27. Diuretics Flashcards
Draw a nephron and indicate
where diuretic drugs exert their
effects.
fig 27.1
pg 129
How does mannitol exert its
effects?
> Mannitol is a sugar alcohol solution,
which works as an osmotic diuretic.
> The drug has a molecular weight of
182 Daltons and so is freely filtered
by the glomerulus but not reabsorbed.
> It increases the osmolality of the
filtrate and so water
follows the drug to be excreted.
> Osmotic activity occurs mainly at
proximal convoluted tubule and loop of Henle.
What is the major indication for
using mannitol?
Mannitol is used primarily in the treatment
of raised intracerebral pressure
(ICP). It reduces ICP by:
> Decreasing the formation of CSF.
> Decreasing plasma volume and
thereby encouraging water to move
out of the brain, reducing oedema.
Mannitol does not cross the intact
blood–brain barrier.
However, if the membrane is disrupted,
mannitol can cross it and worsen oedema
by drawing water with it.
Hence, unless a patient is actively coning,
it should only be used on
the advice of a neurosurgeon.
> It is free radical scavenger and
so may afford some additional neuroprotection
Can mannitol be used repeatedly?
No, mannitol is used to ‘buy time’ until
raised ICP can be treated definitively.
The dose cannot be repeated indefinitely,
as it will cause an unacceptable
rise in serum osmolality
and circulatory overload.
With repeated dosing it will
eventually cross the
blood–brain barrier and cause a rise in ICP.
How are diuretics used in renal failure?
Diuretics do not reverse renal failure,
but they can be used to control its
symptoms.
The use of diuretics,
particularly loop diuretics, reduces:
> Hypertension, mediated by
decreased sodium excretion
and water retention
> Congestive cardiac failure
caused by circulatory overload
> Oedema.
Large doses of the drugs may
be needed as their efficacy is decreased in
the face of low renal blood flow,
reducing delivery to their target organ.
It may be necessary to give the drugs by continuous infusion and to combine
various diuretics to achieve optimum results.
FUROSEMIDE
(and also bumetanide)
MOA
ADME
USES
FUROSEMIDE
(and also bumetanide)
Loop diuretic
MOA
• Act mainly on thick ascending limb
loop of Henle,
and less so on early
distal convoluted tubule
• Inhibit reabsorption of
Na+ and Cl-
• This impairs counter-current multiplier system
• Medulla becomes less
hypertonic so less water
reabsorbed
METABOLISM
AND EXCRETION
• Excreted mostly
unchanged in urine
ABSORPTION/
DISTRIBUTION
• Both well absorbed
orally
• Bioavailability =
Frusemide – 65%
Bumetanide – 95%
• Protein binding >95%
USES
• CCF
• Peripheral and
pulmonary oedema
• To force diuresis in acute
and chronic renal failure
Furosemide
Effects
EFFECTS
CVS
• Arteriolar vasodilation
causes ↓ SVR and ↓ preload
RENAL
• ↑ Renal blood flow
• ↑ GFR
BIOCHEMISTRY • ↓ K+ • ↓ Cl– • ↓ H+ • ↓ Na+ • ↓ Mg2+
• ↑ Ca2+
(less common than
thiazides)
• ↑ Uric acid causes gout
(less common than with
thiazides)
METABOLIC
• Hyperglycaemia
(less common than with
thiazides)
• ↑ Cholesterol and triglycerides – though they return to baseline with long-term treatment
OTHER • Ototoxicity – rapid IV injection can cause deafness, higher risk in patients in renal failure or on aminoglycosides
INTERACTIONS
• Raise serum lithium levels
BENDROFLUMETHIAZIDE
prep
dose
MOA
ADME
USES
BENDROFLUMETHIAZIDE
Thiazide diuretics
• Tablets: 2.5/5 mg DOSE
• 2.5–5 mg od PO
MOA
• Act on early distal convoluted tubule
• Inhibit reabsorption of Na+ and Cl-
• ↑ Na+ and Cl- excretion
and =↑ H2O excretion
METABOLISM
AND EXCRETION
• Hepatic metabolism
to active compounds
• Metabolites and
unchanged drug
(30%) excreted in
urine
ABSORPTION/ DISTRIBUTION • Well absorbed orally • Effective in 90 min • Lasts 18–24 hours
USES
• Hypertension
• Heart failure
BENDROFLUMETHIAZIDE
Effects
EFFECTS
CVS
• ↓ BP as ↓ circulating vol
RENAL
- ↓ Renal blood flow
- ↓ GFR
BIOCHEMISTRY • ↓ K+ • ↓ Cl- • ↓ Na+ • ↓ Mg2+ • ↓ H+ • ↑ Ca2+ • ↑ Uric acid causing gout METABOLIC • ↓Glycogenesis • ↓ Insulin secretion • ↑ Glycogenolysis • ↑ Cholesterol and triglycerides So, use with caution in diabetics
HAEMATOLOGY
• Blood dyscariasis including:
• Anaemia – aplastic and
haemolytic
• Leucopenia
• Agranulocytosis
• Thrombocytopenia
OTHER
• Impotence
• Rash
• Photosensitivity
• Pancreatitis
INTERACTIONS
• Metolazone shows
synergism when used with
loop diuretics
• Effects antagonised by
NSAIDs
AMILORIDE
AMILORIDE
K+ sparing diuretics
• Tablets: Co-amilofruse
(Amiloride/Frusemide
2.5 mg/20 mg or 5 mg/
40 mg)
DOSE
• 1–2 tablets per day
MOA
• Act at distal D convoluted tubule
• Blocks Na+/K+ exchange so less K+ lost in urine
METABOLISM
AND EXCRETION
• Not significantly metabolised
CHEMICAL PROPERTIES
• Nil
ABSORPTION/
DISTRIBUTION
• Poorly absorbed orally
• Minimal protein binding
USES • In combination with loop diuretic to decrease hypokalaemia, e.g. co-amilofruse
(frusemide + amiloride)
EFFECTS
METABOLIC
• Hyperkalaemia
SPIRONOLACTONE
MOA
Dose
Chem
USES
SPIRONOLACTONE
Aldosterone antagonist
• Tablets: 25/50/100 mg
DOSE
• 100–400 mg/day
MOA
• Acts at distal convoluted
tubule and collecting
ducts
• Competitive antagonist of
aldosterone
• Aldosterone stimulates
reabsorption of
Na+
in exchange for
K+
• NB limited diuresis as Na+ reabsorbtion stimulated by aldosterone only accounts for 2% of total water reabsorbed
CHEMICAL PROPERTIES
• Nil
USES • Ascites • Nephrotic syndrome • Conn’s syndrome (primary hyperaldosteronism)
Spirinolactone
ADME
METABOLISM AND EXCRETION • Hepatic metabolism • Excreted in urine ABSORPTION/ DISTRIBUTION • Oral bioavailability 70% • Protein binding > 90%
EFFECTS
BIOCHEMISTRY
• ↑ K+
• ↑Na+
HORMONAL
• Gynaecomastia in men
• Irregular menstruation
due to anti-androgenic
effects
OTHER • Nausea and vomiting • ↓ Response to vasopressors • ↑ Response to cardiovascular depressants
ACETAZOLAMIDE
ACETAZOLAMIDE
Carbonic anhydrase inhibitor
• Tablets: 250 mg
• Clear colourless solution:
500 mg/vial
DOSE
• Oral: 250 mg – 1 g/day in
divided doses orally
• IV: 250 mg – 1 g 4 hourly
MOA
• Acts at proximal convoluted tubule
• Non-competitive inhibitor
of carbonic anhydrase (CA)
• CA catalyses:
CO2+ H2O
H2CO3-
H+ and HCO3 -
• Affects Na+ exchange for
H+ in PCT so, fewer H+ ions
generated for excretion
• This causes alkaline urine &
mild metabolic acidosis which counteracts the respiratory alkalosis associated with
ascending to altitude
USES • Weak diuretic • Mountain sickness (prophylaxis and treatment) • Glaucoma
ACETAZOLAMIDE
ABSORPTION/ DISTRIBUTION • Oral bioavailability 100% • Protein binding 70–90% • t½ up to 6 hours
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in urine
EFFECTS
RS
• ↑ RR in response to
↑ CO2
CNS
• ↓ Intra-ocular pressure
by ↓ rate of aqueous
humour production
• ↓ ICP by ↓ rate of CSF
production
GI
• ↓ Gastric secretions
• ↓ Pancreatic secretions
RENAL
• Mild diuresis
• ↓ Excretion of uric acid
OTHER • Hyperchloraemic metabolic acidosis and alkaline urine as H+ excretion decreased and bicarbonate not reabsorbed
MANNITOL
USE
DOSE
MOA
ADME
Osmotic diuretic
• 10–20% clear colourless
sugar alcohol solution
DOSE
• 0.5–1 g/kg bolus
over 20 min
MOA
• Freely filtered by glomerulus and not reabsorbed
(Mol weight 182 Da)
• Water follows mannitol
as osmolality of
filtrate
is increased
USES
• To reduce raised
intracranial pressure
• To force diuresis in major vascular surgery (this is no longer in vogue)
METABOLISM
AND EXCRETION
• Not significantly
metabolised
• Freely filtered at
glomerulus
ABSORPTION/
DISTRIBUTION
• Given IV
• t½ 100 min
