Drugs affecting kidney function Flashcards
What are the roles of the kidney?
- regulation of water and electrolyte balance
- endocrine functions (eg EPO for RBC growth)
- excretion of endogenous waste from cellular metabolism
- excretion of exogenous compounds (eg pharmacological drugs)
How does drug elimination occur?
- by a combination of:
- metabolism in the liver
- excretion in the kidneys of drugs or their metabolites
Pharmacokinetics
what the body does to the drug
Pharmacodynamics
what the drug does to the body
What are the four steps of pharmacokinetics?
- Administration - give the drug
- Absorption - drug enters circulation
- Distribution - drug spreads through body
- Elimination - drug removed from body
- Metabolism - chemical changes
- Excretion - physical expulsion
Filtration occurs in the
Glomerulus
Tubular secretion occurs in the
Proximal tubule
Reabsorption occurs in the
- LOH (significant)
- distal tubule
- some in collecting duct
What is reabsorbed in the proximal tubule?
- 60-70% NaCl
What is secreted at the proximal tubule?
- organic acids and bases (eg drugs)
- bicarbonate
What is absorbed at the LOH?
- 20-30% NaCl reabsorption
- Water
- K+
What is reabsorbed in the distal tubule?
- 5-10% NaCl (remainder in collecting duct)
What is secreted at the LOH and distal tubule?
K+
What types of drugs have therapeutic actions on the kidney?
- diuretics
- drugs that affect urine pH
- eg using bicarb to tx aspirin overdose by +pH to ionize aspirin so that it cannot be reabsorbed
- drugs that alter secretion of organic molecules
- eg probenecid to inhibit secretion of banned substances
What is the function of diuretics?
- decrease Na+ and Cl- reabsorption to increase their excretion
- osmotically following this there is secondary water excretion
What are the considerations with using diuretics?
- local affect on the nephron
- distal consequences ie more NaCl in the tubule distal to the LOH
What are the classes of diuretics?
- loop diuretics
- thiazide diuretics
- potassium-sparing diuretics
- osmotic diuretics
Loop diuretics cause
- torrential wee
- excretion of 15-20% of Na+ in filtrate (most powerful)
Frusemide (furozimide)
- loop diuretic
What is the mechanism of loop diuretics?
- act on thick ascending LOH
- inhibit Na+/K+/2Cl- carrier into cells (luminal side)
- normally the Na+ it pumps in is exchanged on the interstitial side (Na/K, K/Cl exchangers) to pump Na out creating a hypertonic interstitium that promotes water reabsorption from the nephron
- inhibition decreases Na and tf H20 reabsorption from the lumen
- hypotonicity decreases osmotic pressure of interstitium
- reduces water reabsorption
- increases Na+ in the distal tubule (tf +osmotic pressure) and decreases H2O absorption from DT (+torrentiality of wee)
What are the pharmacokinetics of loop diuretics?
- well absorbed in the gut: onset <1 hour
- strongly bound to plasma protein tf excreted by (proximal) tubular secretion
- this is what gets it to the lumen in the LOH
- needs to work on this side bc that’s where Na/K/2Cl cotransporter is
- this is what gets it to the lumen in the LOH
- duration of action is 3-6 hours
What are the adverse effects of loop diuretics?
- K+ loss from the distal tubule
- +[Na] causes +Na reabs and +K+secretion via Na/K-ATPase
- leads to hypokalaemia tf given with a K+ supplement or K+-sparing diuretic
- H+ excretion leading to metabolic alkalosis
- reduced extracellualr fluid volume (in elderly)
- hypovolaemia and hypotension
Loop diuretics are prescribed with
K+ supplements
(or K+-sparing diuretics)
What are the clinical uses of loop diuretics?
- salt and water overload in:
- acute pulmonary oedema
- chronic heart failure
- ascities (liver cirrhosis)
- renal failure
- hypertension with renal impairment to decrease fluid load and tf BP
Thiazide diuretics are prescribed with what other drugs?
ACE inhibitors (prils) and ARBs (sartans)
bendrofluazide, hydrochlorothiazide
‘true’ thiazide diuretics
indapamide
thiazide-like diuretic (similar mechanism of action)
What is the mechanism of thiazide diuretics?
- act on distal convuluted tubule (transporter setup is different to that of LOH)
- tf not as good as loop diuretics as DCT is less involved in NaCl reabsorption than the LOH
- inhibit Na+/Cl- cotransporter on the lumenal surface
- same result as loop diuretics –> decreased interstitial osmotic pressure leads to decreased water reabsorption
What are the pharmacokinetics of thiazide diuretics?
- orally active (tablets)
- excreted by tubular secretion
- this gets them into the lumen at the PCT
- slower absorption than loop diuretics tf max effect takes 4-6 hours
- duration ~8-12 hours
- less violent wee
What are the adverse effects of thiazide diuretics?
- loss of K+ from the collecting duct (distal to the DCT)
- tf also develop hypokalemia and req cotx with K+ supplements
- increased uric acid in plasma by inhibiting its tubular secretion
- this increases uric acid in the blood, causing gout
- these effects are lessened in thiazide-like diuretics (indapamide) due to their slightly different mechanism
What needs to be coprescribed with thiazide diuretics?
K+ supplement
What are the clinical uses of thiazide diuretics?
- hypertension
- severe resistant oedema
- in combination with loop diuretics
What are the two classes of potassium-sparing diuretics?
- epithelial sodium channel blockers
- amiloride and triamterene
- aldosterone antagonists
- spironolactone and eplerenone
Potassium-sparing diuretics are used
- in combo with K+-losing diuretics to prevent hypokalemia
- relatively limited diuretic effect
What is the general mechanism of potassium-sparing diuretics?
- acting on the distal nephron at the collecting tubule and collecting ducts
- minimal NaCl reabs occurs here tf limited diuretic effect
What is the mechanism of spironolactone?
- aldosterone antagonist
- acts on collecting tubule and collecting duct
- aldosterone normally activates Na+ channels to pump Na+ in from the lumen, and the synthesis of the Na/K exchanger on the interstitial side
- spironolactone is an analogue of aldosterone
- binds receptor and inhibits activation of Na+ channels and Na/K pump synthesis (can’t bind DNA)
- tf cannot reabsorb Na from lumen in distal nephron, and cannot pump K+ in from the interstitium, reducing K+ loss
What are the pharmacokinetics of spironolactone?
- orally active
- slow onset due to its effect on Na/K pump synthesis
- preventing aldosterone from binding its receptor and entering the nucleus as a complex to increase mRNA synthesis and tf protein production
- short half-life
- metabolised in ~10 minutes
- but metabolite half-life is 16 hours
What are the adverse effects of spironolactone?
- hyperkalaemia if used alone
- used in combo with a K+-losing diuretic
- gastrointestinal upset (local effect)
What is spironolactone always prescribed with?
a K+-losing diuretic to prevent hyperkalaemia
What are the clinical uses of spironolactone?
- K+-sparing diuretic
- tf in combo with loop or thiazide (K+-losing) diuretics to prevent hypokalaemia
- heart failure
- hyperaldosteronism
What is the mechanism of triamterene and amiloride?
- epithelial sodium channel blocker K+-sparing diuretics
- act in collecting tubules and collecting ducts (distal nephron)
- block luminal sodium channels
- inhibit Na+ reabs from the lumen
- consequentially inhibit K+ secretion from the interstitium
What are the pharmacokinetics of triamterene and amiloride?
- epithelial sodium channel blocker K+ sparing diuretics
- triamterene:
- well-absorbed
- tf onset ~2 hours, duration 12-16 hours
- well-absorbed
- amiloride:
- poorly absorbed (takes longer to achieve significant concentration in plasma and then in the kidney tubule)
- tf slow onset, duration ~24 hours
- poorly absorbed (takes longer to achieve significant concentration in plasma and then in the kidney tubule)
What are osmotic diuretics?
- do not act at receptors (parmacologically inert)
- induce osmotic effects (eg mannitol)
- main effect on water-permeable parts of nephron:
- proximal tubule
- descending LOH
- collecting tubules
- reduce passive water reabsorption
- small reduction in Na+ reabsorption
Mannitol
- osmotic diuretic
- sugar (small, polar molecule) tf filtered and not reabsorbed (doesn’t cross membranes)
- reduces passive water reabsorption at water-permeable parts of nephron
- proximal tubule, descending LOH, collecting tubules
- doesn’t act on Na+ reabsorption
What are the clinical uses of osmotic diuretics?
- raised intracranial pressure (post head injury)
- raised intraocular pressure (glaucoma)
- prevention of acute renal failure
- when GFR so low that all NaCl and water is reabsorbed from the tubule
- OD results in water retention in the tubule (mannitol bc Na+ is gone)
- not for Na+ retention
What compounds have adverse effects on the kidney?
- heavy metals
- antibiotics
- antineoplastic agents
Why is the kidney susceptible to toxicity?
- receives 25% of blood supply
- concentrates substances (eg drugs)
- carries out metabolism and tf can generate ROS
- contribution from extrarenal events (volume, BP, nervous changes, other drugs with extrarenal active sites)
What is the mechanism of kidney toxicity?
- either direct or via metabolite
- ROS –> cell damage
- interference with Ca2+ metabolism required for homeostasis
- protein/enzyme binding that can ihibit function or initiate immune responses (autoimmune disease)
How do heavy metals cause kidney toxicity?
e.g. mercury
- direct toxicity and vasoconstriction that alters renal blood supply
- binds to thiol groups in proteins inducing immune glomerulonephritis
- damage to proximal tubule:
- loss of brush border membranes
- changes in mitochondria that affect energy function
- apoptosis through an immune-mediated mechanism
How do antibiotics cause renal toxicity?
e.g. gentamicin for G- infections
- causes:
- proteinuria
- reduced GFR
- altered concentrating ability
- site of action is apical membrane of the proximal tubule
- alters Ca2+ levels, impairing mito and cellular resp
- greater toxicity in:
- pt with renal disease
- pt taking nephrotoxic drugs
- elimination is via renal excretion
- nephrotoxicity can impaire its excretion from the body
- needs to be closely monitored via blood tests
How do anti-neoplastics cause renal toxicity?
e.g. cisplatin
- cytotoxic cancer agent
- treatment of prostate tumours and testicular cancer
- causes dose-limiting nephrotoxicity (can’t give as much as you would like to) and:
- proteinuria
- increase in blood urea
- electrolyte imbalance
- forms reactive chemical species that bind nucleophilic cell components (thiol groups)
- mainly in distal tubule and collecting ducts
- causes focal tubular necrosis
- glomeruli left intact
