S3 L2 Diuretics Flashcards
What are the main functions the kidney?
- Regulatory
- Fluid balance
- Acid-base balance
- Electrolyte balance - Excretory
- Waste products
- Drug elimination
→ Glomerular filtration
→ Tubular secretion - Endocrine
- Renin
- Erythropoetin
- Prostaglandins
- 1α- calcidol - Metabolism
- Vit D
- Polypeptides
→ Insulin
- Drugs
→ Morphine
→ Paracetamol
Where do different drugs act on the renal tubule?
- Carbonic anhydrase inhibitors → PCT
- Osmotic diuresis → PCT and throughout
- SGLT2 inhibitors → PCT
- Loop Diuretic → TAL
- Thiazide → DCT
- Potassium sparing diuretics → DCT and CD
- Aldosterone antagonists → CD
- ADH antagonists → CD
Define:
- Diuretics?
- Natriuretic?
- Aquaretic?
D- Increased production
N- Loss sodium in the urine
A- Loss of water without electrolytes
What do carbonic anhydrase inhibitors do?
Prevent carbonic anhydrase working Stops conversion: - CO2 + H2O ←→ H2CO3 ←→ H+ + HCO3- Loss of NaCO3 → 66% of filtered and 85% of NaHCO3 is normally reabsorbed in the proximal tubule Hypokalaemic metabolic acidosis → HCO3- excreted in urine → Enhanced Na+ delivery to the CD, taken up by ENaC, K+ excreted into urine Tolerance develops after 2-3 days
What are osmotic agents?
Mannitol
- Can’t be reabsorbed
- Increases the osmolality in the filtrate
- Draw water out of cells
- Reduced intracellular volume
- Hypernatremia risk
What are SGLT2 inhibitors?
Inhibit Na+ and glucose uptake in PCT ↑osmolality in the filtrate → water follows ↑Plasma glucose ↓Body weight ↓BP ↓Plasma uric acid ↓Glomerular hyperfiltration
How do loop diuretics work?
Inhibit the Na+/K+/2Cl- channel
- Loss of Na+ and H2O (25% of filtered reabsorbed)
- Hypokalemic metabolic alkalosis
→ Enhanced Na+ delivery to the CD, taken up by ENaC, K+ excreted into urine
- Increase Ca2+ loss
→ Normally K+ uptake and then K+ excreted, build up of +ve change forces Ca2+ and Mg2+ paracellularly
What do thiazide diuretics do?
Block Na+/Cl- cotransporter 5% of filtered reabsorbed - Loss of Na+ and H2O - Hypokalaemia metabolic alkalosis - Increased Ca2+ reabsorption as Na+/ Ca2+ exchanger works in opposite direction- more Na+ brought out of plasma into cell, Ca2+ goes into plasma so then more Ca2+ reabsorbed - hypercalcaemia
How does aldosterone work?
Increase expression of ENaC and Na+/K+ ATPase in principle cells of the collecting duct
How do amiloride and spironolactone work?
Amiloride → ENaC channel blocker (potassium sparing)
Spironolactone → aldosterone blocker → stop ↑ENaC and ↑Na+/K+ ATPase expression therefore reducing Na+ uptake
How are amiloride ad spironolactone potassium sparing?
Only affect Na+ reabsorption
Reduced the activity of the Na+/ K+ ATPase resulting in less K+ being excreted
What are ADH antagonists?
Aquaretics- no affect on Na+ just water loss
1. Tolvaptan
ADH anatogonist
Diuretic but not natriuretic
Used to treat hyponatraemia (looks like low Na+ because of ↑H2O) (and prevent cyst enlargement in APCKD)
2. Lithium
- Treat bipolar disorder
- Inhibits action of ADH
- Need to keep up with water intake to avoid dehydration
How do the ADH antagonists work?
Tolvaptan block the ADH receptors
Lithium work on G protein along the cascade
Prevents insertion of aquaporin into the collecting duct
Preventing reabsorption of water
What other substance can have an diuretic action?
Alcohol- inhibits ADH release
Caffeine- ↑GFR and ↓tubular Na+ reabsorption
What are some of the adverse reactions that diuretics can cause?
Hypovolemia and hypotension
- Activate RAAS
- → AKI (hypoperfusion)
Electrolyte disturbance (Na+, K+, Mg2+ and Ca2+)- expect aquaretic
Metabolic Abnormalities (depends on individual drug)
Anaphylaxis/ photosensitivity, rash etc… rare
What are some of the common adverse drug reactions for thiazides?
Gout → Uric acid reabsorption Hyperglycaemia Erectile dysfunction ↑LDL ↑TG Hypercalcaemia
What are some of the common adverse drug reactions for frusemide?
Ototoxicity
Alkalosis - remove the H+
↑LDL ↑TG
Gout
What are some of the common adverse drug reactions for spironolactone?
Hyperkalaemia - potassium sparing
Impotence
Painful gynaecomastia
What are some of the common adverse drug reactions for bumetanide?
Myalgia - pain or tenderness in one or more muscles of the body
How do the drug interact with each other?
ACEi and K+ sparing → hyperkalaemia - cardiac problems
Aminoglycoside + loop diuretics → ototoxicity and nephrotoxicity
Digoxin + thiazide and loop → Hypokalaemia - increased digoxin binding and toxicity
B-blockers + thiazide → hyperglycaemia, hyperlipidaemia, and hyperuricaemia
Steroids + thiazide + loop → Hypokalaemia
Lithium + thiazide + loop → Lithium toxicity (thiazides), reduced lithium levels (loop)
Carbamazepine + thiazide + loop → Increased risk of hyponatraemia
What are the uses of diuretics?
Hypertension Heart failure Decompensated liver disease Nephrotic syndrome Chronic kidney disease
What diuretics are used to treat hypertension?
Thiazide diuretics
Spironolactone → secondary hypertension, Liddle syndrome (ENaC channels are always on), inhibits aldosterone preventing expression of ENaC channels
Loop diuretic - accommodation downstream (compensated for)
(ACEi/ ARBs and B blockers also used)
How is heart failure treated?
Traditional - Loop Diuretics - Spironolactone (- ACEi/ ARB + B blockers)- not diuretics Novel - SGLT-2 inhibitors - Tolvaptan
What is secondary hyperalodersteonism?
Body trying to compensate for things that have gone wrong
Arterial ↓BP - either due to hypovolemia (trauma associated) or HF- sense hypovolemia because heart not pumping very well + blood flow is reduced but actually volume is normal or ↑
Activate RAAS and sympathetic system to ↑ Volume= fluid overload- need diuretics
What is decompensated liver disease treatment?
Similar to HF- detects effective fluid volume has decreased BUT because everything has gone leaky (not in blood stream) due to decrease albumin levels from liver
Traditional
- Spironolactone
- Loop Diuretics
Novel
- Tolvaptan - prevent aquaporins insertion + water reabsorption
What is nephrotic syndrome?
Kidney function is normal but loose albumin in the urine so loose oncotic pressure hence fluid leaks into tissue- secondary aldosteronism
- Loop diuretics needed
- (+/-) Thiazides
- (+/-) Potassium sparing diuretic/potassium supplements
What is chronic kidney disease?
Glomerular doesn’t function as well → Loose nephrons
↓GFR leads to salt and water retention
Loop Diuretics
Alkalosis and kalliuretic (↓remove K+) effects potentially beneficial
Generally avoid K+ sparing diuretics
- Role for SGLT2 inhibitors in the future - reduce speed of kidney damage
What is diuretic resistance?
Initially starts off really well - loose loads of fluids
Then gradually the kidney accommodates
Upregulation of channels further downstream
What affects diuretic delivery to the renal tubule?
Different parts of the absorption and metabolism can be affected…
1. Gut wall- need to absorb tablet- oedema- don’t absorb all the renal tablet
2. Blood- needs to bind to albumin to be transported- need enough albumin
3. Uptake into PCT epithelial cell - Actively transported via OATs (apical 1 or 3, basolateral 4)
4. PCT lumen
Patients actually need a lot more frusemide to get it to where it is actually needed
What is the importance of salt in the diet?
Drugs to reduce salt
Need to ensure you reduce salt in the diet
Problem- hedonistic behaviour - loose salt become thirsty and crave salt
What is refractory oedema?
Get rid of salt and water
Body detect loss
Reabsorbs it further down the nephron
How is refractory oedema managed?
Check salt intake- 24hours sodium excretion if necessary
Give fruosemide IV if gut oedema likely
Find minimum effective dose
Give repeated bolus or infusion (short t1/2)
What is the mechanism for managing BP?
↓BP and BV Baroreceptors and kidney detect ↑CO, vasoconstriction, thirst, ↑NaCl and water reabsorption ↑ECF volume ↑BP
How should diuretics be used to increase effectiveness?
Used in combination
Why is there a difference in electrolyte balance between thiazide and loop diuretics?
Thiazide→ disrupt the electrolyte balance more than loop diuretics, acts on the isosmotic part of the kidney, so inhibiting it has less effect on tonicity- less effect on NaCl and K+ so less effect on water
Loop diuretics→ ascending limb, Na+ reabsorbed helps concentrate the medulla and maintain counter current mechanism, high osmolality in the medulla- water, urea absorption due to hypertonic interstitium
What is Bartter’s and Gitelman’s syndrome?
Bartter’s syndrome → Blockage of Na+/K+/2Cl- channels
Gitelman’s syndrome → Blockage of Na+/Cl- channel
No reabsorption of these electrolytes so no reabsorption of water
Results in hypotension
What is Liddle’s syndrome?
Syndrome results from increased function
Increased ENaC
Results in hypertension
Give a brief summary of the diuretics and what they are used for?
Carbonic anhydrase inhibitors → glaucoma, altitude sickness
Osmotic diuretics → reduce high intracerebral pressure
Loop diuretics → oedema (+/- hypertension in advanced CKD)
Thiazides and thiazide-like → hypertension
Potassium sparing diuretics → low potassium where diuretic required
Aldosterone antagonists → HF, ascites, hypertension, hypoadrenalism
ADH antagonists → Hyponatraemia
