Diuretics Flashcards
Classes of diuretics and conditions they are used for
Thiazide diuretics (HTN, edema)
K+ sparing diuretics (HTN, edema)
Loop diuretics (HTN, edema)
Aquaretics (hyponatremia)
Carbonic anhydrase inhibitors (urinary alkalinization, mountain sickness, glaucoma)
Osmotic diuretics (maintain urine flow, pull water from cells for excretion)
3 drugs in thiazide diuretic class
Hydrochlorothiazide
Metolazone
Chlorthalidone
4 drugs in loop diuretic class
Furosemide
Torsemide
Bumetanide
Ethacrynic acid
Drugs in K+ sparing diuretic class
Na+ channel blockers:
Amiloride
Triamterene
Aldosterone antagonists (also used as antifibrotics in heart failure): Spironolactone Eplerenone
2 drugs in aquaretic diuretic class
Conivaptan
Tolvaptan
Carbonic anhydrase inhibitor diuretic used for urinary alkalinization, mountain sickness, and glaucoma
Acetazolamide
Osmotic diuretic used to maintain urine flow
Mannitol
Site of action of osmotic diuretics
Proximal tubule
Thin descending LoH
Site of action of carbonic anhydrase inhibitor diuretics
Proximal tubule
Site of action of loop diuretics
Thick ascending LoH
Site of action of thiazide diuretics
Distal convoluted tubule
Site of action of Na+-channel blocker Spironolactone
Cortical collecting duct
Site of action of the Vaptans (aquaretics)
Collecting duct [site of ADH-regulated water reabsorption]
K+ losing diuretics
NaCl cotransporter blockers = thiazides
Na+K+2Cl cotransporter blockers = loop diuretics
Carbonic anhydrase inhibitors (seldom used)
Nonreabsorbable solutes: osmotic diuretics
Effects of hyperkalemia on the heart
Tall T waves Prolonged PR interval Widened QRS Arrhythmias including bradycardia, Vtach, fibrillation Sinus arrest or nodal rhythm
Effects of hypokalemia on the heart
Flattened T waves ST depression Prolonged QT Tall U waves Atrial arrhythmias Vtach or Vfib
Which of the diuretics contain sulfa?
Furosemide
Torsemide
Bumetanide
MOA of furosemide
Directly inhibits reabsorption of Na and Cl in thick ascending LoH by blocking Na/K/2Cl cotransporter
Indirectly inhibits paracellular reabsorption of Ca and Mg by the TAL d/t loss of K+ backleak responsible for lumen+ transepithelial potential
Effects of furosemide (what gets excreted?)
Increased excretion of water, sodium, potassium, chloride, magnesium, and calcium
Clinical applications of furosemide
Management of edema associated with heart failure, hepatic disease, or renal disease
Acute pulmonary edema by decreasing preload (decreases EC volume, rapid dyspnea relief)
Tx of HTN (alone or combined with other hypertensives) — note that unlike thiazides, works in pts with low GFR
Potential toxicities associated with furosemide
Hypokalemia Hyponatremia Hypocalcemia Hypomagnesemia Hypochloremic metabolic alkalosis Hyperglycemia Hyperuricemia (increased gout risk) Increased cholesterol and triglycerides Ototoxicity
Risk of sulfonamide hypersensitivity/allergy
Loop diuretic that works similarly to furosemide but with longer half-life, better oral absorption, and some evidence that it works better in heart failure
Torsemide
Loop diuretic that is a sulfonamide working similar to furosemide, but more predictable oral absorption
Bumetanide
Non-sulfonamide loop diuretic reserved for those with sulfa allergy
Ethacrynic acid
Loop diuretics can be used for HTN that is unresponsive to other diuretics; unlike thiazides, they still work when ____ and ____ are low
RBF; GFR
MOA of HCTZ
Inhibits sodium reabsorption in the distal tubules via blockade of Na/Cl cotransporter
Results in increased urine excretion of Na and H2O as well as K+ and Mg++ [potassium-losing diuretics]
Clinical applications of HCTZ
Management of mild-to-moderate HTN alone or in combo with other hypertensives (note: not effective in those with low GFR)
Treatment of edema (adjunct role)
Off-label: calcium nephrolithiasis, nephrogenic diabetes insipidus
Toxicities associated with HCTZ
Orthostatic hypotension Hypokalemia Hypomagnesemia Hyponatremia Hypochloremic metabolic alkalosis Hypercalcemia Hyperglycemia Hyperuricemia
Risk of sulfonamide allergy
Thiazide similar to HCTZ, but half-life of 40-60 hours allowing for prolonged/stable response with proven benefits
Chlorthalidone
Long-acting thiazide diuretic that is favorite of cardiologists for use as an adjunct diuretic in the tx of CHF
Metolazone
MOA of amiloride
Blocks epithelial sodium channels (ENaC) in the CDs responsible for Na/K exchange
Causes small increase in Na excretion, blocks major pathway for K elimination so K+ is retained
H, Mg, and Ca excretion are also indirectly decreased
Clinical applications of amiloride
Counteracts K+ loss induced by other diuretics in the tx of HTN or heart failure
Off-label: ascites, pediatric hypertension
Toxicities associated with amiloride
Hyperkalemia (box warning) Hyponatremia Hypovolemia Hyperchloremic metabolic acidosis Dizziness, fatigue, headache N/V, bloating, diarrhea, constipation
_____ = used similar to amiloride for edema and off-label for HTN, rapidly absorbed, duration of action is 6-9 hours, eliminated as drug metabolites
Triamterene
MOA of spironolactone
Competitive antagonist of aldosterone receptors, decreases aldosterone stimulated gene expression
Side effects due in part to it being a partial agonist at androgen receptors
It is a K+ sparing diuretic that blunts ability of aldosterone to promote Na/K exchange in the CDs
Clinical applications of spironolactone
Counteracts K+ loss induced by other diuretics in tx of HTN, heart failure, and ascites
Tx of primary hyperaldosteronism
Off-label: reduce fibrosis post-MI heart failure, hirsutism, tx of androgenic alopecia in females
Onset and duration of action of spironolactone
Has steroid-like effects, thus it is slow onset and long-duration of action
Toxicities associated with spironolactone
Hyperkalemia
Amenorrhea, hirsutism, gynecomastia, impotence
Tumorigen in chronic animal toxicity studies — box warning states to avoid use unless necessary
Similar to spironolactone but more selective aldosterone antagonist, approved for use in post-MI heart failure and alone or in combo for HTN
Eplerenone
Drug interactions to be aware of with K+ sparing diuretics
Should “never” be given with drugs that increase plasma potassium levels….but note that they may be used cautiously with ACE inhibitors in heart failure
MOA of conivaptan
Non-peptide arginine vasopressin receptor antagonist (AVP aka ADH antagonist); has affinity for ADH receptor subtypes V1A and V2
Promotes excretion of free water (decreased Uosm, increased Posm)
Clinical applications for conivaptan
Tx of euvolemic and hypervolemic hyponatremia in patients who are hospitalized, symptomatic, or not responsive to fluid restriction
Toxicities associated with conivaptan
Orthostatic hypotension
Fatigue
Thirst
Polyuria, bedwetting
Monitor plasma sodium and neurologic status closely because too rapid serum sodium correction can lead to seizures, osmotic demyelination, coma, or death
Selective V2 receptor antagonist admistered orally
Tolvaptan
What are some important considerations when choosing to use Tolvaptan for diuresis?
Used ONLY in hospital setting where plasma sodium can be closely monitored
Must use for less than 30 days for hyponatremia — longer use can lead to potentially fatal hepatotoxicity (used to slow progression of adult polycystic kidney dz but must monitor liver tests)
MOA of conivaptan (IV) and tolvaptan (PO)
Increase free water clearance by preventing ADH-mediated insertion of aquaporins into luminal membrane of principal cells in collecting duct
[prevents reabsorption of water, therefore increasing water excretion —> decreased plasma volume and increased plasma osmolality, primarily d/t increase in plasma sodium concentration]
Adverse effects of the “vaptans”
Orthostatic hypotension
Fatigue
Thirst
Polyuria, bedwetting
Hypernatremia, hyperkalemia, hyperuricemia
Drug interactions to consider with the “vaptans”
Metabolized by CYP3A4, so inhibitors and inducers of this enzyme can alter its half-life and potential for toxicity
Selective water loss means possibility of hypovolemia which may increase concentration of drugs leading to toxic levels
Prototypical carbonic anhydrase inhibitor developed from a sulfonamide after it was discovered to cause metabolic acidosis and alkaline urine
Acetazolamide
MOA of carbonic anhydrase inhibitors
Na+ bicarbonate diuresis
[bicarbonate ion remains in early proximal tubule, H+ cycling lost — inhibiting Na/H exchange]
Carbonic anhydrase inhibitors are now rarely used for diuresis. What are some therapeutic uses still recognized?
Urinary alkalinization
Metabolic alkalosis
Glaucoma: acetazolamide, dorzalamide
Acute mountain sickness
Adverse effects of carbonic anhydrase inhibitors
Hyperchloremic metabolic acidosis
Nephrolithiasis
Potassium wasting
What type of diuretics can be used to help eliminate excess intracellular volume?
Osmotic diuretics
Prototypical osmotic diuretic and its MOA
Mannitol (can also use urea, glycerin, and isosorbide)
MOA: the inability to reabsorb mannitol keeps water in the PT lumen; this water is delivered to the distal portions of the nephron where much of it is excreted
Mannitol acts throughout the body to pull water out of the cells with net effect of TBW excretion in excess of plasma electrolytes
Pharmacokinetics of mannitol
Distributes in ECF, must give IV in large amounts sufficient to raise its osmolality (e.g., 50-200g over 24 hours)
Effects noticable w/i 30-60 mins, and is fully eliminated unchanged in urine over period of 6-8 hours
Adverse effects of osmotic diuretics
ECV is acutely increased because mannitol sucks water out of cells, which can exacerbate heart failure
HA, nausea, vomiting, and fluid/electrolyte imbalances also occur
Therapeutic uses of mannitol
Prophylaxis of renal failure (keeps some fluid volume in tubules to prevent them from collapsing when glomerular filtration rate is very low)
Reduction of intracranial pressure
Reduction of intraocular pressure when no response to other therapies
What is important to remember about alternative medicines used for diuresis?
While some have been shown to be effective, active ingredients and MOAs are generally unknown — should not be mixed with conventional diuretics
What’s the deal with European licorice?
European licorice contains glycyrrhizic acid which potentiates aldosterone effects in the kidney in dose-dependent manner, increasing systolic BP
Diuretic therapy algorithm for edema caused by renal insufficiency or nephrotic syndrome
Start with loop diuretic
Add thiazide if needed
Add distal diuretic drug if ClCr > 75 mL/min, for K+ homeostasis, or for added natriuresis (if urinary excretion of sodium is decreased and urinary excretion of potassium is increased)
Diuretic algorith for edema caused by cirrhosis
Start with spironolactone
If ClCr > 50 mL/min, add HCTZ
If ClCr is < 50 mL/min, add a loop diuretic (can subsequently add thiazide then distal diuretic drug)
Diuretic therapy algorithm for edema caused by cardiac disease (CHF)
If mild disease, with ClCr > 50 mL/min, start with HCTZ
If more severe disease, start with loop diuretic, then add thiazide, then distal diuretic
Common causes of diuretic resistance
Incorrect dx
Inappropriate NaCl or fluid intake
Inadequate drug reaching tubule lumen in active form
Inadequate renal response
What are some causes of inadequate diuretic drug reaching tubule lumen in active form?
Nonadeherence
Dose inadequate or too infrequent
Poor absorption (uncompensated HF)
Decreased RBF (HF, cirrhosis, elderly)
Decreased functional renal mass (AKI, CKD, elderly)
Proteinuria
What are some causes of inadequate renal response to diuretics?
Low GFR (AKI, CKD)
Decreased effective arterial volume (edematous conditions)
Activation of RAAS (edematous conditions)
Nephron adaptation (prolonged therapy)
NSAIDs (e.g., Indomethacin, ASA)
Tx of central diabetes insipidus
Exogenous ADH agonist (dDAVP)
Desmopressin
Tx of nephrogenic diabetes insipidus
If NOT caused by Lithium —> tx with thiazide diuretics
Lithium therapy is MCC of nephrogenic DI, when lithium is the cause —> tx with amiloride
