0812 - Modulation of Clearance by Diuretics - RM Flashcards
Explain the molecular mechanisms of the listed diuretics Outline the rationales for use of each group List some adverse effects limiting their use in certain patient groups (contraindications)
What is the mechanism of action of osmotic diuretics?
Mannitol, Sorbitol, Urea
The drug is filtered/secreted but not resorbed by the kidney, so increase first plasma, then urine osmolarity, drawing water from ICF into ECF then urine. Most important site of action is PT and TAL.
What is the mechanism of action of Carbonic Anhydrase inhibitors?
Oldest and least effective diuretics. -amide drugs.
Predominantly in PT (then CD), inhibit CAH, which decreases HCO3- resorption. This in turn decreases H+ excretion into lumen (Na/H exchanger) preventing Na+ resorption.
Self-limiting as loss of HCO3- leads to acidosis, providing substrate for Na/H exchanger.
What is the mechanism of action of loop diuretics?
Furosemide, Bumetanide
In TAL, immobilises Na/2Cl/K symporter which increases filtrate and urine osmolarity, and interferes with countercurrent multiplier by preventing these ions entering medullary interstitium - kidneys can no longer concentrate urine (at least in short term - minutes).
What is the mechanism of action of thiazide diuretics?
-thiazide drugs. Not particularly powerful, but widely used.
In DT, antagonise Cl- binding site of Na/Cl-symporter. Increased [Na] then causes excretion of K+ and H+ in CD.
Can interfere with secretion of other organic acids (drug interactions - e.g. penicillin)
What is the mechanism of action of epithelial Na-channel (ENaC)-inhibiting diuretics?
Act beyond the kidney - wherever ENaCs are expressed.
Blocks luminal Na+ channels, reducing Na+ resorption and K+ excretion (no Na for Na/K ATP-ase).
What is the mechanism of action of mineralocorticoid (MC) receptor antagonist diuretics?
Spironolactone - poor diuretic, but potassium-sparing.
Antagonises MC receptors, blocking aldosterone effects and production of aldosterone-induced proteins (gene expression). Ultimately reduces Na+ resorption and K+ secretion, but works better with high [aldosterone].
When would you use osmotic diuretics?
Almost exclusively hospital setting (ICU) for:
Brain oedema
Impending anuria (e.g. crush syndrome)
Forced diuresis (intoxications)
Other conditions where increase in extracellular osmolarity is required.
When would you use Carbonic Anhydrase inhibitors?
Open angle glaucoma
Oedema (cardiac or toxic, mountain sickness)
When would you use loop diuretics?
Oedemas Forced diureseis (intoxications etc) Impending anuria (e.g. crush syndrome)
When would you use thiazide diuretics?
Oedemas with good GFR
hypertension
When would you use epithelial Na-channel (ENaC)-inhibiting diuretics?
Hypertension (in combination with other diuretics).
When would you use mineralocorticoid (MC) receptor antagonist diuretics?
Hypertension (in combination with other diuretics)
Hyperaldosteronism
Diuretic of choice in hepatic cirrhosis.
What are the adverse effects and contraindications of osmotic diuretics?
Adverse effects - lowers paracellular transport, causing Mg++ loss (among others)
Contraindications - Heart failure and related conditions (lung oedema), and persisting oliguria/anuria (need to be able to excrete them).
What are the adverse effects and contraindications of Carbonic Anhydrase inhibitors?
Adverse effect - metabolic acidosis
Contraindication - any acidosis (would be ineffective)
What are the adverse effects and contraindications of loop diuretics?
Adverse effects:
Loss of electrolytes
Increased uric acid excretion (acute) but decreased long-term (leads to gout)
Furosemide has weak CAH inhibition, leading to metabolic acidosis.
Contraindications:
Coma Hepaticum (hepatic encephalopathy)
Anuria
