What are the two major components of fluid balance in capillaries?
What changes in fluid balance will cause oedema?
Increased capillary pressure
Decreased oncotic pressure
What is nephrotic syndrome?
A disorder of filtration that allows large plasma proteins to enter the filtrate
How does a decrease in oncotic pressure cause oedema?
The decrease in oncotic pressure allows an increase in interstitial fluid
This reduced blood volume and thus cardiac output (Frank-Starling mechanism)
RAAS is activated
Sodium and water are retained
This increases capillary pressure, leading to more oedema
How does heptic cirrhosis with ascites cause oedema?
Increased pressure in the hepatic portal vein, combined with decreased production of albumin, causes loss of fluid into the peritoneal cavity and oedema (ascites)
Activation of the RAAS occurs in response to decreased circulating volume
Sodium and water retention causes increased capillary pressure
Where do loop diuretics have their effect and against which co-transporter?
Thick ascending limb of the loop of Henle
The ascending limb loses its diuretic effect
Where do thiazide diuretics have their effect and on what transporter?
The distal convoluted tubule
Where do potassium-sparing diuretics have their effect and on which transporter?
Na+/K+ exchange on collecting tubule
What happens to the concentration of plasma protein with diuretic use?
Concentration increases due to the decreased volume (excretion of water)
This increases plasma oncotic pressure and water/oedema is drawn back into the capillaries
What kind of drugs do organic anion transporters deal with?
Negatively charged, acidic drugs
e.g. thiazide and loop diuretics
What kind of drugs do organic cation transporters deal with?
Positively charged, basic drugs
How are organic anions (OA-) transported into the filtrate using organic ion transporters?
At the basolateral membrane, OA- enters the cell by diffusion or in exchange for α-KG using OATs
qα-KG is transported into cell (against a concentration gradient) via a Na+-dicarboxylate (NaDC) transporter
OA- is transported into the lumen either via multidrug resistance protein 2 (MRP2), or OAT4 (in exchange for α-KG)
How do organic cations (OC+) enter the filtrate?
At the basolateral membrane organic cations (OC+) enter the cell either by diffusion, or OCT, (both driven by negative potential of cell interior and against a concentration gradient)
At the apical membrane, OC+ enters the lumen via either multidrug resistance protein 1 (MRP1), or OC+/H+ antiporters (OCTN)
How do loop diuretics work?
Inhibit the Na+/K+/2Cl- carrier by binding to the Cl- site and thus:
Decrease the tonicity of the interstitium of the medulla
Prevent dilution of the filtrate in the thick ascending limb
Increase the load of Na+ delivered to distal regions of the nephron (causing K+ loss)
Increase excitation of Ca2+ and Mg2+
What are some examples of loop diuretics?
Furosemide and Bumetanide
How do loop diuretics enter the nephron?
Organic anion transport mechanism
What are some of the adverse affects of loop diuretics?
Shift in acid-base towards alkaline side (metabolic alkalosis) – caused by increased H+ secretion from intercalated cells in collecting tubule
Hypocalcaemia and hypomagnamesia
What is the mechanism of action of thiazide diuretics?
Inhibit the Na+/Cl- carrier by binding to the Cl- site and thus:
Prevent the dilution of filtrate in the early distal tubule
Increase the load of Na+ delivered to the collecting tubule (causing K+ loss)
Increase reabsorption of Ca2+
How much sodium do loop diuretics cause to be excreted?
How much filtered sodium do thiazide diuretics cause to be excreted?
What are some examples of thiazide diuretics?
Bendroflumethiazide (bendrofluazide) and hydrochlorothiazide
Which diseases are thiazide diuretics widely used in?
Mild heart failure
What are some of the adverse affects of thiazide diuretics?
Male sexual dysfunction
Impaired glucose tolerance
What is the mechanism that causes hypokalaemia with diuretic use?
Increased sodium in the filtrate caused by diuretic use causes enhanced reabsorption of sodium
Resulting charge separation makes lumen more negative and causes depolarisation
Increased driving force on K+ across the lumenal membrane leads to enhanced secretion of K+ (Secretion of H+ is similarly affected)
K+ and H+ washed away in urine - diuretics cause increased urine output
How do potassium-sparing diuretics amiloride and triamterene work to prevent hypokalaemia caused by other diuretics?
Block the apical sodium channel decrease Na reabsorption, preventing the depolarisation that drives K+ secretion
How do spironolactone and epinerleone work to prevent hypokalaemia?
Compete with aldosterone to bind to intracellular receptors causing:
1. decreased gene expression and reduced synthesis of a protein mediator that activates Na+ channels in the apical membrane (site 1)
2. decreased numbers of Na+/K+ATPase pumps in the basolateral membrane (site 2)
When are aldosterone antagonists used?
Primary hyperaldosteronism (Conn’s syndrome)
Resistant essential hypertension
Secondary hyperaldosteronism (due to hepatic cirrhosis with ascites)