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Learning Objectives
Following this lecture, students should be able to:
Comment upon the mechanism of action and clinical use of osmotic diuretics and
inhibitors of carbonic anhydrase
Describe the utility of agonists and antagonists of vasopressin receptors in
neurogenic diabetes insipidus and hypervolaemic hyponatraemia, respectively
Describe the role of renal prostaglandins (PGE2 and PGI2) in renal function and their
importance when renal blood flow is compromised
Note the recent introduction of inhibitors of sodium-glucose co-transporter 2
(SGLT2) inhibitors in type 2 diabetes mellitus (T2DM) and the characteristics of this
transporter vs. sodium glucose co-transporter 1 (SGLT1)
Recognise the now limited role of uricosuric agents in the treatment of gout
Recommended reading• Rang and Dale’s Pharmacology (7th. Ed.) Chapter 28• Bailey CJ (2011). Renal glucose reabsorption inhibitors to treat diabetes. Trends
Pharmacol. Sci, 32, 63-71. (Excellent review – very easily read and understood)
Osmotic Diuretics (1)
Osmotic diuretics (e.g. mannitol i.v.)
Are membrane impermeant polyhydric alcohols
(hence i.v. administration). Pharmacologically inert
Enter nephron by glomerular filtration, but are not reabsorbed
Increase the osmolality of the filtrate, opposing the absorption of
water in parts of the nephron that are freely permeable to water
Secondarily decrease
sodium reabsorption in
the proximal tubule (larger
fluid volume decreases
sodium concentration and
electrochemical gradient
for reabsorption) From Lüllmann et al. (2000), Color Atlas of Pharmacology
Major site of action in the
kidney is the proximal
tubule where most iso-
osmotic reabsorption of
water occurs
Are used in acutely raised intracranial and intraocular pressure. The
solute does not enter the eye, or brain, but increased plasma
osmolality extracts water from these compartments
For their effect upon the kidney, used only in the prevention of acute
hypovolaemic renal failure to maintain urine flow
Osmotic diuresis may also occur
• in hyperglycaemia – reabsorptive capacity of the proximal tubule
for glucose (by SGLT1 and SLGT2) is exceeded. Glucose
remaining in the filtrate retains fluid (note: SLGT2 is now a target in
treatment of T2DM – see later)
• as a consequence of the use of iodine-based radiocontrast dyes in
imaging. Dye is filtered at the glomerulus, but it not reabsorbed
constituting an osmotic load. Patients with borderline
cardiovascular status may experience hypotension due to
reduction in intravascular volume
Carbonic Anhydrase Inhibitors (and Urinary pH)
Carbonic anhydrase inhibitors (e.g. acetazolamide)
No longer have a role as diuretic agents, but are useful in:
glaucoma and following eye surgery (to reduce intraocular pressure
by suppressing formation of aqueous humour)
prophylaxis of altitude sickness
some forms of infantile epilepsy
Increase excretion of HCO3- with Na+, K+ and H2O – alkaline* diuresis
and metabolic acidosis result
*Alkalinising the urine with other agents (e.g. citrate salts given orally which
generate HCO3- via the Krebs cycle) can be useful in:
relief of dysuria
prevention of the crystallization of weak acids with limited aqueous solubility
(remember Henderson-Hasselbalch equation!) – favours ionised form
enhancing the excretion of weak acids (e.g. salicylates, some barbiturates) –
favours ionised form that is not reabsorbed
Aldosterone and Vasopressin at the Collecting Tubule
Enhanced tubular Na+
reabsorption and salt
retention
Aldosterone
secretion from
adrenal cortex
Vasopressin (anti-
diuretic hormone)
secretion from
posterior pituitary
Enhanced H2O
reabsorption
K+
Na+Na+
K+
Na+
H2O
H2OAldosterone binds to
cytoplasmic
mineralocorticoid receptor
to alter gene expression
Vasopressin binds to V2
GPCR to cAMP
Na+ channel (ENaC)
K+ channel (ROMK)
Aquaporin
Collecting Tubule
Vasopressin
increases
number
Aldosterone
increases
activity
Aldosterone
increases
synthesis
Na+/K+ ATPase
Diabetes Insipidus
Symptoms similar to diabetes mellitus (thirst, polydipsia, polyuria) but
a completely different etiology. Urine is copious and dilute.
*may also be of value (along with other measures) in the treatment of nocturnal enuresis
(bed wetting) in older (>10 yrs) children
Disturbance of signalling by vasopressin (ADH): one of two types
Neurogenic diabetes insipidus – lack of vasopressin secretion from
the posterior pituitary. Treated with desmopressin* (synthetic analogue
of vasopressin with V2 receptor selectivity – avoids increase in blood
pressure associated with V1 receptor activation)
Note: ethanol inhibits secretion of vasopressin; nicotine enhances
Nephrogenic diabetes insipidus – inability of the nephron to respond
to vasopressin. Rare and usually caused by recessive and X-linked
mutations in the V2 receptor gene (AVPR2) – no current
pharmacological treatment
Note: action of vasopressin on the kidney is inhibited by: Lithium (used in bipolar disorder)
Demeclocycline – antibiotic but has been used to block effects of excessive
release of vasopressin (e.g. tumours)
‘vaptans’ – next slide
‘Aquaretics’ ‘Vaptans’
Act as competitive antagonists
of vasopressin receptors
(which occur as V1A, V1B and V2
GPCR subtypes)
V1A receptors mediate
vasoconstriction; V2 mediate
H2O reabsorption in collecting
tubule by directing aquaporin 2
(AQP2)-containing vesicles to
the apical membrane
Blockade of V2 receptors
causes excretion of water
without accompanying Na+ and
thus raises plasma Na+
concentration
Place of ‘vaptans’ (i.e. conivaptan (V1A and V2 antagonist) and tolvaptan (V2
antagonist) in treatment of heart failure is still being determined – most likely of
value in hypervolaemic hyponatraemia (to reduce preload)
Tolvaptan is used in syndrome of inappropriate anti-diuretic hormone secretion
(SIADH) to correct hyponatraemia (conivaptan not listed in BNF, but FDA approved)
Inhibitors of Sodium Glucose Co-transporter 2 (SGLT2) (1)
Reabsorption of glucose occurs in the proximal tubule mediated by
sodium glucose co-transporters (SGLT) 1 and 2 - normally 100%
efficient – glucose only appears in urine if filtrate concentration of
glucose exceeds the renal threshold (about 11 mmol l-1)
Reabsorption is by secondary active transport (apical membrane) and
facilitated diffusion (basolateral membrane)
SGLT1 is expressed in both the
intestine (enterocytes) and the
kidney, SGLT2 is almost
exclusively confined to the
proximal tubule of the latter –
drugs that selectively block
SGLT2 affect only renal
reabsorption of glucose
SGLT2 (S1 segment) and
SGLT1 (S2/3 segment reabsorb
up to 90% and 10%) of filtered
glucose, respectively
Inhibitors of Sodium Glucose Co-transporter 2 (SGLT2) (2)
Both SGLT1 and SGLT2 transport glucose
against a concentration gradient by coupling it
to Na+ influx glucose
Transporter stoichiometry is SGLT1 2Na+:1
glucose and SGLT2 1Na+: 1 glucose
SGLT2: low affinity, high capacity
SGLT1: high affinity, low capacity
Inhibition of SGLT2 results in glucosuria [note
this mimics the condition familial renal
glucosuria (FRG) which tends to be benign]
Canagliflozin, dapagliflozin and empagliflozin are
competitive inhibitors of SGLT2 recently available
in the UK to treat T2DM as part of combination
therapy (note independent of insulin)
SGLT2 inhibitors cause:
excretion of glucose
decreases in HbA1c
weight loss (calorific loss and mild osmotic
diuresis contribute)
Clinical experience limited – most common adverse effects reported are increased
incidence of genital bacterial and fungal infections
Prostaglandins and Renal Function
Prostaglandins are part of a family of molecules (prostanoids) formed
from the fatty acid arachidonic acid by the cyclo-oxygenase enzymes
(COX1 and 2)
The major prostaglandins synthesised by the kidney are:
PGE2 – medulla
PGI2 (prostacyclin) – glomeruli
Both act as vasodilators, are natriuretic, and are synthesised in
response to ischaemia, mechanical trauma, angiotensin II, ADH and
bradykinin
Under normal conditions, prostaglandins have little effect upon on
renal blood flow (RBF), or glomerular filtration rate (GFR)
Prostaglandins gain importance under conditions of vasoconstriction,
or decreased effective arterial blood volume, where they cause
compensatory vasodilation
Non-steroidal anti-inflammatory drugs (NSAIDS) inhibit COX and may
precipitate acute renal failure (greatly decreased GFR) in conditions
where renal blood flow is dependent upon vasodilator prostaglandins
(cirrhosis of the liver, heart failure, the nephrotic syndrome)
Prostaglandins affect GFR by:
a direct vasodilator effect upon the afferent arteriole
releasing renin leading to increased levels of angiotensin II that
vasoconstricts the efferent arteriole – filtration pressure increases
Combination of ACEI (or ARB), diuretic and NSIAD may be particularly
detrimental the ‘triple whammy’ effect
Uricosuric Agents
Uric acid is formed by the catabolism of purines
Elevated plasma urate predisposes to gout - deposition of urate
crystals in joints and soft tissues
Probenecid and sulfinpyrazole can be useful in the treatment of
gout by blocking reabsorption of urate in the proximal tubule
(although largely supplanted by allopurinol which inhibits urate
synthesis)
1
2
3
1 Urate filtration
2 Urate secretion - blocked by low –
subtherapeutic – doses of probenecid
and sulfinpyrazole
Urate secretion and reabsorption - blocked by
therapeutic doses of probenecid and sulfinpyrazole
– net effect enhanced excretion
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