Flashcards in Kruse - Diuretics Deck (85):
What is the fxn of a diuretic
- increase Na excretion + urine production by kidney
- adjust volume/composition of body fluids
What is fxn of natriuretic
- Increase in renal sodium excretion
- Diuretic = increase urine volume
- Natriuretic called diuretic sometimes because it inevitably increases urine volume
Where are diuretics usually delivered?
To the luminal side of the tubule
What is reabsorbed at the thin descending limb of the loop of henle? Ions or water?
Water = descending loop
What is reabsorbed at the thick ascending limb of the Loop of Henle
25% of filtered Na+
Which transporter maintains the ion concentration gradient in the interstitium?
It is located in the TAL
What is the fxn of NaK2Cl cotransporter?
- Creates increase in intracellular K+
- reabsorbs 25% Na
- this drives K+ to diffuse back into lumen to create a + potential
- Mg, Ca+ ions in the lumen diffuse from lumen into blood paracellulary to escape the + potential created by K+
***blocking this transporter results in excretion of many ions in urine
What happens at the DCT?
- 10% of NaCl is reabsorbed = dilutes tubular fluid
- impermeable to H20
- NaCl transported via thiazide-sensitive NaCl cotransporter
- Ca+ is passively reabsorbed by calcium channesl (PTH sensitive)
Function of the Collecting Duct
- reabsorbs 2-5% of NaCl via ENaC
- most important site of K secretion
- secrete H+ into lumen = acidic urine
Diuretics that act upstream of the CD, will ______ Na delivery to the CD and _____K+ secretion
What is the fxn of aldosterone?
- Increases the expression of both the ENaC on luminal side = Na reabsorption into cell
- increase in basolateral Na+ K+ ATPase = increased Na reabsorption + K+ secretion = increase bp
Fxn of ADH (vasopressin)?
- control permeability of CD to H20
- controls aquaporin-2 channels at apical membrane
Without ADH = CD impermeable to H20 = dilute urine
How does alcohol affect ADH release?
Alcohol DECREASES ADH release and increases urine production
Prototype of Carbonic Anhydrase Inhibitor?
Metabolism and excretion?
- well absorbed after oral intake
- excreted by secretion in PCT ---- need to reduce dose if renal insufficiency
- no hepatic metabolism/breakdown
MOA of Acetazolamide (CA Inhibitor)
- inhibits membrane bound + cytoplasmic CA = no NaHCO3 reabsorption in PCT
- decreased NHE3 (Na/H exchanger) activity = increased diuresis because more sodium left in lumen
- 45% more bicarb excreted = blood acidosis
- within few days, drug efficacy decreases b/c rest of nephron makes up for lack of Na reabsorption at PCT by reabsorbing at other spots in nephron
How long before urine alkalosis seen when using a CA inhibitor
Within 30 minutes
Adverse effects of CA Inhibitor?
- metabolic acidosis
- Renal stones because calcium salts are more insoluble at basic urine pH
- potassium wasting (hypokalemia) = increase Na in CCT increases K+ secretion
- sleepy + tingling @ large doses
- Hypersensitivity rxn = rare
Contraindications of CA I
Patients with cirrhosis
- increase. Urine pH due to CAI = decrease urine excretion of ammonia --> hyperammonemia + hepatic encephalopathy
Patients with hyperchloremic acidosis or severe COPD
- CA I = makes metabolic or respiratory acidosis worse
Clinical indications for CAI
- rarely used as diuretics
- used for glaucoma = common
- reduces aqueous humor formation + decrease intraocular pressure
- acute mountain sickness
- adjuvants in epilepsy
How are CA I used to help excrete uric acid, cystine, and other weak acids?
Because it causes urinary alkalinization
*basic urine decreases excretion of NH4 (basic)
Prototypes of loop diuretics?
Furosemide + ethacrynic acid
Metabolism of loop diuretics (furosemide + ethacrynic acid)
- rapidly absorbed after oral administration
- can be taken IV for some
- eliminated by kidney
- secreted into lumen at PCT, acts on luminal side of nephron --- halflife related to kidney fxn
Why is coadministering loop diuretics with other weak acids (Ex. NSAIDs) bad?
Can cause reduced loop diuretic secretion into lumen = less effect
B/c competition for secretion of other weak acids
MOA of loop diuretics (furosemide + ethacrynic acid)
- inhibit NaK2CL cotransporter in TAL
- ion transport in TAL pretty much stops because lumen-positive potential is not created, so Mg + Ca are not reabsorbed
- more Na delivered to DCT/CD, so more K and titratable acid is excreted as Na is reabsorbed into body to make up for lack of Na reabsorption at TAL
- H+ released into lumen as well (3 Na taken in, 2 K pumped out, so maybe secrete H+ to balance out?)
Loop diuretics induce the production of _____
Renal PG (prostaglandins)
Note: NSAID reduce loop diuretics ability to make PG
Loop diuretics can be weak inhibitors of
Loop diuretics increase
RBF (renal blood flow) via PG-mediated vasodilation
Too much loop diuretics (toxicity) can cause:
- depletion of total-body Na+ = hyponatremia, decreased GFR, circulatory collapse, thrombohemolytic episodes, hepatic encephalopathy in pts with liver disease
- hypokalemic metabolic alkalosis
- hyperuricemia = gout b/c too much uric acid reabsorbed at PCT
When is loop diuretics contraindicated?
- Bad for pts with hepatic cirrhosis, borderline renal failure, HF
- postmenopausal women b/c of hypocalcemia = osteoporosis
Which 3 loop diuretics should not be used b/c they may cause allergic rxns in pts with sulfonamide sensitivity?
What drugs do loop diuretics interact with?
Clinical indications for loop diuretics
- most efficient diuretic
- acute pulmonary edema
- HTN + heart failure
- tx for hyperkalemia b/c loop diuretics promote K+ excretion
- anion overdose
Prototype for thiazide diuretics
thiazides are given ______.
Which thiazide is not lipid soluble?
- given orally
- Chlorothiazide = not lipid soluble --- so give in large doses
Which thiazide is the longest acting thiazide?
47 hours = halflife
Where are thiazides secreted?
PCT by organic acid secretory system
- competes with secretion of uric acid ...so may get increased uric acid in blood
Thiazides Inhibit ______ cotransporter
Thiazides increase _____ reabsorption. Why?
- Inhibits Na/Cl cotransporter in luminal side in DCT
- increase Ca reabsorption to bring more Na into epithelial cell (Na/Ca antiporter on basolat side) = HELP STOP STONES
- NaCl not reabsorbed from the luminal side
Thiazides are a weak inhibitor of
Too much thiazides = toxicity
- Hypokalemic metabolic alkalosis + hyperuricemia (like loop diuretics)
- Decreased glucose tolerance = hyperglycemia
- hypercalcemia + hyperuricemia
- Paresthesias (tingling)
- allergic rxn
- sulfonamide hypersensitivity
Thiazides can diminish effects of?
Agents used to treat gout
Thiazides increase the effect of
Use thiazides with caution if patient has
B/c thiazides cause hyperglycemia by decreasing glucose tolerance
Taking thiazides with _____ + _______ decreases thiazide efficacy
NSAID + COX2 inhibitor (b/c inhibit PG synthesis)
Use thiazides to treat:
- HTN + HF
- nephrolithiasis (renal stones) by decreasing hypercalciuria
- nephrogenic diabeties inspidus (intense thirst and heavy urination)
Potassium sparing diuretics
Mineralocorticorticoid receptor (aldosterone) antagonist prototype is:
Potassium sparing diuretics
Na channel inhibitor prototype:
How are spironolactone + EPLERENONE inactivated
- Inactivated in liver after several days
- both given orally
What is eplerenone
Analog of spironolactone with greater selectivity for MR
Amilordie + triamterene are given
How is triamterene and amiloride metabolized ? What type of diuretic are they?
Potassium sparing - renal Na channel inhibitor
Triamterene metabolized by liver and has shorter half life
Amiloride not metabolized
MOA of spironolactone + eplerenone (Aldosterone antagonists - potassium sparing diuretic)
MR antagonists = synthetic steroids that act as competitive inhibitors of aldosterone binding MR
MR antagonist reduces NA reabsorption in CD = less K secretion
Which diuretic is the only on that doesnt need access to tubular lumen to induce diuresis?
What does MR regulate?
Na channel (ENaC)
Na/K ATPase in DT + CD
MOA of amiloride + triamterene
Inhibit Na reabsorption by blocking EnaC in apical membrane of CD = less K secretion
Excessive potassium sparing diuretics results in
- metabolic acidosis b/c increased H+ secretion
- gynecomastia, impotence, BPH (since MR antagonists are steroids that can react with other hormone receptors)
Triamterene __________ in the urine and can cause _______.
When combined with ______, it can cause kidney failure
Precipitates; kidney stones
What increases risk of hyperkalemia
Renal disease or use of b-blockers, NSAIDS (reduce renin) or AngII activity (ACEI, or ARBs)
Contraindications for potassium sparing diuretics
- pts with chronic renal insufficiency
- vulnerable to fatal hyperkalemia
- using K sparing diuretics with b-blockers, NSAD, ACEI, ARBs
- pts wtith liver disease = impaired metabolism of spironolactone + amterene
- inhibitors of CYP3A4 = increase blood levels of eplerenone
Clinical indications to use K sparing diuretics
- thiazides + loop diuretics cause secondary hyperaldosteronism = renal wasting of K+ ....so use K sparing drugs to prevent wasting of K
- treat heart failure
Agents that alter water excretion
Osmotic agents, ADH antagonist, ADH, agonists
Example of osmotic agent
- absorbed poorly, so give it via IV
- not metabolized
- excreted in GFR within 30-60 min, but not reabsorbed = promotes water diuresis
Osmotic agents MOA
- Increases osmotic pressure of glomerular filtrate = inhibits tubular reabsorption of H20 + electrolytes = increased urine output
- opposite ADH effect in CD
What does increased water diuresis by osmotic diuretics do?
- increase urine flow rate
- decrease contact time btw fluid + tubular epithelium = less Na reabsorption
Note: natriuresis is less than water diuresis = too much water lost + too much sodium in body (hypernatremia)
too much mannitol causes
Extracellular volume expansion
- b/c too much water extracted from cells
When is mannitol contraindicated
Severe renal disease (anuria)
Severe pulmonary edema or congestion
When to use mannitol? (Osmotic diuretics)
- increase/maintain urine volume
- reduce intracranial/intraocular pressure
ADH agonist causes:
- increased water reabsorption
- increase H20 permeability + reabsorption in CD
ADH agonists are used for?
Pituitary diabetes inspidus
Nocturnal enuresis (urinating)
ADH agonists names
ADH antagonist prototype
Given via? Half life?
- given via IV
- half life is 5-10 hours
ADH antagnoist used for?
- to treat medical conditions (ex. Heart failure, SIADH) that cause water retention b/c too much ADH == hyponatremia
MOA of ADH antagonist
Antagonist of ADH receptors in CD
ADH antagonist toxicity can cause
nephrogenic diabetes inspidus
Why would you combine Loop agents + thiazides ..what does it do
- helps diuresis If usual dose of loop diuretics dont work
Why would one diuretic be not as effective as two diuretics?
- Na/H20 reabsorption in TAL (blocked by loops) or DCT (blocked by thiazides) can increase when other is blocked
- inhibiting both = diuresis
- thiazides produce slight natriuresis in PCT that is masked by increased absorption in TAL
- combo drugs can inhibit Na reabsorption at PCT, TAL, DCT
Why should not use loops and thiazides as outpatient
- significant diuresis!
- K wasting is common
Effect of K sparing + loop/thiazides?
To treat hypokalemia (by preventing K secretion) which is a side effect of loop/thiazides as Na is reabsorbed
Hypokalemia initially managed by restricting NaCl or KCl suppplementation
When should K sparing diuretics + loops be avoided?
For pts with renal insufficiency and ppl getting Ang antagonists
Common use for diuretics
Reduce peripheral or pulm edema
Tx for heart failure, kidney disease + hepatic cyrrhosis
How does pulm or interestial edema occur due to heart failure?
HF decrease CO = decreased bp + decreased RBF = kidney wants to retain Na + H20 = pulm + intersitial edema
When do diuretics help and NOT HELP if pt has kidney disease?
Loss of renal fxn = decreased GFR = natriuresis doesnt occur, so diuretics cant help
- diuretics help with glomerular diseases (SLE or DM) where renal H20/Na occurs
Loop + thiazides are helpful for ppl with ________ when they also have early stage renal failure
When to not use aggressive diuretics?
Liver disease (hepatic cirrhosis)
- though diuretics can help with edema + ascites