Pharmacology Flashcards
name 6 classes of drugs which act on the kidney
diuretics
vasopressin receptor agonists/antagonists
SGLT2 (sodium-glucose co-transporter 2 inhibitors)
uricosuric drugs (promote excretion of uric acid)
drugs for renal failure
drugs altering pH of urine
what do diuretics do?
increase urine flow, normally by inhibiting reabsorption o electrolytes (sodium) in nephron
enhance excretion of salt and water in conditions where increased volume of ECF (e.g oedema/tissue swelling)
what causes oedema?
imbalance between rate of secretion and absorption of interstitial fluid
- hydrostatic pressure in capillary (Pc)
hydrostatic pressure in interstitial fluid (Pi)
- oncotic pressure of plasma (Mp)
- oncotic pressure of interstitial fluid (Mi)
calculation for formation of interstitial fluid?
(Pc-Pi) - (Mp - Mi)
name 3 disease states which can increase Pc or decrease Mp
nephrotic syndrome
congestive heart failure
hepatic cirrhosis with ascites
what causes nephrotic syndrome?
disorder of glomerular filtration allowing for large proteins (mainly albumin) to appear in urine
is protein in the urine always abnormal?
no
small proteins can occur in urine after heavy exercise
how does decreased plasma oncotic pressure cause oedema/
decreased Mp > increased formation of interstitial fluid > reduced blood volume and CO > activation of the RAAS > aldosterone and angiotensin II cause Na+ and H2O retention > only salt and water added back, not protein so protein concentration in the blood is diluted > reduces plasma oncotic pressure even further and increases Pc > oedema
how does heart failure cause oedema?
reduced CO > renal hypoperfusion > activation of RAAS > blood volume expands and protein conc decreases > increased Pc and decreased Mp > oedema
how does cirrhosis cause ascites?
increased pressure at portal vein + decreased albumin production > loss of fluid into peritoneal cavity > oedema/ascites > RAAS activated
how do diuretics work (diagram)?
..
how is Na+ reabsorbed in the proximal tubule and what blocks this?
Na+/H+ exchange
blocked by carbonic anhydrase inhibitors (diuretics)
- site of 70% of sodium reabsorption
how is Na+ reabsorbed in the thick ascending limb of loop of henle and what blocks this?
triple co-transporter - Na+/K+/2Cl-
blocked by loop diuretics
how is sodium reabsorbed in the early distal tubule?
Na+/H+ exchange
- blocked by CA inhibitors
Na+/Cl- (mainly)
- blocked by thiazide diuretics
how is Na+ reabsorbed in the collecting tubule and duct?
Na+/K+ exchange
- blocked by potassium sparing diuretics
what type of diuretic can cause hypokalaemia?
any which increases reabsorption of Na+ in distal tubule (apart from potassium sparing ones)
a small inhibition of reuptake of NaCl can cause a large increase in Na+ excretion, true or false?
true
- as so much sodium is filtered
where do most diuretics act?
apical membrane of tubular cells
- therefore must enter the filtrate to act on these cells
how can diuretics enter the filtrate?
glomerular filtration (cant enter glomerular filtration if bound to large plasma proteins)
organic anion transporter (transport acidic drugs - thiazides and loops)
organic cation transporter (transport basic drugs - triamterene and amiloride)
secretion of diuretic into the filtrate allows what?
concentrate the diuretic in the filtrate (urine)
gives pharmacological selectiveness of the drug (makes sure it only works in renal system)
describe the organic anion transporter
basolateral and apical transport processes
basolateral
- anions enter cell against conc gradient in exchange for α-KG via OAT channels
- α-KG enters cell against conc gradient via NaDC3 transporter
apical membrane
- once in the cell, anion crosses to the lumen via multidrug resistance proteins 2 and 4 and BCRP via primary active transport
- anion crosses from the lumen via OAT4 channel in exchange for α-KG
name drugs which use anion transporter
diuretics simvastatin penicillin NSAIDs endogenous urate
how do diuretics increase acute gout risk?
impair ability to secrete urate out of the blood and into the urine (organic anion transporter)
describe organic cation transporter
basolateral membrane
- organic cations enter cell via OCT2 channel driven by -ve potential, against conc gradient
apical membrane
- cation enters the lumen in rate limiting manner via electroneutral multidrug and toxin extrusion transporters (MATES) an active transport via MDR1
what drugs use organic cation transporter?
diuretics atropine metformin morphine procainamide catecholamines
…
blocks triple transporter > low intracellular Na+ > drives reabsorption of Na+
…
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what are the 2 principle loop diuretics and how do they work in general terms?
furosemide
bumetanide
inhibit the triple transporter by binding to the Cl- site and thus
what is the impact of inhibiting the triple transporter?
decrease tonicity of medulla interstitium
prevent dilution of filtrate in thick ascending limb
increase load of Na+ delivered to distal nephron causing K+ loss
increased excretion of calcium and magnesium
causes 15-25% of filtered Na+ to be excreted
what additional action of loop diuretics can be helpful in acute pulmonary oedema before the diuretic action kicks in?
venodilator action
which loop is better in heart failure?
bumetonide
pharmacokinetics of loop diuretics?
absorbed by GI tract (subject to variation in CHF)
bind to plasma protein
enter nephron via OAT
indications for loop diuretics?
reduce salt and water overload associated with cardiac/renal failure, cirrhosis or nephrotic syndrome
to increase urine volume in AKI
treat hypertension
to reduce acute hypercalcaemia
how may nephrotic syndrome affect loop diuretic action?
reduce effectiveness
drug binds to high amount of protein in urine
contraindications for loop diuretics?
severe hypovolaemia or dehydration
use with caution in hypokalaemia/hyponatraemia, hepatic encephalopathy and gout
side effects of loop diuretics?
low electrolyte states (including metabolic alkalosis due to H+ secretion)
hypovolaemia/hypotension
hyperuricaemia (gout)
dose-related hearing loss
where is the triple transporter found in the nephron?
thick ascending limb of loop of henle
what do thiazide diuretics block?
sodium chloride co-transporter
principle thiazide and thiazide-like diuretics?
bendroflumethiazide thiazide like - chlortalidone - indapamide - metolazone
what do thiazide like diuretics do?
inhibit Na+/Cl- co-transporter by binding to Cl- site and therefore
- prevent dilution of filtrate/urine in early distal tubule
- increase load of Na+ delivered to collecting tubule causing K+ loss
- increased reabsorption of calcium
causes up to 5% of filtered Na+ to be secreted (modest diuresis)
additional action of thiazides?
vasodilator action
- benefit in hypertension
pharmacokinetics of thiazides?
well absorbed from GI tract
enter nephron via OAT mechanism
indications for thiazides?
mild heart failure
hypertension (indapamide or chlotalidone)
severe resistant oedema
renal stone disease (reduced Ca2+ excretion discourages Ca2+ stone formation- less calcium in urine so less likely to precipitate out)
nephrogenic diabetes (reduced ADH response in collecting ducts)
contraindications for thiazides?
hypokalaemia
use with caution - hyponatraemia, gout
side effects of thiazides?
hypokalaemia metabolic alkalosis hypovolaemia/hypotension hypomagnesia (not hypocalcaemia) hyperuricaemia (gout) erectile dysfunction impaired glucose tolerance
which diuretic is best to use in elderly person with osteoporosis and why?
thiazide
- don’t cause loss of calcium
function of aldosterone?
acts via cytoplasmic receptors to increase reabsorption of Na+ in the late distal and collecting tubule via increasing ENac (sodium) channel and Na+/K+ ATPase
how does aldosterone affect potassium?
increased Na+ reabsorption = increased K+ excretion
how does Na+ reabsorption cause K+ excretion?
charge separation makes lumen more -ve and depolarizes the luminal/basolateral membrane
this causes an increased driving force of K+ across the luminal membrane leading to enhanced secretion of K+ (Sgk1 increases ROMK K+ channel numbers in apical membrane)
secreted K+ is washed away by increased urinary flow rate that also indirectly activates the ROMK channel leading to development of hypokalaemia
name 4 potassium diuretics?
amiloride
triamterene
spironolactone
eplerenone
how do amiloride and triamterene work?
enter nephron via organic cation transport system in proximal tubule and block apical sodium channels in collecting tubules and decrease Na+ reabsorption
how does spironolactone and eplerenone work?
enter cell via basolateral membrane and compete with aldosterone for binding to intracellular cytoplasmic receptors preventing the actions of steroid described previously
- increase Na+ excretion
- decrease K+ excretion
indications for potassium sparing diuretics?
given in conjunction with other agents that cause potassium loss (as they cause hyperkalaemia) ... . . .
contraindications of potassium sparing diuretics?
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