Question 2

Outline the sites and mechanisms of action of diuretics. Give one example of drug acting at each site and list two side effects for each drug.

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College Answer

Good answers to this question were those that had a tabular format to the structure of the answer — for example columns headed mechanism, sites, drug and side effects. Most  common omissions were not to further describe how the different mechanisms of action of diuretics increased urine output, e.g. "disruption of the counter current multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid". There was often little mention of increased urine solutes and the effect the electro chemical effect had in promoting a diuresis. Examples of drugs were well done.

Discussion

Site Mechanism of diuretic effect Representative drug & its side effects
Glomerulus Increased glomerular filtration rate due to afferent arteriolar vasodilation

Fenoldopam

  • Tachycardia
  • Hypotension and vasodilation
Increased glomerular filtration rate due to increased cardiac output

Caffeine

  • Tachycardia
  • Hypertension
Proximal tubule Carbonic anhydrase inhibition: decreased reabsorption of bicarbonate and sodium;  therefore increased tubular fluid osmolality

Acetazolamide

  • Metabolic acidosis
  • Hypokalemia
  • Hyponatremia
  • Hyperchloremia
Unresorbable fully filtered solute, therefore markedly increased tubular fluid osmolality

Mannitol

  • Hypo-everythingaemia
    (all electrolytes are lost as a side effect, but to different degrees)
  • Hypotension
Thick ascending limb

NKCC2 sodium-chloride-potassium transport inhibition; therefore "disruption of the counter current multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid"

Furosemide

  • Hypotension (esp.orthostatic)
  • Hypokalemia
  • Metabolic alkalosis (hypochloraemia)
  • Hypernatremia (as sodium is retained by ENaC)
  • Hypomagnesemia
  • Hypophosphatemia
  • Acidification of the urine
  • Ototoxicity
Distal convoluted tubule NCC sodium and chloride transporter inhibition; therefore increased delivery of sodium to the distal nephron, preventing the reabsorption of urinary water by decreasing the tubulo-medullary osmotic gradient

Hydrochlorothiazide

  • Hypokalemia
  • hyponatremia
  • unexplained vasodilatory antihypertensive effects in the long term
Collecting duct Aldosterone receptor inhibition, leading to decreased ENaC channel expression and therefore decreased sodium reabsorption

Spironolactone

  • Hyponatremia
  • Hyperkalemia
  • Metabolic acidosis (Type 4 RTA),
  • gynaecomastia (by cross-reactivity with other steroid receptors, eg. sex hormones)

ENaC channel blockade, therefore decreased sodium reabsorption and decreased  tubulo-medullary osmotic gradient

Amiloride

  • Hyponatremia
  • Hyperkalemia
Blockade of vasopressin receptors (V2), decreasing the expression of aquaporins and thereby decreasing the reabsorption of water

Tolvaptan

  • Hypernatremia
  • Hyperkalemia
  • Hepatotoxicity
Blockade of water reabsorption by inducing a conformational change in aquaporin proteins

Mercurial diuretics

  • Sialorrhoea
  • Neurotoxicity

References

Wile, David. "Diuretics: a review." Annals of clinical biochemistry 49.5 (2012): 419-431.

Lang, H-J., and M. Hropot. "Discovery and development of diuretic agents." Diuretics. Springer, Berlin, Heidelberg, 1995. 141-172.

Puschett, Jules B. "Pharmacological classification and renal actions of diuretics." Cardiology 84.Suppl. 2 (1994): 4-13.

Clarke, Paul, and Karen H. Simpson. "Diuretics and renal tubular function." Bja Cepd Reviews 1.4 (2001): 99-103.

Brater, D. Craig. "Diuretic pharmacokinetics and pharmacodynamics." Diuretic Agents. Academic Press, 1997. 189-208.