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Cardiovascular & Respiratory Pharmacology (Karen) > Drugs affecting kidney function > Flashcards

Drugs affecting kidney function Flashcards

1
Q

What are the roles of the kidney?

A
  • 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)
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2
Q

How does drug elimination occur?

A
  • by a combination of:
    • metabolism in the liver
    • excretion in the kidneys of drugs or their metabolites
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3
Q

Pharmacokinetics

A

what the body does to the drug

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4
Q

Pharmacodynamics

A

what the drug does to the body

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5
Q

What are the four steps of pharmacokinetics?

A
  • Administration - give the drug
  • Absorption - drug enters circulation
  • Distribution - drug spreads through body
  • Elimination - drug removed from body
  • Metabolism - chemical changes
  • Excretion - physical expulsion
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6
Q

Filtration occurs in the

A

Glomerulus

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7
Q

Tubular secretion occurs in the

A

Proximal tubule

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8
Q

Reabsorption occurs in the

A
  • LOH (significant)
  • distal tubule
  • some in collecting duct
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9
Q

What is reabsorbed in the proximal tubule?

A
  • 60-70% NaCl
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10
Q

What is secreted at the proximal tubule?

A
  • organic acids and bases (eg drugs)
  • bicarbonate
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11
Q

What is absorbed at the LOH?

A
  • 20-30% NaCl reabsorption
  • Water
  • K+
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12
Q

What is reabsorbed in the distal tubule?

A
  • 5-10% NaCl (remainder in collecting duct)
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13
Q

What is secreted at the LOH and distal tubule?

A

K+

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14
Q

What types of drugs have therapeutic actions on the kidney?

A
  • 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
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15
Q

What is the function of diuretics?

A
  • decrease Na+ and Cl- reabsorption to increase their excretion
  • osmotically following this there is secondary water excretion
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16
Q

What are the considerations with using diuretics?

A
  • local affect on the nephron
  • distal consequences ie more NaCl in the tubule distal to the LOH
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17
Q

What are the classes of diuretics?

A
  • loop diuretics
  • thiazide diuretics
  • potassium-sparing diuretics
  • osmotic diuretics
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18
Q

Loop diuretics cause

A
  • torrential wee
  • excretion of 15-20% of Na+ in filtrate (most powerful)
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19
Q

Frusemide (furozimide)

A
  • loop diuretic
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20
Q

What is the mechanism of loop diuretics?

A
  • 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)
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21
Q

What are the pharmacokinetics of loop diuretics?

A
  • 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
22
Q

What are the adverse effects of loop diuretics?

A
  • 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
23
Q

Loop diuretics are prescribed with

A

K+ supplements

(or K+-sparing diuretics)

24
Q

What are the clinical uses of loop diuretics?

A
  • 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
25
Q

Thiazide diuretics are prescribed with what other drugs?

A

ACE inhibitors (prils) and ARBs (sartans)

26
Q

bendrofluazide, hydrochlorothiazide

A

‘true’ thiazide diuretics

27
Q

indapamide

A

thiazide-like diuretic (similar mechanism of action)

28
Q

What is the mechanism of thiazide diuretics?

A
  • 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
29
Q

What are the pharmacokinetics of thiazide diuretics?

A
  • 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
30
Q

What are the adverse effects of thiazide diuretics?

A
  • 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
31
Q

What needs to be coprescribed with thiazide diuretics?

A

K+ supplement

32
Q

What are the clinical uses of thiazide diuretics?

A
  • hypertension
  • severe resistant oedema
    • in combination with loop diuretics
33
Q

What are the two classes of potassium-sparing diuretics?

A
  • epithelial sodium channel blockers
    • amiloride and triamterene
  • aldosterone antagonists
    • spironolactone and eplerenone
34
Q

Potassium-sparing diuretics are used

A
  • in combo with K+-losing diuretics to prevent hypokalemia
  • relatively limited diuretic effect
35
Q

What is the general mechanism of potassium-sparing diuretics?

A
  • acting on the distal nephron at the collecting tubule and collecting ducts
    • minimal NaCl reabs occurs here tf limited diuretic effect
36
Q

What is the mechanism of spironolactone?

A
  • 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
37
Q

What are the pharmacokinetics of spironolactone?

A
  • 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
38
Q

What are the adverse effects of spironolactone?

A
  • hyperkalaemia if used alone
    • used in combo with a K+-losing diuretic
  • gastrointestinal upset (local effect)
39
Q

What is spironolactone always prescribed with?

A

a K+-losing diuretic to prevent hyperkalaemia

40
Q

What are the clinical uses of spironolactone?

A
  • K+-sparing diuretic
    • tf in combo with loop or thiazide (K+-losing) diuretics to prevent hypokalaemia
  • heart failure
  • hyperaldosteronism
41
Q

What is the mechanism of triamterene and amiloride?

A
  • 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
42
Q

What are the pharmacokinetics of triamterene and amiloride?

A
  • 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
43
Q

What are osmotic diuretics?

A
  • 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
44
Q

Mannitol

A
  • 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
45
Q

What are the clinical uses of osmotic diuretics?

A
  • 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
46
Q

What compounds have adverse effects on the kidney?

A
  • heavy metals
  • antibiotics
  • antineoplastic agents
47
Q

Why is the kidney susceptible to toxicity?

A
  • 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)
48
Q

What is the mechanism of kidney toxicity?

A
  • 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)
49
Q

How do heavy metals cause kidney toxicity?

A

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
50
Q

How do antibiotics cause renal toxicity?

A

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
51
Q

How do anti-neoplastics cause renal toxicity?

A

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

Cardiovascular & Respiratory Pharmacology (Karen) (15 decks)

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