Drugs that Act on the Kidneys III Flashcards
What is an example of an osmotic diuretic?
Mannitol IV
What are osmotic diuretics?
Membrane impermeant polyhydric alcohols = pharmacologically inert
How do osmotic diuretics enter the nephron?
By glomerular filtration = are not reabsorbed
What effect do osmotic diuretics have on the filtrate?
Increase the osmolarity = opposes the absorption of water in parts of the nephron that are freely permeable to water
Where is the major site of action in the kidneys of osmotic diuretics?
The proximal tubule = area where most iso-osmotic reabsorption of water takes place
What is the secondary action of osmotic diuretics in the proximal tubule?
Decrease sodium reabsorption = larger fluid volume decreases sodium concentration and electrochemical gradient for reabsorption
What are the uses of osmotic diuretics?
Prevention of acute hypovolaemic renal failure to maintain urine flow
Urgent treatment of acutely raised intracranial and intra-ocular pressure
What are the adverse effects of osmotic diuretics?
Transient expansion of blood volume, hyponatraemia
How can hyperglycaemia cause osmotic diuresis?
Reabsorptive capacity of proximal tubule for glucose is exceeded = glucose remaining in filtrate retains fluid
How can iodine-based radiocontrast dyes cause osmotic diuresis?
Dye filtered at glomerulus but not reabsorbed = constitutes osmotic load
What is an example of a carbonic anhydrase inhibitor?
Acetazolamide = increases excretion of HCO3-with Na+, K+ and H2O
What do carbonic anhydrase inhibitors cause?
Alkaline diuresis and metabolic acidosis
What conditions are carbonic anhydrase inhibitors used to treat?
Glaucoma and following eye surgery
Prophylaxis of altitude sickness
Some forms of infantile epilepsy
What are the benefits of alkanising urine?
Relief of dysuria, prevention of weak acid crystallisation, enhanced weak acid excretion
What does aldosterone cause in the kidneys?
Enhanced tubular Na+ reabsorption and salt retention
What does ADH cause?
Enhanced H2O reabsorption
What are the symptoms of diabetes insipidus?
Similar to diabetes = polyuria, thirst, polydipsia
Urine is copious and dilute
What is neurogenic diabetes insipidus?
Lack of ADH secretion from posterior pituitary = treated with desmopressin
What is desmopressin?
Synthetic analogue of ADH with V2 selectivity
What is nephrogenic diabetes insipidus?
Inability of nephron to respond to ADH = rare, caused by recessive and X-linked mutations in AVPR2
What are some substances that inhibit the action of ADH?
Lithium, demeclocycline, vaptans
What are vaptans?
Act as competitive antagonists of ADH receptors = V1A, V1B, V2
What do V1A receptors mediate?
Vasoconstriction
What do V2 receptors mediate?
H2O reabsorption in collecting tubule = direct AQP2-containing vesicles to apical membrane
What does block of V2 receptors cause?
Excretion of water without accompanying Na+ = raises plasma Na+ concentration
What are some indications of vaptan use?
Hypervolaemic hyponatraemia = to reduce preload
Tolvaptan can be used in syndrome of inappropriate ADH to correct hyponatraemia
What are some examples of vaptans?
Conivaptan = V1A and V2 antagonist Tovaptan = V2 antagonist
Where does reabsorption of glucose occur?
In the proximal tubule of the kidney mediated by SGLT1 and SGLT2
When does glucose appear in the urine?
Reabsorption normally 100% = glucose only appears in urine if filtrate concentration of glucose exceeds renal threshold (about 11 mmol/l)
Where are SGLT1 and SGLT2 expressed?
SGLT1 = by enterocytes and the kidneys SGLT2 = almost exclusively confined to the proximal tubule
What effect do drugs that selectively block SGLT2 have?
Only have an effect on renal reabsorption of glucose
How much glucose is reabsorbed by SGLT1 and SGLT2?
SGLT2 = S1 segment, reabsorbs up to 90% SGLT1 = S2 and 3 segments, reabsorbs up to 10%
How is glucose reabsorbed in the proximal tubule?
By secondary active transport and the apical membrane and facilitated diffusion at the basolateral membrane
How do SGLT1 and SGLT2 transport glucose against a concentration gradient?
By coupling it to Na+ influx
What is the transport stoichiometry of SGLT1 and SGLT2?
SGLT1 = 2Na+:1 glucose, high affinity, low capacity SGLT2 = 1Na+:1 glucose, low affinity, high capacity
What does SGLT2 inhibition result in?
Glucosuria
What are some examples of SGLT2 inhibitors?
Canagliflozin, dapagliflozin, empagliflozin
What are the effects of SGLT2 inhibitors?
Excretion of glucose, decrease in HBA1c, weight loss
Adverse effects = genital bacterial and fungal infections
What are prostaglandins?
Part of prostanoid family = formed from fatty acid arachidonic acid by COX 1 and 2
What are some features of prostaglandins?
Act as vasodilators and are natriuretic
Synthesised in response to ischaemia, mechanical trauma, angiotensin II, ADH and bradykinin
What are the two major prostaglandins synthesised by the kidney?
PGE2 = medulla PGI2 = glomeruli
What effect do prostaglandins have in normal conditions?
Have very little effect on renal blood flow or GFR
Under what conditions do prostaglandins cause compensatory vasodilation?
During decrease effective arterial blood volume or vasoconstriction
How do prostaglandins affect GFR?
Direct vasodilator effect upon afferent arteriole
Releases renin leading to increased levels of angiotensin II
Vasoconstricts efferent arteriole (increases filtration pressure)
Why can NSAIDs cause acute renal failure in conditions where renal blood flow is dependent on prostaglandin compensatory action ?
Inhibit COX so may reduce prostaglandins = occurs in liver cirrhosis, heart failure and nephrotic syndrome
What is three drugs make up the “triple whammy” effect that may cause acute renal failure in conditions dependent on compensation by prostaglandins?
ACE inhibitors/ARBs, diuretics and NSAIDs
What is uric acid formed as a result of?
Purine synthesis
What does elevated plasma urate predispose to?
Gout
What are some examples of uricosuric agents?
Probenecid and sulfinpyrazole = may help treat gout by blocking absorption of urate in proximal tubule
What are the points of action of uricosuric agents?
Urate secretion = blocked by low sub-therapeutic doses
Urate secretion and reabsorption = blocked by therapeutic doses, net effect is enhanced excretion
