Diuretics

Question 1

Mannitol

Answer 1

Osmotic diuretic.
Carbohydrate derivative. Used to reduce ICP in the presence of cerebral oedema or in neurosurgery. Prepared in water in a 10 or 20% solution.
Initial dose is 1g/kg.

Question 2

Mannitol MOA

Answer 2

Freely filtered at the glomerulus but not reabsorbed in the tubules. Increases osmolality of the filtrate so that the volume of urine produced is increased by an osmotic effect.
Unable to pass through blood brain barrier so by virtue of increased plasma osmolality it draws extracellular brain water in to the plasma.

Question 3

Mannitol effects

Answer 3

CVS - causes an initial increase in circulating volume before diuresis ensues. In susceptible patients this may cause heart failure.
Renal - osmotic diuresis and increased renal blood flow
CNS - acute reduction in ICP

Question 4

Mannitol kinetics

Answer 4

Following IV administration mannitol is distributed throughout the extracellular fluid space. Freely filtered at the glomerulus and not reabsorbed.
Elimination half life of 100min.

Question 5

Acetazolamide

Answer 5

Carbonic anhydrase inhibitor. Weak diuretic more commonly used as prophylaxis against mountain sickness

Question 6

Acetazolamide MOA

Answer 6

non-competitive inhibitor of carbonic anhydrase which catalyses the formation of H+ and HCO3- from carbon dioxide and water via H2C03 in the proximal tubule. As a result less H+ available for anti-port with Na+ (less sodium reabsorbed). And less HCO3- reabsorbed from tubule - metabolic acidosis.

Question 7

Acetazolamide effects

Answer 7

H+ excretion inhibited and HCO3- not reabsorbed resulting in alkaline urine. Na+ also not reabsorbed in by H+/Na+ antiport so there is an increased portion of Na+ at distal tubule causing increased K+ secretion

Question 8

Acetazolamide kinetics

Answer 8

Bioavailability of >95%. Highly protein bound and excreted unchanged in urine.

Question 9

Frusemide

Answer 9

Loop diuretic used in severe heart failure to reduce peripheral and pulmonary oedema (fluid overload)

Question 10

Frusemide MOA

Answer 10

Inhibits NKCC2 channel, thus decreasing reabsorption of Na+ and Cl- in the TAL of Henle
Impairs counter-current multiplier system and reduces hypertonicity of medullary interstitum which reduces reabsorption of water from the collecting duct.
NKCC2 channel has large capacity for Na+ reabsorption so has marked effects - most potent diuretic

Question 11

Frusemide effects

Answer 11

CVS - Produce vasodilation so decrease SVR
Biochemical - hyponatraemia, hypokalaemia, hypomagnaseamia and a hypochloraemic alkalosis. Hyperuricaemia is sometimes seen and may precipitate gout.
Can be ototoxic and cause deafness if a large dose is given rapidly and is more common in renal failure.

Question 12

Frusemide kinetics

Answer 12

Oral bioavailability of 65%. Highly protein bound (>95%) and excreted unchanged in the urine.

Question 13

Amiloride MOA

Answer 13

Potassium sparing diuretic. Works at the distal convoluted tubule and blocks Na+/K+ exchange creating a diuresis and decreasing K+ excretion. (blocks eNAC channel)
Often used in conjunction with loop diuretics

Question 14

Spironolactone MOA

Answer 14

Competitive aldosterone antagonist. Normally aldosterone stimulates the reabsorption of Na+ in the distal tubule which provides a driving force for excretion of K+.
When aldosterone is antagonised K+ excretion is reduced while increased Na+ excretion produces diuresis. Only limited diuresis as only 2% of Na+ reabsorption is under the control of aldosterone.

Question 15

Spironolactone effects

Answer 15

Biochemical - hyperkalaemia is most common in patients with renal impairment
Hormonal - can cause gynaecomastia in men and menstrual irregularity in women

Question 16

Spironolactone kinetics

Answer 16

Incompletely absorbed from the gut and highly protein bound. Rapidly metabolised and excreted in urine.

Question 17

Bendrofluazide MOA

Answer 17

act mainly on the early segment of the distal tubule by inhibiting sodium and chloride reabsorption. Leads to increased sodium and water excretion.
Increased Na+ load reaching distal tubule stimulates an exchange with K+ and H+ so that thiazides tend to precipitate a hypokalemic, hypochloraemic alkalosis

Question 18

Bendfrofluazide effects

Answer 18

CVS - Produce antihypertensive effect by a reduction in plasma volume and systemic vascular resistance.
Biochemical - may cause a hypokalaemic, hypochloraemic alkalosis
Miscellaneous - can precipitate pancreatitis. Impotence, rash and photosensitivity can occur

Question 19

Bendrofluazide kinetics

Answer 19

Well absorbed from the gut. Produce effect within 90 min. Duration of action 18-24 hours. 70% metabolized in liver to active metabolites. Rest excreted unchanged in urine

Question 20

Amiloride MOA

Answer 20

Potassium sparing diuretic. Works at the distal convoluted tubule and blocks Na+/K+ exchange creating a diuresis and decreasing K+ excretion. (blocks eNAC channel)
Often used in conjunction with loop diuretics

Question 21

Spironolactone MOA

Answer 21

Competitive aldosterone antagonist. Normally aldosterone stimulates the reabsorption of Na+ in the distal tubule which provides a driving force for excretion of K+.
When aldosterone is antagonised K+ excretion is reduced while increased Na+ excretion produces diuresis. Only limited diuresis as only 2% of Na+ reabsorption is under the control of aldosterone.

Question 22

Spironolactone effects

Answer 22

Biochemical - hyperkalaemia is most common in patients with renal impairment
Hormonal - can cause gynaecomastia in men and menstrual irregularity in women

Question 23

Spironolactone kinetics

Answer 23

Incompletely absorbed from the gut and highly protein bound. Rapidly metabolised and excreted in urine.

Question 24

Bendrofluazide MOA

Answer 24

act mainly on the early segment of the distal tubule by inhibiting sodium and chloride reabsorption. Leads to increased sodium and water excretion.
Increased Na+ load reaching distal tubule stimulates an exchange with K+ and H+ so that thiazides tend to precipitate a hypokalemic, hypochloraemic alkalosis

Question 25

Bendfrofluazide effects

Answer 25

CVS - Produce antihypertensive effect by a reduction in plasma volume and systemic vascular resistance.
Biochemical - may cause a hypokalaemic, hypochloraemic alkalosis
Miscellaneous - can precipitate pancreatitis. Impotence, rash and photosensitivity can occur

Question 26

Bendrofluazide kinetics

Answer 26

Well absorbed from the gut. Produce effect within 90 min. Duration of action 18-24 hours. 70% metabolized in liver to active metabolites. Rest excreted unchanged in urine

Question 27

Carbonic anhydrase inhibitors

Answer 27

Non-competitive inhibition of the enzyme carbonic anhydrase.
Means less H+ and HCO3- formed in tubular cell, less H+ excreted in to tubular lumen in exchange for sodium and less H+ available to aid HC03- reabsorption.
Net result is decreased reabsorption of sodium and bicarbonate. Results in metabolic acidosis which is why it is useful in altitude sickness

Question 28

Osmotic diuretics

Answer 28

Inert substances that do not undergo metabolism and are freely filtered at the glomerulus. Administration causes increased plasma and renal osmolality resulting in an osmotic diuresis

Question 29

Loop diuretics

Answer 29

Inhibit activity of NKCC2 channel thus decrease reabsorption of sodium, potassium and chloride.
Most potent diuretics

Question 30

Thiazide diuretics

Answer 30

Inhibit Na / Cl cotransporter in cortical portion of LOH and DCT

Question 31

Potassium sparing diuretics

Answer 31

Act on collecting ducts via two methods

1. Block eNAC channel so prevent sodium reabsorption (independent of spironolactone). - amiloride
2. Aldosterone receptor blockers - prevent synthesis and activation of aldosterone dependent basal cell sodium potassium ATPase pump. - spironolactone