Drugs Acting on the Kidney 1 Flashcards
What are diuretic drugs?
A drug that prevents the reabsorption of electrolytes (usually sodium) causing loss of water
Why does oedema develop?
An imbalance between the rate of formation and absorption of interstitial fluid
Which forces contribute to the formation of the interstitial fluid?
- Hydrostatic pressure in the capillary (Pc)
- Hydrostatic pressure in the interstitium (Pi)
- Oncotic pressure in the capillary (πp)
- Oncotic pressure in the interstitium (πi)
Why is the oncotic pressure greater within the capillary versus the interstitium?
Higher protein concentration (plasma proteins) within capillary
This creates an oncotic drag
How does oedema develop?
- Either Pc increases or πp decreases
- Interstitial fluid formation increases causing oedema occurs
- Blood volume and cardiac output decrease due to lower blood volume
- RAAS activated in response
- Sodium and water retention occurs at kidneys
- Blood volume increases
- Cycle repeats
Why does nephrotic syndrome specifically cause oedema?
- πp decreases (as protein is lost)
- Interstitial fluid formation increases causing oedema occurs
- Blood volume and cardiac output decrease due to lower blood volume
- RAAS activated in response
- Sodium and water retention occurs at kidneys
- Blood volume increases increasing Pc and further decreasing πp
- Cycle repeats
Why does congestive heart failure result in the formation of oedema?
- Reduced cardiac output
- Lowered BP and renal perfusion
- RAAS activated
- Blood volume increased
- Pc increases and πp decreases
- Oedema occurs
For which two key reasons does ascities occur in hepatic cirrhosis?
- Increased hepatic portal vein pressure
- Decreased albumin production (πp lowered)
Why are loop diuretics useful for reducing oedema?
Sodium (and water) are excreted and blocked from reabsorption
Haemoconcentration occurs as protein concentrates in vessels
This means oedema will travel back into vessels
Which part of the nephron and which transported do loop diuretics act on?
Thick ascending loop of Henle
Na+/K+/2Cl- co-transporter
Which part of the nephron and which transported do thiazide diuretics act on?
Distal convoluted tubule
Na+/Cl- co-transport
Which part of the nephron and which transported do potassium sparing diuretics act on?
Collecting tubule
Na+/K+ exchange
Why must diuretics enter the filtrate?
Many act on the apical membrane of tubular cells
In which ways can diuretics enter the filtrate?
- Glomerular filtration (if the drug is not bound to plasma protein)
- Secretion via transport processes in the proximal tubule
- Organic anion transporters (OATs) for acidic drugs
- Orgabic cation transporters (OCTs) for basic drugs
Why do diuretics not act on all tissues of the body?
The action of the kidneys allows the concentration of the drug in the filtrate to far surpass that in the plasma
Describe the process by which organic ion transporters (OATs) act
- Basolateral membrane
- Organic anions enter the cell by diffusion or in exchange for alpha-ketoglutarate (via OATs)
- Alpha-ketoglutarate remain in high concentration inside the cell due to the Na+-dicarboxylate transporter
- Apical membrane
- Organic anions enter the lumen via multidrug resistance protein 2 (MRP2) or OAT4 in exchange for alpha-ketoglutarate
Describe the process by which organic cation transporters (OCTs) act
- Basolateral membrane
- Organic cations enter the cell by diffusion or by OCTs
- Apical membrane
- Organic cations (OC+) enter the lumen via multidrug resistance protein 1 (MRP1) or by OC+/H+ antiporters (OCTN)
Which transporter is blocked by loop diuretics?
Na+/K+/2Cl- co-transporter
Loop diretics bind to which site on the Na+/K+/2Cl- co-transporter?
Cl- site
How do loop diuretics affect the tonicity of the medulla?
Decrease it
(Less sodium and chloride enter the the medulla if the Na+/K+/Cl- channel is blocked)
What is the overall effect of blocking the Na+/K+/Cl- co-transporter?
Filtrate in the thick ascending limb cannot be diluted
This means more sodium and chloride is excreted in the urine
Since water will follow sodium, water is also lost
Which secondary mechanism of loop diuretics affects the veins?
Venodilatation
Reduces preload and work the heart must do
This occurs before diuresis
Which electrolytes do loop diuretics cause to be lost more than usual?
Calcium
Magnesium
Potassium
Loop agents _______ in compromised renal function, thiazides ________
Loop agents work in compromised renal function, thiazides don’t
How do loop diuretics enter the nephron?
OATs
(this is because they are bound to palsma proteins)
How are magnesium and calcium ions normally reabsorbed?
Paracellularly via a passive process created by an electrochemical gradient due to potassium recycling
Why do loop diuretics cause magnesium and calcium excretion?
Potassium recycling is disrupted
This means the interstitium is more positively charged than it should which repels magnesium and calcium
They are then kept in the filtrate
Why must digoxin be used carefully with loop diuretics?
Both digoxin and potassium compete at the potassium binding site at Na+/K+ATPase
Loop diuretics cause hypokalaemia which means digoxin has a stronger effect
Besides digoxin, which other drug class must be used with care with loop diuretics?
Class III antidysrhythmics
(these drugs are potassium channel blockers and hypokalaemia strengthens their action)
How do loop diuretics cause metabolic alkalosis?
There is increased distal delivery of sodium ions
- In the distal tubules, the The Na/K-ATPase channels in luminal cells can exchange sodium ions for hydrogen ions (as well as potassium ions) leading to acid loss
- Negatively charged chloride ions leave the body disproportionately to any positively charged counterparts. The body begins to produce bicarbonate (HCO3-) to replace the lost anions and an alkalosis develops
Why are diuretics associated with gout?
Uric acid competes with loop agents for the OAT in the proximal tubule
This means less is excreted
Why does the effectiveness of loop diuretics wane over time?
The Na+/K+/Cl- co-transporter upregulate in response to continuous blockade
The effect is therefore reduced
Which transporter do thiazide diuretics block?
Na+/Cl- co-transporter
(in the distal convoluted tubule)
Which site on the Na+/Cl- co-transporter do thiazide diuretics bind?
Cl- site
Why do thiazide diuretics cause potassium loss?
The Na/K-ATPase sodium channel in luminal cells can exchange sodium ions for potassium ions
By preventing sodium reabsorption, more travels to the collecting duct, the filtrate volume increases and potassium concentration decreases
By diffusion potassium travels into the filtrate and is lost
How do thiazide diuretics affect calcium reabsorption?
Increase it
Why can thiazide diuretics be used for hypertension?
Reduce blood volume
Vasodilator action
Why are thiazide diuretics useful for renal stone disease?
Reduce urinary excretion of calcium
Which protein channels does aldosterone induce synthesis of?
- Na+/K+ ATPase (basolateral membrane)
- Epithelial Na+ Channel (ENaC)
Why do diuretics induce potassium loss?
- Increased Na+ load
- Enhanced Na+ reabsorption (near collecting tubule)
- Lumen becomes more negative
- Increased driving force of potassium into lumen
- Secreted K+ (and H+) passed in urine
- Hypokalaemia (and metabolic alkalosis) induced
What are the different types of potassium sparing diuretics?
- Sodium channel blockers (Amiloride, Triamterene)
- Aldosterone antagonists (Spironolactone, Eplerenone)
How do the sodium channel blocker potassium sparing diuretics prevent potassium loss?
- Sodium is prevented from entering the late distal and collecting tubule luminal cells through apical sodium channels
- This reduces the available sodium to power the Na+/K+ATPase on the basolateral membrane
- Hence, less potassium enters the luminal cells and less will leave out the potassium channels into the lumen
How do the aldosterone antagonists function to minimise potassium loss?
Since aldosterone is blocked its actions are too
- There is decreased gene expression and reduced synthesis of a protein mediatormwhich activates Na+ channels in the apical membrane
- There are decreased numbers of Na+/K+ATPases recruited in the basolateral memebrane
How does spironolactone impact potassium levels?
Hyperkalaemia
Clinically, when will potassium sparing diuretics be utilised?
In conjunction with other agents which cause potassium loss
