Drugs Affecting the Kidney Flashcards
Diuretic Agents
A diuretic: a drug that increases the excretion of both fluids and solutes
Natriuretic: Increases Na+ excretion, Kaliuretic: increases K+ excretion
Most diuretics increase excretion of Na+ and water by the kidneys - reduced Na+ reabsorption = increased water loss
Aquaretic agents increase urine excretion without increasing Na+ excretion
2 modes of action of diuretics: direct action on nephron, and modification of content of the filtrate
Why use diuretics
Reduce circulating fluid volume & removal of excess body fluid (oedema)
Uses: hypertension, chronic heart failure, liver cirrhosis, renal disease, premenstrual oedema, toxic oedema, increase elimination of drugs, rapid weight loss
Other uses - reduced intraocular pressure with glaucoma, and reduces CSF pressure for epilepsy
Loop diuretics
Work on Ascending LOH
Most effective diuretics available
Increase Na+ delivery to DT (exchanged for K+ in DT - which is excreted)
Inhibit Na+/K+/2Cl- transporters
Single dose: can increase urine volume from 200 to 1200mls over 3 hrs
Clinical uses: Acute pulmonary oedema, Chronic heart failure, Cirrhosis of the liver, Resistant hypertension – used for more acute cases; and nephrotic syndrome/AKI (reduced urinie production.
Unwanted effects: dehydration, hypokalaemia, metabolic alkalosis, deafness
Thiazide Diuretics
Act in DT to inhibit apical Na+/Cl- cotransporter
Cause moderate but sustained Na+ and water excretion
Lower diuresis than loop diuretics, but well absorbed and duration of action: up to 24 hours
Clinical uses: hypertension, oedema, mild HF
Unwanted effects: Plasma K+ depletion, metabolic alkalosis, increased plasma uric acid, hyperglycaemia, increased plasma cholesterol, male impotence
Problems with hypokalaemia
Due to increased loss of K+, loop diuretics and thiazides can cause hypokalaemia - an unwanted effect:
Mild hypokalaemia: fatigue, drowsiness, dizziness, muscle weakness
Severe hypokalaemia: abnormal heart rhythm, muscle paralysis, death
Potassium-sparing diuretics can avoid this problem - Act on distal tubules to inhibit Na+ reabsorption; however, K+ is not secreted into the distal tubule
Two subcategories:
Aldosterone antagonists (e.g. eplerenone, spironolactone)
Non-Aldosterone antagonists (e.g. amiloride, triamterene)
Potassium sparing diuretics - aldosterone antagonists - Spironolactone (& Eplerenone)
Spironolactone metabolised to canrenone (its active metabolite) - a competitive antagonist of aldosterone (mineralocorticoid) receptor
Reduced Na+ channel formation and its absorption from distal tubule
Limited diuretic action (not as potent as loop or thiazide)
As mechanism depends on reduction of protein expression in distal tubular cells, effects normally take several days to develop
Clinical uses: HF, oedema, resistant hypertension; not long term
Unwanted effects: hyperkalaemia, metabolic acidosis, GI upset, gynaecomastia, menstrual disorders, testicular atrophy
Potassium sparing diuretics - Triamterene and Amiloride
Weak diuretics - act on DT to inhibit Na+ reabsorption & decrease K+ excretion
Blocks luminal Na+ channel by which aldosterone produces its main effects
Useful in combination with K+ depleting diuretics
Unwanted effect: hyperkalaemia, metabolic acidosis, GI disturbances, skin rashes
Diuretics in combination
Increase diuretic effect: some patients do not respond well to just one type of diuretic - combination provide a synergistic action
Avoid unwanted effects of hypokalaemia: combinations of loop diuretics or thiazides with potassium-sparing diuretics; Diuretic preparations containing K+
Diuretic combinations
Loop diuretics with spironolactone
Loop diuretics with amiloride or triamterene
Thiazides with spironolactone
Thiazides with amiloride or triamterene
Carbonic Anhydrase inhibitors (azetozolamide)
Blocks sodium bicarbonate (NaHCO3) reabsorption in PT
These were the earliest diuretic agents developed
Causes only weak diuresis so not now commonly used as diuretic agent
Used for treatment of glaucoma (reduces intraoccular pressure) & epilepsy (reduces volume and pressure of CSF)
Unwanted effects: metabolic acidosis (due to excretion of HCO3-), and enhances renal stone formation (due to alkaline urine)
Osmotic Diuretics (mannitol)
Non-reabsorbable solute which undergoes glomerular filtration
Excreted within 30-60 min (Diuresis begins in 30-60 min and persists for 6-8 h)
Clinical uses: treatment of raised intercranial pressure (cerebral oedema), treatment of intraoccular pressure (glaucoma), if given orally, can cause ‘osmotic diarrhoea’ – eliminates toxins, may be useful for treatment of acute renal failure
Unwanted effects: presence in blood also exerts osmotic pressure leading to increased plasma volume – can’t be used in patients with hypertension
Water as a diuretic
Under normal conditions, increased water intake leads to increase in volume of urine excreted
Process is controlled by a hormone: antidiuretic hormone
Normally some ADH is present in the circulation, maintaining urine volume at approximately 1.5 L/day
However, this can be adjusted in various ways…e.g. effects of alcohol, nicotine
Increased fluid intake leads to reduced secretion of ADH from the posterior pituitary due to reduced in plasma osmolarity
Reduced expression of AQP2 receptors on apical surface of DT and collecting duct cells means more water excretion
ADH Antagonists - possible new diuretic agents
Potential ADH Antagonists
Investigational drugs which inhibit the effects of ADH at the collecting tubule
Two nonselective agents (orally active) - Lithium (Li+) and demeclocycline (also Amphotericin B).
Toxicity is a Problem – can cause diabetes insipidus, renal failure reported for both Li+ and demeclocycline, Li+ can cause tremors, mental confusion, cardiotoxicity, thyroid dysfunction and leukocytosis, Demeclocycline shouldn’t be used in patients with liver disease
Coffee as a weak diuretic
Produce their weak diuretic effect by increasing cardiac output
Possibly also some vasodilatation of the glomerular afferent arteriole
Results in increased renal and glomerular blood flow which increases glomerular filtration rate and urine output
Rarely used clinically due to gastric irritant effects
