Diuretics Flashcards
Carbonic anhydrase inhibitors
acetazolamide
osmotics
mannitol
glycerin
isosorbide
urea
Na+/K+/2Cl- Blockers (Loop Diuretics)
furosemide
ethacrynic acid
bumetanide
Na+/Cl- blockers
hydrochlorothiazide
chlorthalidone
indapamide
inhibitors of ENaC
Amiloride
triameterene
Aldosterone antagonists
sprionolactone
epelereone
vasopressin (ADH) antagonists
tolvaptan
conivaptan
What are the two major clinical indications for diuretic therapy
- edematous states
2. hypertension
What are the major edema-causing conditions where diuretics are used
heart failure
pulmonary edema
nephrotic syndrome
hepatic cirrhosis
How is the steady state of the kidney defined?
intake = excretion
How do diuretics change steady state?
They create a new steady state where excretion is increased, to a point, over intake so homeostasis is less body fluid
What is diuretic “braking”
The adaptational effects of diuretic use that prevent endless excretion and volume depletion. Usually through modification of the Renin-Ang and ADH pathways
What is the most effective medication for edematous states?
Loop diuretics
What is the most effective medication for hypertension?
Thiazides (hydrochlorothiazide)
Decrease BP by decreasing cardiac output and decreasing total peripheral resistance (TPR)
What is the main determinant of extracellular fluid volume ECFV?
Na+
Therefore most diuretics aim to decrease EDFV by increasing Na+ excretion
Why prescribe a loop and thiazide combo?
Loop diuretics can be refractory due to compensatory Na+ reabsorption. Thiazides counteract this. However, this combo requires careful hemodynamic monitoring!
What can you do to counteract the K+ wasting of loops and thiazides?
Advise patient to restrict sodium and to take K+ supplements.
If this is not enough, add K+ sparing diuretics
List the major classes of diuretics in order based on their site of action on the nephron: PCT through CD
Carbonic Anhydrase inhibitors: PCT (plus CD)
Osmotic Diuretics: tDLH (plus PT, CD)
Loops (Na+K+2Cl- blockers): TALH
Thiazides (Na+Cl- blockers): DCT
ENaC inhibitors: late DCT, CD
Aldosterone (Mineralocorticoid)Antagonists: late DCT, CD
Vasopressin (ADH) Antagonists: CD
Which diuretics are K+ wasting?
Loops: Furosemide, ethacrynic acid, bumetanide
Thiazides: Hydrocholorothiazide, chlorthalidone (indapamide)
Why doesn’t a patient on diuretics end up looking like a raisin?
Diuretic Braking
What is the MOA of Carbonic anhydrase inhibitors? (Acetazolamide)
They interfere with bicarbonate reabsorption and H+ secretion, thereby decreasing Na+ absorption
Why are carbonic anhydrase inhibitors weak diuretics?
Increased tubular Na+ activates tubuloglomerular feedback (TGF) causing decreased GFR (adenosine causes afferent restriction and renin causes EA relaxation)
What is the effect of carbonic acid inhibitors on Urine and Plasma?
Urine: increased bicarb (alkalinuria), Na+, K+
Plasma: decreased bicarb and H+ (acidemia) and K+, increased Cl- (chloremia)
What are the indications for carbonic acid inhibitors?
Metabolic alkalosis, prophylaxis re respiratory alkalosis from Acute Mountain Sickness, intraoccular pressure, urinary alkalization to excrete acids
What are the adverse effects of carbonic acid inhibitors?
Generally well-tolerated; renal stones due to alkaline pH of urine (Ca++ salts less soluble)
What is the mechanism of action of osmotic diuretics (Mannitol)?
They change the osmotic gradient so less water is reabsorbed. They act like albumin, attracting water, pulling water from the ICF to ECF, from tissues into blood, and then into the tubular lumen.
Does mannitol come in pill form?
No. It is not absorbable in the GI tract so it must be IV
What is the effect of osmotic diuretics in the urine and plasma?
Urine: increased Mg++ (reason not understood)
Plasma: acute: draws fluid into blood causing relative hyponatremia which can cause pulmonary edema, CHF, HA, N/V
Later: draws fluid into lumen causing relative hypernatremia -> hyperkalemia because as cells shrink, relative K+ concentration in cells which exits into plasma
What are the indications for osmotic diuretics?
Intracranial or intra-ocular pressure pre- and post- surgery
acute glaucoma
dialysis disequilibrium
What is the mechanism of action of loop diuretics? (Furosemide, ethacrynic acid)
Inhibit the Na/K/2Cl symporter in the TALH
What are the adverse effects of loop diuretics?
Hypokalemia, hypomagnesia --> arrhythmia Hypocalcemia, hypochloremia Alkalemia Hypotension -> falls re elderly Ototoxicity Hyperuricemia -> gout
Decreased Na/K/2Cl symporter leads to decreased K+ backleak leads to decreased Ca++ and Mg++ reabsorption.
Excess Na+ in lumen -> excess K+ secretion
Excess Cl- in lumen -> excess K+ and H+ excretion
What are the indications for loops?
Decrease morbidity and mortality in HF
Hypertension: first choice re HT with CHF
Edema (pulmonary, cardiac, hepatic)
Acute hypercalcemia, mild hyperkalemia
Acute renal failure (to increase urine flow)
What is the effect of loop diuretics on the urine and plasma?
Urine: increased excreation of ALL IONS: Na+, Cl-, K+, Mg++, CA++ (and HCO3- re furosemide)
Plasma: hypochloremic alkalosis and hypokalemia
Why do loop diuretics cause PROFOUND diuresis?
They also block the Na/K/2Cl channels in the macula densa so they do not sense the increased Na+. They release prostaglandins causing AA dilation causing increased renal blood flow
What is the MOA of the Thiazides?
Inhibition of Na/Cl symport in the DCT
What is the effect of thiazides on the urine and plasma?
Urine: decreased Ca++ excretion, increased K+ and H+ excretion (aciduria)
Plasma: hypokalemia, metabolic alkalosis.
What are the adverse effects of thiazides (and why)?
Hypokalemia –> cardiac arrhythmia
Hypercalcemia, Hyperuricemia
Hypotension
Hyperglycemia (not understood why) -> hyperlipidemia so C/I re DM patients
Less Na+ is reabsorbed to less Ca++ is excreted; more Na+ in lumen causes more K+ excretion -> more H+ excretion -> aciduria and alkalemia
What are the indications of thiazides?
Decreased morbidity and mortality re HF and HTN
First choice for simple essential HTN
CHF, hypercalciuria (to prevent kidney stones)
Nephrogenic diabetes insipidus
What is the MOA of ENaC inhibitors?
Epithelial Na+ Channels (ENaC) in the principal cells in the late distal tubule and CD reabsorb less Na+
What are the side effects of ENaC inhibitors and why?
hyperkalemia (esp re renal failure), kidney stones, acute renal failure (esp with Triamterene with indomethacin)
Less Na+ reabsorption -> less K+ secretion/excretion therefore hyperkalemia
What are the effects of ENaC inhibitors on the urine and plasma?
Urine: decreased K+ and H+ excretion
Plasma: increased K+
What are the indications of ENaC inhibitors?
Amiloride + HCTZ decrease morbidity (strokes) in elderly with HTN
(Decreased stroke risk when added to thaizides and loops due to K+ sparing.)
What is the MOA of aldosterone antagonists? (Spironolactone)
Metabolite is competitive inhibitor for the mineralocorticoid receptor (MR) for aldosterone, so most effective when aldosterone is high.
NOTE: aldosterone in CD and DCT stimulates luminal Na+ (and K+) channels and increases Na/K/ATPas channel expression on the interstitial side, both to absorb Na+
What is the effect of aldosterone antagonists on the urine and plasma?
Urine: decreased K+, mildly increased Na+, Cl- and water excretion
Plasma: hyperkalemia (serum K+ should be monitored even if using K+ wasting diuretics!)
What are the side effects of aldosterone antagonists and why?
Hyperkalemia (especially with ACEIs)
Gynecomastia and menstrual irregularities (antiadrenergic effect)(Spironolactone only - not eplerenone)
What are the indications of aldosterone antagonists ?
Decrease morbidity and mortality in HF in combo with loops or thaizides (due to K+ sparing)
Primary and secondary hyperaldosteronism
Secondary hypertension
What is the MOA of Vasopressin Antagonists? (Tolvaptan, conivaptan, “-vaptans”)
V2 ADH receptor antagonists thereby decreasing aquaporin (AQP2) insertion in the basolateral (not luminal) side of the CD thereby decreasing water reabsorption
What is the effect of vasopressin antagonists on urine and plasma?
Urine: increased volume and decreased osmolarity
Plasma: increased sodium
What are the side effects of vasopressin antagonists and why?
Hypernatremia: less water is reabsorbed so more water excreted without Na+
What are the indications for vasopressin antagonists?
Syndrome of Inappropriate ADH (SIADH)
hyponatremia
