Diuretics Flashcards
Volume sensors regulate
– Vascular tone – to control organ perfusion
– Renal Na+ excretion - to control total fluid volume
Low pressure sensors in pulmonary vasculature → PNS→CNS→
– renal sympathetic nerves
– renin-angiotensin aldosterone axis
– pituitary release vasopressin
Vasopressin/ Anti-diuretic hormone ADH
– secreted by pituitary in response to low blood volume
– receptors are GPCR
» V1 (smooth muscle) → ↑Ca+ →vasoconstriction
» V2 (collecting duct) → ↑aquaporin 2 → ↑water reabsorption
Desmopressin
» 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
Renal Sympathetic nervous system
– β1 receptors
– → ↑renin production juxtaglomerular cells
– stimulate afferent arteriole constriction →↓glomerular
pressure →↓GFR
Natriuretic peptides ANP, BNP, CNP
– receptors with intrinsic guanyl cyclase activity→cGMP
– relax smooth muscle →vasodilation
– increase renal GFR (constrict efferent renal arteriole)
what is an oedema
– 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
what is hypovolemia
decrease in blood volume
diuretics are used in which conditions
- Oedema
- Hypertension
- Hypercalcemia
- Renal failure
- Diabetes Insipidus: paradoxical
Structure of a nephron
draw
Proximal tubule
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.
Carbonic anhydrase inhibitors
• Rarely used as diuretic
– initially effective
– rapid development of tolerance
• used in treatment of glaucoma
Loop of henle
Thick ascending loop
Thin ascending loop
Thin descending loop
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
Loop diuretics
• Indications
– 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
Loop diuretics
• Drugs
– 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
Loop diuretics • PK
– 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
Loop diuretics
• ADR
– 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 ?
Loop diuretics (3) • Cautions
– can cause gout –avoid if history of gout
– can cause/ worsen diabetes (hypokalemia affects insulin secretion?)
Loop diuretics (3) • Contrindictions
– patients with hypokalaemia, hypovolemia
– avoid in pregnancy – risk of hypovolemia
Loop diuretics (3) • druginteractions
– 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
Model of NSAID & loop diuretic interaction
draw
NSAID inhibits COX which reduces PG, reduced renal blood supply and reduced glomerular filtration
NSAID inhibit loop diuretic
Diuretic drug interactions are often pharmacodynamic in origin - which drugs cause ototoxicity
Aminoglycoside antibiotic
Diuretic
Thiazide & thiazide-like diuretics • Drugs
• 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
Thiazide & thiazide-like diuretics • indications
• 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
Thiazide & thiazide-like diuretics • PK
• 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
Thiazide & thiazide-like diuretics • ADR
• 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
Hypokalaemia
• < 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
Hypokalaemia • Treatment
– K+ sparing diuretic
– K+ supplement
– diet - bananas!
Thiazide diuretics (3) • Cautions
– can precipitate gout –avoid if history of gout
– can cause/ worsen diabetes
Thiazide diuretics (3) • Drug interactions
– sulphonylureas – Not with antiarrhythmic agents that prolong QT (eg sotalol, quinidine) » risk torsades des pointes – cardiac glycosides – NSAIDS
Potassium sparing diuretics
• Indications
– 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
Potassium sparing diuretics drug
• 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
Potassium sparing diuretics
• ADR
– 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
Metabolic acidosis
• 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
Metabolic alkalosis
• 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
Osmotic diuretics
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
ANP, BNP and CNP from where
Natriuretic peptides ANP (from atria), BNP (from ventricles), CNP (from vascular endothelium)
Diuretic drug interactions are often pharmacodynamic in origin - which drugs cause Arrhythmia
Cardiac glycoside (ADR) Diuretic
High pressure sensors in atria
– natriuretic peptides → vasodilation and Na+ secretion from kidney
Distal convoluted tubule
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.
Cortical Collecting Duct
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.
What do diuretics increase and decrease?
Diuretics increase Na+ and water excretion but decrease the reabsorption of Na+ and an accompanying anion (usually Cl-) from the filtrate.
When are diuretics indicated
In cardiovascular disease and renal disease
What does each nephron consist of
Glomerulus, proximal tubule, loop of henle, distal convoluted tubule and collecting duct
The most important mechanism for Na+ entry into proximal tubular cells from the filtrate occurs by..
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.
Which limp is permeable to water and which is impermeable
Descending limb is permeable to water.
Ascending limp is impermeable to water.
Where is the excretion of Ca2+ regulated
Distal tubule
What does Acetazolomide do in proximal tubule
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.
Loop diuretics work in..
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
Thiazide diuretics work in..
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
Model of thiazide induced hyponatraemia
Water uptake is increased which dilutes Na+
Hyponatraemia refers to Na+ conc not total amount
Thiazide can increase and
Sulfonylureas decrease
blood glucose
Where does amiloride act.. (PSD)
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
Where do spironolactone and eplerenone act? (PSD)
CCD
Aldosterone agonist
turn off ENaC
