Diuretics Flashcards
What is natriuresis?
the process of excretion of sodium in the urine, therefore decreasing [Na+] plasma
What are some promoting factors of natriuresis?
ventricular and arterial natriuretic peptides and calcitonin
What is diuresis?
An increase in urine production
What are some types of diuretics?
Osmotic diuretics
Carbonic anhydrase inhibitors
Loop diuretics
Thiazide diuretics
K+ sparing diuretics
Where in the kidneys do osmotic diuretics work?
- Proximal tubules
- Loop of Henle
- Collecting duct
What are some examples of osmotic diuretics?
Mannitol
Isosorbide
Glycerin
Urea
Uses of mannitol
- Prevention of acute renal failure in pigment load (E.g. transfusion reaction)
- Excretion of toxic substances
- Reducing intra-ocular pressure
- Reducing intracranial pressure and cerebral oedema
Uses of isosorbide
Reducing intra-ocular pressure
Uses of glycerin
Reducing intra-ocular pressure
Uses of urea
Reducing intra-ocular pressure
Reducing intracranial pressure and cerebral oedema
Why is mannitol the preferred osmotic diuretic?
Mannitol is prefered over the other agents because it is inherently non-toxic, freely filtered, non-reabsorbable and not metabolised
What are some possible adverse reactions of osmotic diuretics
Cardiovascular toxicity (Immediate)
Pulmonary oedema
Headache
Nausea
Vomiting
How can osmotic diuretics cause cardiovascular toxicity?
Osmotic pull of interstitial fluid into plasma increasing blood volume and so workload of the heart
Describe the MOA of osmotic diuretics
Their MOA is to inhibit water and Na+ reabsorption
Osmotic diuretics are less permeant through biologic membranes than water, and so remain in the tubular fluid
As they are osmotically active, they bind water osmotically and retain water in the lumen
Normally, when Na+ is reabsorbed, water follows to maintain the same Na+ concentration in the tubular fluid, however, in this case, water does not follow, decreasing tubular fluid [Na+] and therefore breaking down the concnetration gradient out into the tubular cells, meaning Na+ remains in the tubular fluid and is excreted alongside water
There is also movement of water from the tubular interstitium into the tubule due to osmotically active osmotic diuretic and Na+
Osmotic agents shift water between compartments because osmotic agents are less permeant through biological membranes than water
Their own permeance varies from relatively high (Urea) to very low (Mannitol)
Why can osmotic agents only be given IV?
Body cells lack transport mechanisms for polyhydric alcohols such as mannitol and sorbitol, which are thus prevented from penetrating cell membranes, meaning they have to be given intravenously
Where do carbonic anhydrase inhibitors act?
Proximal tubules
What are some examples of carbonic anhydrase inhibitors?
- Dorzolamide
- Brinzolamide
- Acetazolamide
Describe the MOA of carbonic anhydrase inhibitors
Their MOA is to inhibit bicarbonate reabsorption
CA plays a major role in acid base balance to conserve bicarbonate
CA converts CO2 and H2O into H2CO3, which is broken down into HCO3- and H+
HCO3- can then be reabsorbed
H+ is then excreted into the urine via the Na/H antiporter
With each H+ ion excreted, an Na+ ion is reabsorbed
Carbonic anhydrase inhibitors inhibit CA and therefore prevent the formation of H2CO3 and therefore the formation of the H+ ions
This prevents action of the Na/H antiporter, therefore preventing reabsorption of Na+ and therefore water
What are some side effects of carbonic anhydrase inhibitors?
- Metabolic acidosis
- Increased Na+ and K+ excretion
What are some uses of carbonic anhydrase inhibitors?
- Not commonly used as diuretics
- Mostly used to reduce intraocular pressure in glaucoma through blocking the enzyme in the eye and the formation of aqueous humour
Where do loop diuretics act?
- Thick ascending limb of the loop of Henle
What are some examples of loop diuretics
- Furosemide
- Bumetanide
- Torsemide
What is the MOA of loop diuretics
Their MOA is to inhibit Na+, K+ and Cl- transport
They block the Na+/K+/2Cl- co-transporter (NKCC2) in the thick ascending loop of Henle
This decreases Na+ and Cl- reabsorption, which in turn causes water movement from the surrounding interstitium, increasing urine [NaCl] and volume of water
What are some interactions of loop diuretics
- Greater risk of digoxin toxicity due to hypokalaemia
- Change in plasma concentrations of drugs excreted by the kidneys
Where do thiazide diuretics act?
Early distal convoluted tubule
What are some examples of thiazide diuretics?
- Bendroflumethiazide
- Indapemide
- Chlorothiazide
What is the MOA of thiazide diuretics
Their MOA is to inhibit Na+, Cl- co-transport
They act to inhibit reabsorption of Na+ and Cl- from the distal convoluted tubules in the kidney by blocking the thiazide-sensitive Na+/Cl- symporter
By lowering [Na+] in the epithelial cells, they increase the activity of the Na+/Ca2+ exchanger on the basolateral membrane, so more Ca2+ is reabsorbed
What are some uses of thiazide diuretics?
- Hypertension
- Congestive heart failure
- Oedema due to heart failure, cirrhosis, CKF, steroids and nephrotic syndrome
What are some interactions of thiazide diuretics?
- Efficacy reduced by NSAIDs
- Drugs that contribute to hypokalaemia should be avoided
- Increases risk of digoxin toxicity
What are some contraindications of thiazide diuretics?
- Hypotension
- Gout
- Renal failure
- Lithium therapy
- Hypokalaemia
- Diabetes
How can thiazide diuretics cause hypokalamia?
Potassium loss occurs with thiazides in 1 of 3 ways
The kidney is very good at reabsorbing Na+ and since this was blocked early in the DCT, there is more vigourous Na+ reabsorption later on in the DCT
This is primarily mediated by aldosterone which reabsorbs Na+ and increases K+ secretion
Hypochloraemic alkalosis (Loss of Cl- through thiazides) also aids in potassium loss
How can thiazide diuretics increase uric acid levels?
Thiazides reduce the clearance of uric acid since they compete for the same transporter, and so raise uric acid levels in the blood
Where do K+ sparing diuretics work?
- Late distal convoluted tubule
- Collecting duct
What are the 2 main classes of K+ sparing diuretics?
Aldosterone antagonists
Na+ channel inhibitors
What are some examples of aldosterone antagonists?
Spironolactone
Eplerenone
What are some examples of Na+ channel inhibitors?
Amiloride
Triamterene
What is the MOA of aldosterone antagonists
Their MOA is to inhibit Na+ reabsorption and K+ secretion
Aldosterone normally evoke expression of the Na+/K+ pump and ENaC promoting Na+ reabsorption
Aldosterone receptor antagonists reduce this expression of the Na+/K+ pump and ENaC and so reduce Na+ reabsorption and K+ secretion
What is the MOA of Na+ channel inhibitors
Na+ channel inhibitors inhibit Na+ reabsorption by blocking ENaC on the apical membrane and reducing K+ secretion by a downstream reduction in the Na+/K+ pump activity on the basolateral membrane
What are some interactions of K+ sparing diuretics
- ACEi and ARBs increase plasma K+ and so can significantly contribute to hyperkalaemia when taken with K+ sparing diuretics
- Do not take potassium supplements with these
How do the kidneys play a role in acid-base balance?
Kidneys participate in the regulation of H+ concentrations in the body fluids
The kidneys can excrete acidic or alkaline urine
Why do the kidneys usually create acidic urine?
to compensate for the bodies tendency to decrease body pH due to metabolic production of CO2 (Glycolysis)
They compensate by secreting H+ into the tubular fluid and conserving HCO3-
How is K+ excretion regulated in the kidney?
In the collecting duct, K+ is transported into cells via the Na+/K+ ATPase on the basolateral membrane
Na+ passes through Na+ channels on the apical membrane
Influx of Na+ causes a depolarisation of the apical membrane
Depolarisation leads to a -ve potential across that cell, driving the force for K+ secretion
This means that the levels of K+ that are excreted in urine is regulated by the amount of Na+ which is reabsorbed
Normal serum Na+
133-146mmol/L
Normal serum K+
3.5-5.3mmol/L
Normal serum Cl-
95-108mmol/L
Normal serum Ca2+
2.2-2.7mmol/L
Normal serum Mg2+
0.7-1.0mmol/L
