K5; Diuretics Flashcards
How are diuretics used?
Important cardiovascular drugs:
- Management of chronic heart failure
- Anti-hypertensive (third-line)
How do diuretics work?
- Increase Na+ excretion; natriuresis (normally reabsorbed along with water)
- Na+ movement is thus followed osmotically by water (diuresis)
- Decreasing extracellular/plasma volume (reduce oedema in CHF etc, reduces BP)
What 4 factors determine the overall effectiveness of a diuretic?
- ) Where it acts in the nephron (dependent on how much Na+ secretion is enhanced e.g. blocking reabsorption at LoH = 25% excretion)
- ) Response of segments not affected directly by the diuretic
- ) Delivery of the diuretic to its site of action (within the lumen; diuretics have to gain access to the lumen by getting in to the filtrate = secretion at PCT into the lumen)
- ) Size of effect on the extracellular volume (decreasing extracellular volume activates RAAS, releasing renin from granular juxtaglomerular cells of the afferent/efferent arterioles etc, Ang II and aldosterone ‘correct’ change»_space;> the bigger the change in extracellular volume the greater the RAAS activation = compensatory adaptive response means some diuretics have limited window of activity)
What are the classes of different diuretic agents and where do they work?
- Osmotic agents; PCT
- Loop diuretics; LoH
- Thiazide diuretics; early DCT
- K+ sparing diuretics; late DCT and CD
Give examples of osmotic diuretics.
- Mannitol
- Glucose when hyperglycaemic (causes osmotic diuresis; glycosuria etc.)
What are the properties of osmotic diuretics?
- Pharmacologically inert (don’t activate/inhibit a molecular target)
- Freely filtered (get through glomerular filter easy) and poorly/not reabsorbed
- Increases osmolality of the tubular fluid/filtrate in PCT and LoH
- Reduces passive reabsorption of H2O; stays in higher osmolality
When are osmotic diuretics not used (and where are they used)?
- Hypertension
- Peripheral oedema
Used in:
- Acute medicine e.g. cerebral oedema (increased osmolality removes extracellular fluid from the body and fluid from brain)
What are some examples of loop diuretics and their characteristics?
E.g. furosemide, bumetanide
- ‘High-ceiling’ diuretics due to powerful diuresis ‘torrential’ (10-fold increase in OG urine production)
- Causes 15-25% of filtered Na+ to be excreted (25% normally reabsorbed at LoH)
- Water thus accompanies Na+
Where do loop diuretics act and what does this mean for drug delivery?
- On the inside of the thick ascending limb of the LoH
- Molecular target: blocking Na+/K+/2Cl- symporter
(may block at the Cl- binding site) - Need to be secreted into the tubular lumen (at PCT) via organic anion (weak acid) transporter (as not much is filtered)
What are the consequences of blocking the Na+/K+/2Cl- symporter? (loop diuretics)
- Decrease Na+ reabsorption (thus more is excreted, and water follows); disrupt process of countercurrent multiplication
- Hyperosmotic interstitium is reduced
- Decreased ability of the kidney to concentrate urine
What are the other effects of loop diuretics besides its principle Na+/K+/2Cl- symporter blocking effect?
- Causes an increase in K+ loss
- Loss of transepithelial potential (as not moving 2Cl- across into tubular cell; loss of +10mV P.D.) reducing absorption of divalent cations (paracellularly down their electrochemical gradient) thus causing the loss of Ca2+ and Mg2+ in the urine (thus can be used for hypercalcaemia)
- Decreased NaCl entry into macula densa (as Na+/K+/2Cl- symporter in macula densa at the top of the ascending limb of the LoH is sensor for NaCl, cells think there’s low NaCl); promotes renin release (from granular cells) thus increasing Ang II activity (compensatory mechanism; RAAs activation, aldosterone enables Na+/water reabsorption) - kidney becomes refractory to loop diuretics for some hours after use
When are loop diuretics used?
- Used in CHF (chronic heart failure); reducing pulmonary oedema (breathlessness) secondary to LVF (Left Ventricular Failure; back pressure thus fluid build-up in lungs etc) and peripheral oedema (particurlarly in RVF)
- Used in renal failure (impaired Na+ reabsorption etc./filtering = water retention) to improve diuresis
What are some examples of thiazide/thiazide-like diuretics and how potent are they?
- Bendroflumethiazide
- Thiazide-like: chlortalidone, indapamide
- Moderately powerful diuretics (5% of filtered Na+ is excreted; not as powerful as loop though)
Where do thiazide diuretics act and how do they get there?
- They block the Na+/Cl- symporter of the early DCT (inhibiting active Na+ reabsorption and accompanying Cl- transport)
- Need to be secreted into the tubular lumen (at the PCT) via organic anion (weak acid) transporter (not particularly well filtered otherwise)
What is the net effect of a thiazide diuretic?
- Decreased Na+ & Cl- reabsorption
- Thus NaCl stays within filtrate and water follows, decreasing H2O reabsorption (normally in the late DCT and CD)
- Increased solute in tubular fluid thus decreasing H2O reabsorption gradient
- Reducing circulating volume
What are thiazides/thiazide-like diuretics used for?
- Third-line drugs for hypertension (A + C + D; > 55 years)
- Used in mild/moderate heart failure (move to loop with advanced; greater oedema)
When are thiazides not suitable?
- In renal impairment; may have decreased capacity to secrete in the PCT
- Limited secretion = less likely for thiazides to gain access to the tubular lumen and act at the early DCT (loop diuretics still effective in renal failure due to potent agent)
What are the main adverse effects associated with loop diuretics/thiazides?
- Hypokalaemia
- Metabolic acidosis
How does hypokalaemia develop with loop/thiazide diuretic use?
K+ loss in the urine (kaliuresis):
- ) Activation of RAAs; aldosterone secretion (and some Ang II activity) stimulates Na+ reabsorption (and thus water) and accompanying K+ loss (K+ excretion; increases expression of K+ channels in P cells of Late DCT/CD)
- ) Increased Na+ delivery to late DCT, promoting K+ loss
How do loop/thiazide diuretics inadvertently stimulate RAAs?
- Decreased Na+ in ECF (extracellular fluid, activating renin release)
- Volume depletion; decrease in blood volume from diuresis “diuretic hypovolameia’
- Loop diuretics block NaCl entry (blocking Na+/K+/2Cl- symporter) into macula densa cells stimulating renin release from granular cells
How does increased Na+ delivery to the late DCT/CD bring about K+ loss? (loop/thiazide diuretics)
- Increased Na+ means increased Na+ entry to the tubular cell (down its electrochemical gradient; created by the Na+/K+ ATPase on the basolateral membrane)
- Lumen becomes more electronegative as a result (loss of positive Na), encouraging greater K+ secretion via its K+ channel down its electrochemical gradient
What is kaliuresis?
Increased potassium in the urine
How can thiazide/loop diuretic induced hypokalemia be countered in antihypertensive therapy?
- Combining thiazides with beta-blockers (blocking β-receptors on granular cells inhibiting renin release)
- Or with ACEis (inhibiting Ang I > Ang II in RAAs bringing about a hyperkalaemic effect)
What is the clinical issue with hypokalaemia?
- More negative membrane potential (cells are less excitable)
- Thus can lead to cardiac arrhythmias
- Reduces activity of Na+/K+ ATPase pump (particularly in myocytes) potentiating the action of digoxin
How do loop/thiazide diuretics lead to metabolic alkalosis?
- Due to the increased Na+ delivery to the late DCT/CD which leads to enhanced Na+ reabsorption; associated with H+ secretion/loss
- As (more) electronegative lumen encourages loss of H+ from I cells (where K+ is being lost from P cells, and Na+ is being reabsorbed)
- Greater loss of H+ ions means losing acid in acid-base balance (decreased urine pH) = alkalosis (increased blood pH)
- Also via activation of RAAs (from decreased ECF volume); leads to aldosterone activity acting on plasma membrane receptors increasing H+ secretion (H+ ATPases?)
What are the types of potassium-sparing diuretics and their potency?
- Aldosterone receptor antagonists
- Na+ channel blockers
- Weak diuretics; but can reduce K+ loss if given with K+-losing agents (loop/thiazide)
What antihypertensive(s) negate the effect of potassium-sparing agents?
ACEis; cause hyperkaleamia so may negate K+ sparing effect.
Give examples of aldosterone receptor antagonists and explain their actions.
- Antagonises aldosterone receptors; preventing upregulation/insertion of Na+ pumps (Na+/K+ ATPase) and channels (ENaC)
- Blocking mineralocorticoid receptor means there’s no switching on of gene expression
When is aldosterone used?
- Used in primary/secondary hyperaldosteronism
- In oedema/ascites (fluid build up in the peritoneal cavity) associated with liver failure
- Low-dose spironolactone used in CHF to block actions of aldosterone on the heart
How do sodium channel blockers work? Give examples.
- Block apical epithelial Na+ channels (ENaC; simple selective Na+ channel) in the late DCT (P cells) and CD
- Results in decreased Na+ reabsorption and K+ excretion too
E..g. amiloride, triamterene
How are ACEi (and ATRA) associated with renoprotection?
- Microvascular complications prevalent in diabetes; renal nephropathy (a leading cause of chronic renal failure)
- ACEis appear to slow renal damage and are advocated in diabetic nephropathy (even in absence of hypertension)
- Blocking inappropriate RAAs activation
What are the key counselling points for diuretics?
- Best taken in the morning (don’t want to disrupt sleep)
- Patients will experience an increase in urine production (up to 10x with loop; warn patients)
- Advise patients to avoid excess salt in the diet (hinders diuretic efficacy in kidney)
- May cause postural hypertension (from loss of fluid) esp. in elderly
- Thiazides (and loop diuretics less so) may uncover/worsen diabetes
- Thiazides and loop diuretics may worsen gout
- NSAIDs may reduce the effects of loop diuretics (NSAIDs reduce production of (renal) PGs that maintain good renal blood flow)
- Electrolytes should be monitored (may be excess losses)
