Diuretics Flashcards
Edematous states caused by abnormal renal function
Heart failure
Hepatic ascites
Nephrotic syndrome
Premenstrual edema
Non-edematous states caused by abnormal renal function
Hypertension
Hypercalcemia
Diabetes insipidus
Loop diuretics MOA and actions
Furosemide
‘High-ceiling diuretic’ = has most dramatic effect on urine output. Highest efficacy in removing Na+ and Cl- from body
Acts on thick ascending limb of Loop of Henle –> blocks NKCC2 Na+/Cl-/K+ triple co-transporter –> normal K+ secretion from ROMK blocked too as there is no K+ reabsorption –> negative lumen potential causes paracellular secretion of Na+, Mg2+ and Ca2+
Actions:
- Increased urinary excretion of Na+, K+, Ca2+ and Mg2+
- Increased prostaglandin synthesis (induces COX2)
- Decreased renal vascular resistance (due to PG)
- Increased renal blood flow
Loop diuretics clinical applications and PK
Diuretics of choice for managing edema associated with heart failure, hepatic or renal disease
Hypertension (moderate-severe) - 2nd/3rd line
Oral and IV
Short half life = 2-4h
Loop diuretics AE
Ototoxicity
Hypokalemia - Increased Na+ delivery to distal tubule –> reabsorb Na+, increased secretion of K+
Hyperuricemia - competition of secretion system transporters in PCT
Acute hypovolemia
Hypomagnesemia
Hypocalcemia
Allergic reactions
Contraindication: sulfur allergy
Thiazides MOA and actions
Hydrocholothiazide
Chlorthalidone
Metolazone
Act on DCT –> block NCCT Na+/Cl- cotransporter –> decreased Na+ reabsorption so activity of Na+/Ca2+ exchanger on basolateral side is enhanced –> Pulls and reabsorbs Ca2+ from urine
Actions:
- Increased urinary excretion of Na+, Cl-, K+, Mg2+
- Decreased urinary excretion of Ca2+
- Decreased peripheral vascular resistance –> initially due to decreased volume –> with chronic therapy, volume recovers –> decreased PVR not due to the increased urine output
Thiazides clinical applications and PK
Hypertension (1st line)
Heart failure (if mild edema)
Premenstrual edema
Hypercalciuria –> inhibit Ca2+ excretion therefore useful to treat kidney stones
Diabetes insipidus –> produces hyperosmolar urine which leads to decreased thirst –> only time where diuretics cause a decrease in urine volume
PK:
Oral
Long half life: 40h –> takes 1-3 weeks to produce a stable effect
Metalozone: more potent. Causes Na+ excretion in advanced kidney failure
Thiazides AE
Hyperglycemia (secretion of insulin is K+ dependent) Hyperlipidemia Sexual dysfunction Hyperuricemia Hypercalcemia Hypokalemia Hyponatremia Allergic reactions
Contraindication: sulfur allergy
K+ sparing diuretics
Aldosterone antagonists:
Spironolactone
Eplerenone
Na+ channel inhibitors: Amiloride
Triamterene
Spironolactone and Eplerenone MOA
Act in collecting duct –> antagonize aldosterone at intracellular cytoplasmic receptor sites –> prevent translocation of receptor complex to nucleus –> inhibit affects of aldosterone on ROMK and ENaC channels –> decreased Na+ reabsorption and decreased K+ secretion
Spironolactone and Eplerenone clinical applications
Heart failure - adjunct to prevent cardiac remodelling Hypertension - 2nd line drugs Used alone when there is excess aldosterone Primary hyperaldosteronism (diagnosis and treatment) Edema - associated with excess aldosterone excretion
Spironolactone and Eplerenone AE
Gastric upset Peptic ulcers Hyperkalemia Nausea, lethargy, mental confusion Endocrine effects: - Spironolactone can act as androgen receptor antagonist - Gynecomastia and reduced sperm count in men - Galactorrhea in women
Amiloride and Triamterene MOA and clinical applications
Act in collecting duct –> block ENac channels directly –> decreased Na+ reabsorption and decreased K+ secretion
Not very efficacious alone so used in combination to prevent K+ loss associated with thiazides and furosemide
Amiloride and Triamterene AE
GI upset Leg cramps Hyperkalemia Hyponatremia Diziness, pruritus, headache, minor visual changes
Acetazolamide MOA
Carbonic Anhydrase inhibitor –> acts in PCT –> decreased HCO3- reabsorption and decreased intracellular H+ in PCT epithelial cells –> H+/Na+ exchanger will not work –> decreased Na+ reabsorption –> mild diuretic effect
Decreases activity of Na+/K+ ATPase (diuresis)
Increases urinary pH
Acetazolamide clinical applications and PK
Prophylaxis for mountain sickness (more bicarb entering urine –> metabolic acidosis –> will cause hyperventilation to blow off CO2 –> can create the acidosis to compensate for the drop in oxygen)
Glaucoma (HCO3- is an important component of aqueous humor in eye)
Epilepsy
Metabolic alkalosis
PK:
Oral and well-absorbed
IV for acute treatment of closed angle glaucoma
Half-life: 3-6h
Acetazolamide AE
Metabolic acidosis Hyponatremia Hypokalemia Crystalluria Malaise, fatigue, headache, depression, drowsiness GI upset Paresthesia
Mannitol MOA
Osmotic diuretic - only drug that truly increases urine volume
Acts everywhere –> raises osmotic pressure of the plasma –> draws H20 out of body tissues –> does not affect Na+ excretion directly
Osmotic diuretics clinical applications and PK
Increase urine flow in patients with acute renal failure
Reduce intracranial pressure and treatment of cerebral edema
Excretion of toxic substances
Can be used to reduce IOP in glaucoma
PK: Given IV only
Osmotic diuretics AE and contraindications
Extracellular water expansion
Tissue dehydration
Contraindications:
Pulmonary edema
Congestive heart failure
Conivaptan MOA
Acts at collecting ducts –> ADH antagonist –> antagonist at V1 and V2 receptors –> tubule is impermeable to water due to absence of ADH –> dilute urine
Conivaptan clinical applications and PK
Hypervolemic or euvolemic hyponatremia
SIADH
Heart failure (only if benefits outweigh risks)
IV only
Metabolised by and potent inhibitor of CYP3A4
Conivaptan AE and contraindications
Infusion site reactions Thirst Atrial fibrillation GI and electrolyte disturbances Nephrogenic diabetes insipidus
Contraindications:
Hypovolemic hyponatremia
Renal failure
