Diuretics

Question 1

Volume sensors regulate

Answer 1

– Vascular tone – to control organ perfusion

– Renal Na+ excretion - to control total fluid volume

Question 2

Low pressure sensors in pulmonary vasculature → PNS→CNS→

Answer 2

– renal sympathetic nerves
– renin-angiotensin aldosterone axis
– pituitary release vasopressin

Question 3

Vasopressin/ Anti-diuretic hormone ADH

Answer 3

– secreted by pituitary in response to low blood volume
– receptors are GPCR
» V1 (smooth muscle) → ↑Ca+ →vasoconstriction
» V2 (collecting duct) → ↑aquaporin 2 → ↑water reabsorption

Question 4

Desmopressin

Answer 4

» synthetic agonist with low affinity for V1
(no vasoconstriction)
» Indication – diabetes insipidus – excess dilute urine due to lack of vasopressin secretion from pituitary
» nasal spray, last 4-6 hours

Question 5

Renal Sympathetic nervous system

Answer 5

– β1 receptors
– → ↑renin production juxtaglomerular cells
– stimulate afferent arteriole constriction →↓glomerular
pressure →↓GFR

Question 6

Natriuretic peptides ANP, BNP, CNP

Answer 6

– receptors with intrinsic guanyl cyclase activity→cGMP
– relax smooth muscle →vasodilation
– increase renal GFR (constrict efferent renal arteriole)

Question 7

what is an oedema

Answer 7

– increase in interstitial fluid in any organ
– eg pulmonary oedema, causes severe breathlessness
– nephrotic syndrome
» renal damage→↑ permeability of glomerular basement membrane → proteinuria and; ↓ protein in plasma →↑interstital fluid
» swelling of ankles & legs
– in heart failure,
» decreased cardiac output triggers kidney to respond as if hypovolemia, causing increased salt and fluid retention
– hepatic cirrhosis
» portal vein flow obstructed →fluid escape into peritoneal cavity

Question 8

what is hypovolemia

Answer 8

decrease in blood volume

Question 9

diuretics are used in which conditions

Answer 9

• Oedema
• Hypertension
• Hypercalcemia
• Renal failure
• Diabetes Insipidus: paradoxical

Question 10

Structure of a nephron

Answer 10

draw

Question 11

Proximal tubule

Answer 11

draw

• Epithelium of the proximal convoluted tubule is leaky (permeable to ions and water, permitting passive flow in either direction)
• The is prevents the build up of large conc gradient and even though 60-70% of Na+ is reabsorbed in PT, this transfer is accompanied by passive absorption of water so that the fluid leaving PT remains approx isotonic to the glomerular filtrate.
• After passage through the PT, tubular fluid passes onto the loop of henle.

Question 12

Carbonic anhydrase inhibitors

Answer 12

• Rarely used as diuretic
– initially effective
– rapid development of tolerance
• used in treatment of glaucoma

Question 13

Loop of henle
Thick ascending loop
Thin ascending loop
Thin descending loop

Answer 13

draw

• the loop of henle consists of a ascending and descending part.
• allows to excrete urine
• NaCl is actively reabsorbed in the thick ascending loop, causing hypertonicity of the interstitium.
• In the descending loop water moves out and the tubular fluid becomes progressively more concentrated as it approached the bend
• Ions move out of the thick ascending limb of the loop of henle across the apical membrane by a Na+/K+/2Cl- co transporter, driven by Na+ gradient produced by Na+-K+-ATPase.
• Most of the K+ taken into the cell by a Na+/K+/2Cl- returns to the lumen but some K+ is reabsorbed along with Mg2+ and Ca2+.
• Tubular fluid is hypotonic

Question 14

Loop diuretics

• Indications

Answer 14

– Most efficacious diuretics – used to treat marked oedema
» commonly after heart failure
» acute pulmonary oedema – i.v. admin
» Other oedema – p.o.
– Hypertension – generally less useful - only if no response to other diuretics/antihypertensives.
– hypercalcaemia (hyperparathyroidism)
» loop diuretics promote Ca2+ secretion; cf thiazides
– hyperkalaemia
» (resulting from renal insufficiency/drugs causing K+ retention)
– hyponatraemia (!)
» in some circumstances eg hypervolaemia

Question 15

Loop diuretics

• Drugs

Answer 15

– Furosemide
» t1/2 1 hr; p.o, but variable absorption; also used i.v and i.m
» short t1/2 - b.i.d. & doesn’t interfere with sleep;
» cleared by kidney
– Bumetanide
» t1/2 ~ 1.5hr; well aborbed p.o.;
» cleared by hepatic metabolism (potential advantage if
renal function impaired)
– Torasemide
» t1/2 ~ 3 hr, well absorbed p.o.;
» cleared by hepatic metabolism

Question 16

Loop diuretics • PK

Answer 16

– secreted into proximal tubule
» by weak acid anion transporter
» necessary to reach target!
– highly protein bound –lowers GFR
– timing
» onset:
– p.o diuresis within 20 min
– i.v. more rapid onset,
» duration 2-3 h

Question 17

Loop diuretics

• ADR

Answer 17

– generally well tolerated; greater risk of ADR with
furosemide in renal disease (previous slide)
– hypokalaemia
» (increased Na+ delivered to collecting duct
» slide on CCD)
» arrhythmia, muscle weakness,
» metabolic alkalosis
– “sulpha” allergy
» all are sulfonamides
– hypotension – obvious!?
– hypocalcaemia & hypomagnesaemia
» (see mechanism slide)
» risk of arrhythmia
– hyperuricaemia & Gout
» ↓uric acid secretion&↑ reabsorption
– ototoxicity
» deafness and vertigo
» Furosemide> bumetanide – switch if necessary ?

Question 18

Loop diuretics (3)
• Cautions

Answer 18

– can cause gout –avoid if history of gout

– can cause/ worsen diabetes (hypokalemia affects insulin secretion?)

Question 19

Loop diuretics (3)
• Contrindictions

Answer 19

– patients with hypokalaemia, hypovolemia

– avoid in pregnancy – risk of hypovolemia

Question 20

Loop diuretics (3)
• druginteractions

Answer 20

– aminoglycosides antibiotics –also causes ototoxicity
– cardiac glycosides –arrhythmia
– NSAIDS (esp indomethacin) may reduce effectiveness:
» ↓PG synthesis→↓renal blood flow
» competition for anion transporter
– may be less effective in renal failure – requires secretion into tubular lumen to reach site of action- larger dose then required
– can inhibit Li+ secretion – Li+ dose may need adjusting

Question 21

Model of NSAID & loop diuretic interaction

Answer 21

draw

NSAID inhibits COX which reduces PG, reduced renal blood supply and reduced glomerular filtration

NSAID inhibit loop diuretic

Question 22

Diuretic drug interactions are often pharmacodynamic in origin - which drugs cause ototoxicity

Answer 22

Aminoglycoside antibiotic

Diuretic

Question 23

Thiazide & thiazide-like diuretics • Drugs

Answer 23

• Drugs
– Bendroflumethiazide
» t1/2 ~ 6 hr
– Indapamide
» t1/2 ~16 hr
» lowers bp at dose where no effect on diuresis (for hypertension)
– Metolazone
» t1/2 ~4 hr
» preferred in advanced renal failure
– Chlortalidone

Question 24

Thiazide & thiazide-like diuretics • indications

Answer 24

• Indications
– Mild oedema
» Less efficacious diuretics than loop diuretics
» eg in heart failure, hepatic cirrhosis, nephrotic syndrome
» widely used because cheap, easy to administer, well tolerated
– Hypertension
» after 3-7 days, bp stabilizes and maintained indefinitely
– Diabetes insipidus

Question 25

Thiazide & thiazide-like diuretics • PK

Answer 25

• PK – all well absorbed p.o. and mostly excreted unchanged – slower onset but longer duration than loop diuretics – plasma protein bound » reduces GFR » secreted into renal tubular lumen to site of action by organic acid transporter

Question 26

Thiazide & thiazide-like diuretics • ADR

Answer 26

``` • ADR – hypokalaemia » diabetes – decreased insulin secretion? » metabolic alkalosis – nocturia (avoid by taking early) & urininary frequency – hypotension – hyponatremia » more common than with loop diuretics – hypomagnesaemia – decreased Ca2+ excretion » not understood! » may exacerbate existing hypercalcaemia (eg hyperparathyroidism) – impotence ```

Question 27

Hypokalaemia

Answer 27

• < 3.5 mM serum K+ • common with loop or thiazide diuretics • problem more severe with thiazide because of their longer t1/2 • increased risk if high aldosterone (eg liver cirrhosis) see CCD slide • Can cause: – arrhythmia - especially in case of myocardial ischaemia or co-treatment with drugs that prolong QT – encephalopathy (esp if liver disease) – diabetes mellitus because of reduced insulin secretion – fatigue and lethargy

Question 28

Hypokalaemia • Treatment

Answer 28

– K+ sparing diuretic – K+ supplement – diet - bananas!

Question 29

``` Thiazide diuretics (3) • Cautions ```

Answer 29

– can precipitate gout –avoid if history of gout | – can cause/ worsen diabetes

Question 30

Thiazide diuretics (3) • Drug interactions

Answer 30

``` – sulphonylureas – Not with antiarrhythmic agents that prolong QT (eg sotalol, quinidine) » risk torsades des pointes – cardiac glycosides – NSAIDS ```

Question 31

Potassium sparing diuretics | • Indications

Answer 31

– Mild diuretics on own – often used in combination with loop diuretics or with thiazides to counteract K+ loss – particularly useful for: » conserving potassium if loop diuretic or thiazide used; » concomitant digoxin therapy » secondary hyperaldosteronism » elderly – generally not used on own to treat oedema – advantage – avoid extensive diuresis

Question 32

Potassium sparing diuretics drug

Answer 32

• Spirinolactone – variable absorption, but improved if taken with food – short t1/2~1 hr but rapidly metabolised to more stable metabolite “canrenone” t1/2 ~20 hr (Important learning point!) – slow onset of effect because of mechanism of action • Amiloride – different mechanism – direct inhibition of ENaC – long t1/2 – rapid onset of action

Question 33

Potassium sparing diuretics | • ADR

Answer 33

– hyperkalemia » see mechanism slide – reduced K+ loss at CCD » esp in elderly/renal disease or co-treatment with ACE inhibitor or angiotensin receptor antagonist – metabolic acidosis » H+ secretion at CCD is also inhibited – spirinolactone also inhibits androgen receptor (a related steroid receptor) » impotence and gynecomastia in men » irregular menstrual cycle in women » “Eplerenone” more selective for aldosterone receptor • Interactions – NSAIDS can impair renal function and cause hyperkalemia with spirinolactone

Question 34

Metabolic acidosis

Answer 34

``` • Metabolic acidosis – increased blood acidity » K+ sparing diuretics inhibit H+ loss at CCD (see slide on CCD) – rapid breathing, confusion, lethargy – may lead to shock or death ```

Question 35

Metabolic alkalosis

Answer 35

``` • Metabolic alkalosis – increased alkalinity » loop and thiazide diuretics cause H+ loss at CCD (see slide on CCD) – tremor, muscle twitching – numbness – lightheaded, confusion, possible coma ```

Question 36

Osmotic diuretics

Answer 36

``` Mannitol • Undergoes glomerular filtration →not reabsorbed in renal tubule→decreases osmotic gradient in descending limb of loop of Henle→less water reabsorbed more diuresis • Indications – emergency use –cerebral oedema • PK – iv infusion – excreted unchanged in urine • ADR – heart failure – hypokalaemia ```

Question 37

ANP, BNP and CNP from where

Answer 37

Natriuretic peptides ANP (from atria), BNP (from ventricles), CNP (from vascular endothelium)

Question 38

Diuretic drug interactions are often pharmacodynamic in origin - which drugs cause Arrhythmia

Answer 38

``` Cardiac glycoside (ADR) Diuretic ```

Question 39

High pressure sensors in atria

Answer 39

– natriuretic peptides → vasodilation and Na+ secretion from kidney

Question 40

Distal convoluted tubule

Answer 40

draw - NaCl reabsorption coupled with impermeability to water further dilutes the tubular fluid. - Transport is driven by Na+/K+/ATPase - This lowers cytoplasmic Na+ conc and Na+ enters the cell from the lumen down its conc gradient accompanied by Cl- by Na+/Cl- co-transporter.

Question 41

Cortical Collecting Duct

Answer 41

draw - Distal tubule empty into the CD - CT reabsorb Na+ and secrete K+. - NaCl is absorbed by aldosterone - Water is absorbed by ADH - Aldosterone enhances Na+ reabsorption and promotes K+ excretion. - Ethanol inhibits secretion of ADH causing water diuresis.

Question 42

What do diuretics increase and decrease?

Answer 42

Diuretics increase Na+ and water excretion but decrease the reabsorption of Na+ and an accompanying anion (usually Cl-) from the filtrate.

Question 43

When are diuretics indicated

Answer 43

In cardiovascular disease and renal disease

Question 44

What does each nephron consist of

Answer 44

Glomerulus, proximal tubule, loop of henle, distal convoluted tubule and collecting duct

Question 45

The most important mechanism for Na+ entry into proximal tubular cells from the filtrate occurs by..

Answer 45

Na+/H+ exchange. Intracelluar carbonic anhydrase is essential for production of H+ for secretion into the lumen - Na+ is reabsorbed from TF into cytoplasm of PT in exchange for cytoplasmic H+ - Then transported out of the cells into the interstitium by Na+-K+-ATPase pump in the basolateral membrane. - Reabsorbed Na+ then diffuses into blood vessels.

Question 46

Which limp is permeable to water and which is impermeable

Answer 46

Descending limb is permeable to water. | Ascending limp is impermeable to water.

Question 47

Where is the excretion of Ca2+ regulated

Answer 47

Distal tubule

Question 48

What does Acetazolomide do in proximal tubule

Answer 48

Acetazolomide is a carbonic anhydrase inhibitor, you block reabsorption of CO2 so less bicarbonate inside cell so less bicarbonate driving Na+ bicarbonate transport so more Na+ in cell so smaller gradient drive Na+/H+ so less Na+ reuptake, Na+ stays in lumen of kidney so reduces water uptake. Na+/k+/ATPase still works fine so CAI not effective.

Question 49

Loop diuretics work in..

Answer 49

Thick ascending loop 30% of Na+ is reabsorbed Loop diuretics block NKCC2 (K+, 2Cl-, Na+ in) and so theres a reduced Na+ in interstitial tissue so reduced gradient driving water reabsorption so water stays in tubule and lost by urination. - Whole process is not electrically neutral, net voltage is created by this process. More positive on apical side and more negative on basolateral side -Voltage drives reabsorption for Ca2+, Mg2+, Na+ but loop diuretics impair this

Question 50

Thiazide diuretics work in..

Answer 50

Lumen of DCT - less effective than loop as loop diuretics work in loop of henle where more filtered sodium gets reabsorbed. - TD inhibit NCC1 so less water reabsorbed and more is secreted - Also inhibit Mg2+ and induce Ca2+ reabsorption

Question 51

Model of thiazide induced hyponatraemia

Answer 51

Water uptake is increased which dilutes Na+ Hyponatraemia refers to Na+ conc not total amount

Question 52

Thiazide can increase and | Sulfonylureas decrease

Answer 52

blood glucose

Question 53

Where does amiloride act.. (PSD)

Answer 53

CCD - Sodium absorbed through ENaC channel so it is not electrically neutral, Amiloride inhibits this - K+ and H+ is excreted to balance electrical gradient - basolateral side is positively charged

Question 54

Where do spironolactone and eplerenone act? (PSD)

Answer 54

CCD Aldosterone agonist turn off ENaC