55 - Drugs and Kidney Function Flashcards
Four roles of the kidneys
- regulation of water and electrolyte balance
• endocrine functions
• excretion of endogenous waste
• excretion of exogenous compounds
*Schematic view of the nephron
EPHRON
What happens in the proximal tubule regarding NaCl?
60-70% of water and NaCl reabsorbed.
Organic acids and bases, bicarbonate secreted into lumen.
What happens in loop of Henle regarding NaCl?
20-30% of NaCl reabsorbed
What happens in distal tubule regarding NaCl?
5-10% of NaCl reabsorbed
Where in the nephron does secretion take place?
Proximal tubule
Where in the nephron is K+ reabsorbed?
Proximal tubule
Where in the nephron is K+ secreted?
Distal tubule, collecting ducts
Types of drugs with effects on the kidneys
1)
2)
3)
1) Diuretics
2) Drugs that affect urine pH (EG: sodium bicarbonate to treat aspiring poisoning)
3) Drugs that alter secretion of organic molecules (EG: probenecid inhibits secretion of banned drugs for sport urine tests)
Common effect of altering NaCl reabsorption in proximal tubule.
Distal tubule changes NaCl reabsorption to balance out change in proximal tubule.
Diuretics
Drugs that increase Na+ and water excretion by decreasing NaCl reabsorption
Four classes of diuretics
1) Loop diuretics
2) Thiazide diuretics
3) Potassium-sparing diuretics
4) Osmotic diuretics
Most powerful class of diuretics
Loop diuretics
Mechanism of loop diuretic action
Act on thick ascending limb in loop of Henle.
Inhibit Na+/K+/2Cl- carrier (transports from lumen into cells).
*Normal mechanism of reabsorption in kidneys
NORMAL REABSORPTION
Effect of normal Na+/K+/2Cl- cotransporter function
Interstitium becomes hypertonic, so water leaves nehphron to tissues.
Reduces Na+ in distal tubule, which reduces water reabsorption
Effect of inhibiting Na+/K+/2Cl- cotransporter
Reduction in hypertonicity of interstitium (reduced water reabsorption)
Increased Na+ in distal tubule (increases osmotic pressure in tubule, reduces water reabsorption)
Pharmacokinetics of loop diuretics
Well-absorbed from gut (onset in less than an hour)
Plasma protein-bound. Reaches site of action via secretion
3-6 hour duration
Adverse effects of loop diuretics
1)
2)
3)
1) K+ loss from distal tubule
2) H+ excretion (can lead to metabolic alkalosis)
3) Reduced extracellular fluid (in elderly)
How do loop diuretics result in hypokalaemia?
1)
2)
1) Increased [Na+] in distal tubule
2) As K+ is cotransported from the lumen with Na+, this increases amount of K+ secreted.
Clinical uses of loop diuretics
1) a, b, c, d,
2)
1) salt and water overload in
a) acute pulmonary oedema
b) chronic heart failure
c) ascites (liver cirrhosis)
d) renal failure
2) hypertension (renal impairment)
Power of thiazide diuretics
Moderate. Not as powerful as loop diuretics.
Mechanism of thiazide diuretic action
Act on the distal convoluted tubule.
Inhibit Na+/Cl- cotransporter.
Pharmacokinetics of thiazide diuretics 1) 2) 3) 4)
1) Orally-active
2) Excreted in urine (tubular secretion)
3) Maximum effect is 4-6 hours
4) Duration is 8-12 hours
Adverse effects of thiazide diuretics
1)
2)
1) K+ loss from collecting ducts
2) Increase in plasma uric acid (inhibits tubular secretion of uric acid)
Clinical uses of thiazide diuretics
1)
2)
1) Hypertension
2) Severe resistant oedema (often in combination with loop diuretics)
Potassium-sparing diuretics power
Limited diuretic activity
Use of potassium-sparing diuretics
Used in combination with K+-losing diuretics to prevent K+ loss
Two broad groups of potassium-sparing diuretics
1) Spirolactone - Aldosterone receptor antagonist (prevents aldosterone binding to aldosterone receptor, which binds to DNA). Reduces activation of Na+ channels and stimulates Na+ pump synthesis.
2) Triamterene and amiloride block Na+ channels in collecting tubules and ducts. Inhibits Na+ reabsorption and K+ secretion.
Spirolactone pharmacokinetics
1)
2)
3
1) Orally-active
2) Slow onset
3) Short half-life (ten minutes), but metabolite has a long half-life (16 hours). So effect has a long duration.
Adverse events of spirolactone
1) Hyperkalaemia (if used alone)
2) GIT upset
Clinical uses of spirolactone
1)
2)
3)
1) Combine with loop or thiazide diuretics
2) Heart failure
3) Hyperaldosteronism
Osmotic diuretics mechanism 1) 2) 3) 4)
1) Pharmacologically-inert (don’t interact with receptor)
2) Filtered, not reabsorbed.
3) Reduce passive water reabsorption.
4) Have main effect on water-permeable parts of nephron (proximal tubule, descending limb of loop of Henle, collecting tubules)
Clinical uses of osmotic diuretics
1)
2)
3)
1) Elevated intracranial pressure
2) Raised intraocular pressure
3) Prevention of acute renal failure (when GFR is so low that all NaCl and water is reabsorbed)
Why are the kidneys so susceptible to toxicity? 1) 2) 3) 4)
1) Receives 20% of blood supply
2) Substances can be concentrated
3) Kidneys can carry out metabolism
4) Kidneys affected by extrarenal events (EG: increased bp)
Hg kidney toxicity
1)
2)
3)
1) Direct toxicity and vasoconstriction
2) Binds to thiol groups in proteins, leading to immune glomerulonephritis (type III hypersensitivity)
3) Damage primarily in proximal tubule (loss of brush-border membranes, mitochondrial changes, apoptosis)
Side effects of gentamycin
1)
2)
3)
1) Proteinuria
2) Reduced GFR
3) Altered concentrating ability
Which part of the kidney does gentamycin affect?
Apical membrane of proximal tubule
Mechanism of gentamycin toxicity 1) 2) 3) 4) 5)
1) Cationic drug binds anionic phospholipids
2) Altered PIP2 generation
3) This alters intracellular Ca2+ levels
4) Impaired mitochondrial respiration
5) Apoptosis
‘Vicious cycle’ of gentamycin nephrotoxicity
Gentamycin is renally eliminated.
Nephron damage from gentamycin reduces ability to excrete drug.
Example of an antineoplastic agent that damages kidneys
Cisplatin
Cisplatin
1)
2)
1) Cytotoxic anticancer agent, used for treating prostate tumours
2) Causes dose-limiting nephrotoxicity (proteinuria, increase in blood urea, electrolyte imbalance)
Cisplatin mechanism of nephrotoxicity
1)
2)
3)
1) Activated inside cells.
2) Active form forms highly-reactive species, which bind nucleophilic cellular components (EG: thiols in proteins)
3) This occurs in distal tubule and collecting ducts (causes focal tubular necrosis, with glomeruli intact)
