How can liver disease alter the response to drugs?
Impaired drug metabolism = accumulation, reduced first pass metabolism, failure to form active or inactive substance. More free drug due to hypoalbuminuria. Worse effects of hepatotoxic drugs.
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What is first pass metabolism and which drugs undergo substantial first pass metabolism?
Drug is metabolised by the liver, and the drug concentration is greatly reduced before it reaches the systemic circulation (reduced bioavaliability). Examples include: aspirin, morphine, levodopa, salbutamol and propranolol
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Name some hepatotoxic drugs
Paracetamol, statins, methotrexate, isoniazid, phenytoin, aspirin, alcohol and oral contraceptives
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Hepatic drug clearance - definition and effects of liver disease
The volume of blood that is perfusing the liver that is cleared of drug per unit time. Reduced in liver disease
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Definition of extraction ratio
The fraction of drug removed from the perfusing blood during its passage through the organ. Ratio of hepatic drug clearance to hepatic blood flow. High = >0.7 Intermediate = 0.3-0.7 Low =
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Relevance of extraction ratio to liver disease
High extraction ratio (>0.7) means that the drug normally undergoes a high level of first pass metabolism by the liver. Doses must be reduced, esp in high extraction ratio drugs, in liver disease (reduced metabolism and increased drug accumulation)
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How do you work out the new dose of drug in liver disease, for drugs with a high extraction ratio?
Reduced dose = normal dose x % bioavailability (1 - extraction ratio) / 100
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Why should you avoid aspirin, warfarin and heparin in liver impairment?
Liver damage = pro-bleeding state (reduced clotting factors) = worsened by these drugs so significant risk of bleeding
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Why should you avoid sedatives, duiretics and drugs which cause constipation in liver impairment?
Why should you avoid NSAIDs, steroids and other sodium-containing drugs (e.g. antacids) in liver impairment?
Cause Na+ retention = exacerbate fluid overload and ascites (already present with liver disease)
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Impact of renal disease on drug metabolism
Depends on metabolic pathway of drug. The kidneys biotransform drugs to metabolites which are then excreted - renal disease prevents this
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Impact of renal disease on drug excretion
Excretion decreases in line with GFR (for renally excreted drugs) = half-life increases and plasma drug concentration increases
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Renal clearance calculation
CLr = rate of urinary excretion (rate of filtration + rate of secretion - rate of reabsorption) / plasma drug concentration
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If a rugby player and his grandmother had the same serum [creatinine], who would have the highest GFR and why?
Rugby player would have the highest GFR. Would expect lower [creatinine] in grandmother as she is smaller and older with less muscle mass. However, if her creatinine is high, this indicates low GFR and poor renal function.
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Creatinine clearance calculation
CLr = rate of urinary excretion of creatinine / average serum creatinine concentration. Estimated by Cockcroft and Gault equation (takes into account sex, age and weight)
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Effects of kidney disease on pharmacokinetics
Increased risk of toxicity (reduced excretion), sensitivity, side effects and ineffectiveness of the drug
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Why should opioids be used carefully in renal disease?
Patients with renal disease are more sensitive to the effects of opioids, are more likely to accumulate opioids (risk of toxicity) and are more sensitive to toxic effects e.g. pruritus
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Drugs causing pre-renal damage
ACEi = hypotension (dilatation of efferent arterioles) and small risk of renal artery stenosis = reduced perfusion to kidney
Aminoglycosides (genatamicin and vancomycin), NSAIDs, penicillins, phenytoin, rifampicin, thaizide duiretics and sulphonamides
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Drugs causing post-renal damage
Block the passage of urine causing renal damage = anticholinergics and methotrexate
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Principals of dose adjustment in renal impairment
Reduce the dose depending on renal function (eGFR or CLr), avoid drugs with narrow therapeutic index, avoid nephrotoxic drugs. Reduce individual doses or increase dosing interval
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Dose adjustments based on creatinine clearance
30-60ml/min needs a modest decrease in dose, 15-30ml/min needs a moderate decrease in dose and
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Corrected dose in renal impairment
Normal dose x (patient's creatinine clearance / normal creatinine clearance)
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Other cards in this set
Card 2
Front
What is first pass metabolism and which drugs undergo substantial first pass metabolism?
Back
Drug is metabolised by the liver, and the drug concentration is greatly reduced before it reaches the systemic circulation (reduced bioavaliability). Examples include: aspirin, morphine, levodopa, salbutamol and propranolol
Card 3
Front
Name some hepatotoxic drugs
Back
Card 4
Front
Hepatic drug clearance - definition and effects of liver disease
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