Diuretics

Question 1

Learning outcomes

Answer 1

Define the term diuretic
Classify diuretics by their pharmacological site and mechanism of action
Relate the different diuretic actions to their preferred clinical use, with particular reference to systemic hypertension and congestive heart failure
Identify patient characteristics that may influence diuretic prescribing
Recognize adverse effects common and specific to diuretics
Predict drug interactions that may occur when introducing diuretic therapy

Question 2

Learning outcomes

Answer 2

Define the term diuretic
Classify diuretics by their pharmacological site and mechanism of action
Relate the different diuretic actions to their preferred clinical use, with particular reference to systemic hypertension and congestive heart failure
Identify patient characteristics that may influence diuretic prescribing
Recognize adverse effects common and specific to diuretics
Predict drug interactions that may occur when introducing diuretic therapy

Question 3

Diuretics overview

Answer 3

•Greek: Diureticos–prompting urine
•Diuresis= increased urine volume
•3(+1) main types of diuretic in modern use
–categorised based on their mode of action on the kidney
1.(Osmotic diuretics / carbonic anhydrase inhibitors)
2.Loop diuretics
3.Thiazide/ thiazide-like diuretics
4.Potassium sparing diuretics

Question 4

Drugs acting mainly on proximal convoluted tubule- mannitol

Answer 4

•Osmotic diuretics: mannitol–freely filtered, act on parts of nephron most water-permeable (PCT and early Loop of Henle)
–reduce H2O reabsorption (water retained in filtrate due to osmosis)
–reduce electrolyte reabsorption (leak back into tubule down concentration gradient)
•Osmotic diuretics: mannitol
•Infused i.v. mainly for raised intracranial pressure (cerebral oedema) and intraocular pressure
•Side-effects (uncommon): hypotension, fluid and electrolyte disturbance

Question 5

Carbonic anhydrase inhibitors

Answer 5

• Example: Acetazolamide
• Mode of action: Inhibits carbonic anhydrase in PCT •enzyme interconverts CO2/H20 and H+/HCO3-(controls acid-base balance)
• Acetazolamide reduces Na+ and HCO3-reabsorption
• Weak diuretic (action partially compensated by greater Na+ reabsorption in DCT)
• Clinical indications: glaucoma and acute altitude sickness
• Adverse effects: metabolic acidosis, hypokalaemia, renal stone formation (due to alkaline urine

Question 6

Loop diuretics

Answer 6

•given orally (preferred route) or i.v.
•>95% bound to proteins in plasma, limiting glomerular filtration
•secreted into tubular lumen by PCT cells via organic anion transporters (OAT)
Examples:furosemide, bumetanide, torasemide NB. –ideis a common Group ending NOT specific for loop diuretics
•inhibit Na+/K+/2Cl-co-transporter in ascending limb of Loop of Henle (impermeable to water)
• decreased osmolarity of medullary interstitium (relative to that of tubule lumen) leading to decreased reabsorption of water from collecting duct
•also increase renal prostaglandin production which produces vasodilatation, increasing renal blood flow, and assisting diuresis

Question 7

Mode of action of loop diuretics in thick loop of henle

Answer 7

(1) Loop diuretics block Na+ /K+ /2Cl-transporter preventing absorptionand promoting tubular excretion of Na+ and Cl-
(2) Loop diuretics also ↓ potentialdifference across tubule cell which isgenerated by recycling of K+
(3) As a result, ↑ excretion of Ca2+ and Mg2+ occurs because of inhibitionof paracellular diffusion

Question 8

Loop diuretics: clinical indications and use

Answer 8

• Congestive heart failure
• Resistant hypertension
• Liver ascites
• Nephrotic syndrome
• Acute hypercalcaemia i.e. used for oedema as Loop diuretics are good at getting rid ofexcess water

Powerful, rapid (<1 hour) but short-lived (<6 hour) diuretic action leading to excretion of 15-25% filtered Na+ (and water) –‘high ceiling’

Loop Diuretics: clinical use•mainly used i.v. for acute relief of symptoms by ↓ pre-load in left ventricular failure (pulmonary congestion) and orally to reduce signs and symptoms of chronic heart failure (ankle oedema)

Question 9

Loop diuretics: adverse effects

Answer 9

• Hypovolaemia and dehydration
• Hypokalaemia (cramps, arrhythmias)
• Hypomagnesaemia
• Hyponatraemia
• Hyperuricaemia (gout)
• Oto and renal toxicity (high doses)
• Allergic reactions to skin and kidney (rare)

Question 10

Thiazide/ thiazide-like diuretics

Answer 10

•Thiazides:Bendroflumethiazide,hydrochlorothiazide
Have H2NSO2 group (thiazide group)
•Thiazide-Like: Chlortalidone, Indapamide and Metolazone
sulfonamide group but no thiazide group

Question 11

Diuretics overview

Answer 11

•Greek: Diureticos–prompting urine
•Diuresis= increased urine volume
•3(+1) main types of diuretic in modern use
–categorised based on their mode of action on the kidney
1.(Osmotic diuretics / carbonic anhydraseinhibitors)
2.Loop diuretics
3.Thiazide/ thiazide-like diuretics
4.Potassium sparing diuretics

Question 12

Drugs acting mainly on proximal convoluted tubule- mannitol

Answer 12

•Osmotic diuretics: mannitol–freely filtered, act on parts of nephron most water-permeable (PCT and early Loop of Henle)
–reduce H2O reabsorption (water retained in filtrate due to osmosis)
–reduce electrolyte reabsorption (leak back into tubule down concentration gradient)
•Osmotic diuretics: mannitol
•Infused i.v. mainly for raised intracranial pressure (cerebral oedema) and intraocular pressure
•Side-effects (uncommon): hypotension, fluid and electrolyte disturbance

Question 13

Clinical indicatons of thiazides

Answer 13

Now relegated to 2nd or 3rd line in uncomplicated hypertension (indapamide, chlortalidone) in UK
-often tolerated less well than calcium channel modulators esp. due to electrolyte and metabolic disturbance, gout–but consider 1st or 2nd line instead of calcium channel modulator if oedema present or (high risk of developing) heart failure, very elderly–conventional thiazides being phased out in favour of thiazide-like diuretics
•occasionally in resistant oedema in heart failure (in combination with loop –with caution) or other causes of oedema but loop diuretics still first line
•protective in osteoporosis and for prevention of renal calcium stones?–promote calcium retention

Question 14

Loop diuretics

Answer 14

•given orally (preferred route) or i.v.
•>95% bound to proteins in plasma, limiting glomerular filtration
•secreted into tubular lumen by PCT cells via organic anion transporters (OAT)
Examples:furosemide, bumetanide, torasemide NB. –ideis a common Group ending NOT specific for loop diuretics
•inhibit Na+/K+/2Cl-co-transporter in ascending limb of Loop of Henle (impermeable to water)
• decreased osmolarity of medullary interstitium (relative to that of tubule lumen) leading to decreased reabsorption of water from collecting duct
•also increase renal prostaglandin production which produces vasodilatation, increasing renal blood flow, and assisting diuresis

Question 15

Mode of action of loop diuretics in thick loop of henle

Answer 15

(1) Loop diuretics block Na+ /K+ /2Cl-transporter preventing absorptionand promoting tubular excretion of Na+ and Cl-
(2) Loop diuretics also ↓ potentialdifference across tubule cell which isgenerated by recycling of K+
(3) As a result, ↑ excretion of Ca2+ and Mg2+ occurs because of inhibitionof paracellular diffusion

Question 16

Loop diuretics: clinical indications and use

Answer 16

• Congestive heart failure
• Resistant hypertension
• Liver ascites
• Nephrotic syndrome
• Acute hypercalcaemia i.e. used for oedema as Loop diuretics are good at getting rid ofexcess water

Powerful, rapid (<1 hour) but short-lived (<6 hour) diuretic action leading to excretion of 15-25% filtered Na+ (and water) –‘high ceiling’

Loop Diuretics: clinical use•mainly used i.v. for acute relief of symptoms by ↓ pre-load in left ventricular failure (pulmonary congestion) and orally to reduce signs and symptoms of chronic heart failure (ankle oedema)

Question 17

Loop diuretics: adverse effects

Answer 17

• Hypovolaemia and dehydration
• Hypokalaemia (cramps, arrhythmias)
• Hypomagnesaemia
• Hyponatraemia
• Hyperuricaemia (gout)
• Oto and renal toxicity (high doses)
• Allergic reactions to skin and kidney (rare)

Question 18

Loop diuretics: interactions

Answer 18

• Increased risk of electrolyte disturbance when combined with thiazidediuretics (see later)
• Increased oto and nephrotoxicity when combined with aminoglycosideantibiotics (e.g. gentamicin)
• > risk of hypotension when combined with ACE inhibitorsand other vasodilator drugs (but can be combined for therapeutic benefit)
• Impaired diuresis when combined with non-steroidal anti-inflammatory drugs (NSAIDs) (reduce vasodilatory prostaglandin dependent renal blood flow)

Question 19

Thiazide/ thiazide-like diuretics

Answer 19

• Thiazides:Bendroflumethiazide,hydrochlorothiazide

* Thiazide-Like: Chlortalidone, Indapamideand Metolazone

Question 20

Thiazide (like) diuretics mode of action in early distal convoluted tubule

Answer 20

(1) thiazide diuretics increase excretion of Na+ and Cl-by inhibiting Na+ /Cl-cotransporter (bind to Cl-site)
(2) (3) reabsorption of Ca2+is increased due to stimulation of Na+ /Ca2+ counter-transport as consequence of increased concentration gradient for Na+ across basolateral membrane

Question 21

How do thiazides lower BP?

Answer 21

• modest reduction in blood volume, pre-load and cardiac output•when given as monotherapyprogressive activation of counter-regulatory mechanisms (↑ RAAS, SNS) blunts BP lowering effect •work better in those already volume-expanded (Black African, elderly)
• action as anti-hypertensive agents poorly related to diuretic activity, so near maximum BP lowering can be achieved at low doses while minimising biochemical disturbance?
• additional mechanisms (activate ATP-regulated outward K+channel current on resistance arterioles?)

Question 22

Clinical indicatons of thiazides

Answer 22

Now relegated to 2nd or 3rd line in uncomplicated hypertension (indapamide, chlortalidone) in UK –NICE NG136–often tolerated less well than calcium channel modulators esp. due to electrolyte and metabolic disturbance, gout–but consider 1st or 2nd line instead of calcium channel modulator if oedema present or (high risk of developing) heart failure, very elderly–conventional thiazides being phased out in favour of thiazide-like diuretics
•occasionally in resistant oedema in heart failure (in combination with loop –with caution) or other causes of oedema but loop diuretics still first line
•protective in osteoporosis and for prevention of renal calcium stones?–promote calcium retention

Question 23

Thiazide adverse effects

Answer 23

Same as loop diuretics except:
-•associated with > urate retention
•> increase in cholesterol and hyperglycaemia (at high dose, more common in South Asians)
•reduced calcium excretion (hypercalcaemia)
•less otoand nephrotoxicity in combination with aminoglycosides

Question 24

Thiazide diuretics: interactions

Answer 24

Thiazide Diuretics: Interactions
•Same as loop diuretics except:
-•hypotension is less likely in combination with ACE inhibitors and other vasodilators
•more likely to cause lithium toxicity when co-prescribed with lithium
•more likely to cause hyponatraemia when co-prescribed with SSRI antidepressants (especially elderly)

Question 25

Potassium- sparing diuretics

Answer 25

Potassium-sparing Diuretics
•sodium channel blockers (aldosterone independent)
–amiloride ( ide not specific)
–triamterene

•aldosterone receptor antagonists
–spironolactone
–eplerenone (one not specific)
•action localised to late DCT/early collecting duct
•weak natriuretic, diuretic action (~2% filtered Na+)

Question 26

Mode of action of amiloride and triamterine in late distal tubule and collecting duct

Answer 26

block apical Na+channels
↓ potential difference across principal cell
↓ driving force for K+ secretion from principal cell and H+ from intercalated cell
leading to ↑ Na+ excretion and ↓K+ and H+ excretion

Question 27

Mode of action of spironolactone and eplerenone in late distal tubule and collecting duct

Answer 27

Aldosteroneis a steroid hormone acting on a nuclear receptor to ↑ synthesis of proteins (AIPs) which activate silent Na+ channels, ↑ synthesis of K+ channels, Na+ K+ATPase, Na+ /H+ counter-transporter, H+ ATPase, ATP production by mitochondria

i.e. ↑ potential for Na+ retention, K+/H+loss

Spironolactone andeplerenone block effects of aldosterone leading to ↑ Na+excretion and ↓K+ and H+ excretion

Question 28

Potassium sparing diuretics- clinical indications

Answer 28

• Potassium sparing diuretics are occasionally still used to prevent thiazide or loop diuretic-induced hypokalaemia
• Spironolactone is prescribed in conditions associated with primary (Conn’s syndrome) and secondary hyperaldosteronism (heart failure, liver ascites)
• also attenuates aldosterone-related oxidative stress, ventricular hypertrophy and fibrosis

Question 29

Potassium sparing diuretics- adverse effects and interactions

Answer 29

• Hyperkalaemia (K+retention)
• Metabolic acidosis (H+retention)
• Gynaecomastia, impotence and testicular atrophy, menstrual irregularities (spironolactone only)

•Hyperkalaemiawhen combined with:-ACE inhibitorsAngiotensinII receptor antagonistsRenininhibitorsBeta adrenoceptorantagonistsNon steroidal anti-inflammatory drugs