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
