Drugs Acting on the Kidneys 2

Question 1

Mechanism of action of K+ sparing diuretics?

Answer 1

Usually, with diuretics, the decrease in BP causes a reflex increase in renin and aldosterone

These drugs blunt the action of aldosterone and prevent hypokalaemia; thus, aldosterone antagonists potentiate the actions of thiazide and loop agents by blocking the effect of aldosterone

Question 2

Potency of K+ sparing diuretics?

Answer 2

Weak diuretics on their own

Compound preparations with thiazide or loop diuretics

Question 3

2 categories of K+ sparing diuretics (based on their mechanisms of actions)?

Answer 3

Amiloride and Triamterene:
• Block the apical Na+ channel in the late distal tubule and collecting tubules, decreasing Na+ reabsorption

Spironolactone and Eplerenone - compete with aldosterone for binding to intracellular receptors causing:

1. Decreased gene expression and reduced synthesis of a protein mediator that activates Na+ channels in the apical membrane (preventing reabsorption of Na+)
2. Decreased numbers of Na+/K+ ATPase pumps in the basolateral membrane (prevents Na+ reabsorption and K+ excretion)

Question 4

How do Amiloride and Triamterene?

Answer 4

Enter the nephron via the organic cation transport system in the proximal tubule

Question 5

Potency and absorption of Amiloride and Triamterene?

Answer 5

Amiloride is 10x more potent than Triamterene

Triamterene is better absorbed from the GI tract compared to Amiloride

Question 6

Metabolism of Spironolactone?

Answer 6

Rapidly metabolised in the liver to active metabolite Canrenone (has a longer 1/2-life than Spironolactone)

Question 7

Side effect of aldosterone antagonists?

Answer 7

Hormonal disturbance:
• Gynaecomastia
• Impotence
• Menstrual irregularities

Question 8

Clinical uses of aldosterone antagonists?

Answer 8

Heart failure (moderate-severe CHF)

Secondary hyperaldosteronism, due to hepatic cirrhosis with ascites or nephrotic oedema)

Primary hyperaldosteronism (Conn’s syndrome)

Resistant essential hypertension

Question 9

When do aldosterone antagonists entail a risk of hyperkalaemia?

Answer 9

Potassium supplements (NOT to be given; advise against)

ACEIs or ARBs

Question 10

In the body, where is carbonic anhydrase present?

Answer 10

Present in:
• Renal tubules (PT)
• Gastric mucosa
• Pancreas
• Eyes
• Brain
• RBC

Question 11

Mechanism of action of carbonic anhydrase inhibitors?

Answer 11

Inhibit CAase reversibly; they increase excretion of HCO3- with Na+, K+ and H2O

Self-limiting diuretic action (weakly)

Question 12

Side effects of carbonic anhydrase inhibitors?

Answer 12

Alkaline diuresis

Hypokalaemia

Metabolic acidosis (alkaline urine)

Question 13

Extra-renal uses of carbonic anhydrase inhibitors?

Answer 13

Glaucoma - reduce intraocular pressure by decreasing formation of aqueous humor:
• Dorzolamide eye drops
• Brinzolamide eye drops

Acute mountain sickness (prophylaxis and treatment)

Alkalinise urine - induce for:
• Dysuria
• UTI
• Excretion of weak acids, e.g: salicylates, barbiturates)

Some forms of infantile epilepsy

Question 14

Why is mannitol used as an osmotic diuretic?

Answer 14

Ideal to be used as osmotic diuretic because it is pharmacologically inert and is not metabolised in the body

It does not enter cells and is freely filtered at the glomerulus; it undergoes limited reabsorption

Question 15

Major site of action in the kidney of Mannitol?

Answer 15

Proximal tubule is where most iso-osmotic reabsorption of water occurs

Question 16

How is mannitol administered?

Answer 16

IV 10-20% solution (no oral absorption)

Question 17

Uses of osmotic diuretics?

Answer 17

Used in raised intracranial and intraocular pressure, e.g:
• Head injury
• Brain/ocular surgery
• Acute congestive glaucoma

Prevention of IMPENDING acute renal failure (due to shock, severe trauma and cardiac surgery), as it maintains GFR and urine flow

Question 18

Why are osmotic diuretics used for raised ICP and IOP when they do not enter the eye or brain?

Answer 18

Increased plasma osmolality extracts water from the brain parenchyma, CSF and aqueous humor

Question 19

Common side effect of osmotic diuretics?

Answer 19

Hyponatraemic headache

Question 20

Receptors for ADH?

Answer 20

ADH/vasopressin receptors are GPCRs:
• V1a and V1b - mediate vasoconstriction
• V2 - more sensitive and mediates vasodilatation and increased water reabsorption in the renal collecting duct (by directing aquaporin 2-containing vesicles to the apical membrane)

Question 21

Examples of vasopressin analogues?

Answer 21

Desmopressin - oral or intranasal administration available; it is more potent and has a longer duration of action than vasopressin

Terlipressin

Question 22

Types of diabetes insipidus?

Answer 22

Neurogenic - lack of vasopressin secretion from the posterior pituitary

Nephrogenic diabetes insipidus - inability of the nephron to respond to vasopressin:
• Rare, X-linked recessive mutations in the V2 receptor gene
• Drugs, e.g: lithium, demeclocycline

Question 23

Treatment of diabetes insipidus?

Answer 23

Neurogenic - desmopressin

Nephrogenic - paradoxical anti-diuretic effect of thiazides

Question 24

Treatment of nocturnal enuresis (bedwetting) in children >10 years?

Answer 24

Oral/intranasal desmopressin

Question 25

Treatment of variceal bleeding in portal hypertension?

Answer 25

Vasopressin infusion / terlipressin

Question 26

What are the aquaretics/vaptans?

Answer 26

Competitive antagonists of vasopressin receptors

By blocking the V1a, vasoconstriction is prevented

By blocking V2, H2O reabsorption in the collecting tubule is prevented

Question 27

Effects of vasopressin receptor antagonists (aquaretics/vaptans)?

Answer 27

Electrolyte-free aquaresis

Reduced urine osmolarity

Raised serum Na

Question 28

Main clinical indications for aquaretics/vaptans?

Answer 28

In conditions of excess of direct/indirect ADH to correct hyponatraemia:
• SIADH
• CHF
• Cirrhosis

Question 29

Examples of aquaretics/vaptans?

Answer 29

Conivaptan - non-selective (blocks both V1a and V2); can only be given as an IV formulation

Oral and V2 selective drugs:
• Tolvaptan
• Lixivaptan
• Satavaptan

Question 30

Main side effect of aquaretics/vaptans?

Answer 30

Increased thirst