Pharm - Drugs and the Kidney

Question 1

How are drugs excreted from the body?

Answer 1

Most drugs are excreted from the body by a combination of metabolism
by the liver and excretion via the kidneys.

• Most parent drug molecules and their phase I metabolites are extensively
  reabsorbed at the level of the kidney tubules
• The more water soluble
  phase II conjugates are only minimally reabsorbed and readily
  excreted
• Some parent drugs are almost exclusively excreted by the kidneys
  without prior detoxification. This means that changes to kidney function directly influence toxicity:
• Oxybarbiturates
• Gentamicin
• Furosemide
• Ampicillin
• Sotalol
• Methotrexate

Question 2

Describe how drugs are handled as they pass through the kidney

Answer 2

1. Glomerular filtration
   - Rate is governed by GFR
   - Drugs are readily filtered if they have low molecular weight (<60 000 Daltons) and aren’t protein bound e.g. fluconazole, ofloxacin
   - Most IV anaesthetic agents have low molecular weight but are highly protein bound e.g. propofol
   - Heparin is too large to be filtered
2. Active secretion at the proximal tubules
   - Rate is governed by renal blood flow
   - Energy dependent, carrier mediated process that can secrete drugs against their concentration gradients
   - 80% of renal blood flow escapes glomerular filtration and from this, drugs are actively secreted into the proximal tubules
   - This mechanism is more important for acidic than basic drugs (due to different carrier systems used)
   - Efficient system even for protein bound drugs
   - Some drugs compete for the same carriers and limit the other’s secretion,
   e.g. probenecid administered with penicillin
3. Passive reabsorption at the distal tubules
   - As water is reabsorbed along the tubule, the drug’s increasing
   concentration gradient drives the process of passive reabsorption.
   - Highly lipid-soluble drugs, e.g. fentanyl, are reabsorbed into the
   circulation as they pass down the distal convoluted tubule.
   - Some drugs are too lipid insoluble to undergo reabsorption, e.g. digoxin,
   aminoglycosides and glucuronide and sulphate conjugates
   from phase II metabolism.
   > Changes in urine pH can alter the tubular reabsorption of weakly acidic or
   basic drugs by altering their degree of ionisation and consequently their
   lipid solubility. This, in turn, affects their speed of elimination.
   > Weak bases become more ionised (lipid insoluble) in acidic urine and
   therefore less well reabsorbed.
   > Weak acids become more ionised in alkaline urine. This is applied
   clinically in the administration of sodium bicarbonate for aspirin OD

Question 3

What are the effects of age on renal drug metabolism

Answer 3

1. Increasing age is associated with progressive loss of kidney structure and
   function
2. Both GFR and renal blood flow decrease (after 40, GFR decreases by 8 per decade from approx 140 and RBF decreases by 10% per decade)
3. Consequently, drug elimination is reduced
4. The elderly are at
   increased risk of acute renal failure in the post-operative period.

Decline in renal function is due to structural, haemodynamic and systemic changes:

Structural changes:

• Reduced renal mass, in particular the cortex
• Reduced number of glomeruli, more sclerotic glomeruli
• Hyalinisation of afferent arterioles, development of aglomerular arterioles (direct channels between the
  afferent and efferent arterioles)
• Tubulointerstitial fibrosis

Haemodynamic changes:
* Glomerular capillary flow rate decreases
* Reductions in glomerular capillary permeability and surface area for filtration leads to reduced ultrafiltration coefficient
* Reduction in afferent arteriolar resistance and increase in
glomerular capillary hydraulic pressure causes proteinuria
and progressive glomerular sclerosis.

Systemic changes
* Altered cardiovascular haemodynamics (reduced cardiac output and
increased systemic blood pressure)
* Altered responsiveness to vasoactive stimuli (vasoconstrictor responses enhanced, vasodilatory responses impaired).

Examples of drugs where elimination may be significantly affected:
> Analgesics: morphine, remifentanil, oxycodone, gabapentin
> Neuromuscular blocking agents: aminosteroid group (vecuronium >
rocuronium > pancuronium)
> Neuromuscular blocking agent antagonists: neostigmine and
sugammadex
> Cardiovascular drugs: ACE inhibitors, digoxin
> Diuretics: furosemide, thiazides, amiloride
> Antibiotics: amikacin, gentamicin, ciprofloxacin, levofloxacin,
streptomycin.