Drugs and the kidney Flashcards
Why are kidneys so susceptible to drug induced AKI?
1) High vascularity
2) Large surface area for binding and transport of molecules
3) Reabsorption of water from kidneys concentrates some drugs in the nephron
4) Main route of excretion for most drugs
What is a diuretic and what are the 5 classes of diuretics?
A substance that promotes the excretion of urine
1) Carbonic anhydrase inhibitors
2) Osmotic diuretics
3) Loop diuretics
4) Thiazide (& related) diuretics
5) Potassium sparing diuretics
How do carbonic anhydrase inhibitors work?
Example: Acetazolamide
Inhibits carbonic anhydrase enzyme in the proximal tubule.
This enzyme normally converts bicarbonate (HCO3-) ions into CO2 and H2O on the luminal surface of tubular cells. This in turn drives some Na+ reabsorption in exchange for H+.
Carbonic anhydrase inhibitors block this process and so Na+ and HCO3- ions remain in the tubule.
However, carbonic anhydrase inhibitors have weak diuretic action - as only relatively small amount sodium is reabsorbed in this way.
These drugs also prevent excretion of H+ into urine and therefore a side effect can be higher pH in blood and metabolic acidosis
How do osmotic diuretics work?
Example: Mannitol
Increases the osmolality of the filtrate and therefore reduces water reabsorption
Acts best where most osmotic reabsorption occurs (i.e. proximal tubule and descending loop of Henle)
Main uses nowadays:
Reduction of cerebral oedema (e.g. from head trauma)
Reduction of intra-ocular pressure (e.g. glaucoma)
How do loop diuretics work?
Powerful diuretics
Example: Furosemide
Act on thick ascending limb of Loop of Henle
Inhibit the Na+K+2Cl- co-transporter (compete with Cl- binding)
As a result of loop diuretic action, Na+ (and also K+) remain in tubule
Reduced NaCl reabsorption in thick ALH causes reduced osmotic concentration in medulla (so reducing ADH mediated H2O absorption)
Other effects – potentially adverse:
Increased delivery of NaCl to the distal tubule causes increased Na+ uptake there by principal cells, with a correponding loss of K+ (and H+)
Also reduced Ca2+ and Mg2+ reabsorption can occur
What are the main uses of loop diuretics and what can be some side-effects?
Peripheral oedema in cases of chronic heart failure
Acute pulmonary oedema
Can be used in resistant hypertension
Selected side-effects:
Hypovolaemia & hypotension
Hyponatraemia and hypokalaemia
How do thiazide diuretics work?
Examples: Bendroflumethiazide, hydrochlorothiazide, indapamide, chlortalidone
Act on early distal tubule
Inhibit the Na+Cl- co-transporter (compete with Cl- binding)
What are the main uses and side effects of thiazide diuretics?
Weak/moderate diuresis (well tolerated)
Slower acting, but longer lasting than loop diuretics
Main uses:
Peripheral oedema in chronic heart failure
Hypertension
Selected side-effects:
Hyponatraemia / hypokalaemia
Increase plasma uric acid (gout)
Hyperglycaemia
How do loop and thiazide diuretics cause hypokalaemia?
Loop and thiazide diuretics increase delivery of NaCl to the distal nephron and this lowers blood volume and pressure in the kidney
This drives greater potassium secretion by:
1) Increased tubular flow rate – greater volume in tubules
2) Increased activity of Na+/K+ ATPase via increased [Na+]i and activation of RAAS (increased aldosterone)
How do potassium sparing diuretics work?
Act on principal cells in late distal & cortical collecting tubule
Either inhibit epithelial sodium channels (ENaC) or inhibit the mineralocorticoid receptor (and therefore prevent aldosterone binding)
Reduce K+ secretion into lumen
How do ENaC antagonists (sub-group of potassium sparing diuretics) work?
Example: amiloride
Blocks the Epithelial Na+ Channels (ENaC) and decreases luminal permeability to sodium
Weak diuretic alone
Used in combination with thiazide or loop diuretics
(e.g. with hydrochlorothiazide in co-amilozide® - like Mrs Hope in the current CBL Case!)
Reduced K+ secretion into lumen
Therefore K+ is retained in the blood.
How do aldosterone antagonists (sub-group of potassiums sparing diuretics) work?
Examples: spironolactone, eplerenone
These drugs are aldosterone antagonists, as they bind to the mineralocorticoid receptor (MR) and block receptor activation by aldosterone
Weak diuretic if used alone
Prevents synthesis of ENaC and also Na+/K+ ATPase activation and thus reduced potassium secretion into tubular lumen. Thus potassium is retained.
What are the main uses and side effects of potassium sparing diuretics?
Main uses (especially aldosterone antagonists):
Chronic heart failure
Peripheral oedema & ascites caused by cirrhosis
Resistant hypertension
Can be used in combination to prevent K+ loss from use of loop or thiazide diuretics – a major use for ENaC antagonists
Selected side effects:
Hyperkalaemia (can interact with RAAS drugs)
(Dangerously high K+ can cause arrhythmia)
What are common diuretic combinations?
Loop diuretics and thiazides
As loop diuretics increase amount of NaCl delivered to distal nephron, this increases efficiency of thiazides
Can cause very large volume losses and K+ loss
Loop (or thiazides) and K+ sparing diuretics
Examples: Co-amilofruse; co-amilozide
Get good diuretic function without loss of K+
Beware K+ retention – hyperkalaemia risk
Where do RAAS blocking drugs act?
1) ACE-inhibitors eg Ramipril block ACE in endothelium of lungs
2) Angiotensin Receptor Blockers (ARB) eg. Losartan inhibit Angiotensin II receptors
3) Aldosterone antagonists eg. spironolactone inhibit mineralocorticoid receptors
