Drugs Acting on the Kidneys 2 Flashcards
Mechanism of action of K+ sparing diuretics?
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
Potency of K+ sparing diuretics?
Weak diuretics on their own
Compound preparations with thiazide or loop diuretics
2 categories of K+ sparing diuretics (based on their mechanisms of actions)?
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:
- Decreased gene expression and reduced synthesis of a protein mediator that activates Na+ channels in the apical membrane (preventing reabsorption of Na+)
- Decreased numbers of Na+/K+ ATPase pumps in the basolateral membrane (prevents Na+ reabsorption and K+ excretion)
How do Amiloride and Triamterene?
Enter the nephron via the organic cation transport system in the proximal tubule
Potency and absorption of Amiloride and Triamterene?
Amiloride is 10x more potent than Triamterene
Triamterene is better absorbed from the GI tract compared to Amiloride
Metabolism of Spironolactone?
Rapidly metabolised in the liver to active metabolite Canrenone (has a longer 1/2-life than Spironolactone)
Side effect of aldosterone antagonists?
Hormonal disturbance:
• Gynaecomastia
• Impotence
• Menstrual irregularities
Clinical uses of aldosterone antagonists?
Heart failure (moderate-severe CHF)
Secondary hyperaldosteronism, due to hepatic cirrhosis with ascites or nephrotic oedema)
Primary hyperaldosteronism (Conn’s syndrome)
Resistant essential hypertension
When do aldosterone antagonists entail a risk of hyperkalaemia?
Potassium supplements (NOT to be given; advise against)
ACEIs or ARBs
In the body, where is carbonic anhydrase present?
Present in: • Renal tubules (PT) • Gastric mucosa • Pancreas • Eyes • Brain • RBC
Mechanism of action of carbonic anhydrase inhibitors?
Inhibit CAase reversibly; they increase excretion of HCO3- with Na+, K+ and H2O
Self-limiting diuretic action (weakly)
Side effects of carbonic anhydrase inhibitors?
Alkaline diuresis
Hypokalaemia
Metabolic acidosis (alkaline urine)
Extra-renal uses of carbonic anhydrase inhibitors?
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
Why is mannitol used as an osmotic diuretic?
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
Major site of action in the kidney of Mannitol?
Proximal tubule is where most iso-osmotic reabsorption of water occurs
How is mannitol administered?
IV 10-20% solution (no oral absorption)
Uses of osmotic diuretics?
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
Why are osmotic diuretics used for raised ICP and IOP when they do not enter the eye or brain?
Increased plasma osmolality extracts water from the brain parenchyma, CSF and aqueous humor
Common side effect of osmotic diuretics?
Hyponatraemic headache
Receptors for ADH?
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)
Examples of vasopressin analogues?
Desmopressin - oral or intranasal administration available; it is more potent and has a longer duration of action than vasopressin
Terlipressin
Types of diabetes insipidus?
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
Treatment of diabetes insipidus?
Neurogenic - desmopressin
Nephrogenic - paradoxical anti-diuretic effect of thiazides
Treatment of nocturnal enuresis (bedwetting) in children >10 years?
Oral/intranasal desmopressin
Treatment of variceal bleeding in portal hypertension?
Vasopressin infusion / terlipressin
What are the aquaretics/vaptans?
Competitive antagonists of vasopressin receptors
By blocking the V1a, vasoconstriction is prevented
By blocking V2, H2O reabsorption in the collecting tubule is prevented
Effects of vasopressin receptor antagonists (aquaretics/vaptans)?
Electrolyte-free aquaresis
Reduced urine osmolarity
Raised serum Na
Main clinical indications for aquaretics/vaptans?
In conditions of excess of direct/indirect ADH to correct hyponatraemia:
• SIADH
• CHF
• Cirrhosis
Examples of aquaretics/vaptans?
Conivaptan - non-selective (blocks both V1a and V2); can only be given as an IV formulation
Oral and V2 selective drugs:
• Tolvaptan
• Lixivaptan
• Satavaptan
Main side effect of aquaretics/vaptans?
Increased thirst
