Diuretics Flashcards
Most diuretics exert effects at ___ of renal tubule cells
luminal (urine) surface
Mechanisms of actions for diuretics include
- Interactions with membrane transport proteins–(thiazides, furosemide, triamterene)
- Interactions with enzymes– (acetazolamide) or hormone receptors– (spironolactone)
- Osmotic effects preventing water reabsorption– (mannitol)
___ is the major extracellular cation and its movement is controlled by ___
Na+
regulated activated transport via Na-K ATPase
how do diuretics affect Na+
decrease Na+ reabsorption at various sites in the nephron
*increased amounts of Na+ (and other ions) enter urine with H2O passively to maintain osmotic equilibrium
***THEY DO NOT INHIBIT NA/K ATPase!!!!
What are the diuretics of choice to treat hypercalcemia
saline infusion +/- loop diuretics
The most
useful diuretic agent in the treatment of recurrent
calcium stones (hypercalcuria) is
hydrocholorthiazide
What are the diuretics of choice to treat Edema from HF
loop of henle agents
osmotic agents-mannitol, ADH antagonists
What are the diuretics of choice to treat HTN
thiazides
What are the diuretics of choice to treat refractory edema
loop + thiazide
What are the diuretics of choice to treat alkalosis
Carbonic anhydrase inhibitors (acetazolamide)
What diuretics can have a side effect of causing arrhythmias
- loop of henle agents
- thiazides
- loop + thiazides
(–1-3 decrease K+) - aldosteron antagonists and Na channel blockers (increase K+
What diuretics have a side effect of causing gout?
- loop of henle agents
- thiazides
*increase uric acid
What diuretics can cause high K+
Aldosterone antagonist (spironolactone)
**K+ sparing
(lisinopril can also cause high K+)
what is reabsorbed in the proximal convoluted tubule
Almost all of
- glucose,
- amino acids,
- NaHCO3, and
- other metabolites are reabsorbed here.
- 60-70% of Na+ reabsorbed
- (Cl- and H2O follow passively)
Where/how do Carbonic anhydrase inhibitors work?
inhibit carbonic anhydrase (CA) enzyme in the proximal convoluted tubule, which results in retention of HCO3- in urine (Lumen) with mild alkaline diuresis
What kind of diuresis do carbonic anhydrase inhibitors create?
alkaline diuresis (retained HCO3- in urine)
What diuretics are carbonic anhydrase inhibitors
“-amides”
- Acetazolamide
- Dorzolamide*
- Brinzolamide*
*available topically to avoid systemic complications
What are the clinical uses of carbonic anhydrase inhibitors
- chronic management of open angel glaucoma (decrease aqueous humor production and IOP)
- urinary alkalinization
- chronic metabolic alkalosis
- acute mountain sickness
*infrequent use as a diuretic agent (NOT USED IN HF!!)
What diuretic inhibits formation of aqueous humor and CSF that is dependent on HCO3- transport?
carbonic anhydrase inhibitors
What diuretics are commonly used for chronic open angel glaucoma
- Dorzolamide
- Brinzolamide
*available topically to avoid systemic complications
(carbonic anhydrase inhibitors)
how do CA inhibitors tx acute mountain sickness
slows progression of pulmonary or cerebral edema (via decrease in formation of CSF and pH of CSF)
What are adverse drug reactions of CA inhibitors
Minor
- loss of appetite
- drowsiness
- confusion
- tingling in extremities
- hypersensitivity rxns
- hyperchloremic metabolic acidosis
- renal stones (via increase in urinary pH)
- K+ wasting
What are the loop diuretics
- Furosimide
- Bumetanide
- Torsemide
- ethacrynic Acid
What are osmotic diuretics
Mannitol
Where/How do osmotic diuretics work?
diuretic osmotic action limits H20 reabsorption renal segments permeable to water:
- Proximal tubule
- Descending loop of Henle 3. Collecting tubule
**Does not affect Na+ reabsorption
Describe the transport of ions and water in the loop of henle (descending and ascending limbs)
- Descending limb: water removal as a result of hypertonic osmotic forces (HCO3-, glucose, osmotic diuretics)
- Ascending limb: impermeable to H20, but active NaCl reabsorption via Na/K/2Cl cotransport
- leads to excessive intracellular K+ which then diffuses back into urine which drives the reabsorption of Mg2+ and Ca2+ back into the blood
Where/how do loop diuretics work?
inhibit NaCl transport (Na/K/2Cl transporter) in the thick ascending loop
- this increase Mg and Ca excretion and
- increased renal blood flow via RA and prostaglandin system
What effect to loop diuretics have on electrolytes?
Decrease K+, H+, Ca2+, Mg2+
increase: uric acid
a decrease in Na+ reabsorption at the thick ascending loop by loop diuretics means more Na+ at collect tubule, ultimately this results in _____
more K+ and H+ loss –> hypokalemic metabolic alkalosis
What effect to CA inhibitor diuretics have on electrolytes?
decrease: K+ (a little), and HCO3- (A LOT)
what diuretic works extremely fast with IV
furosemide
What loop diuretics have the following duration of effects:
2-3 hrs:
4-6 hrs:
6 hrs:
2-3 hrs: furosemide
4-6 hrs: torsemide
6 hrs: bumetanide
What are the uses of loop diuretics
- CHF** (enhanced w/ salt restriction, less than 2g/day)
- acute pulmonary edema
- refractory edema
- hypercalcemia
Patients with HF have reduced diuretic response (ie. to loop diuretics) related to:
- decreased drug delivery to kidney due to
- decreased RBF and
- hypoperfusion activation of RAAS and SNS
What is the preferred diuretic class because of greater efficacy
loop diuretics
how do loop diuretics help treat acute pulmonary edema
- rapid reduction in ECF and venous return
2. hemodynamic response via decrease in RV output and pulmonary vascular pressure
what diuretic is used for refractory edema. Used if no response to Na+ restriction or thiazide diuretic - especially useful if renal disease and fluid overload present.
loop diuretic
Why are loop diuretics given with a saline infusion when treating hypercalcemia?
to prevent ECF volume depletion
describe the use of low vs high ceiling diuretics
High-ceiling (loop): higher dose for severe CHF and oliguria
low-ceiling (low dose thiazides): lower dose for HTN and mild CHF
What are adverse reactions of loop diuretics
- hypokalemic metabolic alkalosis (due to increased K+ and H+ loss)
- hyperuricemia– may precipitate a gout attack
- hypomagnesemia
- hypocalcemia
- Ototoxicity (ethacrynic acid)
- OD- rapid blood volume depletion- dizziness, HA, orthostatic hypotension
there is a higher incidence for ototoxicity with ethacrynic acid (loop diuretic) with:
diminished renal fxn and concomitant aminoglycoside (AG) Abx
hypokalemic metabolic alkalosis (often seen with loop diuretics) predisposes a patient to
- ectopic pacemakers and arrhythmias
- weakness
- paretheasias
describe the transport of ions and water in the distal convoluted tubule
- relatively impermeable to H20
- NaCl reabsorption via Na/Cl cotransporter
- active Ca2_ reabsorption via Na/Ca exchanger (regulated by PTH)
Where/how do thiazide diuretics work?
inhibits NaCl cotransporter in the distal convoluted tubule which increases urinary excretion of NaCl
*INCREASE reabsorption of Ca2+ (unlike loop diuretics which decrease it)
a decrease in Na+ reabsorption at the distal convoluted tubule with thiazide diuretics means more Na+ at collect tubule, ultimately this results in _____
more K+ and H+ loss –> hypokalemic metabolic alkalosis
What are thiazide diuretics
- hydrochlorithiazide
2. chlorthalidone
What effect do thiazide diuretics have on electrolytes?
- decrease K+
- decrease H+
- INCREASE ca2+
- increase uric acid
describe the PK of thiazide diuretics
best to take early in day
HCTZ: 2x/day
chlorthalidone: 1x/day
Uses of thiazide diuretics
- Hypertension
- CHF
- Hypercalciuria (renal stones)
- refractory edema
how do thiazides work to treat hypertension?
counters Na/H20 retention seen with vasodilator use
-moderate reduction in circulatory volume-possible vasodilating effect on vascular smooth muscle
Reduced urinary excretion of Ca++ decreases incidence of kidney stones
hypercalciuria
adverse reactions for thiazide diuretics
- hypokalemia (ectopic pacemakers)
- hyperglycemia (impaired carb tolerance)
- hyperuricemia (gout)
- hyperlipidemia (if used to long-term for HTN)
- volume contraction may lead to secondary hyperaldosteronism
- allergic rxns: skin rashes (sulfonamide structure)
What are sodium channel blockers diuretics
Amiloride
Triamterene
What are aldosterone receptor antagonist diuretics
Spironolactone
Eplerenone
describe the movement of ions in the collecting tubule
- Na+ is driven into the cell exceeds that of K+ leaving
- Cl- is driven into cells
- K+ is driven out of cells
*K+ excretion is coupled to Na+ reabsorption
____, through effects on gene transcription, increases the number and activity of both Na+ (ENaC) and K+ membrane channels and the Na+-K+-ATPase in the collecting tubule
Aldosterone
How/where do sodium channel blockers and aldosterone receptor antagonist diuretics work?
decrease Na+ reabsorption and decrease K+ excretion in the collecting tubule:
- by being a competitive antagonist at aldosterone recepto–> blocks synthesis of Na and K channels- Na/K ATPase
and
-blocking the Na channels on collecting duct lumen to decrease Na reabsorption
Direct effect to block the Na+-channels on collecting duct lumen to decrease Na+ reabsorption (and thus decreases coupled K+ secretion)
Triamterene / Amiloride
K+ excretion is loosely coupled to Na+ reabsorption, describe how this affects K+ with different diuretics
loop-thiazide: blocks proximal Na reabsorption–> increase K+ excretion (HYPOkalemia- K+ wasting)
Diuretics that block collecting tubule (aldosterone antagonists/Na channel blockers) Na reabsorption receptor–> decrease K excretion (HYPERkalemia- K sparing)
No utility in HF - do not block pro-fibrotic actions of
aldosterone
Triamterene / Amiloride
Uses of Spironolactone
- CHF (blocks aldosterone receptors on heart rather than kidney)
- block anti-remodeling action in CHF caused by alderosterone on the heart (hypertrophy and fibrosis)
- primary hyperaldosteronism, hypokalemia
- HTN (in combo w/ thiazides)
- Hirsutisim of PCOS (block androgen receptor)
Uses of Eplerenone
- CHF if spironolactone not tolerated,
2. HTN
Uses of Triamterene/Amiloride
- edema of secondary hyperaldosteronism
2. HTN (with thiazides)
What are the adverse reactions of K+ sparing diuretics?
- Hyperkalemia–> conduction abnormalities, arrhythmias
- Gynecomastia (not w/ eplerenone)
- mild: GI upset, drowisness
the risk of hyperkalemia w/ K+ sparing diuretics are increased by:
- increasing age
- underlying renal dysfunction
- higher doses
- combo use of ACEI or ARB
- use of NSAID analgesics
Uses of Mannitol
- increase urine volume in ACUTE renal failure
- reduce ICP rapidly in acute head injury
- reduce intraocular pressure acutely in glaucoma
How does mannitol reduce ICP rapidly in acute head injury
via decrease in extracellular volume
-can’t cross BBB–> edema fluid moves into plasma compartment via osmotic action of mannitol
adverse reactions of mannitol
- expansion of ECF in periphery leading to initial HYPOnatremia as acute effect
- HA
- N/V
- Dehydration and hypernatremia w/ chronic excessive use w/o water replacement
-Rapid distribution of mannitol to ECF moves H
ICF diluting extracellular Na+ -Additionally this in ECF volume can complicate CHF
and produce pulmonary edema
mannitol
