Diuretics Flashcards
What do each other following types of drugs cause: diuretic, natriuretic, aquaretic?
Diuretic - increased production of urine
Natriuretic - loss of sodium in urine
Aquaretic - loss of water without electrolytes
Where do the following drugs work on the nephron: Thiazides K+ sparing diuretics Carbonic Anhydrase inhibitors Osmotic diuretics ADH blockers Loop diuretics SGLT2 inhibitors ?
DCT
Collecting duct
PCT
Everywhere but mostly PCT
Collecting duct
AL LOH
PCT
How do carbonic anydrase inhibitors work?
85% of H2CO3 is reabsorbed in the PCT
Normal mechanism:
NA/ H exchanger -> H+ moved into lumen from cell + HCO3- -> H2CO3 (carbonic anhydrase) -> H2P + CO2 -> diffuses back into cell (carbonic anhydrase) -> H2CO3 -> transported into blood (H+ + HCO3-) through channel
CAI inhibit carbonic anhydrase so this can’t occur -> loss of NaHCO3 in urine
What are carbonic anhydrase inhibitors used to treat? What are the side effects and why?
✅glaucoma
✅mountain sickness
❌ bc there is more NaHCO3 reaching the collecting ducts - increased ENAC channels to help reabsorb Na but this drives Na/ K exchanger so can -> hypokalaemia metabolic acidosis (feel sick)
Tolerance develops after 2-3days
How do osmotic agents work? Give an example. Side effects? What’s it used to treat?
They act as a solute in the lumen to increase water lost in the urine
E.g. Mannitol
❌loss of water - reduced intracellular volume - hypernatremia risk
✅ raised ICP
Mostly PCT
How do SGLT2 inhibitors work? Why is this also beneficial to people with metabolic syndrome and hypertension?
Pct
They block the SGLT2 Na/ glucose cotransporter (from lumen to cell) increasing excretion glucose + Na
✅diabetes
-> increased Uric acid secretion (✅metabolic syndrome = hyperuraemia)
✅hypertension - acts as diuretic + increased detection Na macula densa DCT stops hyperfiltration/ RAAS
How do loop diuretics work? Give an example. Why can this be used to treat hypercalcaemia? Side effect
AL LOH
Block the Na/K/ 2cl channel (from lumen to cell)
E.g. furosemide
K in cell diffuses back into lumen via ROMK this (back-diffusion creates positive luminal membrane Vm this drives cation reabsorption) increases reabsorption Ca2+ + Mg
❌hypokalaemia metabolic alkalosis (increased excretion CL compared bicarbonate) - increased ENAC (which drives Nakatpase -> K excretion ) collecting duct
How do thiazide diuretics work? How does this effect calcium? Side effects?
DCT
Block Na/ CL cotransporter (from lumen to cell)
Less Na in cell upregulates Ca/ Na exchanger (Na in, Ca into blood) and the TRPV5 Ca channel (lumen to cell) to increase Ca reabsorption
❌more Na-> CD ENAC increases -> more K lost in urine -> hypokalaemic metabolic alkalosis (increased excretion CL compared to bicarbonate)
❌hyperuricaemia -> gout
How do K+ sparing diuretics work and why are they K+ sparing?
Collecting duct
Normally:
Aldosterone binds to mineralocorticoid receptor -> increased ENAC expression
But: spironolactone stops aldosterone binding. Amiloride/ triamterene block ENAC channels
ENAC causes Na reabsorption and K+ excretion through Na/K ATPase so when blocked the body keeps more K
How do aquarectics work? Give two examples and what they’re typically used to treat
On principle cells
ADH antagonists
Tolvaptan - blocks V2 receptors to stop ADH binding and preventing insertion of aquaporins-2
✅hyponatraemia
✅adult polycystic kidney disease - prevents cyst enlargement
Lithium -
✅bipolar but unwanted side effect is inhibits ADH (Through G protein inhibition)
❌ polyuric -> dehydration
What are two non-pharmacological substances which act as diuretics and how do they work?
Alcohol - inhibits ADH release
Caffeine - increases GFR and decreases tubular Na reabsorption
Generic adverse drug reactions to diuretics
Fluid loss -> hypovolaemia + hypotension -> activates RAAS -> acute kidney injury
Electrolyte disturbance - Na, k, mg, Ca
Metabolic abnormalities - acid/ base balance
Anaphylaxis/ photosensitive rash etc
Adverse thiazide reactions and drug drug interactions
Gout Hyperglycaemia Erectile dysfunction Increased LDL, TG Hypercalcaemia
hypokalaemia -> increased digoxin binding and toxicity
+ beta-blockers -> hyperglycaemia, hyperlipidemia, hyperuricaemia
+ steroids -> increased risk hypokalaemia
+ lithium -> lithium toxicity
+ carbamazepine -> increased risk of hyponatraemia
Adverse affects of frusemide
Ototoxicity
Alkalosis
Increased LDL, TG
Gout
Adverse affects of spironolactone
Hyperkalaemia
Impotence
Painful gynaecomastia (enlargement man’s breast)
Adverse affect of bumetanide
Myalgia
Drug drug interactions with K+ sparing
+ ACE inhibitors -> increased hyperkalaemia -> cardiac problems
Drug drug interactions with loop diuretics
+ aminoglycosides -> ototoxicity & nephrotoxicity
Hypokalaemia -> increased digoxin binding and toxicity
+ steroids -> increased risk hypokalaemia
+ lithium -> reduced lithium levels
Best drugs for treating hypertension
Diuretics:
Thiazide (vasodilation+)
Spironolactone
Loop diuretics
ACE inhibitors/ angiotensin 2 antagonists
Beta blockers
Best drugs for heart failure
Diuretics:
Loop diuretics
Spironolactone
ACE inhibitors/ ang 2 antagonists
Beta blockers
Maybe:
SGLT2- inhibitors
Tolvaptan?
Best drugs for decompensated liver disease
Diuretics:
Spironolactone
Loop
Maybe
Tolvaptan
Best drugs for nephrotic syndrome
Loop diuretics
Maybe thiazides
Maybe K sparing/ k supplements
Why are loop diuretics used for chronic kidney disease?
In CKD: water retention, acidosis, hyperkalaemia
Generally avoid K sparing diuretics
In patients with: chronic renal failure, nephrotic syndrome, heart failure etc why might they be gaining weight and becoming more oedematous when taking furosemide?
- oedema = swollen gut - don’t absorb pill
- lack albumin (e.g. nephrotic syndrome) can’t transport furosemide in blood
- furosemide moves through organic anion transporters blood-> PCT epithelial cell -> PcT lumen but in CKD lots of toxins which compete for OATs (non-specific)
- reduced nephron numbers in CKD
- heart failure - puma not working to move furosemide through blood
All these things mean need higher dose
What do you need to ensure your patient isn’t doing if you’re giving them a naturetic ?
Not consuming loads of salt
Why do diuretics start working less effectively on day 3/4? How can you avoid this?
Body detects more Na being excreted so upregulates channels and increases Na reabsorption
Use a combination of different diuretics
What is refractory oedema? How can you prevent this?
Peripheral oedema that doesn’t respond to dietary Na restriction and combined diuretic treatment often caused by cardiac/ pulmonary condition
- check salt intake (24hrs Na excretion if necessary)
- give furosemide IV if gut oedema likely
- find min effective dose
- give repeated bolus or infusion with short t1/2
Why is a thiazide much more likely to cause hyponatraemia and hypokalaemia than a loop diuretic?
Loop work at AL LOHso inhibit the hairpin method used to increase medulla concentration therefore less H20 reabsorbed at DL and collecting ducts so end up loosing more solutes (as conc is effectively less)
Thiazides work at DCT - less effect on tonicity