Drugs acting on the kidneys Flashcards
What are diuretics?
agents that increase urine output through causing a net electrolyte and water loss
What do the organic anion transporters transport?
acidic drugs eg thiazides and loop agents
What do organic canion transporters tranposrt?
basic drugs
Where do loo/p diuretics work
ascending loop of Henle
What transporter do loop diuretics inhibit?
Na/K/2Cl cotransporter
Where do thiazides work?
DCT
Where does spironolactone work?
collecting duct
Why do loop diuretics cause hypokalaemia?
increase the load of sodium to DCT which results in compensatory mechanisms to get sodium back in exchange for potassium
What other electrolyes are depleted with looop diuretics?
calcium and magnesium
What action do loop diuretics have on blood vessels?
venodilator
What acid-base abnormality can be cause by loop diuretics?
metabolic alkalosis
What are the adverse effects of loop diuretics?
hypokalaemia; hypomagnesaemia; hypocalcaemia; hyperglycaemia; hyperuricaemia; hearing loss; hypovolaemia
Why do loop diuretics cause hearing loss?
there are the same cotranporters in endolymph
What transporter do thiazides work on?
bind to Na/Cl symprter
What effect do thiazides have on calcium?
increase reabsorption of calcium
Why are thiazides not as potent as loops?
because by DCT lots of sodium has already been reabsorbed
What effect do thiazides have on vessels?
vasodilator
What are the uses of thiazides?
mild HF; HT; nephrolithiasis (hypercalciuria); nephrogenic DI
Are thiazides and loops effective in renal failure?
loops are, thiazides arent
What extrarenal metabolic disturbances do thiazides cause?
hyperglycaemia and hyperlipidaemia
What are the side effects of thiazides?
postural hypotension; metabolic alkalosis; hypokalaemia; hyponatraemia; hypomagnesaemia; hypercalcaemia; hyperuricaemia; low blood counts; impotence; pancreatitis; cholestasis; pneumonitis; photosensitivity
What does risk of hypokalaemia depend on?
duration of action of the drugs
Which type of diuretic is less likely to cause hypokalaemia?
loop- shorter duration of action
Waht are teh signs of hypokalaemia?
weaknss; myalgia, fatigue, arrhythmias
How do loop diuretics cause metabolic alkalosis?
The increased sodium at the DCT causes the DCT to increase sodium reabsorption using Na/H transports and Na/K transports leading to hypokalaemia and alkalsis, the loss of chloride also leads to loss of anions so body gets more bicarb to replace
What is the main problem associated with loop and thiazides?
cause secondary hyperaldosteronism
What is the use of potassium sparing diuretics?
although weak diuretics on their own they blunt the secondary hyperaldosteronism with other diuretics so are useful in adjucts
What is the action of amiloride and triamterene?
block the apical sodium channel to decrease sodium reabsorption
What is the action of spironolactone and eplerone?
compete with aldosterone
What type of receptor does spironolactone compete with aldosterone for?
intracellular receptors
What does the competitive antagonism of spironolactone cause?
decreased gene expression and reduced synthesis of a protein mediator that activates sodium channels in the apical membrane and decrease the numebrs of sodium potassium pumps in the basolateral membrane
How do amiloride and triamteren enter the nephron?
via organic cation tranport system in the PT- basic drugs
What is the active metabolite of spironolactone?
canrenone
What is the difference between amiloride and traimterene?
although amilordie is 10x more potent, triamterene is better absorbed fro mthe GI tract
What hormonal disturbances does spironolactone cause?
gynaecomastia, impotence and menstrual irregularities
When are there increased risk of hyperkalaemia assocaited with sprionolactone?
with used with potassium suppements and ACEi/ARBs
Where is the carbonic anhydrase enzyme present?
renal tubules; gastric mucosa; pancreas, eye, brain and RBCs
What is the actions of CA inhibitiors?
increase excretion of bicarbonate with sodium, potassium and water
What can CAi result in?
alkaline diuresis; hypokalarmia and metabolic acidosis
What are carbonic anhydrase inhibitors used for?
glaucoma; acute mountain sickness;
What is the name of osmotic diuretics?
mannitol
What is the major site of action in the kidneys of mannitol?
proximal tubule
How is mannitol given?
IV
How does mannitol get into the tubule?
freely filtered at the glomerulus
What are the pharmacology properties of mannitol?
pharmacologically inert; not metabolised in the body; does not enter cells
What are osmotic diuretics used for?
raised ICP and IOP; prevention of impending acute renal failure
What type of receptor does ADH work on?
GPCR
What do V1 receptors do?
vasconstriction
What do V2 receptors do?
vasodilatory; increase water reaborption in renal CD
What are aquaretics/vaptans?
competitive antagonsits of vasopressin receptors
What do vasopressin receptor antagonists cause?
electrolyte free aquaresis; reduce urine osmolality; raise seum Na
What is the main SE of osmotic diuretics?
hyponatraemic headache
What is the main SE of aquaretics/ vaptans?
increased thirst
What is the MOA of mannitol?
The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing sodium as well as water reabsorption.
How are prostaglandins formed?
from the fatty acid arachidonic acid in membrane phospholipids by the COX enzymes
Which COX enzyme is mainly active during inflammation?
COX2
What are hte PGs important in the kidneys?
PGE2 and PGI2
What is the function of PGs in the kidney?
they are vasodilators and so increased renal blood flow and eGFR; increase water, Na and K excretion
When are PGs most important?
in angiotensin induced vasoconstriction in volume deleted states
When is renal blood flow dependent upon vasodilator prostaglandins?
CHF; cirrhosis and nephrotic syndrome
What is the effect of NSAIDs?
tend to retain salt and water by inhibiting COX and PG synthesis
What is the triple combination of drugs that can cause serious renal problems?
ACEi + diuretic + NSAID
What is the difference between the action of uricosuric agents vs allopurinol?
allopurinol inhibits urate synthessis whereas uricosuric drugs reduce reabsorption of urate
How do uricosuric agents reduce reabsorption of urate?
block the active transport of organic acids
Who are uricosuric agents unsuitable for use in?
patients with renal impairment of hx of renal stones
Why must high doses of uricosuric agents be given rather than low dose?
at low dose, uricosuric agents block urate secretion- increasing blood urate levels
Give examples of uricosuric agents?
probenecid; sulfinpyrazole
What uricosuric agent may be used in mild renal impairment?
benzbromarone
What other drugs have mild uricosuric properties?
losartan and fenofibrate
What should patients be told to do when started on a uricosuric agent?
increase fluid intake to 2-3 litres daily
What drugs antagonise uricosuric drugs in the proximal ubule?
aspirin and other salicylates
Gvie examples of SGLT2 inhibitors?
dapaglilofzin and empagliflozin
What drugs cause uricaemia?
thiazides and loops
How do SGLT work?
transport glucose against a conc gradient by coupling it to sodium influx
What are the effects of SGLT2 inhibitors?
excretion of glucose, decrease in HbA1c and weight loss (calorific loss and mild osmotic diuresis); increased genital infections
