Lecture 16: Diuretics

Question 1

Edematous states

Answer 1

• Heart failure (kidneys respond as if there was hypovolemia, increasing blood volume)
• Hepatic ascites (increased portal BP & secondary hyperaldosteronism)
• Nephrotic syndrome (damaged glomerular membranes allow leakage of plasma proteins, reducing osmotic pressure. Low plasma volume stimulates aldosterone secretion)
• Premenstrual edema (hormone imbalances)

Question 2

Non-edematous states

Answer 2

• Hypertension
• Hypercalcemia
• Diabetes insipidus: Thiazides very effect in treating DI

Question 3

Loop diuretics

Answer 3

• Furosemide, Torsemide
• aka ‘High-Ceiling’ diuretics
• Highest efficacy in removing Na+ & Cl- from body • Act on ascending limb of Loop of Henle

Clinical applications:

• Diuretics of choice for managing edema associated with heart failure, hepatic or renal disease
• Hypertension

MOA

• Act in the ascending limb of the loop of Henle
• Block NKCC2 Na+/Cl-/K+ cotransporter
• [Na+] & [Cl-] & [K+] in tubular fluid -> incr H20 excretion

Actions

• Increased Ca2+ excretion: to treat hypercalcemia
• Increased Mg2+ excretion
• Decreased renal vascular resistance • Increased renal blood flow
• Increased prostaglandin synthesis

PK

• Oral & parenteral
• t1/2 = 2-4 h (short acting is beneficial; long acting would cause hypotension)

Adverse

• Ototoxicity
• Hyperuricemia
• Acute hypovolemia
• K+ depletion
• Hypomagnesemia
• Allergic reactions

Question 4

Thiazides

Answer 4

• ex. hydrochlorothiazide
• Act on distal tubule – all have equal maximum effects

Clinical applications:

• Hypertension (either alone or in combination with other antihypertensives)
• Heart failure (mild-moderate)
• Hypercalciuria (inhibit Ca2+ excretion, particularly useful for kidney stones)
• Diabetes insipidus (produce hyperosmolar urine)
• Premenstrual edema

MOA

• Act predominantly in distal convoluted tubule
• Block NCCT Na+/Cl- cotransporter
• incr [Na+] & [Cl-] in tubular fluid -> incr H20 excretion

Actions

• Increased Na+ & Cl- excretion
• Increased K+ excretion
• Increased Mg2+ excretion
• Decreased urinary Ca2+ excretion
• Decreased peripheral vascular resistance
  
  • Initially, Due to decrease in blood volume. With continued therapy, volume recovery occurs although hypotensive effects remain

PK

• Orally effective (In emergency, don’t give thiazides)
• t1/2 = 40h (take 1-3 wks to produce stable effect)
• Related Compounds:
  
  • Chlorthalidon: Long duration of action: t1/2 = 40-60 h (used to treat hypertension once daily).
  • Metolazone: Most potent, causes Na+ excretion in advance kidney failure.

Adverse

• Hypokalemia
• Hyponatremia
• Hyperuricemia
• Volume depletion
• Hyperglycemia
• Hyperlipidemia
• Hypersensitivity

Question 5

Metolazone

Answer 5

thiazide

Question 6

Chlorthalidone

Answer 6

thiazide

Question 7

K+-sparing: Aldosterone antagonists

Answer 7

• Aldosterone antagonists: Spironolactone, Eplerenone
• Used alone when there is excess aldosterone
• Potassium levels must be closely monitored
• Act mainly in collecting tubule

Clinical applications:

• Heart failure (to treat refractory edema or as adjunct to standard therapy)
• Hypertension (adjunct to standard therapy)
• Primary hyperaldosteronism (diagnosis & treatment)
• Edema (associated with excessive aldosterone excretion)

MOA

• Act in collecting duct
• Antagonize aldosterone at intracellular cytoplasmic receptor sites (prevents translocation of receptor complex -> nucleus)
• Na+ reabsorption & K+ excretion

PK

• Oral & strongly protein bound (t1/2 = 2-3 days)
• Spironolactone has an active metabolite (canrenone)

Advanced

• Gastric upset & peptic ulcers
• Endocrine effects (antiandrogen)
• Hyperkalemia
• Nausea, lethargy, mental confusion (rare)

Adverse

• Hyperkalemia (esp. in patients taking ACEIs/ARBs,
• K+ supplements or who have renal failure)
• GI disturbances (gastritis, peptic ulcer)
• CNS effects (lethargy, confusion)
• Endocrine abnormalities (gynecomastia, decreased libido, menstrual irregularities)

Question 8

K+-Sparing: Na+ channel inhibitors

Answer 8

• Amiloride, Triamterene
• Block Na+ transport channels ( Na+/K+ exchange)
• Do not rely on presence of aldosterone
• Usually used in combination (not very efficacious)
• Can prevent K+ loss associated with thiazides & furosemide

MOA

• Act on CD
• Directly block epithelial sodium channel (ENaC) -> decreasing Na+/K+ exchange
• decr Na+ reabsorption & decr K+ excretion

Adverse

• Hyperkalemia
• Hyponatremia
• Leg cramps
• GI upset
• Dizziness, pruritus, headache & minor visual changes

Question 9

CA Inhibitors

Answer 9

• Acetazolamide
• Act mainly in proximal tubular epithelial cells
• Less efficacious than other diuretics
• Often used for other pharmacological properties

Clinical applications:

• Glaucoma (reduce elevated intraocular pressure)
• Epilepsy (used alone or with other antiepileptics)
• Mountain sickness prophylaxis
• Metabolic alkalosis: by inducing metabolic acidosis

MOA

• Inhibits intracellular carbonic anhydrase
• Decreases ability to exchange Na+ for H+
• Decreases activity of Na+/K+ ATPase (diuresis)
• HCO3- is retained in lumen (increasing urinary pH)

PK

• Oral & well absorbed
• t1/2 = 3-6 h.
• Increase urine pH

Adverse

• Metabolic acidosis
• Hyponatremia
• Hypokalemia
• Crystalluria
• Malaise, fatigue, depression, headache, GI disturbances, drowsiness, paresthesia

Question 10

Osmotic diuretics

Answer 10

• Raises osmotic pressure of the plasma thus draws H20 out of body tissues & produces osmotic diuresis
• Does not effect Na+ excretion directly

Clinical applications :

• Increase urine flow in patients with acute renal failure
• Reduce increased intracranial pressure & treatment of cerebral edema
• Promote excretion of toxic substances

PK: IV (only small amount absorbed from GI tract)

Adverse

• Extracellular water expansion (can lead to hyponatremia)
• Tissue dehydration

Question 11

ADH Antagonists

Answer 11

Conivaptan is an antagonist at V1 and V2 receptors

ADH controls permeability of collecting tubule to H20

In the absence of ADH, tubule is H20 impermeable -> dilute urine

Clinical applications :

• Euvolemic and hypervolemic hyponatremia
• SIADH (syndrome of inappropriate ADH secretion)
• Heart failure (only when benefits outweigh risks – safety not established)

PK

• IV only
• Metabolized by & potent inhibitor of CYP 3A4

Adverse

• Infusion site reactions
• Thirst
• Atrial fibrillation
• GI & electrolyte disturbances
• Nephrogenic diabetes insipidus

Contraindications

• Hypovolemic hyponatremia
• Renal failure