6. Drugs and the Kidney Flashcards
How are drugs excreted from the body?
More phase 1 or 2 excretion?
Examples of drugs exclusively excreted by kidney
> 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, whereas their more watersoluble phase II conjugates are only minimally reabsorbed and readily excreted.
> Some parent drugs are almost exclusively excreted by the kidneys without prior detoxification, such that any alteration in kidney function can
result in toxicity.
Examples include: • Oxybarbiturates • Gentamicin • Furosemide • Ampicillin • Sotalol • Methotrexate
Describe how drugs are handled as they pass through the kidney, illustrating your answer with examples.
The kidney affects drug elimination at three main stages:
> Glomerular filtration
> Active proximal tubular secretion
> Passive distal tubular reabsorption
- Glomerular filtration
Rate filtration goverend by what
what are freely filtered
what about anaesthic agents
> The rate of filtration is governed by the glomerular filtration rate.
> Drugs that are of low molecular weight (<60000 Daltons) and that are not plasma protein bound (PPB) are readily filtered,
e.g. fluconazole and
ofloxacin.
> Most intravenous anaesthetic agents are of low molecular weight
but are highly protein bound, e.g. Propofol (98% PPB).
> Heparin is a large molecule that cannot be filtered.
Active proximal tubular secretion
> The rate of tubular secretion is governed by renal blood flow.
> It is an energy-dependent process and is carrier mediated.
> Two types of carrier exist:
- Those for acidic drugs, e.g. furosemide, penicillin, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucuronide and sulphate conjugates
- Those for basic drugs, e.g. histamine and dopamine
> Tubular secretion is more important for acidic rather than basic drugs.
> Many drugs are actively secreted from the renal blood vessels into the proximal tubules because most of the renal blood flow (80%) escapes filtration by the glomeruli, e.g. angiotensin-converting enzyme (ACE)
inhibitors and penicillin.
> Some drugs compete for the same carriers and limit the other’s secretion, e.g. probenecid administered with penicillin and sulphonamides administered with indomethacin.
Tubular secretion can secrete drugs against their concentration gradients.
It is an efficient system even for highly protein-bound drugs.
Passive distal tubular reabsorption
how
urine pH
> 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, aminoglycoside antibiotics, 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 to alkalinise the urine in overdoses of aspirin and phenobarbital
What are the effects of age on renal drug metabolism?
Renal function, notably GFR decreases with age.
> Increasing age is associated with progressive loss of kidney structure and function with decreases in glomerular filtration rate (GFR) and renal blood
flow (RBF).
> Consequently, drug elimination is reduced, and the elderly are at increased risk of acute renal failure in the post-operative period.
> GFR (140 ml/min/1.73 m2 in adulthood) and thus creatinine clearance declines by about 8 ml/min/1.73 m2 per decade after the age of 40.
> Serum creatinine remains within the normal range because although less is excreted, less creatinine is also produced
(less muscle mass and less physical activity).
> RBF is well maintained at 500–600 ml/min until the fourth decade, and then declines by about 10% per decade.
Both structural and haemodynamic changes are responsible for reduced kidney fxn with age
> Haemodynamic changes:
- Reduced glomerular capillary plasma flow rate
- Reduced glomerular capillary ultrafiltration coefficient (due to reductions in both the glomerular capillary permeability and the surface area available for filtration)
- Reduction in afferent arteriolar resistance, with an increase in glomerular capillary hydraulic pressure, and accompanying proteinuria and progressive glomerular sclerosis.
> Structural changes:
• Reduced renal mass, in particular the cortex (adult kidney 400 g, declines by eighth decade to 300 g)
- Reduced number of glomeruli (absolute and functional)
- Hyalinisation of afferent arterioles
- Development of aglomerular arterioles (direct channels between the afferent and efferent arterioles)
- Increased percentage of sclerotic glomeruli (5% by 30 years; 30% by 80 years)
• Tubulointerstitial fibrosis.
In addition, ageing is associated with other systemic changes that contribute to reductions in RBF and GFR:
> Altered cardiovascular haemodynamics (reduced cardiac output and
increased systemic blood pressure)
Altered responsiveness to vasoactive stimuli (vasoconstrictor responses
are enhanced, while vasodilatory responses are impaired).
Examples of drugs where elimination may be significantly affected in aging
The above changes decrease renal elimination of many drugs and doses or their frequency needs adjusting:
> 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.
Most other anaesthetic agents and adjuvant drugs require dose adjustments in the elderly for reasons other than reduced renal elimination.
