotic so not reabsorbed, and it retains water (minor effect)
LOH: wipes out hypertonicity of medulla by increasing medullary blood flow; results in less water reabsorbed in DLH
(Change renal hemodynamics resulting in less water reabsorption in TDLH)
Effects of osmotic diuretics on LOH
Extract water from tissues
Decrease blood viscosity
Inc medullary renal flow, reduce tonicity
What is an example of an osmotic diuretic?
Mannitol
What are the side effects of mannitol?
Volume overload (bc large dose and osmolarity up) Contraindicated in cardiac failure
Do osmotic diuretics cause more free water excretion?
yes
What are osmotic diuretics still used for?
Dialysis disequilibrium
Reduce intracranial pressure
Reduce intraocular pressure
These effects are very immediate
MOA of Loop diuretics
Inhibit Na/K/2Cl symporter in TALH Causes MD to inc filtration by blocking it from sensing Na (uses NaKCl transporter to) Up biosynthesis of prostaglandins Inc total RBF Maintain GFR Renin secretion increases
Do loop diuretics affect the urine concentrating ability?
Yes, decrease ability to concentrate
How do loop diuretics affect the filtration fraction?
Increase by about 5%
What about prostaglandins and loop diuretics
More prostaglandins made which increase blood flow to kidneys
How to loop diuretics change the afferent artery?
Decrease resistance to inc GFR
How do loop diuretics contribute to renin release?
Inhibiting the macula densa
Activating SNS
Stimulating intrarenal bareoreceptors
Loop diuretics increase excretion of which ions?
NaCL K H Ca Mg
Which kind of diuretic is the most potent NaCL mobilizer and diuresis inducer?
Loop diuretics
What are the therapeutic uses for loop diuretics?
Edema, inc. cardiac, hepatic, renal, pulmonary
Hypercalcemia
Protect against renal failure (esp post-op)
Wash out toxins
Where does furosemide enter the nephron?
Secreted in by proximal tubule
Why does furosemide have a high therapeutic window?
In renal disease patients, PCT secretions are reduced so you can give a lot more of drug
Why do you need to make sure that people on loop diuretics stay well hydrated?
So they don’t form kidney stones of Ca from increased urinary excretion
What kind of vascular changes does furosemide cause?
Venodilation somehow
What are the side effects of furosemide?
Hypokalemia - give supplement pH disorders esp alkalosis BUN up Hyperglycemia Hyperuricemia Ototoxicity and sialadentitis
What are some major drug interactions of furosemide?
Li+ urinary excretion
Indomethacin - prostaglandin inhibitor
Probenecid - inhibits furosemide secretions
Warfarin - compete for protein binding
What are the three loop diuretics
Furosemide
Bumetanide
Torsemide
Which is most potent loop diuretic?
Bumetanide
How do loop diuretics cause hypokalemia?
Increased distal sodium delivery causes lots of reabsorption in distal CT and CD, making a steep gradient for K+ to be secreted into (-) lumen
Thiazide diuretics MOA
Inhibit NaCl reabsorption in Na/K aldosterone-independent segment of distal tubule
Which diuretics are used chronically?
Thiazides
What ions do thiazide diuretics affect?
Increase Mg excretion
Decrease Ca excretion (unlike loops)
What are the uses for thiazides?
Edema from CHF, cirrhosis, nephrotic Hypercalciurea/calcium stones Reduce blood pressure Augment antihypertensives Osteoporosis - dec urine calcium Nephrogenic DI
Why are thiazides used in HT?
Unknown how, but they are vasodilators
What is the difference between class I and II diuretics?
Class I - use when GFR > 50 mL
Class II - use when GFR between 50-30
What are the Class I thiazides?
Hydrochlorothiazide
Clorthalidone
Quinethazone
What are the Class II thiazides?
Metolazone
Indapamide
What are the aldosterone antagonists?
Spironolactone
Eplenerone
Are aldosterone antagonists K sparing or wasting?
Sparing
Spironolactone PK
pro-drug extensively metabolized
Side effects of spironolactone
Hyperkalemia
Gynecomastia, hirsutism, uterine bleeding
Clinical uses for aldosterone antagonists
Think CHF!
Also cirrhosis
Why is eplenerone better than spironolactone?
Much more mild side effects
What do aldosterone antagonists do to ion levels?
Increase Na excretion
Decrease K excretion
What are the K-sparing diuretics (class)?
Triamterene
Amiloride
What are the side effects of K sparing?
Hyperkalemia
Megaloblastic anemia in pts with cirrhosis
What is MOA of K sparing
Inhibit Na reabsorption in late distal tubule
Where does ANP act?
Induces guanylyl cyclase to make cGMP, which inhibits Na reabsorption
What is the ANP drug?
Nesiritide
Nesiritide MOA for Na excretion
Inhibits CNG nonspecific cation channel in CD
Inhibits RAAS
Why is nesiritide useful in CHF?
Decreases systemic vascular resistance through NO production
Decreases LV filling pressure
Increase cardiac output
What is the best combo for hypertension?
Diuretics with ACE inhibitors
What diuretic would you give to someone with mild to moderate hypertension?
Thiazide
When would you absolutely need to use a loop diuretic instead of another in terms of GFR?
GFR below 30
What diuretic would you give to someone with severe hypertension who doesn’t respond to thiazides?
Loop diuretics
What would you give to someone who has acute pulmonary edema or a hypertensive crisis?
Furosdemide
What drug class should patients avoid while using loop diuretics?
NSAIDs
What diuretic would you give to a patient with hyperuricemia?
K sparing or aldosterone antagonist
What diuretic would you give to a patient with cirrhosis?
Spironolactone
Are thiazides or K-sparing diuretics more useful for antihypertensives?
Equally useful PUNK’D
Where are V1 receptors found?
Vascular smooth muscle
What does AVP do when it binds to V1?
PLC cascade that causes vasoconstriction
Where are V1 receptors found?
Principal cells in collecting ducts
What type of cascade is coupled to the V2 receptor?
GS GPCR cascade that causes PKA phosphorylation of AQP2, resulting in translocation to apical membrane
What are the V1-receptor agonists?
vasopressin (discontinued)
terlipressin
Why do you use V1 receptor agonists
GI and vascular smooth muscle contraction
What are the clinical uses for V1 agonists
Post-op ileus
Reduce bleeding during acute hemorrhagic gastritis
What are the causes of diabetes insipidus
Inadequate AVP secretion (central)
Insufficient kidney response to AVP (nephrogenic)
How can you distinguish between nephrogenic DI and central DI?
Give a V2R agonist (desmopressin) and see if urine osmolarity increases. If it does, they have central. If not, nephrogenic.
What is the most common causes of central DI?
Head injury, CNS ischemia, tumors, V2R gene mutations
How are thiazide diuretics helpful in DI?
Cause mild depletion of EC water and Na, activating renal compensation to increase reabsorption in PCT. Reduces volume delivered to distal tubule.
What are the three drug classes that can cause SIADH?
Psychotropics
Sulfonylureas
Vinca alkyloids
How are V2 receptors targeted in SIADH patients
Demeclocycline which antagonists V2R
What are the selective V2R antagonists?
Tolvaptan
Conivaptan
What is the black box warning for V2R antagonists?
Can only be used in a hospital setting
