3.2 Diuretics Flashcards
what are the four functions of the renal system?
regulatory
excretory
endocrine
metabolism
what are the regulatory functions of the renal system?
fluid balance
acid-base balance
electrolyte balance
what is the excretory function of the renal system?
waste products (protein metabolism) drug elimination (glomerular filtration and tubule secretion)
what is the endocrine function of the renal system?
renin
erythropoietin
prostaglandins
1-alpha calcidiol
what is the metabolic function of the renal system
vitamin D
polypeptides (insulin)
drugs (morphine and paracetamol)
what is the function of carbonic anhydrase inhibitors
reduce the absorption of NaHCO3 in the proximal convoluted tubule. Cause hypokalaemic metabolic acidosis initially but tolerance develops after a few days
what is the function of mannitol?
mannityol is an osmotic agent that causes diuresis. It has a high oncotic pressure and draws water into the lumen of the proximal convoluted tubule. Causes reduced intracellular pressure and a hypernatraemia risk
what is the function of SGLT2 inhibitors?
they inhibit the sodium glucose co transporter in the proximal convoluted tubules. This increases glucosuria and decreases plasma glucose levels. it also causes increased uric acid secretion and decreases plasma uric acid which helps in metabolic syndromes. other clinical findings include decreased body weight, decreased blood pressure and decreased glomerular hyperfiltration
what is the function of loop diuretics
loop diuretics act on the loop of henle to inhibit the Na/K/2Cl cotransporter. This results in the loss of sodium and water. It can cause hypokalaemic metabolic acidosis and increased calcium loss.
why do loop diuretics cause electrolyte disturbances?
usually K+ is transported into the cells of the thick ascending limb via the Na/K/2Cl cotransporter. This then allows back diffusion of the K+ through ROMK channels to create a positive luminal membrane. This positive charge provides a driving force for the absorption of divalent cations such as calcium and magnesium paracellularly. As loop diuretics inhibit the Na/K/2Cl cotransporter, this gradient isnt as strong and there is greater loss of calcium and magnesium.
what is the function of thiazide diuretics?
block the Na/Cl cotransporter in the distal convoluted tubule. This causes loss of sodium and water in urine. also causes hypokalaemic metabolic alkalosis and increased calcium reabsorption
why do thiazide diuretics cause increased calcium reabsorption?
as there is less sodium reabsorption, there is greater activation of the Na/Ca exchanger on the basolateral surface of the distal convoluted tubule cells. Calcium enters the cell via TRPV5 transporters.
why do thiazide diuretics cause alkalosis?
as less sodium is being reabsorbed, there is increased activation of the Na/H+ exchanger in the distal convoluted tubule resulting in a loss of hydrogen ions
what drug class is tolvaptan?
ADH antagonist
where is the site of action of amiloride?
the ENAC channels in the apical membrane of the principal cells of the collecting ducts
where is the site of action of spironolactone?
the intracellular aldosterone mineralcorticoid receptor in the principle cells of the collecting ducts
what is the mechanism of action of tolvaptan?
acts to block the V2 receptor of ADH on the cells of the collecting ducts. results in less aquaporin-2 channels and therefore less water reabsorption. as there is less water reabsorbed, less sodium is reabsorbed.
what is tolvaptan used to treat?
hyponatraemia
prevent cyst enlargement in APCKD
How is lithium a diuretic?
used to treat bipolar disorder but also has the unwanted side effect of inhibiting ADH.
what are the diuretic effects of alcohol and caffeine?
alcohol inhibits ADH release from the posterior pituitary
caffeine increases GFR and decreases tubular sodium release
what are some of the common ADRs of diuretics?
Hypovolaemia & hypotension
– Activates RAAS
– Can lead to acute kidney injury
Electrolyte Disturbance (Na+, K+, Mg2+, Ca2+)
Metabolic Abnormalities (depends on individual drug)
Anaphylaxis / photosensivity rash etc (rare)
what are some of the common ADRs associated with thiazide diuretics?
gout hyperglycaemia erectile dysfunction increased LDL and TG hypercalcaemia
what are some of the common ADRs associated with frusemide?
ototoxicity
alkalosis
increased low density lipoproteins and triglycerides
gout
what are some of the common ADRs associated with spironolactone?
hyperkalaemia
impotence
painful gynaecomastia
what are some of the common ADRs associated with bumetanide?
myalgia
what is the drug class of bumetanide?
loop diuretic
what are the potential interaction with lisinopril?
interact with K+ sparing diuretics to cause increased hyperkalaemia resulting in cardiac problems
what are the drug interactions of loop diuretics?
aminoglycosides and loop diuretics interact to cause ototoxicity and nephrotoxicity
what are the drug interactions of thiazide and loop diuretics?
both interact with digoxin, a cardiac glycoside to cause increased digoxin binding and toxicity
interact with steroids to cause hypokalaemia
interact with lithium to cause lithium toxicity with thiazides and reduced lithium with loop diuretics
what drugs are used in treatment of hypertension?
thiazide spironolactone loop diuretics beta blockers ACEi/ ARBs
what drugs are used in the treatment of heart failure?
- Loop diuretics
- Spironolactone – non-diuretic benefits
- ACE Inhibitors / Ang II antagonists
- β-blockers
what drugs are used in the treatment if decompensated liver disease?
spironolactone
loop diuretics
what drugs are used in the treatment of nephrotic syndrome?
Loop diuretic (often big doses needed)
• +/- thiazides
• +/- potassium-sparing diuretic / potassium supplements
how do we treat CKD?
the decrease in GFR leads to salt and water retention and patients become hyperkalaemic and acidotic. treat with loop diuretic and SGLT2s. Avoid potassium sparing diuretics
what are the different stages of CKD?
stage 1 = 90% of the kidney functioning
2 = 90 to 60% of the kidney functioning
3 = 60 to 30 % of the kidney functioning
4 = 30 to 15% of the kidney functioning
5 = less than 15 % of the kidney functioning
what factors can affect the functioning of furosemide?
- gut oedema. can stop the absorption into the epithelial cell
- CKD - furosemide is transported into the PCT epithelial cell via the OAT1 / 3 transporter that is non specific. In CKD the OAT is being used to transport other toxins across the renal tubule. Reduced amounts of nephrons
why do thiazide and loop diuretics cause hyperuricaemia?
Competition at OATs is one mechanism particularly for thiazide like drugs and action at the URAT1 transporter is another. Cardinally their respective diuresis and hypovolemia increase the risk of uric acid crystal formation.
describe how thiazide and loop diuretics cause hyponatraemia and hypokalaemia
Thiazide diuretics are more likely to cause hyponatraemia because they act at the distal convoluted tubule. They do not affect the medullary osmotic gradient. The thiazide diuretics inhibit Na reabsorption (the Na/Cl cotransporter is inhibited). Water is able to be reabsorbed at the collecting duct as the osmotic gradient has been maintained by the action of the Na/K/Cl cotransporter at the ascending loop. Water is reabsorbed (ADH action) and the relative Na concentration in the plasma is lower – more water proportionally to Na. With loop diuretics the osmotic gradient is disrupted because Na is not reabsorbed in the ascending loop (the Na/K/Cl cotransporter is inhibited). Because the gradient is lost, at the collecting duct less water is reabsorbed and so the relative Na concentration to water is maintained – less likely to observe hyponatraemia. It is the increased water reabsorption relative to Na that predominantly results in hyponatraemia, not a loss of Na. Both thiazide and loop diuretics can cause hypokalaemia as K is excreted (K channels) in exchange for Na (ENaC) in the collecting duct mediated by aldosterone
what is Bartter’s and Gitelman’s syndrome?
inherited autosomal recessive conditions resulting in defects of renal tubular excretion and reabsorption of electrolytes.
what is liddle’s syndrome?
autosomal dominant genetic disorder characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Excess reabsorption of sodium and loss of potassium from the renal tubule as there is increased function of the kidney
what are the main uses of carbonic anhydrase inhibitors?
glaucoma
altitude sickness
what are they main uses of osmotic diuretics?
reduce high intracerebral pressure
what are the main uses of loop diuretics
oedema
hypertension in advanced CKD
what are the main uses of thiazides?
hypertension
what are the main uses of amiloride?
low potassium where diuretic is required
what is the main uses of aldosterone antagonists
heart failure
ascites
hypertension
hyperaldrenalism
what are the main uses of ADH antagonist ?
hyponatraemia
what are the main side effects of carbonic anhydrase inhibitors?
acidosis
renal stones
what are the main side effects of osmotic diuresis?
allergic reactions
what are the main side effects of loop diuretics ?
alkalosis metabolic effects ( increase urate and lipids )
what is the main side effects of thiazides?
Electrolyte disturbance Metabolic effects (increased urate, glucose, lipids, impotence)
what are the main side effects of amiloride?
hyperkalaemia
what are the main side effects of aldosterone antagonists
hyperkalaemia
gynaecomastia
what are the main side effects of ADH antagonists
hypernatraemia
