Last updated on February 18, 2021 at 11:31
Diuretics are drugs that promotes diuresis, the rate of urine flow. This enhances the excretion of water from the person taking it, although the mechanism of action is different for the different types.
Most types, except osmotic diuretics, act primarily by decreasing tubular reabsorption of Na+, which in turn decreases the reabsorption of Cl– and water. It’s important to keep in mind that this makes these drugs saluretics primarily (they primarily excrete NaCl), and the diuretic effect comes only secondary to this.
Because they influence the electrolyte excretion, they have the possibility to cause potentially fatal electrolyte imbalances. Those that spare K+ may cause hyperkalaemia, those that spare H+ may cause metabolic acidosis and so on.
There are many indications for the use of diuretics:
- To decrease the elevated extracellular volume
- Any type of oedema
- Increased intracranial pressure
- To decrease the blood pressure in hypertensive patients
- Chronic hypertension
- Acute hypertensive crisis
- To increase urinary excretion of inorganic ions – diuretic is given together with fluids
- Acute hypercalcaemia
- Acute hyperkalaemia
- Lithium intoxication
- Bromide intoxication
- To prevent the development of anuria in acute renal failure
- Nephrogenic diabetes insipidus – to prevent hyperosmolarity
There are also other uses.
Most diuretics can be assigned to one of two groups – they’re either:
- Potassium-sparing like aldosterone antagonists and Na+ channel inhibitors
- Potassium-losing like loop diuretics, thiazides and thiazide-like drugs
Also of note is that drugs that are potassium-sparing are also H+-sparing, and drugs that are potassium-losing are also H+-losing. Let’s see why.
Na+ is reabsorbed in the proximal tubules, the ascending limb of Henle, the distal tubule and the collecting duct. In the distal tubule and collecting ducts, where the Na+ reabsorption is controlled by aldosterone, is Na+ reabsorption paired with K+ and H+ secretion. So, if Na+ reabsorption is increased in the distal tubule or collecting duct will K+ and H+ secretion increase.
Loop diuretics, thiazides and thiazide-like drugs inhibit the Na+ reabsorption before (“upstream”) the distal tubules. This means that more Na+ remains in the filtrate when the filtrate reaches the distal tubules and collecting ducts. This stimulates and increases Na+ reabsorption in these parts of the nephron, which coincidentally stimulates K+ and H+ secretion as well.
Potassium-sparing diuretics like aldosterone antagonists and Na+ channel inhibitors inhibit Na+ reabsorption in the distal tubules and collecting ducts. When this reabsorption is inhibited will the K+ and H+ secretion also be inhibited.
Potassium-sparing diuretics run the risk of inducing hyperkalaemia and acidosis, while potassium-losing diuretics run the risk of inducing hypokalaemia and alkalosis. The ion balance of the patient must therefore be taken into consideration when choosing the appropriate diuretic. Both potassium-sparing and potassium-losing diuretics can be given together to “cancel out” their effects and increase diuresis without a significant change in plasma K+ and H+ level.
The most clinically important osmotic diuretic is mannitol, however also urea has similar clinical uses. Mannitol is a highly effective diuretic.
Cerebral oedema, glaucoma, prevention of anuria during acute renal failure.
Mechanism of action:
Mannitol is a small, water-soluble sugar alcohol. It’s hydrophilic, so it’s not absorbed orally, however it does bind water, which is what it’s used for. It distributes in the whole extracellular space and is freely filtered and not reabsorbed in the kidney.
It is osmotically active, so as it enters the extracellular space it will induce a slight hyperosmolarity that causes water to move from the intracellular space to the extracellular space. This increases the renal blood flow and therefore the GFR, increasing diuresis.
It’s also freely filtered in the glomeruli. When mannitol gets into the filtrate will the osmolarity of the filtrate increase, which pulls water from the interstitium into the filtrate.
The fact that mannitol expands the extracellular volume makes it unfit for use in heart failure. In heart failure is the aim to decrease the preload, however mannitol increases it.
Carbonic anhydrase inhibitors
Carbonic anhydrase inhibitors are weak diuretics. The most important is acetazolamide, although others like brinzolamide, dichlorphenamide and methazolamide exist.
- (Brinzolamide, dichlorphenamide, methazolamide)
Glaucoma and altitude sickness.
Mechanism of action:
Carbonic anhydrase increases HCO3– and Na+ reabsorption and increases H+ secretion. By inhibiting the enzyme will these drugs decrease reabsorption of HCO3– and Na+, increases diuresis. They also inhibit H+ secretion, possibly inducing acidosis (Acetazolamide = Acidosis)
Carbonic anhydrase also forms HCO3– as a component of aqueous humour. These drugs will decrease the production of aqueous humour and therefore reduce the intraocular pressure as well.
By inhibiting carbonic anhydrase these drugs will reduce the RBCs ability to carry CO2 to the lung, causing the CO2 level in the tissues to increase. This stimulates ventilation, which increases O2 levels during altitude sickness.
Acetazolamide has 100% oral bioavailability, and extensive plasma protein binding. Its Vd is 0.25 L/kg. It’s eliminated by tubular secretion with a half-life of 6-9 hours.
Because carbonic anhydrase inhibitors alkalinize the urine they:
- Increase the risk for calcium stones in the urinary tract
- Increase reabsorption of weak basic drugs like amphetamine
- Decrease reabsorption of weak acidic drugs like aspirin and phenobarbital
The loop diuretics like furosemide, bumetanide and torasemide are the most effective diuretics. They can inhibit the reabsorption of up to 25% of the GFR, which equals 35 litres every day! They are K+ and H+-losing as they act upstream of the distal tubules. They’re called loop diuretics as they act on the loop of Henle. They act rapidly.
- Heart failure
- Acute renal failure – to prevent anuria and oliguria
- Hypercalcaemia – due to their Ca2+-excreting properties
- Hyperkalaemia – due to their magic K+-excreting properties
Mechanism of action:
Loop diuretics are secreted into the filtrate via drug transporters OAT1, OAT4 and MRP4. They travel along the nephron to the thick ascending limb of the loop of Henle. There will they bind to and inhibit the Na+/K+/2Cl– symporter (also called NKCC2) of the tubular cells. This symporter is responsible for the reabsorption of Na+, K+ and Cl– in this part of the loop, which creates the cortico-medullary osmotic gradient. With loop diuretics is this osmotic gradient smaller, which reduces water reabsorption in the descending loop and the collecting ducts.
NKCC2 also creates a transepithelial potential difference where the interstitium is more negative than the filtrate. This difference usually drives the reabsorption of Ca2+ and Mg2+. With loop diuretics will this reabsorption be reduced, causing loss of Ca2+ and Mg2+.
Because a similar Na+/K+/2Cl– symporter, called NKCC1, is present in the inner ear do these drugs have the possibility of inducing ototoxicity. They may cause deafness and dizziness. To remember this, think about a rollercoaster loop and the deafening screams of people passing through it.
Furosemide has 50% bioavailability on average, however it varies greatly between individuals. Bumetanide has nearly complete bioavailability. Both have extensive plasma protein binding and low Vd of 0.2L/kg. They’re both mainly eliminated by tubular secretion but 30% by biotransformation. The half-life of furosemide and bumetanide is 2 hours.
NSAIDs decrease the effect of loop diuretics as they reduce the renal blood flow, which increases the cortico-medullary osmotic gradient. Loop diuretics are contraindicated in anuria, as they would never reach the ascending limb if there is no urine production at all.
Thiazides and thiazide-like diuretics
The prototype of this type is chlorothiazide, which is not used anymore. It contains a thiazide ring as the name implies. Hydrochlorothiazide (HCTZ) is built upon the prototype and is in use. The thiazide-like diuretics have similar effects but no thiazide ring.
- Prevention of calcium stones and osteoporosis – due to their Ca2+-saving properties
- Nephrogenic diabetes insipidus
Mechanism of action:
Thiazides and thiazide-likes are secreted into proximal convoluted tubules by OAT1, OAT4 and MRP4, just like loops. They travel with the filtrate until they reach the distal convoluted tubule where they inhibit the Na+/Cl– symporter, inhibiting NaCl reabsorption. They also increase K+ and H+ excretion, however they cause Ca2+ reabsorption.
The oral bioavailability of HCTZ and chlorthalidone is 70%. They distribute in the total body water (Vd = 0.8 L/kg). They’re eliminated by renal excretion. The half-life of HCTZ is 6-9 hours and for chlorthalidone 40 hours.
Na+ channel inhibitors
The two Na+ channel inhibitors are amiloride and triamterene. They have weak diuretic effect but are K+-sparing, so they’re often combined with K+-losing diuretics like HCTZ. You’d be hard pressed to find amiloride in a preparation without HCTZ – they’re almost always combined.
Mechanism of action:
They are secreted by OCT2 and MATE in the proximal tubule, from which they travel to the collecting duct where they inhibit epithelial Na+ channels.
Amiloride is well absorbed orally and barely bound to albumin. Vd = 5 L/kg. It’s eliminated by urinary excretion. Half-life is 6-9 hours, the same as for HCTZ.
The prototype aldosterone antagonist is spironolactone, however eplerenone is also used clinically.
Hypertension, oedema, heart failure, hyperaldosteronism.
Mechanism of action:
Aldosterone binds to mineralocorticoid receptors in the kidney to increase Na+ reabsorption and increase K+ and H+ secretion. By blocking these receptors with aldosterone antagonists can we cause diuresis. Aldosterone also stimulates myocardial fibrosis and hypertrophy, and these drugs block those effects as well.
Spironolactone isn’t selective for mineralocorticoid receptors, as it acts on other steroid receptors as well. This causes the drug to have antiandrogenic and glucocorticoid effects, which causes side-effects, especially in men.
It’s orally absorbed and highly plasma protein bound. It’s rapidly converted into an active metabolite which has a half-life of 16 hours.
2. Drugs acting on the renin-angiotensin-aldosterone system
4. Antiarrhythmic drugs