Diuretics Flashcards
What is the role of the kidney
To maintain the corretc ionic balance in the blood and to remove waste products
How much blood passes through the kidney and how much urine is produced per day
120L of blood
1.5L of urine
Overall 99% of the filtrate will be reabsorbed
Which structures make up the kidney
The core of the kidney is termed the cortex, whilst the outside region is the medulla. The cortex contains the glomerulus, Bowman’s capsule and distal and proximal tubules whereas the loop of Henle drops into the medulla.
What is the functional unit of the kidney, how many of these are there and where can they be found
The nephron. There are 1.4 million of these in an adult kidney, but this number reduces with age and is reduced in hypertensive patients. Nephrons span the cortex and medulla, with the loop of Henle and collecting ducts extending into the medullary pyramids.
How are the nephrons vascularised
Blood enters the nephron from a branch of the renal artery called the afferent arteriole, which forms a dense network of capillaries called the glomerulus, and leaves through the efferent arteriole.
What happens to the fluid which is filtered out of the glomerelus
Fluid filtered out of the glomerulus due to the high hydrostatic pressure enters the proximal tubule and then the descending loop of Henle. The ascending limb is surrounded by vasa rectae, which branch off the efferent arterioles. These blood vessels exchange sodium chloride, water and urea with the filtrate. The filtrate passes back into the cortex of the kidney, through the distal tubule and then passes out of the collecting tubule as urine.
What are ‘leaky’ tight junctions and what purpose do they serve
The proximal tubule has ‘leaky’ tight junctions which allow sodium ions to diffuse down their electrical and concentration gradients into the epithelial cells – this transport is coupled with the uptake of glucose, phosphate, amino acids, lactate, chloride and potassium, along with extrusion of protons.
This part of the nephron is responsible for 60-70% of the total sodium reabsorption.
Many organic acids and bases, such as creatinine and several drugs such as NSAIDs, penicillin and diuretics are actively secreted via the organic anion transporter. Ammonia diffuses into the filtrate down its concentration gradient.
Describe the impact of tonicity in the decending loop of henle
The interstitial fluid surrounding the decending loop of henle is hypertonic to the filtrate, and the concentration (or tonicity) increases as the LoH descends.
This is a way of concentrating interstitial fluid in the renal medulla.
This is achieved through the slow drainage of fluid from the vasa recta and also the close proximity of the descending and ascending limbs of the L o H. The epithelial cells forming this part of the nephron are permeable to water, meaning that water diffuses out of the lumen down it concentration gradient.
What makes the ascending loop of henle different to the decending loop of henle
In contrast to the descending limb, the cells of the ascending limb have a low permeability to water. At the top part (the cortical end), sodium is pumped out of the cell via the basolateral membrane sodium-potassium pump. This creates the gradient for sodium to cross the apical membrane from the lumen via the Na/K/Cl transporter. Some of the potassium is absorbed from the filtrate, but most diffuses back out through apical potassium channels.
What is the distal convoluted tutbule
The DCT is impermeable to water but, like in the ascending limb of the LoH, a small amount of sodium is actively reabsorbed due to the gradient set up by the sodium-potassium pump.
What purpose does the collecting tubule serve
In the collecting duct, up to 15% of the water in the filtrate may be reabsorbed via aquaporin channels. These channels are stored in vesicles until ADH binding to vasopressin receptors causes their insertion into the apical membrane. Removal of this filtered water enables the production of urine which is considerably hypertonic to plasma.
How do diuretic drugs work
Diuretic drugs work by increasing the excretion or reducing the reabsorption of sodium ions to produce natriuresis (increased excretion of Na+ and water).
Increasing the Na concentration of the filtrate causes water to follow. This can be achieved either by acting directly on the nephron or by changing the composition of the filtrate.
What does a small increase in sodium reabsorption produce
A small decrease in sodium reabsorption can result in a large increase in overall sodium excretion.
How do most diuretics reach their active site and what is the exception
Most diuretics are actively secreted into the filtrate through the proximal convoluted tubule, an exception being spironolactone.
What are the three main uses for diuretics
Cardiac failure, liver failure and acute renal failure.
Diuretics increase urine output, what knock on effect does this have theraputically (think about liver falure)
Because they increase urine output, this reduces plasma volume and concentrates plasma, causing interstitial fluid to be drawn into the blood – this reduces oedema, which is a feature of liver failure
How do diuretics work to treat cardiac failure
In cardiac failure, CO is inadequate so there is a resulting increase in interstitial fluid volume (due partly to the increased venous pressure, as result of blood backing up from the right atrium).
Hyperaldosteronism promotes an increase in Na+ retention and hence an increase in plasma volume.
Hypertension can be reversed by reducing plasma volume
How do diuretics work to treat acute renal failure
Acute renal failure is caused by a lack of blood flow to the kidneys and hence they produce small quantities of dilute urine. Diuretics increase the excretion and therefore aid urine production and the concentrating power of the kidneys.
What are loop diuretics and where do they act upon
Loop diuretic induce substantial diuresis. They are capable of promoting the excretion of 15-25% of the filtered sodium ions.
They act on the NaKCl cotransporter in the thick ascending limb of the loop of henle.
Apart from the diuretic effect they can also stimulate vasodilation, which is useful in treatment of hypertension.
Give 3 examples of loop diuretics
Examples are furosemide, bumetanide and torasemide.
Furosemide and torasemide may also be used to treat resistant hypertension.
Descibe how bumetanide reaches its site of action
Bumetanide is more lipid soluble than furosemide and therefore has a higher bioavailability – it can diffuse passively into the filtrate, whereas the other two must be actively secreted. It is used in treatment of oedema.
Which transporter do loop diuretics work on
These drugs act on the Cl- binding site of the Na/K/Cl carrier. As well as blocking sodium reabsorption, K+ and chloride reabsorption are also blocked so these ions are lost in the urine.
What are some indirect effects of blocking the Na/K/Cl pump
Firstly, the sodium-proton exchanger is not affected, so sodium entry still drives proton excretion.
Bicarbonate ions are continuously reabsorbed from the filtrate, so the reduction in plasma volume means that its concentration is increased, leading to alkalosis.
The increased excretion of calcium and magnesium can lead to harmful side-effects.
The reduction in uric acid excretion can precipitate gout.
Because Na reabsorption is blocked, more Na+ is delivered to the distal part of the nephron, so reabsorption of water is reduced even more.
How do we think loop diuretics produce a vasodilating effect
The vasodilator mechanism of loop diuretics may result from a reduced response to Angiotensin II, as this is a potent vasoconstrictor.
Prostaglandins such as PGE2 are potent vasodilators and loop diuretics may increase their production.
These drugs may also reduce the production of the ouabain-like Na+/K+ pump inhibitor, which has vasoconstrictor properties.
It is also possible that loop diuretics exert potassium channel opening effects in resistance arteries.
Why do we see interactions between loop diuretics and nsaids
NSAIDs have been shown to reduce the diuretic action of furosemide. This is thought to be because NSAIDs block production of PGE2, which has been shown to reduce Na+ and Cl- reabsorption in the thick ascending limb of the loop of henle.
NSAIDs will therefore have a diuretic effect.
Also, by competing with loop diuretics for the OAT, this reduces the delivery of diuretics into the renal tubule
What are the indications for loop diuretics
Loop diuretics are used to treat conditions associated with salt or water overload
Chronic heart failure Liver cirrhosis (+ ascites) Nephrotic syndrome Renal failure Hypertension (+ ↓ renal function) Hypercalcaemia
