Pharmacology of Diuretics Flashcards
What is the sole purpose of diuretics?
To increase urine volume.
Drugs which increase the excretion of salts (mainly NaCl) and water by the kidneys.
They decrease blood volume and cardiac output. Many diuretics also dilate arteries.
Fill in:
The kidneys filter large quantities of —- (4% of the plasma CO), reabsorb those substances that the body must —-, and excrete substances that must be eliminated.
plasma
conserve
What does the kidney receive the most of?
Blood flow of any organ.
20% of cardiac output
What are the two things that the kidney controls?
What is in the blood and blood volume.
How does the kidney work to increase urine volume?
They increase salt and hence water secretion.
They reduce Na+ and Cl- reabsorption in the nephron, decreasing reabsorption of water.
How many sodium is usually reabsorbed and what does this mean?
99+% of Na+ and water filtered by the kidneys is normally reabsorbed.
This means a small decrease in % reabsorption will greatly increase urine volume.
What are 3 conditions which loop diuretics can treat?
- Heart failure (increased venous pressure due to reduced cardiac function)
- Renal disease (protein lost via kidneys, plasma protein falls)
- Hepatic disease (lover produces less albumin, plasma protein falls)
All of them are due to fluid being retained by oedoma.
What type of diuretics treats hypertension?
Thiazide-type diuretics
How many litres of blood leaves the vascular system in micro-circulation?
4L (goes into the lymphatic system and back into tissues)
What happens to protein concentration in renal disease and what does this cause?
decrease in protein concentration
the gradient causing water to move back into the capillary will decrease causing oedema to occur
What two absorption processes are proportionate to each other?
Sodium and water reabsorption.
Explain the affects of diuretics on sodium reabsorption
It slightly blocks sodium reabsorption and hence water reabsorption also.
This is what causes blood volume to decrease. Protein in the blood stays the same but the volume it is in decreases so this causes more fluid to be excreted due to diuretics.
What proteins regulate sodium and water reabsorption?
Sodium - angiotensin 2 and aldosterone
Water - ADH
How much sodium and water is reabsorbed in the proximal tubule?
2/3
What molecules are reabsorbed/secreted at the PT?
Reabsorbed = glucose, amino acids, bicarbonate
Secreted = protons and weak acids&bases
Explain how the secretion of weak acids and bases occurs at the PT
Pumps do this along the nephron. Between the capillaries and the PT, pumps move the weak a&b into the nephron. Weak acids are filtered and secreted by these pumps also.
What are two ways diuretics get into the filtrate?
Pumped out or filtered out.
What % of sodium is reabsorbed in the DT?
5-10%
What other ion process is sodium absorption linked to?
Potassium secreted
In terms of potassium, what happens at the DT and collecting duct?
Net secretion of K+ stimulated by aldosterone.
How does ADH work?
Acts in the collecting duct producing aquaporins to cause water absorption. It also allows permeability of urea. A high concentration of urea in medulla which doesn’t build up in the loop of Henle and collecting duct. High conc in medulla increase osmolality to help the water get reabsorbed.
Are there any diuretics that work on the PT?
No
Where are transport processes for sodium reabsorption found?
Luminal membrane of epithelial cells which line the nephron.
What transporter mainly reabsorbs sodium in the PT?
Sodium-hydrogen exchanger
What transporter for sodium reabsorption occurs in the loop of Henle?
What does this transport
Sodium potassium chloride transporter (NKC22)
1 Na+, 1 K+, 2Ca2+
Does the collecting duct have?
No transporter, have tubules instead. One involved in sodium reabsorption and other in potassium secretion.
Explain the sodium concentration gradient formed in the loop of Henle
Sodium concentration in cells is lower than in the loop of Henle so this creates a gradient and membrane potential.
Energetically favourable for sodium to go into a cell and it drags the other ions with it.
Sodium pumped into the interstitial cells and then the capillary to go around the whole body.
What is the most important type of diuretic?
Loop diuretics
Explain the mechanism behind loop diuretics
Block of the Na+, K+, 2Cl- co-transporter in the thick ascending loop of Henle. This strongly inhibits Na+ reabsorption. The sodium then remains in the nephron.
Causes a powerful diuresis because the kidneys lose their capacity to create a hypertonic medullary interstitium needed to drive ADH-induced water reabsorption.
What is the purpose of the sodium left in the medulla that is not reabsorbed?
The sodium which is being reabsorbed is going back into the blood and the rest of it remains in the medulla where it helps to create a high osmolality which ADH uses for water reabsorption.
Give the 6 points on the Na+ transport on the thick ascending limb of loop of Henle
- Na+ pump on basal surface
- Electroneutral Na+:K+:2Cl- cotransporter at luminal surface, inhibited by loop diuretics
- Na+ removed by Na+-K+ pump & some by Na-HC03- transporter
- Cl- diffuses out via CLCN channels
- K+ diffuses back via ROMK channels at luminal surface, so can re-enter the cell
- Tight junction impermeable to H20, but allows diffusion of cations (e.g. Ca2+ and Mg2+) driven by positive potential
What way does potassium move into the cell?
Higher potassium concentration in the cell than in the nephron lumen so K+ goes through the ROMK channels out of the cells.
It moves 2 positive and 2 negatives charges into the cell so the potential is not affected.
K+ diffuses through the channel, creates a potential in which the lumen of the nephron is positive to the cell and the interstitial fluid.
This pushes the negative ions into the interstitium to help the reabsorption of all these cations (especially potassium and magnesium).
What is the main use of loop diuretics?
What happens to calcium and magnesium by loop diuretics?
Oedematous conditions (heart failure, hepatic cirrhosis).
Blocking calcium and magnesium transporter to prevent a membrane potential so less reabsorption of Ca and Mg occur. This can lead to too low concentrations of these.
What are the adverse effects of loop diuretics?
- hypokalaemia (low plasma K+) due to increased Na+-K+ exchange in collecting tubule.
- metabolic alkalosis (decreased plasma volume = contraction alkalosis) This makes the concentration of bicarbonate go up if plasma volume decreases
- depletion of calcium and magnesium ions (decreased potential gradient across TAL - less reabsorption, use for hypercalcaemia)
- obtoxicity (deafness) because of the Cl- handling part of NKCC2 resembles a Cl- channel in the inner ear
- hypovolaemia (blood volume is reduced too much which causes circulatory shock)
What is normal plasma K+?
4mmol
Explain the mechanism behind thiazide-type diuretics?
What are the adverse effects?
Block NCCT (sodium-calcium co-transporter). Block Na+, Cl- co-transport in the distal convoluted tubule, reduce plasma volume, venous return, cardiac output. Also, reduce total peripheral resistance by an unknown mechanism.
Hypokalaemia (too low potassium levels), hyperglyceamia (too high glucose), hyperuriceamia (excess of uric acid in blood)
What are the 5 points about sodium transport pathways in the distal tubule?
- Na+ pump on basal surface
- Electroneutral Na+:Cl- (NCCT) cotransporter at luminal surface, inhibited by thiazide diuretics
- Na+ pumps exchanges Na+ for K+ and Cl- diffuses out via channels
- K+ diffuses back through channels on the basolateral surface
- Both here and the in the loop of Henle, K+ transport across the epithelium is not dependant on Na+ reabsorption
Explain how diuretics leads to K+ loss
By reducing Na+ reabsorption, thiazides and loop diuretics increase delivery of Na+ and fluid to the collecting duct.
This increases Na+ uptake and secretion of K+ and H+ in the collecting tubule.
The K+ secretion can cause hypokalaemia, and the H+ secretion can cause metabolic alkalosis.
Hypokalaemia can be prevented by combining loop/thiazide diuretics with a K+ sparing diuretic or by giving K+ supplements.
Explain the sodium pump creating a flow of Na+ and K+
Sodium pump creating a gradient so sodium flows in from the lumen of nephron into the cells. Creates a membrane potential, depolarises the cell and lots of potassium in cells means K+ is then driven out of the nephron and then excreted.
Another cell has a transporter which exchanges potassium for H+, more K+ means more H+ out the cell and into the urine.
What two things block sodium reabsorption?
- Blocking Na+ channels
- Blocks affects of aldosterone so less proteins expressed
Explain the K+ sparing diuretics 1
- give the two examples
Block sodium channel or the expression of the sodium channels.
Low efficacy due to action in late distal tubule and collecting duct.
Amiloride: block collecting tubule Na+ channels, thus block Na+ reabsorption and K+ secretion.
Spironolactone: aldosterone antagonist (blocks aldosterone receptor), competes for receptor Pro-drug.
Give details on K+ sparing diuretics 2
Not usually used as the sole diuretic since they cause only limited diuresis and have a tendency to cause hyperkalaemia due to inhibition of K+ secretion.
Used with loop or thiazide diuretics to enhance diuresis and prevent hypokalaemia.
