Drugs Acting on the Kidneys

Question 1

What are diuretics?

Answer 1

Agents that increase urine output through causing a net electrolyte (mainly Na+) and water loss

Question 2

Uses of diuretics?

Answer 2

• Hypertension
• Congestive heart failure
• Hepatic cirrhosis with ascites

Question 3

How does the diuretic actually enter the filtrate?

Answer 3

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

Question 4

Why can diuretics cause gout?

Answer 4

OATs are shared by both loop/thiazide diuretics and by uric acid

There is a Tm

Question 5

Which drugs act on the PCT?

Answer 5

Acetazolamide (carbonic anhydrase inhibitor) - inhibits reabsorption of HCO3- in the PCT

Weak diuretic properties

Question 6

Which drugs act on the ascending loop of Henle?

Answer 6

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

Question 7

Which drugs act on the distal convoluted tubule (DCT)?

Answer 7

Thiazides - most commonly used diuretics

Inhibit reabsorption of Na+ and Cl- in the DCT, resulting in retention of wate r

Question 8

Which drugs act on the spironolactone, amiloride and triamterene?

Answer 8

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

Question 9

Mechanism of action of loop diuretics?

Answer 9

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

Question 10

How can loop diuretics cause hypocalcaemia and hypomagnesaemia?

Answer 10

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

Question 11

Absorption of loop diuretics?

Answer 11

Well-absorbed from the GI tract

Rapid onset following IV administration

Effective in severe renal failure

Question 12

Clinical uses of loop diuretics?

Answer 12

• 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

Question 13

Adverse effects of loop diuretics?

Answer 13

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)

Question 14

What are thiazide diuretics?

Answer 14

Moderately potent diuretics that are:
• Mild heart failure
• Hypertension

Occasionally used in:
• Severe resistant oedema (+ a loop diuretic)
• Nephrolithiasis (hypercalciuria)
• Nephrogenic diabeteic insipidus

Question 15

Mechanism of action of thiazide diuretics?

Answer 15

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

Question 16

Absorption of thiazide diuretics?

Answer 16

Well-absorbed orally and act within 1-2 hours of administration (typically early in the day)

Question 17

Side effects of thiazide diuretics?

Answer 17

Diuresis

This is why they are typically taken early in the day, to avoid interference with sleep

Question 18

When are thiazide diuretics ineffective?

Answer 18

In renal failure (ineffective if eGFR is <30 ml/min)

Question 19

Extra-renal actions of thiazide diuretics?

Answer 19

Slow developing fall in BP (direct vascular action)

Metabolic disturbances:
• Hyperglycaemia
• Hyperlipidaemia

Question 20

Clinically prescribed thiazide diuretics?

Answer 20

Bendroflumethiazide (mild/moderate heart failure)

Metolazone (additive diuresis with loop diuretics)

Xipamide (long-acting)

Chlotalidone (anti-hypertensive, long-acting)

Indapamide (anti-hypertensive, lipid soluble)

Question 21

Side effects of thiazide diuretics?

Answer 21

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

Question 22

Symptoms of hypokalaemia?

Answer 22

Weakness

Myalgia

Fatigue

Arrhythmias

Question 23

Prevention and treatment of hypokalaemia?

Answer 23

K+ supplementation

Use of K+ sparing diuretics

Question 24

Physiologically, what happens when Na+ in the filtrate decreases?

Answer 24

Macula densa cells sense this and there is a reflex increase in renin production by the granular cells and thus aldosterone production is increased