Drugs Acting on the Kidneys Flashcards
What are diuretics?
Agents that increase urine output through causing a net electrolyte (mainly Na+) and water loss
Uses of diuretics?
- Hypertension
- Congestive heart failure
- Hepatic cirrhosis with ascites
How does the diuretic actually enter the filtrate?
Glomerular filtration (for drugs not bound to plasma proteins)
Secretion via transport process in the PCT:
• Organic anion transporters (OATs) - transport acidic drugs, e.g: thiazides and loop agents
• Organic cation transporters (OCTs) - transport basic drugs, e.g: triamterene and amiloride
Why can diuretics cause gout?
OATs are shared by both loop/thiazide diuretics and by uric acid
There is a Tm
Which drugs act on the PCT?
Acetazolamide (carbonic anhydrase inhibitor) - inhibits reabsorption of HCO3- in the PCT
Weak diuretic properties
Which drugs act on the ascending loop of Henle?
Loop diuretics: • Bumetanide • Furosemide • Torsemide • Ethacrynic acid
Inhibit the Na+/K+/2Cl- co-transporter in the ascending loop of Henle, resulting in retention of Na+, Cl- and water in the tubule
These drugs are the most efficacious of the diuretics
Which drugs act on the distal convoluted tubule (DCT)?
Thiazides - most commonly used diuretics
Inhibit reabsorption of Na+ and Cl- in the DCT, resulting in retention of wate r
Which drugs act on the spironolactone, amiloride and triamterene?
Spironolactone - aldosterone antagonist inhibits the aldosterone-mediated reabsorption of Na+ and secretion of K+
Amiloride and triamterene - block Na+ channels
These agents can prevent loss of K+ that occurs with thiazide or loop diuretics
Mechanism of action of loop diuretics?
Inhibit the Na+/K+/2Cl- co-transporter in the thick ascending limb binding to the Cl- site:
• Increase the load of Na+ delivered to distal regions of the nephron
• K+ loss (hypokalaemia)
• Increase excretion of Ca2+ and Mg2+ (thus causing hypocalcaemia and hypomagnesaemia)
Also have an indirect venodilator action (before diuresis), helping pulmonary oedema
How can loop diuretics cause hypocalcaemia and hypomagnesaemia?
By blocking Na+/K+/2Cl-, this stops the K+ leak back into the tubule
If this is blocked, Ca2+ and Mg2+ are no longer pushed, paracellularly, by a +ve charge, into the interstitium
Absorption of loop diuretics?
Well-absorbed from the GI tract
Rapid onset following IV administration
Effective in severe renal failure
Clinical uses of loop diuretics?
- Acute pulmonary oedema
- Chronic kidney disease
- Hepatic cirrhosis with ascites
- Chronic heart failure
- Nephrotic syndrome
- Increase urine volume in acute kidney failure (may reduce the need for dialysis)
- Hypercalcaemia and renal stones
Adverse effects of loop diuretics?
Hypokalaemia
Metabolic alkalosis (caused by increased H+ secretion from intercalated cells in collecting tubule; there is a shift in acid-base towards alkaline side)
Hypovolaemia (decreased volume of circulating fluid) and hypotension, part. in the elderly
Depletion of Ca2+ and Mg2+ (paracellular pathway)
Hyperglycaemia
Hyperuricaemia
Hearing loss (Na+/K+/2Cl- transporter is also present in the endolymph of the internal ear)
What are thiazide diuretics?
Moderately potent diuretics that are:
• Mild heart failure
• Hypertension
Occasionally used in:
• Severe resistant oedema (+ a loop diuretic)
• Nephrolithiasis (hypercalciuria)
• Nephrogenic diabeteic insipidus
Mechanism of action of thiazide diuretics?
Bind to the Na+/Cl- symporter in the DCT, inhibiting Na+ reabsorption
They increase the load of Na+ delivered to the collecting tubule (causing K+ loss) and increase the reabsorption of Ca2+
Indirect vasodilator action
Absorption of thiazide diuretics?
Well-absorbed orally and act within 1-2 hours of administration (typically early in the day)
Side effects of thiazide diuretics?
Diuresis
This is why they are typically taken early in the day, to avoid interference with sleep
When are thiazide diuretics ineffective?
In renal failure (ineffective if eGFR is <30 ml/min)
Extra-renal actions of thiazide diuretics?
Slow developing fall in BP (direct vascular action)
Metabolic disturbances:
• Hyperglycaemia
• Hyperlipidaemia
Clinically prescribed thiazide diuretics?
Bendroflumethiazide (mild/moderate heart failure)
Metolazone (additive diuresis with loop diuretics)
Xipamide (long-acting)
Chlotalidone (anti-hypertensive, long-acting)
Indapamide (anti-hypertensive, lipid soluble)
Side effects of thiazide diuretics?
Postural hypotension (more common in elderly)
Metabolic alkalosis
Hypokalaemia, hyponatraemia, hypomagnesaemia
Hyperglycaemia and hyperlipidaemia
Hyperuricaemia and gout
Less common:
• Low blood count
• Impotence (erectile dysfunction)
• Pancreatitis, cholestasis, pneumonitis, photosensitivity
Symptoms of hypokalaemia?
Weakness
Myalgia
Fatigue
Arrhythmias
Prevention and treatment of hypokalaemia?
K+ supplementation
Use of K+ sparing diuretics
Physiologically, what happens when Na+ in the filtrate decreases?
Macula densa cells sense this and there is a reflex increase in renin production by the granular cells and thus aldosterone production is increased
