Drugs that Act on the Kidneys I & II Flashcards
What are some drug classes that act on the kidneys?
Diuretics, ADH agonists/antagonists, SGLT2 inhibitors, uricosuric drugs, renal failure drugs, drugs that alter pH of urine
What are urocosuric drugs?
Drugs that promote the excretion of uric acid into urine
What are the desirable actions that diuretics are most often used for?
Increase urine flow by inhibiting electrolyte absorption at the nephron
Enhance excretion of salt and water in oedema
What causes oedema?
Results from imbalance between the rate of formation and absorption of interstitial fluid
What is the formation of interstitial fluid proportional to?
(Pc-Pi) - (plasma oncotic pressure - interstitial oncotic pressure)
What are some diseases that increase Pc/decrease oncotic plasma pressure and produce oedema?
Nephrotic syndrome, congestive heart failure, hepatic cirrhosis with ascites
What does nephrotic syndrome involve?
A disorder of glomerular filtration, allowing large proteins (usually albumin) to appear in urine (proteinuria)
How does nephrotic syndrome cause oedema?
Decreases plasma oncotic pressure increases interstitial fluid formation = decreased cardiac output and blood volume activates RAAS causing NA+/H2O retention
What causes congestive heart failure?
Reduced cardiac output and subsequent renal hypotension that activates RAAS
How does congestive heart failure cause pulmonary and peripheral oedema?
Expansion of blood volume contributes to increased venous and capillary pressures which combines with reduced plasma oncotic pressure to cause oedema
How does hepatic cirrhosis with oedema cause oedema?
Increased pressure in the hepatic portal vein and decreased albumin production cause loss of fluid into the peritoneal cavity (ascites) and oedema
How does hepatic cirrhosis activate RAAS?
Occurs in response to decreased circulating volume
What may happen if a massive dose of diuretics are used to correct oedema?
May cause collapse or thrombosis
How is sodium absorbed in the proximal convoluted tubule?
Passively along with CL-
Na+/H+ exchanger = blocked by carbonic anhydrase inhibitors
How is sodium absorbed in the thick ascending limb of the loop of Henle?
Na+/K+/2Cl- co-transport = blocked by loop diuretics
How is sodium absorbed in the early distal convoluted tubule?
Na+/H+ exchange = blocked by carbonic anhydrase inhibitors
Na+/Cl- co-transport = blocked by thiazide diuretics
How is sodium absorbed in the collecting ducts and tubule?
Na+/K+ exchange = blocked by K+-sparing diuretics
Where is the site of action of most diuretics?
Apical membrane of the tubular cells = if they are hydrophilic they must enter the filtrate to act
How do diuretics enter the filtrate?
Glomerular filtration = for drug not bound to large plasma protein
Secretion = two mechanisms exist
What are the two mechanisms that allow the secretion of diuretics into the plasma?
Organic anion transporters (OATs) = for acidic drugs
Organic cation transporters (OCTs) = for basic drugs
What does secretion of diuretics into the filtrate result in?
The concentration of the diuretic in the filtrate being higher than the blood = contributes to pharmacological selectivity
What do the secretory pathways of both organic anions and organic cations involve?
Both apical and basolateral transport processes
What is the specificity of organic anion transporters?
Low specificity but high transport rates
What are organic anions exchanged for at the basolateral membrane?
Alpha-ketoglutarate = occurs against the concentration gradient, facilitated by OAT (OAT 1, 2, 3)
How does alpha-ketoglutarate enter cells?
Via Na+ dicarboxylate transporter 3 (NaDG3) = works against concentration gradient
How does organic anion cross to the lumen at the apical membrane?
Via multidrug resistance proteins 2 and 4 (MRP2/4) and breast cancer resistance protein (BCRP) = primary active transport
How does organic anion cross from the lumen?
Via OAT4 in exchange for alpha-ketoglutarate
How do organic cations enter at the basolateral membrane?
Mainly by OCT2 = driven by negative potential of cell interior and against a concentration gradient
How do organic cations enter at the lumen of the apical membrane?
Enters in rate limiting manner via electroneutral multidrug and toxin extrusion transporters (MATES) and active transport by MDR1
What genetic syndrome mimics the effects of loop diuretics?
Bartler syndrome = autosomal recessive mutations in NKCC2, ROMK and ClCKb/barttin
What are the two main loop diuretics used?
Furosemide and bumetanide
How do loop diuretics inhibit the Na+/K+/2Cl- transporter?
By binding to the Cl- site
What effect does the inhibition of the Na+/K+/2Cl- transporter by loop diuretics have
Decreases tonicity of interstitium of the medulla
Prevent dilution of the filtrate in thick ascending limb
Increases Na+ load delivered to distal regions of nephron causing K+ loss
Increases Ca2+ and Mg2+ excretion
Why are loop diuretics classed as high ceiling agents?
Cause 15-25% of filtered Na+ load to be excreted and have rapid onset following IV administration
How are loop diuretics beneficial in treating the pulmonary oedema caused by heart failure?
Have additional indirect vasodilator action (before diuresis)
What are the pharmacokinetics of loop diuretics?
Absorbed from GI tract = subject to variation in CHF
Strongly bind to plasma protein
Enter nephron by OAT mechanism
What are some conditions where loop diuretics are used to reduce salt and water overload?
Acute pulmonary oedema, chronic heart/kidney failure, hepatic cirrhosis with ascites, nephrotic syndrome (proteinuria may reduce effectiveness)
What are some indications for loop diuretic use?
To increase urine volume in acute kidney failure
To reduce acute hypercalcaemia
When are loop diuretics used to treat hypertension?
In patients resistant to other diuretics or anti-hypertensives = usually in presence of renal insufficiency
What are the contra-indications to using loop diuretics?
Severe hypovolaemia or dehydrating
What conditions should loop diuretics be used with caution in?
Severe hypokalaemia and or hyponatraemia, hepatic encephalopathy, gout
What are the adverse effects of loop diuretics?
Causing low electrolyte states = hypokalaemia, metabolic alkalosis, hypocalcaemia, hypomagnesaemia
Hypovolaemia and hypotension (especially elderly)
Hyperuricaemia = may precipitate acute gout
Dose-relate hearing loss
What genetic syndrome mimics the effects of thiazide and thiazide-like diuretics?
Gitelman syndrome = autosomal recessive mutations in NCC
What are some examples of thiazide and thiazide-like diuretics?
Thiazide = bendroflumethiazide Thiazide-like = chlortalidone, indapamide, metolazone
How do thiazide/thiazide-like diuretics inhibit the Na+/Cl- co-transporter?
Bind to Cl- site
What effect does the inhibition of the Na+/Cl- co-transporter by thiazide/thiazide-like diuretics have?
Prevents dilution of filtrate in the early distal convoluted tubule
Increases Na+ load delivered to collecting tubule causing K+ loss
Increases reabsorption of Ca2+
How do thiazide/thiazide-like diuretics cause modest diuresis?
Cause up to 5% of Na+ to be excreted
How are thiazide/thiazide-like diuretics beneficial in the treatment of hypertension?
Possess additional vasodilator action
What are the pharmacokinetics of thiazide/thiazide-like diuretics?
Well absorbed from GI tract
Enter nephron via OAT mechanism
What are thiazide/thiazide-like diuretics widely used for?
Treatment of mild heart failure and hypertension = indapamide or chlortalidone
What are some indications for thiazide/thiazide-like diuretic use?
Severe resistant oedema, nephrogenic diabetes insipidus, renal stone disease
What are the contra-indications and cautions of thiazide/thiazide-like diuretic use?
Contra-indication = hypokalaemia Cautions = hyponatraemia, gout
What are the adverse effects of thiazide/thiazide-like diuretics?
Hypokalaemia, metabolic alkalosis, hypovolaemia and hypotension, hypomagnesaemia, hyperuricaemia, erectile dysfunction, impaired glucose tolerance in diabetes
What receptor type does aldosterone act via?
Cytoplasmic receptors
What effect does aldosterone binding have?
Increases synthesis of CAP1 that activates ENa channel
Increases expression of ENa channel
Increases abundance of Na+/K+-ATPase
Relatively rapidly increases expression of ENa channel via serum glucocorticoid-stimulated kinase (Sgk1)
What channels secrete K+ into the urine in the collecting tubule?
ROMK and BK
How do loop and thiazide diuretics enhance Na+ reabsorption?
By increasing Na+ load
What effect does the increased Na+ reabsorption by thiazide and loop diuretics have on the lumen?
Causes resulting charge separation and depolarises the luminal membrane compared to the basolateral membrane
What does the depolarisation of the lumen due to thiazide or loop diuretic use cause?
Increases the driving force of K+ across the luminal membrane = leads to enhanced secretion of K+, Sgk1 increases ROMK number in apical membrane
What eventually causes hypokalaemia due to loop or thiazide diuretic use?
Secreted K+ is washed away by increased urinary flow rate that also indirectly activates ROMK channel
What are some examples of potassium sparing diuretics?
Amiloride and triamterene = block apical sodium channel and decrease Na+ reabsorption
Spironolactone and eplerenone = compete with aldosterone for binding to intracellular receptors
Why do spironolactone and eplerenone have limited diuretic action?
They are modulated by aldosterone levels
What is the action of spironolactone and eplerenone?
Competitively antagonise the action of aldosterone at cytoplasmic receptors = gain access to cytoplasm via basolateral membrane
What effect do spironolactone and eplerenone have on electrolytes?
Increase excretion of Na+ and decrease excretion of K+
What is spironolactone metabolised to?
Rapidly metabolised to canrenone = accounts for most of action of the drug
Are spironolactone and eplerenone well absorbed from the GI tract?
Yes
What is the action of amiloride and triamterene?
Block luminal sodium channels in the collecting tubule = similar effect on electrolyte flux to spironolactone
How do amiloride and triamterene enter the nephron?
Via the OCT system in the proximal tubule
Are amiloride and triamterene well absorbed from the GI tract?
Triamterene is, but amiloride isn’t
What is the major indication for potassium sparing agents?
In conjunction with other agents that cause potassium loss = cause hyperkalaemia when given alone
How do potassium sparing agents potentiate the actions of loop and thiazide diuretics?
Block the action of aldosterone
What are some conditions treated by potassium sparing agents?
Heart failure, Conn’s syndrome, resistant essential hypertension, secondary hyperaldosteronism (caused by hepatic cirrhosis with ascites)
What are the contra-indications for potassium sparing agents use?
Severe renal impairment, hyperkalaemia, Addison’s disease (aldosterone blockers)
