Lecture 6: Diuretics, mechanisms and clinical use in Biology

Diuretic Mechanisms and Actions

Here we're looking at inducing medical diuresis, which represents a sustained, therapeutic reduction in extracellular fluid volume; although some diuretics may be used in alternative therapeutic contexts. Diuresis is typically accompanied by natriuresis.

Diuretic Mechanisms Overview

Diuretic mechanisms

• Rise in urine osmolality osmotic diuretics

"Blockade of hormone receptors or ion channels

• K+-sparing diuretics

·Inhibition of tubular transport proteins -loop + thiazide & thiazide-like diuretics "Inhibition of tubular enzyme activity carbonic anhydrase inhibitor diuretics

NB: medical diuresis contracts extracellular fluid volume + is accompanied by natriuresis

NB: medical diuresis provokes RAAS activation, which limits further diuresis but does not necessarily prevent therapeutic efficacy" There are several routes to achieving increased urine volume. Very simply:

1. Raising urine osmolality, e.g. with osmotic diuretics, opposes the reabsorption of water from around the renal tubule, wherever there is water permeability (which includes the collecting duct when ADH is active); and this is capable of a large scale (or high ceiling) diuresis.
2. Blocking aldosterone actions in the late renal tubule impacts on the 5% (variable) sodium reabsorption regulated by this hormone, " which leaves more sodium in the filtrate; " and this translates into a small rise in urine volume (a very low ceiling diuresis).

Note: Natriuresis is the process of sodium excretion in the urine through the action of the kidneys.

• In view of aldosterone's role in facilitating potassium excretion (at the same time as driving sodium reabsorption), antagonising this action results in natriuresis with potassium retention (known as a potassium-sparing effect). The inhibition of tubular ion cotransporters, i.e. either the NaK2Cl or NaCl cotransporter, is a mainstream approach to preventing sodium reabsorption and eliciting natriuresis, with attendant diuresis.3)In the case of loop diuretics and NaK2CI cotransporter inhibition (in the thick ascending limb of the loop of Henle), this is a high ceiling diuresis is;

  While NaCl cotransporter inhibition (in the early distal convoluted tubule) with thiazide and thiazide-like diuretics, results in a moderate ceiling diuresis.

" Lastly, 4) inhibiting tubular enzyme activity, i.e. carbonic anhydrase (in the proximal tubule), produces a very low ceiling diuresis.

• You'll see that RAAS activation (aimed at defending blood volume and blood pressure) in the face of diuresis may be limiting but does not necessarily prevent therapeutic effects of diuretics. It's useful to remember here that RAAS inhibitors are expected to have natriuretic and diuretic actions.

Osmotic Diuretics

Osmotic diuretics

• E.g. mannitol Freely filtered + not reabsorbed
• Oppose water reabsorption at multiples sites around nephron, i.e. wherever there is water permeability + promote sodium loss by disrupting tubular sodium gradients
• Disrupt medullary hyperosmotic / hypertonic gradient
• High ceiling diuresis Have local dehydrating effect useful in treating glaucoma + cerebral oedema

▪. We start with osmotic diuretics, such as mannitol. " These freely enter the renal filtrate, are not reabsorbed and essentially act as "water magnets" that osmotically draw water out with them in the urine. . In addition to opposing water reabsorption at multiple points around the renal tubule, osmotic diuretics also promote sodium loss by disrupting the inward tubular sodium gradient (owing to dilution of the filtrate, reflecting the extra filtrate water content), which undermines sodium reabsorption from the filtrate. A reduced accumulation of medullary sodium content leads to disruption of the medullary hyperosmotic (or hypertonic) gradient, which is required for ADH-mediated water reabsorption from the collecting duct.

• The combined outcome of both this and the direct osmotic effects of substances like mannitol, results in a high ceiling diuresis.
• Despite these very strong diuretic properties based in the filtrate, osmotic diuretics can be used therapeutically instead for a local dehydrating effect, e.g. in raised intra-ocular pressure and cerebral oedema, where their action is based within blood.

Loop Diuretics

Loop diuretics

• E.g. furosemide, torasemide, bumetanide Rapid onset (oral) (within 1 h) + short duration of action (within 6 h)
• Freely filtered + secreted by organic anion transporter (OAT), also used by uric acid Inhibit NaK2CI cotransporter in TAL of LH
• Disrupts medullary hyperosmotic / hypertonic gradient
• High ceiling diuresis
• Promotes loss of potassium (kaliuresis) as well as sodium (natriuresis) + also calcium
• Used in e.g. oedema chronic heart failure primary hypertension
• Can cause as side effects e.g. hypokalemia hyponatremia hyperuricaemia + gout exacerbation dizziness diabetes exacerbation metabolic alkalosis hypovolaemia ototoxicity (risk increased by combination with aminoglycoside antibiotics)" Loop diuretics, named after their site of action to inhibit NaK2CI cotransport in the loop of Henle, include furosemide, torasemide and bumetanide.
• They produce a high ceiling diuresis, with a rapid onset and short duration of action.

. These diuretics enter the filtrate freely and are also secreted by the organic anion transporter, for which uric acid is a typical substrate to be excreted. " Their large scale diuretic effect stems from both natriuresis and disruption to the medullary hyperosmotic (or hypertonic) gradient, related to impaired sodium reabsorption from the filtrate to the medulla; and loop diuretics find clinical uses in relieving oedema and in managing primary hypertension. Not only the urinary excretion of sodium is enhanced, but also that of potassium and in addition calcium. This can lead to electrolyte disturbances such as severe hypokalemia and also severe hyponatremia, along with an undesirably reduced blood volume (hypovolaemia).

• Other side effects include: retention of uric acid in the blood and related exacerbation of gout; diabetes exacerbation; metabolic alkalosis; and deafness, the risk of which is increased by aminoglycoside antibiotics.

Thiazide and Related Diuretics

Thiazide & related diuretics

• E.g. (thiazides) bendroflumethiazide
• E.g. (thiazide-like) indapamide, xipamide, chlortalidone, metolazone
• Onset (oral) within 1-2 h with duration of action drug-dependent (but typically 12-14 h) Freely filtered + secreted by organic anion transporter (OAT), also used by uric acid
• Inhibit NaCl cotransporter in early DCT Moderate ceiling diuresis Promote loss of potassium + sodium, but increase calcium reabsorption
• Used in e.g. oedema mild to moderate chronic heart failure primary hypertension
• thiazides may also act as vasodilators nephrogenic or partial pituitary diabetes insipidus Hypercalciuria means excess calcium in the urine.))
• Can cause as side effects e.g. hypokalaemia hyperuricaemia + gout exacerbation metabolic alkalosis hyperglycaemia + diabetes exacerbation postural hypotension erectile dysfunction dry mouth dizziness

Thiazide and related diuretics, i.e. thiazide-like diuretics (that are chemically different from thiazides but share the same renal actions), inhibit NaCl cotransport in the early distal tubule. " Thiazides include bendroflumethiazide; while thiazide-like agents include indapamide, xipamide, chlortalidone and metolazone. They produce a moderate ceiling diuresis, with an onset (oral administration) within 1-2 hours and typically a duration of action between 12-14 hours. " These diuretics, in common with loop diuretics, enter the filtrate freely and are also secreted by the organic anion transporter, with the same repercussions on uric acid excretion.

• Their diuretic effect stems from natriuresis; and thiazide and related diuretics find clinical uses in relieving oedema, treating chronic mild to moderate heart failure and in managing primary hypertension (where low doses are associated with maximal or near-maximal blood pressure lowering effects, in which peripheral vasodilator effects may play some part, with minimal biochemical disturbance).In addition, chlortalidone is indicated for diabetes insipidus (a state of polyuria resulting from either impaired renal ADH signalling or deficient central ADH release), owing to an anti-diuretic action in this specific context. Not only the urinary excretion of sodium is enhanced, but also that of potassium; and this can lead to hypokalaemia. However, in contrast to loop diuretics, thiazide and related diuretics reduce the urinary excretion of calcium, i.e. they exert a hypocalciuric effect (and bendroflumethiazide is indicated for hypercalciuria). Other side effects include: retention of uric acid in the blood and related exacerbation of gout; hyperglycaemia and diabetes exacerbation (with the risk of hyperglycaemia greater than that associated with loop diuretics) and metabolic alkalosis.

Potassium-Sparing Diuretics

K+-sparing diuretics

• E.g. (aldosterone receptor antagonists) spironolactone, eplerenone
• E.g. (sodium channel blockers) amiloride, triamterene
• Oppose aldosterone action in late DCT/CD Very low ceiling diuresis Promote loss of sodium (natriuresis) but retention of potassium
• Used in e.g. oedema ascites in cirrhosis of the liver Nephrotic syndrome heart failure resistant hypertension iatrogenic hypokalaemia
• e.g. with loop or thiazide and related diuretics primary hyperaldosteronism (Conn's syndrome)
• Can cause side effects e.g. hyperkalaemia metabolic acidosis gynaecomastia

Potassium sparing diuretics are a special class of agent that antagonise aldosterone to produce natriuresis (sufficient to provide only a very low ceiling diuresis), together with potassium retention, i.e. reduced urinary potassium excretion. " This class includes eplerenone and spironolactone (as aldosterone receptor antagonists) as well as amiloride and triamterene (as functional aldosterone antagonists, by virtue of blocking the renal tubular luminal sodium channels required for aldosterone- mediated sodium reabsorption). A chief use is in managing iatrogenic hypokalaemia (for which amiloride and triamterene are indicated), related to loop diuretic or thiazide and related diuretic kaliuretric actions; and Conn's syndrome (associated with excess aldosterone secretion) in patients awaiting surgery (and for which spironolactone is indicated). Side effects include an accumulation of blood potassium (hyperkalemia) and metabolic acidosis; and with spironolactone and to some extent eplerenone, endocrine outcomes related to anti-androgen effects.