Diuretics Flashcards
What are the potential effects diuretics have on electolytes?
hyponatremia or dehydration
hypo/hyperkalemia through K+ wasting or sparing effects
Ca+ loss or reabsorption (loop diuretics)
hypomagnesemia
Hypokalemic metabolic alkalosis
Hyperchloremic metabolic acidosis
hyperuricemia (competing with uric acid for OAT)
How do diuretics end up excreting too much potassium in the principle cells of the collecting ducts?
The diurtic blocks Na+ transport upstream of the collecting duct which causes increased delivery of sodium to the collecting ducts.
Increased ENaC reabsorption (by aldosterone) which created an electro-negative chemical gradient in the lumen of the duct leading to K+ excretion (negative pulls the pos. K+ in)
Mechanisms of Diuretic K+-sparing effect in the collecting tubules (principle cells)?
Na+ reabsorption is coupled with K+ secretion
ENaC is blocked (blocking the effects of aldosterone - Na+ and water reabsorption) promoting Na+ / water excretion and K+ reabsorption.
clinical uses of diuretics
Edematous states - CHF, hepatic failure w/ fluid retention, plasma protein decrease (hepatic disease, severe burns), cerebral edema, idiopathic cyclic edema, premenstrial edema, and acute kidney injury.
Non-edmatous states - hypertension, diabetes insipidus
drug intoxication - not first line, alkalizes urine
mountain sickness
Acetazolamide
Hypercalciuria
thiazides - causes calcium reabs
hypercalcemia
Furosemide - enhance renal calcium excretion
Potassium wasting diuretics
CA inhibitors
Loop diuretics
thiazide diuretics
K+ sparing diuretics
ENaC Inhibitors
Mineralocorticoid receptor antagonists
CARBONIC ANHYDRASE INHIBITORS - kinetics, MOA
Acetazolamide - et al
Potent reversible inhibitor
There are some that treat glaucoma (eye drops)
IV and Oral, cross BBB, excreted proximal tubule (site of action) mostly unchanged; ∼8–12h
Blocking CA prevents formation of CO2 and H2O from carbonic acid increases Na+, HCO3- and water excretion.
Effects of Carbonic Anhydrase Inhibitors
Acetazolamide
Weak diuretics, self-limited
-due to compensatory effects of metabolic acidosis where the body decreases filtered HCO3- which in turn enhanced NaCl reabsorption
Increase Urine pH and decrease body pH (mild acidosis)
Hemodynamic effects => decreased renal blood flow and GFR (by way of TG feedback)
Clinical Applications of CA Inhibitors
Acetazolamide
Glaucoma, open-angle: ↓ Rate of aqueous humor
formation
Urinary alkalinization: Solubilization of uric acid, cystine stones
Metabolic alkalosis
Acute mountain sickness: ↑ Ventilation
Epilepsy: antiseizure activity- mild acidosis
Edema - low efficacy
Adverse Effects of and Contraindications of CA Inhibitors
AEs ===> Metabolic acidosis, renal stones, renal K+ wasting, paresthesia, somnolence, ataxia, headache
hypersensitivity - sulfonamide allergy
contraindications:
Hypersensitivity, acidosis, severe renal disease, cirrhosis/severe hepatic disease
(They decrease excretion of ammonium which leads to hyperammonemia, as does cirrhosis, too much NH3 => cerebral encephalopathy.)
Drug interactions of CA inhibitors
CA inhibitors may reduce the excretion rate of weak organic bases, such as amphetamines and quinidine
Drugs that block secretion of CA inhibitor into the proximal tubule
Topiramate, zonisamide => contribute to formation of renal stones and metabolic acidosis.
LOOP DIURETICS - Pharmkin, MOA
Furosemide; oral, IV, IM; short half life
MOA - blockade of the Na+-K+-Cl- symport in the thick ascending limb. (this symport brings the ion out of the urine and into the cell/blood/interstitium) Increases Na+ excretion and decreases medullary osmolarity increasing urine output. (blocking kidney’s ability to concentrate urine)
Highly efficacious diuretic - TAL reabsorbs 25% of all filtered Na+ load.
Furosemide rapidly reduces preload - mediated by prostaglandins.
requires intact kidneys
Effects of Loop Diuretics
Profound ↑ Na+-Cl– excretion
Marked ↑ Mg2+ and Ca2+ excretion
↑ K+ and H+ secretion in collecting tubultes
↓ Uric acid excretion
Increase body pH
Stimulate renin release (powerful)
Furosemide resistance
Resistance is through compensatory mechanism like activation of ANA or RAAS
Decreased BP decreases pressure natriuresis
system may also increase renal epithelial cell transporter expression or make more cells (renal cell epithelial hypertrophy)
all leading to increase sodium reabsorption elsewhere in the nephron and diuretic resistance
called the diuretic braking phenomenon.
Blocking secretion of loop diuretic into the proximal tubule
Short half-life can lead to a post-diuretic Na+ retention
Clinical Applications of Loop Diuretics
Acute pulmonary edema
↑ venous capacitance + natriuresis →↓ LV pressure → relieves pulmonary edema
Chronic congestive heart failure
↓ ECF volume ⇒ minimizes venous and pulmonary congestion
Nephrotic syndrome (edema secondary to salt and water retention) avoid intravascular volume depletion
Ascites of liver cirrhosis - adjunct use
Chronic kidney disease - higher doses required
Acute Kidney Injury - not for prolonged therapy
Can be used for but not perferred — hypertension, OD, hyperCa2+
Adverse Effects of loop diuretics
Furosemide
abnormalities of electrolytes – hyponatremia, hypokalemia, hypomagnesemia,
ototoxicity, hyperuricemia
hypersensitivity
avoid in pregnancy
Drug Interactions involving Loop Diuretics
Furosemide
thiazide - synergistic
anti-HTN - enhanced effects
ACE inhibitors or ARBs - NEPHROTOXICITY by vasodilation
Lithium - enhanced Na+ excretion can lead to lithium toxicity
Digitalis glycosides => hypokalemia => arrhythmias
quinidine/ QT prolonging drugs + diuretic-induced hypokalemia = increased risk of torsades de pointe
Antidiabetic agents - impaired glucose control
probenecid, NSAIDs - blunted effects of diuretic
gucocorticoids, amphotericin B, - hypokalemia
aminoglycosides and cisplatin - ototoxicity and nephrotoxicity
THIAZIDE DIURETICS – Pharmanokinetics, MOA
Na+-Cl– Cotransporter (NCC) Inhibitors
Hydrochlorothiazide
-oral, 2 hour onset, 6-12 duration
Chlorthalidone
-oral (2hr), IV (15min); short half life
↑ Na+ and Cl– excretion and moderate diuresis
transporter is upregged by aldosterone. Found in DCT
Thiazide action depends in part on renal prostaglandin
Effects of Thiazide Diuretics on Na+, Cl–, K+, H+
↑ Excretion of Na+ and Cl-
(Moderate)
↑ Excretion of K+ and H+ (Flow-dependent enhancement of ion secretion, RAAS activation, inc Na+ load to DCT)
Effects of Thiazide Diuretics on uric acid, Ca2+, Mg2+
Inhibition of Na+-Cl− cotransporter
Decrease uric acid secreation
decrease Ca2+ excretion
increase Mg2+ excretion
attenuate kidney’s ability to excrete dilute urine but not to concentrate
Clinical uses for thiazide diuretics
Edematous states – CHF, hepatic cirrhosis, nephrotic syndrome, chronic renal failure, acute glomerulonephritis
Hypertension - causes modent dec in intravascular vol.
=> Hydrochlorothiazide, most used
=> Chlorthalidone, much longer half-life
Moderate restriction of dietary Na+ intake (60-100mEq/d)
Nephrolithiasis: ↓ Ca2+ excretion
Nephrogenic diabetes insipidus
Potential Adverse Effects of thiazide diuretics
Extracellular volume depletion
hypotension
hyponatremia
hypokalemic metabolic alkalosis
hypomagnesemia
hypercalcemia
hyperuricemia/gout
hyperglycemia and hyperlipidemia
hypersensitivity
generally not given to pregnant patients
Drug interactions of thiazide diuretics
Digitalis glycosides and dofetilide => hypokalemia => arrhythmia
Lithium - increase Li+ reabsorption and toxicity
synergystic with loop diuretics and anti-hypertensive drugs
Vit D analogs - pot. enhancment of hypercalcemic effects
blunt the effects of the antidiabetic agent
probenecid - competition
Drugs that may decrease the effectiveness of thiazide diuretics
NSAIDs
-blunted diuretic response
Bile acid sequestrants
=> hypokalemia and nephrotoxicity
(↓ Absorption of thiazide diuretics)
ENaC Inhibitors
Renal Epithelium Na+ Channel inhibitors - Amiloride
Oral, 2hr onset, 24 hr action
blocks channel => messes potential difference (Na+,K+-ATPase function) => K+ sparing and Na+ ditching
H+, Ca2+, and Mg2+ also reabs (decrease body pH)
Therapeutic uses for ENaC Inhibitors
ENaC inhibitor + thiazide diuretic for enhanced diuresis and to counteract K+ loss
adjunct
hypertension or edema
Li+ induced nephrogenic diabetes insipidis (prevents the transportation of Li+ into the principle cell and thus promotes it’s excretion)
Liddle syndrome - ENaC inhibitor + sodium restriction for Tx of hypertension and hypokalemia
Adverse Effects of ENaC Inhibitors
hYPERKALEMIA
Risk factors – old age, high dose, renal impairment, hypoaldosteronism
Drug Interactions –
ACEI / ARB: ↓aldosterone secretion → ↑ K+ reabsorption → risk of hyperkalemia
NSAIDs: ↓ PG-dependent renin release → leads to ↓ANG II-mediated aldosterone secretion → ↑ K+ reabsorption → risk of hyperkalemia
K+ supplements or Salt-substitutes
Mineralcorticoid Receptor Inhibitors
Spironolactone or Eplerenone
Oral, Eplerenone has CYP3A4 metabolism, spironolactone undergoes enterohepatic circulation
competitively inhibit binding of aldosterone to the MR
Spironolactone has antiandrogenic effects (gynecomastia, impotence, low libido) Eplerenone does not have these effects
Therapeutic Uses of Spironolactone and Eplerenone
Edema and hypertension (w/ thiazide or loop diuretic)
Resistant hypertension due to primary aldosteronism (adrenal adenoma, bilateral adrenal hyperplasia)
heart failure due to left ventricular systolic dysfucntion - shown to reduce mortality
hepatic cirrhosis - spironolactone
refractor edema associated with secondary aldosteronism
Acne / hirsutism in women
Adverse Effects of mineralcorticoid antagonists
Both - hyperkalemia, not for use in pregnancy
Spironolactone - gynecomastia, impotence
avoid in pregnacy in first trimester
Drug Interactions of MR Inhibitors
Drugs that increase serum potassium:
K+ supplements, ACEI / ARBs, NSAIDs, k+ diuretics
Spironolactone - decreases digoxin clearance and toxicity
Eplerenone - CYP3A4 inhibits (Grapefruit)
Mannitol
osmotic diuretic
distributed in EC fluid; onset in 1-3 hours, reduction of EC fluid in 15-30 minutes, ICP in 1.5-6 hours.
Extracts water from ECF and increases urine volume and promotes electrolyte excretion
Given by bolus - to avoid accumulation in brain
Therapeutic Uses of Mannitol
Acute increase in intracranial pressure with edema or intraocular pressure
Adjunct to cisplain to minimize nephrotoxicity
(increases osmotic pressure of plasma → water shift out of brain parenchyma / eye tissue)
AEs or cautions of Osmotic Diuretics
ECF expansion => HF complication is pulmonary edema
hypernatremia - in patients with severe renal inpairment
Dehydration and electrolyte imbalance
Nephrotoxicity - especially in high doses
Contraindications of Mannitol use
Allergy
severe dehydration
severe renal disease
renal dysfunction following mannitol administration
active cranial bleeding
progressive heart failure
severe pulmonary edema / congestion
