A. DIURETICS Flashcards
when are diuretics used as CV drugs
- chronic heart failure as reduce oedema
- anti-hypertensives as reduce blood pressure (and BV)
*both due to fluid accumulation
what is the basis of the MoA of diuretics
- increase sodium excretion (natriuresis)
- Na+ movement followed osmotically by water
- therefore decrease extracellular/plasma volume
- increase urine production
what factors determine effectiveness of a diuretic
- site of action: magnitude of natriuresis (LDs limit 25% reabsorption but TDs only limit 5%)
- site of action: increased delivery of Na+ at distal segments, LDs and TDs will cause hypokalaemia and metabolic alkalosis
- delivery of diuretic to site of action (lumen): LDs and TDs need to be secreted, affected by renal impairment
- size of effect on extracellular volume: decreased EC volume activates RAAs so we get hypokalaemia and metabolic alkalosis to correct for loss of fluid (compensatory mechanisms as body tries to retain water it has)
where do osmotic agents act
PCT
where do thiazide diuretics act
early part of DCT
where do K+-sparing diuretics act
late DCT and CD
where do loop diuretics act
thick ascending limb of LoH
example of an osmotic diuretic
- mannitol
- glucose in hyperglycaemia
characteristics of osmotic diuretics
- pharmacologically inert as don’t activate/inhibit a particular molecular target
- freely filtered so poorly/not reabsorbed
how do osmotic diuretics work
- increase osmolality of tubular fluid (filtrate) in PCT and LoH as it’s a highly osmotically active molecule
- reduces passive reabsorption of water and it exits in urine
what is the potency of osmotic diuretics and how does this affect their use
- very potent with a large diuresis effect
- not used to treat hypertension or peripheral oedema
- used in a acute medicine (ICU) ie: cerebral oedema as increases osmolality of blood and hence removes fluid from brain
example of loop diuretics
- furosemide
- bumetanide
characteristics of loop diuretics
- very powerful effect
- cause 15-25% of filtered Na+ to be excreted (normally <1%) and hence water follows
where do loop diuretics need to be secreted to and how
- tubular lumen (of PCT) via organic anion (week acid) transporter to have access to their SoA
- they aren’t filtered well as they bind to plasma proteins
- transporters pull the LD from plasma proteins (AT)
how do loop diuretics work
- block Na+/K+/2Cl- symporter of the thick ascending limb of LoH
(may block at Cl- binding site) - so Na+ reabsorption decreased and process of countercurrent multiplication disrupted
- reduced hyperosmotic interstitium and as CD moves through the medulla there is reabsorption of water by ADH
- decreased ability of kidney to concentrate urine
consequences of loop diuretics
- increase in K+ loss
- loss of transepithelial potential reduces absorption of divalent cations and causes the loss of Ca2+ and Mg2+
*loops can be used in hypercalcaemia - promote renin release, leading to increased AngII activity and aldosterone
how do loop diuretics reduce absorption of divalent cations
- don’t lose 2Cl- due to Na+/K+/2Cl- symporter being blocked
- hence the lumen isn’t slightly +ve, electrochemical gradient is lost and there is a decrease in paracellular diffusion of cations
how do loop diuretics promote renin release
- decrease NaCl entry into macula densa tubular cells due to the Na+/K+/2Cl- symporter being blocked
- renin released from JG granular cells in afferent and efferent arterioles
- RAAs activated
- kidney becomes refractory to LDs for some hrs after use due to Na+ and water retention which negates diuretic effects
uses of loop diuretics
- chronic heart failure as reduce pulmonary oedema secondary to left ventricular failure and peripheral oedema (right ventricle isn’t working well and bringing blood back up to heart)
- renal failure to improve diuresis
example of thiazide diuretic
bendroflumethiazide
example of thiazide-related diuretic
- indapamide
- chlortalidone
(metolazone isn’t a thiazide but in this group as MoA similar)
where do thiazides and related diuretics need to be secreted to and how
- tubular lumen (of PCT) via organic anion (week acid) transporter to have access to their SoA
- they aren’t filtered well as they bind to plasma proteins (to circulate in body)
- transporters pull the LD from plasma proteins (AT)
characteristics of thiazides and related diuretics
- moderately powerful diuretics
- cause ~5% of filtered Na+ to be excreted (small effect)
how do thiazides and related diuretics work
- block Na+/Cl- symporter of early DCT
- inhibit active Na+ reabsorption and accompanying Cl- transport
- and hence decrease water reabsorption gradient in late DCT and CD
why are thiazides and related drugs used as 2nd line drugs in hypertension
- decrease BV so decrease BP
- after some time, direct vascular effects may be more important
*also used in mild-moderate heart failure
what diuretics are effective in renal impairment
- loop diuretics as more potent (moderate-severe)
- thiazides are renally secreted to act on DCT, thiazides are deemed ineffective in moderate renal impairment as not much can get into the lumen (except metolazone)
what are the 2 consequences of loop diuretics and thiazides (ie secondary causes)
- hypokalaemia
- metabolic alkalosis
how is hypokalaemia caused due to LDs and TDs
- kaliuresis due to K+ loss
1. due to activation of RAAs: Na+ retention and K+ loss
caused by aldosterone and some via AngII
- increased Na+ delivery to late DCT and CD (P-cells) due to Na+ reabsorption inhibited in LoH and early DCT so there is a greater gradient for reabsorption of Na+ into tubular cells and this promotes a greater K+ loss as lumen becomes more electro-ve
how does activation of the RAAs cause hypokalaemia
- decrease Na+ in ECF (increased Na+ loss) sensed by JG cells
- volume depletion, low BV due to diuresis (diuretic hypovolaemia) sensed by JG cells
- loop diuretics block NaCl entry into macula densa cells and they block Na+/K+/2Cl- symporter (macula densa cells are the molecular player in sensing NaCl in filtrate)
how can you reduce risk of hypokalaemia in anti-hypertensive therapy
- combine thiazides with beta-blockers (which inhibit renin release) or ACEIs (potential side-effect is hyperkalaemia)
why is hypokalaemia a major clinical problem
- more negative membrane potential causing:
- cardiac arrhythmias
- reduced activity of Na+/K+ ATPase pump (potentiates the action of digoxin which inhibits Na+/K+ ATPase in heart failure), so hypokalaemia and digoxin increases inhibition of ATPase
how is metabolic alkalosis caused due to LDs and TDs
- increased Na+ delivery to late DCT & CD leads to
enhanced Na+ reabsorption which is associated with H+ secretion/loss due to lumen being electro-ve - activation of RAAs with decreased ECF volume leads to aldosterone activity and increased H+ loss
decreased urinary pH
increased blood pH
what type of drugs are potassium-sparing diuretics
- aldosterone receptor antagonists (aka mineralocorticoid receptor antagonists)
- Na+ channel blockers
*can be used in combination with K+-losing agents to reduce K+ loss (ACEIs can cause hyperkalaemia so may be used to negate the effects of K+-losing agent)
what is the potency of potassium sparing diuretics
weak
example of aldosterone receptor antagonists
- spironolactone
- eplerenone
how do aldosterone receptor antagonists work
- antagonise aldosterone (mineralocorticoid) receptors - prevent upregulation/insertion of Na+/K+ ATPase and ENaC
when are aldosterone receptor antagonists used
- primary/secondary hyperaldosteronism
- oedema and ascites associated with liver failure
- low-dose spironolactone used in heart failure to block the actions of aldosterone on the heart
examples of sodium channel blockers
- amiloride
- triamterene
how do Na+ channel blockers work
- block apical ENaC in late DCT and CD in P-cells
- Na+ no longer retained at expense of K+
- decreased Na+ and water reabsorption
- decreased K+ excretion
