Diuretics Flashcards
In a nut shell, what is the action of diuretics?
Decreases salt and water reabosorption in the tubules.
How do the kidneys control the ECM fluid volume?
By adjusting NaCl and H2O excretion
e.g. if NaCl intake > output renal failure results, and oedema develops
How is Na+ reabsorbed in the kidney?
Driven primarily by Na+/K+ ATPase on basolateral membrane (blood side) of epithelial cells throughout the nephron.
This is an energy requiring pump that maintains low Na+ and high K+ within the cell (3Na+ out, 2K+ in).
Na+ moves from the lumen into the cell firstly through passive movement down an electrochemical gradient.
Water accompanies reabsorbed ions (via aquaporin channels to maintain osmotic balance).
Diuretic inhibit this Na+ reabsorption - water is retained in tubules and excreted.
How do osmotic diuretics work?
They are freely filtered into the glomerulus but poorly reabosrbed in proximal tubules. This limits reabsorption of water across water permeable segments (proximal tubule, thin loop of henle and collecting duct)
Osmotic diuretics have their greatest affects in proximal tubules - since this is where most iso-osmotic reabsorption of water happens. This increases urine, and therefore causes diuresis.
Osmotic diuretics are pharmocologically inert but osmotically active.
How do diuretics get into the tubules?
Mannitol (osmotic diuretic) is filtred through glomerulus, whilst other diuretics are highly protein bound and aren’t filtered.
Most diuretics are transported across organic acid transporters into the nephron in the proximal tubule. (since PCT mediates secretio and reabsorption of weak acids/bases)
What are the four sites of diuretic action in the nephron?
- PCT
- DCT
- thick ascending limb
- Collecting duct
*
What class of diuretics act on the thick ascending loop?
Loop diuretics e.g. frusemide
How do loop diuretics work?
They primarily inhibit luminal NKCC2 (Na+, K+, Cl-) co-transporter by competing with Cl- for binding.
The NKCC2 in TAL has capacity to reabsorb ~25% of filtered Na+ load. Downstream nephron elements do not have the reabsorptive capacity to recover this level of filtrate.
Loop diuretics also disrupt the positive transepithelial potential, this increases excretion of Na2+, Ca2+, Mg2+ (a potential difference created by apical ROMK and basolateral CLC-K2 channels to create ~10mV difference to drive paracellular reabsorption of cations).
What are the PK for Frusemide?
- PO (Oral administration): Rapid absorption. Max effect in 1-2 hours, lasts for 4-6 hours in blood.
- IV: Onset wth 2-10 min. Max effect in 30 mins, lasts 2 hours in blood.
- It’s is extensively bound to proteins (90%)
- Does not pass directly into glomerular filtrate but is actively secreted/excreted into proximal tubule by organic acid transporters (remainder 35% metabolised by glucuronidation/CYP 450 mechanisms).
More fun facts
What are the therapeutic uses of Loop Diuretics?
- Hypertension: effective even in patients with impaired renal function
-
Oedema of
- Cardiac, renal or hepatic origin
- Acute pulmonary oedema
- Hyperkalaemia (Since it increases K+ excretion by affecting transepithelial potential)
- Symptomatic hypercalcaemia
What are the side effects and interations of Loop diuretics?
- Hypovolemia, dizziness, syncope
- Na+ loss (hyponatraemia)
- K+ loss (hypokalaemia)
- can predispose digitoxin toxicity
- Mg2+ and Ca2+ depletion
- Metabolic alkalosis
- Hyperuricaemia (uric acid retention) can precipitate gout since loop diuretics compete with uric acid excretion
- Prelonged use:
- Ototoxicity - hearing loss (loss of endolymph electrolytes)
- Can increase renal toxicity of cephalosporin antibitoics (compete for weak organic acid transporters on PT)
How do Thiazide diuretics work? (Bendroflumethiazide, chlorothiazide)
Thiazides are a mild to moderate diuretic.
- They inhibt Na+/Cl- co-transport and reabsorption in cortical diluting segment of distal tubule (only reabsorbs ~5% filtered Na+)
- Leads to modest increase in Na+ and water excretion
- leads to K+ loss as with loop diuretics
What is the MOA of thiazides?
Thiazides are secreted in proximal tubule, and competitively bind to the apical electroneutral eNCC-1 Na+Cl- co-transporter. So more Na+ and Cl- is excreted.
eNCC-1 is upregulated by aldosterone.
What are the PK of Thiazide Diuretics
They are a diverse family consisting of both thiazide and thiazide-like compounds all inhibiting NCC1 (eNCC1)
- Given orally - variable absorption
- Vairable elmination kinetics and therefore vriable half-lives of elmination ranging from hours to days.
- Excreted into proximal tubule in competition with uric acid. Will also be affected by other durgs cometing for organic acid transporter
- Eliminated mostly by renal route or metabolised
What are the therapeutic uses for thiazides?
- Oral delivery used
- hypertension - use in association with ACEIs/ ARBs and CCBs.
- Can be used in renal disease if GFR maintained
- as GFR decreases thiazide diuretics lose the ability to work
- Acute pulmonary hypertension
What are the adverse effects of thiazide diuretics?
- Dehydration and postural hypotension (especially in elderly)
-
Hyponatremia - Can cause confusion in the elderly (usually after prolonged used)
- Increased Na+ loss can also lead to Li+ accumulation in treated patients
- Hypokalaemia and Metabolic Alkalosis due to increaed Na+ delivery to distal tubule
- URIC ACID RETENTION - may precipitate gout
What is the problem we face with high rates of Na+ excretion caused by loop diuretics and thiazides?
This high Na+ load is now presented to the Na+/K+ exchangers at th distal end of the nephron promoting Na+ reabsorption at the expense of K+ and H+ loss.
The K+ loss may prolong QT interval particularly in association with other QT extenders eg sotalol.
The unbalaned K+ can cause an arrythmia.
And this K+ loss can also cause hyperglycaemia, as K+ is needed to secrete insulin in the pancreatic beta cells, low K+ means low insulin.
It can also cause impotence.
How does aldosterone work of the Na+/K+ channels?
- Aldosterone acts in distal tubules and collecting ducts of the kidney to increase plasma Na+ and water retention; this decreses plasma K+
- It synthesises and activates pumps. Promotes Na+ reabsorption from tubule and K+ loss (ie increases exchange of Na+ for K+)
- Aldosterone increases Na+/K+ synthesis
- This increases blood volume; thus increasing cardiac output
How does aldosterone increase the number of eNAC channels? (Na+/K+ channels)
Impacts on corticoreceptors (streroid receptors)
Increase transcription and translation, cause increase in eNaC channels to cause more Na
reabsoprtion
It increase mitochondrial production of ATP, and it also increases expression of Na+/K+ ATPase
RAAS terminates aldosterone release
How does the K+ sparing diuretic Spironolactone work?
It’s an aldosterone antagonist (active metabolic product). It competitively binds to and prevents translocation of mineralcorticoid receptor (also works systemically)
It binds to surface recpeptors on basolateral side does NOT require access to lumen
- Converves K+
- Used as a K+ sparing diuretic (the higher the aldosterone, the greater the diuretic effect)
- By blocking aldosterone it also prevents all it’s downstream effects - e.g. eNAC synthesis and expression, ATP production for Na+/K+ ATPase
What are the PK for spironolactone
can cause gynocomastia since it has a steroid like structure, therefore is can modulate androgen levels and present as gynocomastia
How does the K+ sparing diuretic Amiloride work?
It inhibits Na+ flux associated with the aldosterone-sensitive Na+ pumps (eNaC)
- Similar effects to spironolactone
- Relatively weak effects on overall Na+ balance
- Action complementary to thiazides (don’t use amiloride by itself)
- augments Na+ loss but limits K+ loss.
- Transported by organic acid transporters into lumen at PCT
What are the main uses for K+ sparing diuretics?
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