Diuretics pharmacology

Question 1

How much blood goes into the kidney?
(in 24 hours)
How much is reabsorbed?
How much urine?

Answer 1

120L
99% reabsorbed
1.5L urine

Question 2

Describe reabsorption in the proximal convulted tubule

and drugs

Answer 2

• ‘leaky’ tight junctions between epithelial cells
• responsible for 60-70% Na+ reabsorption (Na+/ H+ exchanger) with it K+ and Cl- and glucose (these 3 driven by sodium movement)
• active secretion of many organic acids + bases (via OAT)

Sodium ions diffuse down their electrical and concentration gradients into the epithelial cells – this transport is coupled with uptake of glucose, phosphate, amino acids, lactate, chloride and potassium, along with extrusion of protons.

Question 3

Name some things that are actively secreted from the proximal convulted tubule

Answer 3

. Many organic acids and bases, such as ammonia (diffuses), creatinine and several drugs such as NSAIDs, penicillin and diuretics are actively secreted (e.g. via the organic anion transporter).

Question 4

Descending loop of henle

Answer 4

Interstitial fluid of medulla hypertonic to filtrate (counter current multiplier)
Cells permeable to water out of the lumen
i.e. water diffuses out of lumen down conc. gradient

concentration of interstitial fluid
Counter-current multiplier is a way of concentrating the interstitual fluid
concentrated as fluid loss from vasa recta
as get more concentrated, close proximity of ascending and descending loops of henle

Question 5

Thick ascending loop of henle

Answer 5

Cells have low permeability to water
20-30% Na+ actively reabsorbed
down to Na+/K+ exchange pump (basolateral membrance)
Na+→interstitial fluid
K+→enters cells
Therefore important to keep intracellular concentration of Na+ low so it can travel via its concentration gradient

This creates the gradient for sodium to cross the apical membrane via the Na/K/Cl transporter. Most of the potassium diffuses back out (goes into urine) through apical potassium channels but some is reabsorbed.

Also Na+ entering cells via Na+/H+ exchanger

Question 6

Distal convulted tubule

Answer 6

Impermeable to water
Na+ (~ 7%) reabsorbed down conc gradient (lesser amount)
Na+ entry coupled with Cl- entry

Question 7

What causes ultrafiltration in kidney to occur?

Answer 7

Higher blood pressure from afferent arteriole

hydrostatic pressure

Question 8

Collecting tubule

Answer 8

Water reabsorbed via aquaporin channels (ADH-mediated) – up to 15%
Na+ reabsorption mediated by aldosterone

i.e. AQP (aquaporin) channels stored in vesicles – ADH binding to the vasopressin receptors causes their insertion into the apical membrane. Can remove as much as 15% of filtered water, making the urine considerably hypertonic to plasma.

important for concentrating urine
AQP normally in vesicles

Adolesterone causes ↑expression of the Na+/K+ pump and insertion of more Na+ channels to ↑Na+

Question 9

Diuretics

Answer 9

↑ excretion of Na+ and water (natriuresis)
Achieved through direct action on nephron cells or changing composition of filtrate
N.B. small decrease in reabsorption → large ↑ Na+ excretion
Most diuretics secreted by cells of PCT into lumen (NOT spironolactone)

i.e. excretion of NaCl causes water to follow.

Question 10

Uses of diuretics

Answer 10

Oedema

• cardiac failure
• hyperadolesteronism (adolesterone reabsorbs Na+ and therefore water)
• liver failure (liver cirrohisis→can cause fluid draining into the peritoneal cavity→produces more aldosterone and hence plasma volume)
• acute renal failure - diuretics to kick start urine production and increase filtration
• hypertension - reduces BP as reducing plasma volume

Question 11

Loop diuretics

Answer 11

-mide
Powerful diuretics (15-25% filtered Na+ excreted)
Inhibit Na+/K+/2Cl- carrier in thick ascending limb of the loop of henle
Also cause vasodilation (often at sub-diuretic doses) before onset of diuresis!
E.g. furosemide, bumetanide, torasemide
Act on loop of Henle (this is why they are powerful)
indicated for
-severe hypertension

Question 12

Mechanism for loop diuretics

Answer 12

Act on the Cl- binding site of the Na/K/Cl carrier. i.e. bicarbonate ions continuously reabsorbed from filtrate – if plasma volume reduced then concentration increased (+ loss of H+). Because Na reabsorption is blocked, there is more Na+ delivered to the distal part of the nephron, so reabsorption of water is reduced even more.

Question 13

where in the kidney produces urine?

Answer 13

Renal pelvis

Question 14

Collecting tubule and loop of henle are where?

Answer 14

medulla

Question 15

what parts of the nephron are in the cortex?

Answer 15

Everything apart from loop of henle and collecting tubule

Question 16

Where are diuretics excreted from?

Answer 16

The proximal convulted tubule (apart from potassium sparing diuretics and spironolactone)

Question 17

Diuretic means

Answer 17

↑urine output→↑reduction in plasma volume

Question 18

Loop diuretic indications

Answer 18

Acute pulmonary oedema
Chronic heart failure (reduce afterload)
Liver cirrhosis (+ ascites)
Nephrotic syndrome 
Renal failure
Hypertension (+ ↓ renal function) 
Hypercalcaemia - increase excretion of calcium

Question 19

Loop diuretics on CHF

Answer 19

i.e. conditions of salt/ water overload. APO arises due to congestion in the pulmonary circulation and therefore inc blood pressure there. In CHF, the heart struggles to eject blood, so reducing the overall blood volume will reduce the workload. In liver cirrhosis, congestion occurs in the hepatic portal vein – this results in fluid loss into the peritoneal cavity – this leads to fluid retention by the kidneys, stimulated by aldosterone. Nephrotic syndrome is a condition in which damage to renal glomeruli causes loss of plasma albumin. As a result, the osmotic pressure of the plasma is reduced, resulting in peripheral oedema – diuretics therefore increase the osmotic pressure in the blood, reversing the oedema. RF can result in production of small volumes of urine. In hypertension with reduced renal function, the kidneys can be kickstarted to increase urine output + reduce blood volume. As loop diuretics increase calcium excretion, they can be used to treat hypercalcaemia.

Question 20

Side effects of loop diuretics

Answer 20

Hypotension (through hypovolaemia)
Hypokalaemia*
Metabolic alkalosis
Gout
Hearing loss (CN VIII damage?)

Question 21

Loop diuretics possible interactions

Answer 21

hyperkalaemia- Increases effects/ toxicity of several drugs, such as digoxin + Type III antidysrhythmic drugs
. must be careful when prescribing loop diuretics in patients treated for heart problems (because digoxin blocks Na/K pump, a low blood potassium will exacerbate this, causing cardiac toxicity). Effects can be reduced by giving potassium supplements or jointly prescribing K+ sparing diuretics.

Question 22

Why do loop diuretics cause hypokalaemia?

Answer 22

Increased Na+ in collecting duct influences Na+/K+ ‘exchange’
i.e. large conc of Na+ remaining in filtrate (as ↓reabsorption in LoH) → drives Na+/K+ pump

Question 23

Pharmacokinetics of loop diuretics

Answer 23

Absorbed through GI tract - stomach and small intestine
Given orally/ i.v. (in emergencies)
Peak effect < 1 hr (30 min i.v.)
Bind strongly to albumin (reach site of action via PCT excretion)
i.e. excreted in urine
T½ = 90 mins

Furosemide absorbed in stomach/ upper small intestine.

Question 24

Thiazide-like and thiazide diuretics

Answer 24

Act on distal tubule
Inhibit Na+/ Cl- cotransporter
Smaller effect than loop diuretics – act in different place, further down nephron
Also has vasodilator effect (later phase)
E.g. chlortalidone, indapamide*, metolazone, (bendroflumethiazide)
Indapamide lowers blood pressure at subdiuretic doses (and with less metabolic disturbance than other diuretics).

Question 25

Indications of thiazides

Answer 25

Hypertension (may be combined with loop diuretics)
Mild – moderate heart failure
Oedema
Nephrogenic diabetes insipidus

N.B. Thiazide-like diuretics better tolerated than loop diuretics + reduce the risk of stroke and MI associated with hypertension.

Question 26

Side effects of thiazides

Answer 26

Increased urinary frequency – is this a big problem?
Erectile dysfunction
Hypokalaemia
Impaired glucose tolerance (inhibits insulin secretion)

Increased freq usually not a great problem because doses used are low. ED – due to red blood pressure? This effect is reversible on stopping taking the drug. i.e. inhibition of insulin sec thought to result from activation of KATP channels in pancreatic islet cells. Could be exacerbated by activation of RAS which promotes insulin insensitivity.

Question 27

Strategies to reduce K+ depeltion

Answer 27

Increase intake in diet
fruit juice
instant coffee
bananas
Give K+ supplements
Alone
combined with diuretic
Use K+ sparing diuretics

Question 28

Thiazides pharmacokinetics

Answer 28

Only effective orally
Excreted in urine
Bendroflumethiazide (2.5mg daily) – peak effect 4-6 hrs (duration 8-12 hrs)
Chlortalidone (25mg daily) – longer-acting

*hypertension

Question 29

Potassium-sparing diuretics

Answer 29

Aldosterone antagonists – block Na+ reabsorption and Na+/ K+ exchange in collecting tubule (limited diuretic action)
Have marked anti-hypertensive effects without hypokalaemia
May be used in combination with thiazide/ loop diuretics
E.g. spironolactone, eplerenone

Question 30

Indications of potassium-sparing diuretics

Answer 30

Spironolactone
Ascites caused by liver cirrhosis
Oedema
Severe heart failure

Eplerenone
Adjunct in patients with left ventricular failure following MI

Question 31

Side effects of potassium sparing diuretics

Answer 31

Hyperkalaemia
GI upset
Gynaecomastia*
Menstrual disorders/ testicular atrophy

• more pronounced with Spironolactone
  i. e. Fewer Na/ K pumps so less K+ taken up from blood, leads to increased plasma potassium. Blocks reabsorption of Na+ from colon, hence water remains in the faeces. Gynaecomastia may be caused by spironolactone displacing androgen from the androgen receptor and sexual-hormone-binding globulin, and by causing increased metabolic clearance of testosterone and higher estradiol production. This imbalance between oestrogen and testosterone can result in menstrual disorders and testicular atrophy.

Question 32

Pharmacokinetics of potassium-sparing diuretics

Answer 32

Spironolactone
Well absorbed from gut
Metabolised to canrenone t½ = 16 hrs
Slow onset of action

Eplerenone
Shorter elimination t½

Question 33

Limited effect of Triamterene and amiloride as diuretics

Answer 33

i.e. very little sodium reabsorption in c.t. Used as an adjunct to thiazide or loop diuretics for hypertension, congestive heart failure, or hepatic cirrhosis with ascites.

Question 34

Side effects triamterene and amiloride

Answer 34

Hyperkalaemia

Not safe to use in patients with renal impairment or on drugs which ↑ K+

Question 35

Pharmacokinetics of triamterene and amiloride

Answer 35

Triamterene
Well absorbed orally
Partially metabolised in liver

Amiloride
Less well-absorbed
Slower onset
Excreted unchanged in urine

Question 36

Combined tablets

Answer 36

Co-amilofruse – amiloride and furosemide combined
Used to treat oedema
Co-amilozide – amiloride and hydrochlorothiazide
Used to treat hypertension/ congestive HF/ oedema

Question 37

Osmotic diuretics

Answer 37

E.g. mannitol
Filtered in glomerulus but not reabsorbed
Increase osmolarity of filtrate
i.e. main effects on PCT, ascending LoH and CD (freely permeable to water)
Increase excretion of water and also Na+*

Question 38

Osmotic diuretics indications

Answer 38

Cerebral oedema
Raised intra-ocular pressure
Acute renal failure
Given with loop/ thiazide diuretics to maintain K+ balance

i.e. reduces plasma volume, therefore increases osmolality. Causes water to be drawn in from interstitial fluid.
In acute renal failure, patients are unable to remove waste products or concentrate urine without losing electrolytes. As reabsorption of Na+ is reduced, there is less drive for Na/K pump so K+ retention occurs. This is limited by use of diuretics which reduce K+.

Question 39

Side effects osmotic diuretics

Answer 39

e.g. mannitol
Hyponatraemia
Headache
Nausea + vomiting

Headache – changes in plasma volume, hence blood flow to brain. N+V due to effect on gut?