Drugs affecting the kidneys Flashcards
what are diuretic agents
a drug that increases the excretion of both fluids and solutes
what is a natriuretic
increases Na+ excretion
what is a kaliuretic
increases k+ excretion
how to increase excretion of na+ and water by kidney
- reduce reabsorption of na+ from the filtrate
2. increased water loss secondary to na+ excretion
what are the 2 modes of action of diuretics
- direct action on the cells of the nephron
2. modification of content of the filtrate
what are the 2 major applications of diuretic agents
- reduce circulating fluid volume
- removal of excess body fluids (oedema)
- via actions on the kidney
name the classes of diuretic agents
- carbonic anhydrase inhibitors
- osmotic inhibitors
- loop diuretics
- thiazides and thiazide like diuretics
- potassium sparing diuretics- aldosterone antagonists, non aldosterone antagonists
where is the main site of action of carbonic anhydrase inhibitors
proximal tubule
what is the main site of action of osmotic diuretics
proximal tubule and descending loop of henle
where is the main site of action of loop diuretics
ascending loop of henle
what is the main site of action of thiazide diuretics
early distal tubule
what is the main site of action of potassium sparing diuretics
late distal tubule and early collecting tubule
where do most diuretic agents act
most are secreted into the proximal tubule and therefore produce their actions from the luminal side of the tubule
give examples of loop diuretics
furosemide, bumetanide
describe the action of loop diuretics
- most effective diuretics available
- often called high ceiling diuretics- lead to torrential urine flow
- inhibit Na+/K+/2Cl- transporters (NKCC2) in the thick ascending limb of loop of henle
- this reduces reabsorption of Na+, k+ and cl- - reduced na+ reabsorption leads to rapid and profound diuresis
- single dose: increases urine volume from 200-1200ml over 3 hours
what are the clinical uses of loop diuretics
- acute pulmonary oedema
- chronic heart failure
- cirrhosis of the liver
- nephrotic syndrome (reduced urine production)
- acute renal failure (reduced urine production)
what are the unwanted effects of loop diuretics
- dehydration
- K+ loss leading to low plasma K+ (hypokalaemia)
- metabolic alkalosis (due to H+ loss in urine)
- hypokalaemia can potentiate effects on cardiac glycosides
- deafness (when used with aminoglycoside antibiotics)
describe the sodium potassium exchange in the distal tubule when using loop diuretics
loop diuretics cause increased na+ delivery to the distal tubule
- this is exchanged for k+ in the distal tubule which is excreted in the urine
- this contributes to the hypokalaemia associated with loop diuretics
describe how thiazide diuretics work
- act in the distal tubule to inhibit the na+/cl- transport system
- cause moderate but sustained na+ excretion with increased water excretion
- moderately powerful diuresis- but maximum diuresis produced is considerably lower than that produced by loop diuretics
- well absorbed from GIT and long duration of action- up to 24 hours
what is the prototype thiazide diuretic
hydrochlorothiazide
give examples of thiazide diuretics
bendroflumethiazide (useful for mild/moderate heart failure)
how to thiazide like diuretics differ from thiazide diuretics
similar but have different molecular structures
give examples of thiazide like diuretics
indapamide, metolazone
what are the clinical uses of thiazide diuretics
- hypertension
- oedema
- mild heart failure
what are the unwanted effects of thiazide diuretics
- plasma k+ depletion (due to urinary k+ loss)
- metabolic alkalosis (due to urinary h+ loss)
- increased plasma uric acid- gout
- hyperglycaemia (increased blood glucose)
- increased plasma cholesterol (with long term use)
- male impotence (reversible)
what is indapamide currently used for
currently the preferred thiazide diuretic for the treatment of resistant hypertension due to lower incidence of unwanted effects
what are the symptoms of mild hypokalaemia
fatigue, drowsiness, dizziness, muscle weakness
what are the symptoms of severe hypokalaemia
abnormal heart rhythm, muscle paralysis, death
how can the issue of hypokalaemia be avoided in the use of diuretics
potassium sparing diuretics can be used
give examples of aldosterone antagonist potassium sparing diuretics
spironolactone and eplerenone
give examples of non aldosterone antagonist potassium sparing diuretics
amiloride and triamterene
describe how aldosterone antagonists work
- spironolactone metabolised to canrenone- active metabolite
- a competitive antagonist of aldosterone receptor - reduces na+ channel formation and its absorption from distal tubule
- limited diuretic action (not as potent as loop diuretics or thiazides)
- as mechanism depends on protein expression in distal tubular cells, so effects may take several days to develop
what are the clinical uses of spironolactone
- heart failure
- oedema
- primary hyperaldosteronism
- secondary hyperaldosteronism
what are the unwanted effects of aldosterone antagonists
- hyperkalaemia (increased plasma k+ levels)
- metabolic acidosis (due to increased plasma h+)
- GI upsets
- menstrual disorders, testicular atrophy
- eplerenone produces less unwanted effects than spironolactone
describe the use of non aldosterone antagonists
- weak diuretics- act on distal tubule to inhibit na+ reabsorption and decrease k+ excretion
- blocks luminal na+ channel by which aldosterone produces its main effects
- of little therapeutic use alone but useful in combination with potassium depleting diuretics as they limit hypokalaemia
what are the unwanted effects of non aldosterone antagonists
hyperkalaemia, metabolic acidosis, GI disturbances, skin rashes
explain why diuretics are sometimes used in combination
- to increase diuretic effect- some patients don’t respond well to one type of diuretic
- combinations of diuretics with different sites of action can sometimes provide a synergistic action - to avoid the unwanted effects of hypokalaemia
- combinations of loop/thiazides with potassium sparing diuretics
- diuretic preparations containing k+
give examples of diuretic combinations designed to minimise hypokalaemia
- loop diuretics with spironolactone
- loop diuretics with amiloride or triamterene
- thiazides with spironolactone
- thiazides with amiloride or triamterene
- diuretics with k+: eg. furosemide and K+
describe how water can act as a diuretic
- the most simple diuretic
- under normal conditions, increased water intake leads to increase in volume of urine excreted
- process is controlled by antidiuretic hormone (regulates water balance)
- normally some ADH is present in circulation, maintaining urine volume at approx 1.5L/day - increased fluid intake leads to reduced secretion of ADH from the posterior pituitary due to reduction in plasma osmolality
- reduced expression of AQP2 receptors on apical surface of distal tubules and collecting duct cells means more water excretion
does water as a diuretic increase excretion of na+
there is no increased excretion of na+
- AQP2 channel moves water only
what are potential ADH antagonists
investigational drugs which inhibit the effects of ADH at the collecting tubule
- 2 non selective agents: Lithium and democlocycline
what unwanted effects have been identified in potential ADH antagonists
- can cause diabetes inspidus
- renal failure reported
- Li+ can cause tremors, mental confusion, cardio toxicity, thyroid dysfunction and leukocytosis
- democlocycline shouldn’t be used in patients with liver disease
give examples of xanthines
caffeine, theophylline, theobromine
describe the effects of xanthines
- commonly found in tea and coffee
- produce their weak diuretic effect by increasing cardiac output and causing renal vasodilation
- results in increased renal blood flow which increases glomerular filtration rate and urine output
- rarely used clinically due to gastric irritant effects
