Diuretic Agents week 1 Flashcards
Carbonic anhydrase inhibitors:
prototype
target
action
toxicities
uses
contraindications
Carbonic Anhydrase Inhibitors
Target: proximal tubule
Action: Catalyzes the dehydraton of H2CO3 to CO2 at the luminal membrane and rehydration of CO2 to H2CO3 in the cytoplasm, thus blocking NaHCO3 reabsorption. More bicarbonate in urine pulls water into the tubule for a diuretic action. What follows is enhanced NaCl re-absorption by remainder of nephron and loss of diuretic effect over several days.
Prototype: acetazolamide
Side effects:
-hyperchloremic metabolic acidosis – reduction of bicarbonate stores
- decreased diuretic action – bicarbonate depletion leads to more Na+ uptake in the distal proximal tubule
- increases propensity of renal stones – calcium salts are relatively insoluble at high pH and less citrate (Ca solubilizing factors), all favor stone formation.
-hepatic encephalopathy – can be caused in patients with liver disease (see contraindications for explanation)
NH3 toxicity
-Renal potassium wasting due to increased sodium presented to collecting duct, thus increasing K loss.
Paresthesias
Metabolic acidosis- “ACID”azolamide causes ACIDdosis
Sulfa allergy
Uses:
Glaucoma – reduces aqueous humor
Urinary alkalinization – acidic drug(s) or agents such as cystine, uric acid, excretion is enhanced by alkalinization (alkalinization last only 2-3 days).
Mountain (altitude) sickness - ↓CSF production & pH ↓ in CSF increase ventilation rate, countering effects of high altitude and thus reducing symptoms of mountain sickness.
Metabolic alkalosis
Pseudotumor cerebri
Contraindications: because carbonic anhydrase alkalinizes urine it decreases ammonia excretion and may thus result in encephalopathy in patients with liver disease and already elevated serum ammonia (NH4).
Loop diuretics:
prototypes
target
action
toxicities
uses
form(s) admistered in (IV, PO, etc)
Explain diuretic resistance with this class of drugs and how it can be overcome.
Loop Diuretics
Target: TAL (thick ascending limb)
Action: Inhibit Na+/K+/2Cl- transporter
Prototype:
furosemide – smooth muscle vasodilator as well as natriuretic (stimulate PGE release–>vasodilation of afferent arteriole, can be inhibited with NSAIDS)
ethacrynic acid – vasodilator and natriuretic (only non sulfonamide derivative)
bumetanide – action only on Na/K/2Cl transporter, no vasodilation
torsemide – action only on Na/K/2Cl, no vasodilation
Side effects:
hypokalemia
hypokalemic metabolic alkalosis
ototoxicity – especially ethacrynic acid
hyperuricemia – result of diuretic action (decreased urea excretion)
loss of cations - hypomagnesemia + hypocalcemia
sulfur allergy – limits use of all except ethacrynic acid
dehydration – due to groups potency (most
potent group of diuretics) – loss of intra vascular
volume.
OH DANG: Ototoxicity, Hyperkalemia, Dehydration, Allergy (sulfa), Nephritis (interstial), Gout
Therapeutic Uses:
Congestive Heart Failure (CHF) – reduces preload
Edema- due to hepatic & renal dysfunction-cirrhosis, nephrotic syndrome, pulmonary edema
Hyperkalemia – diuretics causes K loss
anion overdose (bromide, fluoride, iodide) increase excretion
Hypercalcemia – increase Ca urine loss and can increase stone formation (in urine)
Availability: IV & oral (IV more effective)
Diuretic Resistance: over time less Na+ loss with increasing doses, diuretic effectiveness can be regained by combining with thiazide.
Clinical Pearl: furosemide plus metolazone is an extremely potent diuretic combination overcoming diuretic resistance.
Thiazides:
prototypes
target
action
toxicities
uses
Which thiazide has effects on more than one part of the nephron? Which thiazide is potent when combined with a loop diuretic?
Thiazides
Target: distal convoluted tubule
Action: blocks Na+/Cl- transporter
Prototypes:
hydrochlorothiazide
indapamide
chlorthalidone
metolazone*
Side effects:
hypokalemia
hypokalemic metabolic alkalosis
hyponatremia
hyperuricemia
hyperglycemia
hypercalcemia
increase LDL cholesterol
sulfonamide reactions – allergy to sulfur in diuretic chemical structure – seen with thiazides
HyperGLUC: hyperGlycemia, hyperLipidemia, hyperUricemia, hyperCalcemia
Uses:
-Hypertension – reduces blood volume, reduces vascular “stiffness” by reducing Na content in vascular tissue.
- Adjunctive therapy in CHF to a loop diuretic (especially metolazone)
- Idiopathic hypercalciuria
Prevents Ca stones (when caused by hypercalciuria) – decrease Ca tubular excretion, so less Ca in urine to form stones. Danger is rise in serum Ca.
-Combined with loop diuretics in diuretic resistant states
Nephrogenic diabetes insipidis
Osteoporosis
*metolazone also increases Na loss in proximal tubule, as well as affecting distal tubule (as with all thiazide diuretics). Most potent agent with loop diuretic resistant states.
K+ sparing diuretics:
prototypes
target
action
toxicities
uses
Potassium-Sparing Diuretics
- Target: late distal and cortical collecting duct
- Action: antagonize the effects of aldosterone
Prototypes:
Spironolactone** & eplerenone: antagonism of aldosterone** receptors
amiloride & triamterene: inhibition of Na+ influx through luminal membrane through ENaC (Na+) channels
Toxicities:
-hyperkalemia – especially by one of drugs above combined with ACE, NSAID that also cause K retention. Always ask if pt has normal renal function and if they are on another drug that cause K retention before prescribing K sparing diuretics. hyperkalemia can lead to arrythmias
-hyperchloremic metabolic acidosis
gynecomastia -spironolactone
triamterene-may give urine precipitate
Uses:
K+ depletion (hypokalemia)
hypertension – reduces blood volume
hyperaldosteronism
- 1° - Con’s syndrome – aldosterone producing adenoma or ectopic –adrenocorticotropic hormone (spironolactone or eplerenone blocks).
- CHF (secondary hyperaldosteronism) –aldosterone levels increased in response to ↓ cardiac output and increased angiotensin release.
Osmotic diuretics:
prototypes
target
action
toxicities
uses
form of administration
Osmotic Diuretics
Target: proximal tubule and descending limb of Henle
Action: Agent given IV is filtered at glomerulus, but not reabsorbed thus osmotically active, pulls in water from extracellular space.
Prototype: IV mannitol
Toxicity:
- extracellular volume expansion – can cause CHF(volume overload).
- Hyponatremia – dilutional (more water dilutes NaCl concentration) so relative hyponatremia and/or hypokalemia.
- hyponatremia (acute) – dilutional (more water dilutes NaCl concentration)
- hypernatremia (late) – volume loss in urine so and Na+ concentration increased. less volume in intravascular space
-Dehydration – water loss
Use: kidney protection – brings more fluid in tubule
- contrast agent toxicity – want to “wash out” tubules.
- rhabdomyolysis – myoglobin – want to “wash out” hemolysis
- hemoglobin tubular toxicity -“wash out” hemoglobin that can precipitate.
- reduction of intracranial pressure –water pulled from brain and CSF to intravascular space and then excreted (used in acute head trauma & stroke).
- acute glaucoma emergency – pulls fluid from vitreous humor, decrease intraocular pressure – osmotic effect
ADH antagonists:
prototypes
target
action
toxicities
uses
ADH Antagonists
Target:
-vasopressin 1a receptor (vasoconstriction)
-vasopressin 2 receptor (antidiuretic) receptors in collecting tubule
Action: vasopressin receptor antagonist
Prototype:
conivaptan – V1a & V2 receptor antagonist
tolvaptan - V2 receptors antagonist
Toxicity:
hypernatremia
nephrogenic diabetes insipidus – tubules permit profound loss of water
Uses:
- inappropriate ADH (SIADH, p. 333 of FA ‘15) which causes a dilutional hyponatremia, so to treat increase tubular fluid by antagonizing the vasopressin 2 receptor – diuretic effect (oppose antidiuretic action of vasopressin), (alternative therapies: lithium and demeclocycline)
- hyponatremia in CHF- reverse the dilutional low Na+
