W9 L4 - Pharmacology of Diuretics Flashcards
blood flow through the nephron
- glomerulus where ultrafiltration occurs
- PCT
- Loop of Henle
- DCT
- Collecting duct
- reabsorption into blood of water and electrolytes occurs at PCT, LoH, DCT
Diuretics
- Drugs that increase the amount of fluid and salts excreted by the kidney (diuresis)
- Main uses
To reduce oedema: fluid collection in the tissues
To reduce hypertension: high blood pressure
Diuretics and oedema
- Diuretics increase urine
production - This draws more fluid
from swollen areas in tissue - Reduces swelling and area
returns to normal
Diuretics and high blood pressure
Increase volume of urine produced
Decrease blood volume
Decrease pressure on blood vessels
Decrease blood pressure
How salts move
- via Active transport via pumps / transporters / co-transporters
- Passive transport via channels (this is minimal)
Openings in membrane
Ion selective
No energy required
Classes of diuretics
- Thiazides and related diuretics
- Loop diuretics
- Potassium-sparing diuretics
- Carbonic anhydrase inhibitors (glaucoma and unlicensed us for altitude sickness)
- Osmotic diuretics (used in hospitals for treatment of cerebral oedema)
Loop diuretics
- Site of action:
Thick ascending limb of the Loop of Henlé - Clinical Uses
Oedema: severe heart failure; acute ventricular failure (pulmonary oedema)
Not normally used for hypertension - Metabolised by the liver and excreted in urine
Mechanism of action: Loop Diuretics
- Blocks Na+/K+/2Cl- ATPase (or co-transporter)
- This INCREASES the excretion of
Sodium
Chloride
Potassium
Efficacy of loop diuretics
- Very powerful diuretics as it acts on the main site of sodium reabsorption
Up to 20% of filtered sodium can be excreted
Urine flow rate increases from 1ml/min to 8ml/min
High ceiling concentration - Act within an hour and for up to 6hrs
“Braking” effect after 6hrs due to distal compensation - Can be given twice daily (morning and no later than 4pm)
Side effects with loop diuretics
Hypokalaemia (low potassium) & metabolic alkalosis: confusion, dizziness, arrythmias
Hypo-natraemia, -calcaemia, -magnesaemia (low sodium, calcium & magnesium): tiredness, lethargy, muscle fatigue
Deafness (very high doses IM, IV dosing): 8th cranial nerve damage
Caution needed with pregnancy and breastfeeding
Monitor weight and fluid balance:
if >500-1000ml lost per day, hypovolaemia, hypotension and acute kidney injury can occur
Thiazides and related diuretics
Site of action: distal convoluted tubule
Clinical uses:
Oedema: mild heart failure; liver & kidney disease; steroid / hormone treatment
Hypertension (long term)
Metabolised in the liver and excreted in urine
Mechanism of action: Thiazides & related diuretics
- Blocks Na+/Cl- ATPase (or co-transporter)
- This INCREASES the excretion of
Sodium
Chloride
Potassium due to sodium exchange in collecting duct
Efficacy of thiazides & related diuretics
- Relatively potent diuretics, but less so than loop diuretics
Up to 8% of filtered sodium can be excreted
Urine flow rate increases from 1ml/min to 3ml/min
low ceiling concentration - Act within 1-2hrs and for up to 24hrs
- Take in the MORNING
Side effects with thiazides & related diuretics
Hypokalaemia (low potassium) & metabolic alkalosis : confusion, dizziness, arrythmias
Hypocalcaemia, -magnesaemia (low calcium & magnesium): tiredness, lethargy, muscle fatigue
Hyperuricaemia (high uric acid): gout
Hyperglycaemia (high blood sugar): diabetes
Monitor weight and fluid balance:
if >500-1000ml lost per day, hypovolaemia, hypotension and acute kidney injury can occur
Thiazides & related diuretics: Kidney Disease
- Relatively ineffective in patients with severe chronic kidney disease (stages 4 & 5)
Unless co-prescribed with a loop diuretic - Metolazone is effective when GFR is <20ml/min
Also works on proximal convoluted tubule
Potassium-sparing diuretics
- Sodium channel blockers (triamterene (Dytac®) and amiloride)
- Aldosterone antagonists (spironolactone (Aldactone®) and eplerenone (Inspra®))
- Metabolised by the liver and excreted in urine and bile
- Site of Action: Late Distal Tubule & Collecting Duct
- Clinical Uses:
Oedema -heart failure; liver disease
Hypertension
Hypokalaemia with loop diuretics & thiazides
Primary hyperaldosteronism (Conn’s Syndrome) – spironolactone only
Mechanism of action: potassium-sparing diuretics
Increased SODIUM and water excretion
Chloride and Calcium excreted too
Decreased excretion of POTASSIUM and H+
What does this look like? Normal activity (potassium sparing diuretics)
Normally cells within the collecting duct retain sodium by reabsorbing it through sodium channels which is then exchanged with potassium from the interstitial fluid by Na+/K+ ATPase. The potassium drawn into the cell is then excreted into the lumen by potassium channels and lost in urine.
What does this look like? With diuretic (potassium sparing diuretics)
NA+ channel blockers block Na+ channels, which reduces the activity of Na+/K+ ATPase. This in turn means that less potassium is pumped from the cell into the interstitial space and subsequently lost from the body.
Aldosterone receptor antagonists prevent aldosterone from binding to the receptor and so lead to sodium and water excretion and reduced potassium excretion, hence their name.
Efficacy of potassium-sparing diuretics
- Fairly weak diuretics compared to thiazides & related AND loop diuretics
Up to 2-3% of filtered sodium can be excreted - Act within 1-2hrs and for up to 24hrs
- Take in the MORNING
Side effects with potassium-sparing diuretics
- Hyperkalaemia (high potassium) & metabolic acidosis
- Monitor electrolyte levels: especially if patients
have renal disease
are on ACE-Inhibitors; angiotensin receptor antagonists (sartans); B-adrenoceptor antagonists
Antidiuretics
- Site of action: collecting duct
- Clinical uses:
Central diabetes insipidus (due to lack of ADH, antidiuretic hormone) - Mechanism of action:
increases number of aquaporins which increases passive reabsorption of water - Vasopressin
Very short duration of action
Injection / infusion only
Increase blood pressure (ARVP1 or V1 receptors in smooth muscle) - Desmopressin
Longer duration of action
Nasal spray or tablets
No affect on blood pressure (ARVP2 or V2 receptor selective)
