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)