7. Diuretics Flashcards
What are the roles of the kidney?
Mnemonic REEM
R- regulatory: fluid balance, acid base balance, electrolytes balance
E- excretory: waste products, drug elimination
E- endocrine: renin, erythropoietin, prostaglandins, 1 alpha calcidiol
M- metabolic: vitamin D, insulin, morphine, paracetamol
Name the classes of drugs acting on the renal tubule?
COAL TAP
C: carbonic anhydrase inhibitors O: osmotic diuretics A: Aldosterone antagonists L: Loop diuretics T: Thiazide diuretics A: ADH antagonists P: Potassium sparing diuretics
Name 2 drinks which have a diuretic action and explain why
Alcohol - inhibits the release of ADH and therefore get a diuresis - urinate more than liquid consumed
Caffeine - increases the GFR and decreases sodium reabsorption. If you drink it regularly has no effect
How do diuretics reach their site of action?
- if given orally get absorbed through the gut into blood
- if given IV straight into blood
- can bind to albumin and be delivered to the peritubular capillaries which are next to the PCT
- they travel by OAT 1/3 transporters into PCT epithelial cells
- then travel via OAT 4 transporters to the lumen of the PCT
- from there they can make their way through the nephron to their site of action
In which kinds of patients, will diuretics be difficult to get to the site of action?
- nephrotic syndrome: these patients have an oedematous gut (as well as face, lungs and legs) making it difficult to absorb the diuretic in the gut
- heart failure: for diuretics to br absorbed need to have a good blood supply to the kidneys and gut which isn’t happening
- hypoalbuminaemia: if have low albumin then cannot transport the diuretic to the kidney tubules
Explain normal autoregulation i.e. when there is normal renal perfusion what do we see?
- if there is normal perfusion
- then intrarenal prostacyclin levels will be low
- prostacyclins are prostaglandins which cause afferent vasodilation
- GFR will be normal
- the level of circulating vasoconstrictors will be low
Explain what we would see in terms of autoregulation if there was reduced renal perfusion
- renal artery stenosis or hypovolaemia can lead to reduced renal perfusion
- this will lead to high levels of intrrenal prostacyclins which will lead to afferent vasodilation
- this will increase blood flow into the glomerulus
- this will maintain GFR - i.e. will be normal
- simultaneously there will be activation of RAAS and this will increase the levels of ATII and aldosterone which are circulating vasoconstrictors
- This will cause efferent vasoconstriction
How do NSAIDS and ACE inhibitors affect renal perfusion?
Particularly if someone has a disease state where there is reduced renal perfusion e.g. diabetes, hypertension, kidney disease etc…
- NSAIDs: block the action of prostacyclins (which are prostaglandins) so can prevent the afferent arteriole from vasodilating - hence can get a fall in GFR
- ACE inhibitors: reduce the activity of the RAAS system, so will get less ATII and aldosterone produced and thus reduced levels of circulating vasoconstrictors and hence less efferent arteriole vasoconstriction -hence can get a fall in GFR
In essence they are preventing normal renal autoregulation from occuring
What is the mechanism of action of carbonic anhydrase inhibitors e.g. acetazolamide?
- they inhibit the action of carbonic anhydrase in the PCT
- this prevents the reabsorption of sodium and bicarbonate ions in the PCT
Why would we use Carbonic anhydrase inhibitors e.g. acetazolamide?
- not used as diuretic - this is because any sodium not absorbed in the PCT would be reabsorbed later on
- mainly use for glaucoma and altitude sickness
Name some side effects of Carbonic anhydrase inhibitors
- metabolic acidosis (because not reabsorbing bicarbonate)
- renal stones
How do osmotic diuretics e.g mannitol work?
- osmolarity is the concentration of solute particles per litre
- osmotic diuretics increase the osmolarity of blood and renal filtrate
- this prevents the reabsorption of water along the nephron and so it is lost in urine (diuresis)
What is mannitol (osmotic diuretic) used for?
High intracerebral pressure
Name a side effect of mannitol (osmotic diuretic)
Allergic reaction
What is the mechanism of action of loop diuretics e.g. furosemide?
- they act on the TAL of loop of henle
- on the NKCC2 (sodium, potassium, 2 chloride)
- reduce reabsorption of sodium into the medullary interstitium
- this reduces the osmolarity of the interstitium
- therefore there is less of an osmotic gradient for water to be reabsorbed through aquaporin channels in the collecting duct
- also reduce potassium ion reabsorption
Why might we use a loop diuretic e.g. furosemide?
Oedema e.g. in advanced CKD
Name some side effects of loop diuretics
- Hypokalaemia (not reabsorbing potassium)
- gout (due to hyperuricaemia)
- metabolic alkalosis
- increased LDL, increased triglycerides
- ototoxicity particularly with large rapid IV doses
Note with the diuretic Bumetanide can get myalgia
What is the mechanism of action of thiazide diuretics e.g. bendroflumethiazide?
- DCT (distal convoluted tubule)
- NCC transporter (sodium 2 chloride)
- reduce the reabsorption of sodium from the DCT into the medullary interstitium thus reducing the osmolarity of the interstitium
- as a result, there will be less of an osmotic gradient for water to be reabsorbed from the DCT into collecting duct through aquaporin channels
- additionally, sodium ions move from the interstitial fluid into the epithelial cells by NCX (sodium-calcium exchanger) and this leads to increased calcium in the interstitial fluid
Why might we use thiazide diuretics e.g. bendroflumethiazide?
Hypertension, and it has vasodilatory effects also
What are the side effects of thiazide diuretics?
- hypercalcaemia
- hypokalaemia
- gout
- increased LDL and triglycerides
- hyperglycaemia
- erectile dysfunction
How do loop diuretics diuretics lead to gout?
- diuretics compete with uric acid for secretion into the PCT and thus more uric acid is left behind in the blood
- this can then precipitate leading to the formation of monosodium urate crystals
- this causes gout
How do loop and thiazide diuretics cause hypokalaemia?
- sodium ions move from tubular lumen into principal cells through ENac making the tubular lumen more negatively charged
- more of an electrical gradient for potassium ions to be secreted into the tubular lumen through ROMK channels
- this is why we give these drugs in combination with a potassium sparing diuretic or by giving potassium ion supplements
Which is more effective - loop or thiazide diuretics? Why?
- loop diuretics are more effective
- because 25% of sodium ion reabsorption takes place in the TAL compared to only 5% in the distal convoluted tubule
- so loop diuretics cause a loss of more sodium ions and hence more water
Which drug is more likely to cause hypokalaemia - thiazides or loop?
- both cause hypokalaemia
- thiazides more likely
How do aldosterone antagonists work?
- work in the DCT and CD (collecting duct)
- reduce expressions and activity of the Na-K ATPase and of the ENac
- this reduces sodium ion reabsorption into the medullary interstitium
- this reduces the osmolarity of the medullary interstitium
- therefore there will be less water reabsorption through the aquaporin channels in the collecting duct
- there is less of an electrical gradient for potassium so it wont be secreted through ROMK
When would we use an aldosterone antagonist?
- heart failure
- ascites
- hypertension
- hyperadrenalism
What are the side effects of spironolactone?
- hyperkalaemia - as its potassium sparing
- impotence
- painful gynaecomastia
When we use an ADH antagonist?
- hyponatraemia
- preventing cyst enlargement in adult polycystic kidney disease as aquaporins are related to cyst growth
What are the main side effects of ADH antagonists?
- hyeprnatraemia
- deranged liver function
What is the mechanism of action of ADH antagonists e.g. lithium?
- acts on a-intercalated cells in the late DCT and CD
- inhibits the action of ADH
- reduces the expression of aquaporin channels and therefore less reabsorption of water in late DCT and CD
Name the generic adverse drug reactions to diuretics
- anaphylaxis/photosensitive rash
- hypovolaemia and hypotension - may then lead to activation of RAAS and possible AKI
- electrolyte disturbance
- metabolic abnormalities
What is the danger of giving a loop diuretic with aminoglycosides?
Increased risk of ototoxicity and nephrotoxicity
What is the danger of giving a ACE inhibitor with potassium sparing diuretic?
Can get increased hyperkalaemia which could lead to cardiac problems
What is the danger of giving a Thiazides/loop and digoxin ?
The hypokalaemia can lead to increased digoxin toxicity
What is the danger of giving a thiazide and beta blocker?
Hyperglycaemia
Hyperlipidaemia
Hyperuricaemia
What is the danger of giving a thiazide/loop + steroid?
Increased risk of hypokalaemia
What is the danger of giving a loop and lithium and a thiazide and lithium?
Thiazide: lithium toxicity
Loop: reduced lithium levels
Think loop will make you loopy (cause lithium used for bipolar so a loop diuretic reducing lithium levels can make you unwell)
What is the danger of giving a thiazide and carbamezapine?
Increased risk of hyponatraemia
Name 5 conditions we can use diuretics for
- hypertension
- heart failure
- decompensated liver disease
- nephrotic syndrome
- chronic kidney disease
