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
Glomerulus	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
Proximal tubule	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.

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