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kyleannkelsey
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In a patient with cirrhosis, what relative level of function would you expect for CYP2D6?
Somewhat altered
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In a patient with cirrhosis, what relative level of function would you expect for CYP2C19?
High sensitivity, large change
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Drugs using metabolic pathways effected by liver dysfunction will have higher or lower concentrations, why?
Higher, less active metabolism leading to excretion
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In general liver disease increases or decreases serum drug concentration?
Increases
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Does protein binding change with liver disease?
Yes
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Why does protein binding change with liver disease?
Many drug binding proteins are made by the liver, cirrhosis decreases production of these proteins
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What transporting/drug binding proteins are often of concern with liver disease?
Albumin and Alpha-1-acid glycoprotein
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Is there a clear way to quantify the effect of decreased proteins on drug pharmacokinetics?
No, no method
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Will you have more or less free drug with liver disease due to changes in protein carriers?
More
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With lower amounts of protein binding, will you have more or less free drug entering the hepatocytes?
More
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(True/False) Bound or unbound drug can enter the hepatocyte. False, only unbound can enter the hepatocyte
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When considering a dose for a patient with liver dysfunction what parameter would likely be most useful to measure?
Fu (free drug fraction)
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Pharmacokinetic changes in drug concentration may not be reflected in ___________ drug concentration, but instead only reflected in the ___________ fraction.
Total, Free
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What drugs were given as examples of highly protein bound?
Warfarin, Propranolol, imipramine, Amitriptyline, Diazepam, Chlorpromazine
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What type of drugs are most effected by first pass metabolism?
High ER drugs
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In severe cirrhosis, what level of first pass metabolism exists?
Basically no longer exists
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In high ER drugs how important is protein binding, why?
Not very because only a small protion is available for binding
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If a patient has decreased clearance and increased t1/2, what would you expect the AUC to be?
Larger
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What is acute liver disease caused by?
Drug overdose, etc.
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What are the main issues that need to be addressed with Acute liver disease?
Hepatocellular function = possible reduced availability or capacity of metabolizing enzymes
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What are the main issues that need to be addressed with Chronic liver disease?
Alterations in hepatic blood flow, altered protein binding and possible increased Vd if ascites is present
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Why can Vd increase in hepatic failure patients?
Ascites
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What is the “3rd” spacing?
Ascites fluid space
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What effect can ascites have on drug kinetics?
Create “3rd Spacing”, increase total body weight effecting dosing, increase Vd of aquaphilic drugs (aminoglycosides, Vanco)
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Hepatic encephalopathy (HE) can cause what changes in drug parameters?
Pharmacodynamics of the drug and Additive cognitive effects of some CNS drugs
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What is Hepatic encephalopathy (HE)?
Liver disease patient has a buildup of drugs/toxins in the brain
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Patients with liver disease have a lower or higher sensitivity to many drugs?
Higher
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The greater effect of some drugs on patients with liver disease is especially noticeable with what drug class?
Those acting on the CNS (especially benzodiazepine)
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Why is there a greater effect of some drugs on patients with liver disease?
Increased BBB penetration
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Why is it hard to differentiate the symptoms of hepatic encephalopathy?
Similar symptoms to the enhanced CNS effects of some drugs in patients with liver disease
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What drugs were given as an example for greater penetration in to the CNS in patients with liver disease?
Cimetidine, Ranitidene, Quinolones, Benzodiazapine
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What are the major drug classes that are effected by liver disease?
Benzodiazapine, Estradiol and some Beta blockers, ACEIs, ARBs, CCBs, Antiarrhythmatics, SSRIs
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What Benzodiazapines are not associated with pharmacokinetic changes and are safe to use in liver disease?
Larazepam, Oxazepam, Temazepam
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Why are some Benzodiazapines unsafe for use in liver disease?
Increased CNS effect
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Why is Estradiol not safe in patients with liver disease?
Requires liver transformation become active, highly protein bound and has high first pass metabolism
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What beta blockers are not a good choice in liver disease?
Nebivolol, Carvedilol
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Why are ACEIs not a good choice for liver disease patients?
Need to be activated by the liver
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What ACEI does not need liver activation and so can be used in liver disease patients?
Lisinopril
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What ARBs are not a good choice for patients with liver disease and why?
Losartan and Valsartan, because they have increased AUC
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What ARB is not affected by liver disease?
Irbesartan
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Why are most CCBs not a good choice for patients with liver disease?
Increased AUC
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What antiarrhythmatics are not a good choice for liver disease patients?
Flecainide, Mexiletine, profenone
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Why are the antiarrhythmatics: Flecainide, Mexiletine, profenone not a good choice for patients with liver disease?
Decrease Clearance and increase AUC
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What SSRIs have been shown to increased AUC in patients with liver disease?
Fluvoxamine, Fluoxetine and paroxetine
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Can you usually look up dose changes necessary for liver disease patient in the package insert?
No, not usually there
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Drugs with what characteristics are worrisome for patients with liver disease?
High ER, High Protein binding and Highly aquaphilic drugs
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When are highly aquaphilic drugs a concern for use in liver disease patients?
When ascites is present
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