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Renal lecture 3 2017 18_jap


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This is the updated (2017-18) version of this lecture series, and it contains some additional and fairly recent information.

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Renal lecture 3 2017 18_jap

  1. 1. Drugs Acting on the Kidney (3) Professor John Peters E-mail
  2. 2. 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 kidney 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 • Bailey (2011). Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol. Sci, 32, 63-71. (Excellent review – very easily read and understood) • Neal (2016). ‘Medical Pharmacology at a Glance (8th.ed.) Chapter 14 • Rang, Ritter, Flower and Henderson (2016). 'Rang and Dale's Pharmacology’ (8th. ed.). Chapter 29
  3. 3. Osmotic Diuretics (1) Osmotic diuretics (e.g. mannitol IV)  Are membrane impermeant polyhydric alcohols (hence IV 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
  4. 4. o in urgent treatment of acutely raised intracranial and intraocular pressure. The solute does not enter the eye, or brain, but increased plasma osmolality extracts water from these compartments o in the prevention of acute hypovolaemic renal failure to maintain urine flow  Osmotic diuresis may also occur: o in hyperglycaemia – reabsorptive capacity of the proximal tubule for glucose (by SGLT1 and SGLT2) is exceeded. Glucose remaining in the filtrate retains fluid (note: SLGT2 is now a target in treatment of T2DM – see later) o 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 Osmotic Diuretics (2)  Osmotic diuretics are used:  Adverse effects include: transient expansion of blood volume and hyponatraemia
  5. 5. Carbonic Anhydrase Inhibitors (and Urinary pH) Carbonic anhydrase inhibitors (e.g. acetazolamide)  No longer have a role as diuretic agents, but are useful in: o glaucoma and following eye surgery (to reduce intraocular pressure by suppressing formation of aqueous humour) o prophylaxis of altitude sickness o 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: o relief of dysuria o prevention of the crystallization of weak acids with limited aqueous solubility (remember Henderson-Hasselbalch equation!) – favours ionised form. Can decrease formation of uric acid stones o enhancing the excretion of weak acids (e.g. salicylates, some barbiturates) – favours ionised form that is not reabsorbed
  6. 6. 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 H2O Aldosterone 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
  7. 7. 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 o 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 o 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: o lithium (used in bipolar disorder) o demeclocycline – antibiotic but has been used to block effects of excessive release of vasopressin (e.g. tumours) o ‘vaptans’ – next slide
  8. 8. ‘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)
  9. 9. 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
  10. 10. 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 o SGLT2: low affinity, high capacity o 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 available in the UK to treat T2DM as part of combination therapy (note independent of insulin)  SGLT2 inhibitors cause: o excretion of glucose o decreases in HbA1c o 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
  11. 11. 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: o PGE2 – medulla o 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
  12. 12.  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: o a direct vasodilator effect upon the afferent arteriole o 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
  13. 13. 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 32 +