Drugs affecting kidney function

Question 1

What are the roles of the kidney?

Answer 1

• 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)

Question 2

How does drug elimination occur?

Answer 2

• by a combination of:
  
  • metabolism in the liver
  • excretion in the kidneys of drugs or their metabolites

Question 3

Pharmacokinetics

Answer 3

what the body does to the drug

Question 4

Pharmacodynamics

Answer 4

what the drug does to the body

Question 5

What are the four steps of pharmacokinetics?

Answer 5

• Administration - give the drug
• Absorption - drug enters circulation
• Distribution - drug spreads through body
• Elimination - drug removed from body
• Metabolism - chemical changes
• Excretion - physical expulsion

Question 6

Filtration occurs in the

Answer 6

Glomerulus

Question 7

Tubular secretion occurs in the

Answer 7

Proximal tubule

Question 8

Reabsorption occurs in the

Answer 8

• LOH (significant)
• distal tubule
• some in collecting duct

Question 9

What is reabsorbed in the proximal tubule?

Answer 9

• 60-70% NaCl

Question 10

What is secreted at the proximal tubule?

Answer 10

• organic acids and bases (eg drugs)
• bicarbonate

Question 11

What is absorbed at the LOH?

Answer 11

• 20-30% NaCl reabsorption
• Water
• K+

Question 12

What is reabsorbed in the distal tubule?

Answer 12

• 5-10% NaCl (remainder in collecting duct)

Question 13

What is secreted at the LOH and distal tubule?

Answer 13

K+

Question 14

What types of drugs have therapeutic actions on the kidney?

Answer 14

• 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

Question 15

What is the function of diuretics?

Answer 15

• decrease Na+ and Cl- reabsorption to increase their excretion
• osmotically following this there is secondary water excretion

Question 16

What are the considerations with using diuretics?

Answer 16

• local affect on the nephron
• distal consequences ie more NaCl in the tubule distal to the LOH

Question 17

What are the classes of diuretics?

Answer 17

• loop diuretics
• thiazide diuretics
• potassium-sparing diuretics
• osmotic diuretics

Question 18

Loop diuretics cause

Answer 18

• torrential wee
• excretion of 15-20% of Na+ in filtrate (most powerful)

Question 19

Frusemide (furozimide)

Answer 19

• loop diuretic

Question 20

What is the mechanism of loop diuretics?

Answer 20

• 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)

Question 21

What are the pharmacokinetics of loop diuretics?

Answer 21

• 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
• duration of action is 3-6 hours

Question 22

What are the adverse effects of loop diuretics?

Answer 22

• 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

Question 23

Loop diuretics are prescribed with

Answer 23

K+ supplements

(or K+-sparing diuretics)

Question 24

What are the clinical uses of loop diuretics?

Answer 24

• 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

Question 25

Thiazide diuretics are prescribed with what other drugs?

Answer 25

ACE inhibitors (prils) and ARBs (sartans)

Question 26

bendrofluazide, hydrochlorothiazide

Answer 26

'true' thiazide diuretics

Question 27

indapamide

Answer 27

thiazide-like diuretic (similar mechanism of action)

Question 28

What is the mechanism of thiazide diuretics?

Answer 28

* 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

Question 29

What are the pharmacokinetics of thiazide diuretics?

Answer 29

* 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

Question 30

What are the adverse effects of thiazide diuretics?

Answer 30

* 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

Question 31

What needs to be coprescribed with thiazide diuretics?

Answer 31

K+ supplement

Question 32

What are the clinical uses of thiazide diuretics?

Answer 32

* hypertension * severe resistant oedema * in combination with loop diuretics

Question 33

What are the two classes of potassium-sparing diuretics?

Answer 33

* epithelial sodium channel blockers * amiloride and triamterene * aldosterone antagonists * spironolactone and eplerenone

Question 34

Potassium-sparing diuretics are used

Answer 34

* in combo with K+-losing diuretics to prevent hypokalemia * relatively limited diuretic effect

Question 35

What is the general mechanism of potassium-sparing diuretics?

Answer 35

* acting on the distal nephron at the collecting tubule and collecting ducts * minimal NaCl reabs occurs here tf limited diuretic effect

Question 36

What is the mechanism of spironolactone?

Answer 36

* 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

Question 37

What are the pharmacokinetics of spironolactone?

Answer 37

* 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

Question 38

What are the adverse effects of spironolactone?

Answer 38

* hyperkalaemia if used alone * used in combo with a K+-losing diuretic * gastrointestinal upset (local effect)

Question 39

What is spironolactone always prescribed with?

Answer 39

a K+-losing diuretic to prevent hyperkalaemia

Question 40

What are the clinical uses of spironolactone?

Answer 40

* K+-sparing diuretic * tf in combo with loop or thiazide (K+-losing) diuretics to **prevent hypokalaemia** * heart failure * hyperaldosteronism

Question 41

What is the mechanism of triamterene and amiloride?

Answer 41

* 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

Question 42

What are the pharmacokinetics of triamterene and amiloride?

Answer 42

* epithelial sodium channel blocker K+ sparing diuretics * triamterene: * well-absorbed * tf onset ~2 hours, duration 12-16 hours * amiloride: * poorly absorbed (takes longer to achieve significant concentration in plasma and then in the kidney tubule) * tf slow onset, duration ~24 hours

Question 43

What are osmotic diuretics?

Answer 43

* 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

Question 44

Mannitol

Answer 44

* 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

Question 45

What are the clinical uses of osmotic diuretics?

Answer 45

* 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

Question 46

What compounds have adverse effects on the kidney?

Answer 46

* heavy metals * antibiotics * antineoplastic agents

Question 47

Why is the kidney susceptible to toxicity?

Answer 47

* 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)

Question 48

What is the mechanism of kidney toxicity?

Answer 48

* 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)

Question 49

How do heavy metals cause kidney toxicity?

Answer 49

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

Question 50

How do antibiotics cause renal toxicity?

Answer 50

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

Question 51

How do anti-neoplastics cause renal toxicity?

Answer 51

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