Diuretics Flashcards
Describe the structure of the PCT
Lumen surrounded by tubular cells
Villi and microvilli projecting into the lumen to maximise absorption
Basal interdigitations with many mitochondria
Highly vascularised- so surrounded by lots of capillaries for exchange between the lumen and blood.
What does the body want to do in terms of salt (Na+) and water reabsorption
It wants to reabsorb all the water and Na+ filtered in the glomerulus- it is reabsorbed in the PCT.
Describe Na+ and H2O reabsorption at the PCT
Basal Na+/K+-ATPase effluxes sodium to establish concentration gradient
Sodium enters cell over apical membrane down concentration gradient
Water follows sodium down osmotic gradient via aquaporins, due to oncotic pressure of interstitium (glomerular filtrate has no proteins unlike blood, so draws water) - it will also follow Na+ by osmosis.
This is the transcellular movement of Na+ and H2O
Describe the paracellular movement of Na+ and H2O at the PCT
The blood at the interstitium will have a higher oncotic pressure due to the presence of proteins in the blood (remember proteins can’t be filtered at the glomerulus)- hence water, Na+, Cl- and HCO3- can move into the blood from the lumen paracelluarly.
The bigger the gap between the cells- the greater the flux of ions and water.
In terms of the filtered glucose and amino acids, what does the body want to do to it
Reabsorb it all.
Describe the reabsorption of glucose and amino acids at the PCT
They are co-transported into the tubular cell alongside Na+
They enter the cell via an apical Na+/H+ ATPase, which brings Na+ (along with the glucose and amino acids in) and effluxes the H+.
Describe bicarbonate reabsorption at the PCT
Want to reabsorb bicarbonate- as it is a really good buffer in the blood.
The H+ entering the lumen via the Na+/H+ ATPase is combined with HCO3- and converted into CO2 and H2O via transmembrane carbonic anhydrase.
The CO2 and H2O then diffuse into the tubular cell.
Cellular carbonic anhydrase then converts the CO2 and H2O back into HCO3- and H+.
The HCO3- is co-transported with Na+ into the blood
The H+ leaves the cell into the lumen via the Na+/H+ ATPase
Describe the role of the PCT in excreting exogenous agents
Exogenous agents (e.g drugs that have been metabolised by the Liver and have a glucuronide side chain) enter the PCT at the basal side (i.e in the blood- too big to be filtered)- where a membrane transporter will detect their side chain (i.e glucuronide) and transport them to the lumen to be excreted in the urine.
What percentage of Na+ is reabsorbed in the PCT
65-70%
What is the key difference in the permeability of the descending limb and the ascending limb
Descending limb –
permeable to water
Ascending limb –
impermeable to water
Describe what happens in the descending limb
Water moves transcellularly (via aquaporins) and paracellularly from isotonic tubular lumen to hypertonic interstitial by osmosis.
Describe what happens in the ascending limb
Triple co-transporter of Na+, 2CL- and K+ from the tubular lumen into the cell
(some K+ just leaks back out into the tubule)
Basal K+. Cl- co-transporter- to move these electrolytes into the interstitium (some Cl- can leak into the intersitium)
Na+/K+ ATPase- to maintain conc gradient of Na+ for triple co-transporter
This concentrates the interstitium whilst making the tubular fluid more hypotonic (more water and dilute)
Na+ can also move paracellularly (but the junctions between cells is a lot tighter).
Describe how the counter-current mechanism is established
The filtrate would travel down the loop of Henle and as it goes up the ascending limb (impermeable to water but permeable to ions), Na+ moves from the tubule to the interstitium thus making the interstitium hypertonic and the tubular fluid hypotonic.
Then, more fluid will come down the descending limb (permeable to water) and the hypertonic interstitium will attract water and increase the reabsorption of water from the tubule into the interstitium
This will increase the concentration of fluid reaching the ascending tubule where even more Na+ will be reabsorbed and move into the interstitium
This occurs repetitively and you end up with a hypertonic interstitium and hypotonic tubular fluid leaving the loop of Henle
This hypertonic interstitium is also responsible for increasing water reabsorption in the collecting duct (mediated by vasopressin)
What are the key points to take away from the counter-current mechanism
The fluid in the desceding limb will equilibriate with the fluid in the interstitium. Therefore, if the osmolarity of the intersitium increases (due to more Na+ reabsorption), more water will leave the descending limb, making the fluid leaving the descending limb more hypertonic (concentrated)- propagating the cycle further.
What happens as more fluid arrives
More fluid enters and forces fluid from descending to ascending limb – this fluid has increased in osmolarity due to increased Na+ concn in the medulla.
Remember- the fluid is isotonic to begin with.
Describe what happens in the early distal tubule cell
Na+ and Cl- co-transport from the lumen into the cell
Na+/K+ ATPase (Na+ enters intersitium, K+ moves into cell).
Co-transport of K+ and Cl- into the interstitium.
Describe what happens in the late distal tubule cell
Again, the Na+ and Cl- transport as in the early distal tubule cell, but also:
Aldosterone acting on mineralcorticoid receptor on the basal side of the cell- which will open aldosterone-sensitive Na+ channels on the apical side- leading to Na+ moving into the cell. The Na+ then enters the interstitium via a basal Na+/K+ ATPase
ADH acts on basal V2 receptors, leading to the synthesis of AQP2 on the apical side. Water moves in by osmotic gradient created by the movement of Na+ and Cl-. Water leaves the basal side via AQP3/4
What is a key feature of the DCT and collecting duct
Tight junctions to help regulate the movement of water.
Describe what happens in the collecting duct
Aldosterone-sensitive Na+ channels- Na+ moves into the cell.
Na+ enters the interstium via Na+/K+ ATPase
K+ entering the cell leaks into the tubular fluid.
Cl- leaks into the cell from the tubule and leaks into the interstitum
ADH mediated water reabsorption.
What is a key property of the collecting duct
§ Impermeable to free water re-uptake – osmolarity increases as you pass deeper into the medulla so any free absorption would ruin the gradient as water would pass back into the tubular fluid.
You want to keep a gradient for water to move across so that you can concentrate the urine when necessary.
Summarise the two ways by which diuretics work
o Inhibiting the reabsorption of Na+ and Cl- - raising excretion.
o Increasing the osmolarity of the tubular fluid – decrease osmotic gradient (i.e. osmotic diuretics).
What are the 5 main classes of diuretic
§ 5 main classes of diuretic – only the last 3 are used clinically usually:
o Osmotic diuretic. Mannitol
o Carbonic anhydrase inhibitors. Acetazolamide.
o Loop diuretics. Furosemide (Frusemide).
o Thiazides. Bendroflumethiazide (Bendrofluazide).
o Potassium-sparing diuretics. Amiloride, Spironolactone.
Describe how osmotic diuretics work
This is a pharmacologically inert chemical that can increase plasma and urine osmolarity
It is filtered by the glomerulus but not reabsorbed
Increasing the osmolarity of the filtrate means that less water leaves the lumen and is reabsorbed
Have their effects at the PCT, loop of Henlé and collecting duct
Suggest a use for osmotic diuretics
They are mainly used for their effect in increasing plasma osmolarity – they draw out fluid from cells and tissues (e.g. in oedema)
Describe how carbonic anhydrase inhibitors work
Inhibition of carbonic anhydrase reduces HCO3- reabsorption into the blood
It also reduces the amount of H+ available within epithelial cells to drive the Na+/H+ exchanger and allow Na+ reabsorption
This decreases the osmotic gradient for water to move across.
Acts at the PCT
Describe the importance of diuretics
Furosemide, Bendroflumethiazide and sprinolactone are 3 of the top 100 prescribed drugs in the U.K
Describe how loop diuretics such as frusemide work
They block the Na+,Cl-,K+ triple co-transporter in the ascending limb of the loop of Henlé.
Therefore the Na+ and Cl- reabsorption is inhibited,
The osmolarity of the tubular fluid increases, therefore you decrease the osmolarity of the medullary interstitium, and there is therefore less of an osmotic gradient for water reabsorption in the collecting duct
Therefore the urine volume will increase.
Describe the effects of loop diuretics on Ca2+ and Mg2+ reabsorption
When the triple transporter works normally, the K+ entering the cell normally leaks back out into the tubular fluid.
This creates a positive lumen potential in the tubular fluid, which will drive the paracellular reabsorption of K+, Mg2+, Ca2+ and Na+ down this electrochemical gradient into the interstium
As loop diuretics block this co-transporter, you lose the K+ recycling and hence lose the positive luminal potential, inhibiting the reabsorption of Mg2+ and Ca2+, further leading to more water loss in the urine.
Describe the effects of loop diuretics on K+
As less Na+ is reabsorbed in the Ascending limb, more Na+ will reach the distal tubule.
Your body wants to reabsorb all the Na+, so the DCT will reabsorb more Na+, and this will be at the expense of k= (Na+/K+ ATPase)
Therefore you get increased K+ loss, in common with thiazides.
How much fluid loss can loop diuretics cause
15-20%
Lose 15-30% of your Na+ reabsorption.
Explain why thiazide diuretics are less powerful than loop diuretics
Because thiazide diuretics act on the early DCT, they have no impact on the counter-current mechanism and your ability to concentrate the interstitum.
Thiazide diuretics cause a 5-10% fluid loss, whereas loop diuretics cause a 15-30% fluid loss.
Describe how thiazide diuretics work
They block the Na+, Cl- co-transporter in the early DCT.
Therefore Na+ and Cl- reabsorption is inhibited.
As a result the osmolarity of the tubular fluid increases, decreasing the osmotic gradient for water reabsorption in the collecting duct.
Describe the effect of thiazide diuretics on K+
More Na+ will reach the late DCT
Want to reabsorb all the Na+, this will occur at the expense of K+
Less pronounced K+ loss when compared to loop diuretics.
Describe the effects of thiazide on Mg2+ and Ca2+
Chronic administration of thiazides is frequently associated with negative potassium balance and hypokalemia. Hypokalemia may in turn directly inhibit distal tubular cell magnesium uptake, thereby increasing magnesium excretion
Probably - Increased proximal sodium and water reabsorption due to volume depletion, which leads to increased passive proximal calcium reabsorption
What effect would diuretics have on renin secretion?
Acutely, they would decrease renin secretion- due to decreased Na+ reabsorption resulting in a greater Na+ load reaching the macula densa.
Chronically- As diuretics increase Na+ loss and water loss, you would get a hypovolaemia, reducing the renal perfusion pressure and renal Na+ load, thus stimulating the release of renin.
The macula densa is located near the DCT.
Which diuretic would have the most powerful effect on renin secretion?
Loop diuretics, as these block the Na+,Cl-, K+ triple transporter- which the macula densa cells also use to detect sodium.
With this blocked, the macula densa senses a low Na+ load, thus stimulating the release of renin.
Describe the problem of increased renin release associated with thiazide and loop diuretics
Renin would activate the RAAS, which would therefore stimulate aldosterone release, leading to Na+ and water retention- combating what you are trying to achieve with diuretics.
Therefore, we often Give ACE inhibitors with the diuretics
Describe the two different classes of K+ sparing drugs
Aldosterone receptor antagonists
e.g. spironolactone
Inhibitors of aldosterone-sensitive Na+ channels
e.g. amiloride
Describe how the aldosterone receptor antagonists work
Prevent aldosterone from binding to the nuclear mineralocorticoid receptor in the collecting duct cells.
This reduces the synthesis of the aldosterone-sensitive Na+ channel and the Na+/K+ ATPase, thus reducing the machinery to reabsorb Na+
This will increase tubular fluid osmolarity, thus decreasing the osmotic gradient for water reabsorption in the collecting duct.
Describe how the aldosterone-sensitive Na+ channel inhibitors work
They inhibit the aldosterone mediated Na+ reabsorption- thus increasing the tubular fluid osmolarity and thus decreasing the osmotic gradient for water reabsorption.
Describe the effects of K+ sparing diuretics on H+
They also lead to increased H+ retention (because of reduced Na+/H+ exchange) at the distal tubule
Summarise the side effects of different diuretics
Hypovolaemia – loop diuretics and thiazides.
§ Hyponatraemia – loop diuretics and thiazides.
§ Hypokalaemia – loop diuretics and thiazides.
§ Metabolic alkalosis – loop diuretics and thiazides. (cl- loss)
§ Hyperuricaemia – loop diuretics and thiazides.
o Loop diuretics have a more powerful effect of all.
§ Hyperkalaemia – K+-sparing diuretics.
§ Metabolic acidosis – carbonic anhydrase inhibitors.
What can carbonic anhydrase inhibitors be used to treat
Not used as diuretics but are of value in the treatment of glaucoma
Summarise the main uses of loop diuretics
Acute pulmonary oedema
Oedema due to heart failure, liver disease or renal disease (if refractory to other diuretics
Hypercalcaemia
Hyperkalaemia
Acute renal failure (may facilitate urine flow)
Summarise the main uses of thiazide diuretics
Congestive heart failure
Hypertension
Idiopathic hypercalcaemia
Nephrogenic diabetes insipidus
Where are the macula densa cells found
At the top of the ascending limb of the loop of Henle
The top of the ascending limb comes very close to the afferent arteriole
Describe the uses of spironolactone
Hypertension/heart failure
Hyperaldosteronism
State some unwanted effects of K+ sparing diuretics
Hyperkalaemia – metabolic acidosis
Spironolactone (very non-specific action) – gynaecomastia, menstrual irregularities
Describe how loop diuretics and thiazide diuretics can lead to hyperuricaemia
Both the diuretrics and the uric acid use a basal organic anion transporter to get into the kindey cell.
Diuretics outcompete uric acid for this transporter- leading to hyperuricaemia.
Describe the use of thiazides as first line treatment for hypertension
1st line treatment (or CCB) in salt-sensitive individuals i.e those over 55 or afro-Caribbean in origin
Why may some individuals be salt sensitive
Although the pathogenesis of salt-sensitive hypertension is heterogeneous, it is mainly attributable to an impaired renal capacity to excrete sodium Na+. Partly due to increased MR induced Na+ reuptake, partly due to increased Na+Cl- transporter in distal convoluted tubule
Describe the other steps when thiazide can be incorporated into the treatment plan for hypertension
if >55yo or Afro-Caribbean then started on CCB/Thiazide
Second line is ACEi with CCB OR thiazide
Third line is ACEi and CCB and thiazide
What did the ALLHAT trial show
§ Thiazides > calcium channel blockers > ACEi – for treating high SBP.
Why are thiazides used over other diuretics
o Initial (4-6 weeks) – reduction of BP due to reduction of blood volume.
o After 4-6 weeks – plasma volume restored due to tolerance.
o Chronic thiazides – reduction of TPR due to – activation of eNOS, Ca2+-channel antagonism and opening of KCa-channels. Leads to…
§ NO production, less calcium influx and hyperpolarisation.
Vasodilation
Describe how we know that the anti-hypertensive effects of diuretics is not exclusively due to their reduction in plasma volume
If diuretics simply lowered blood pressure by reducing plasma volume, then one would expect loop diuretics (such as furosemide), which are superior diuretics to thiazides, to be superior antihypertensives. However, loop diuretics do not lower blood pressure to the degree thiazides do.
The chronic thiazide antihypertensive effect is not exclusively due to a loss of blood volume.
Chronic thiazides definitely reduce TPR, although mechanism may be different for different thiazides.
Outline a schemata for heart failure
Systolic HF (multiple heart attacks- necrotic core- can’t eject properly)- bi-directional relationship with a reduced CO
Reduced CO leads to (to try and increase BP):
Activation of RAS
SNS activation
Activation of RAS:
Increased production of Ang II which results in vasoconstriction
Increased aldosterone production- Na and water retention
SNS activation: Vasoconstriction Renin release (activating RAS)
Noradrenaline, Ang II and aldosterone lead to cardiac remodelling- which worsens the HF
The vasoconstriction and salt and Na retention increase the cardiac filling pressure (more blood reaching the heart, but the heart cannot eject all the blood- so there is a backflow leading to ankle oedema.
How does cardiac remodelling worsen the systolic heart failure
Causes hypertrophy, apoptosis, oxidative stress, ion channel gene expression, ischaemia, changes in the shape of the heart
Describe the use of loop diuretics in HF
Loop diuretics –
30% Na+ load
Acute reduction in congestion
Administration of intravenous furosemide to patients with heart failure typically results in a prompt diuretic effect (within 30 minutes) that peaks at 1.5 hours. This effect leads to a decrease in ventricular filling pressures and improvement in symptoms in the majority of patients with heart failure.
However, this will soon activate RAS.
Chronic use associated with resistance
RAS activation
How can we overcome the resistance to loop diuretics seen in HF
Additional use of potassium sparing diuretics
To further increase Na+ excretion and therefore water loss to give a greater decrease in cardiac filling pressure.
This combination showed a 30% reduction in death compared to placebo.
Describe how thiazides can lead to impaired glucose tolerance
Impaired glucose tolerance (see Ch. 32), due to inhibition of insulin secretion, is thought to result from activation of KATP channels in pancreatic islet cells
What is an important drug interaction to consider with the non-K+ sparing diuretics
The effects of hypokalaemia on digoxin.
