Term
Liver removal of drugs/xenobiotics from blood is termed hepatic clearance (ClH)
Hepatic clearance is actually a very complex process due to many steps
Can be simplified to three factors: |
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Definition
Liver blood flow
Liver intrinsic clearance
Fraction of drug not bound to albumin |
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Term
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Definition
Q*(fraction of unbnd drug)X(Cl INT)/
(Q + fxunbd*ClINT) |
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Term
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Definition
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Term
| High Extraction Drugs/ Xenobiotics/ Endogenous Compounds: What makes them different? |
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Definition
Nitroglycerine (mouth)
Lidocaine (IV)
Propranolol (IV = 10% of oral)
Bile Acids |
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Term
| xenobiotics have a high or low 1st pass clearance? |
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Definition
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Term
| What's ClH for low extraction drugs? |
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Definition
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Term
Low Extraction Drugs/ Endogenous Compounds
1. These drugs are efficiently absorbed when given orally.
2. Thus bioavailability of orally administered drugs is high.
3. Drug companies look for these types of products as pills
are easy to take. |
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Definition
Diazepam
Phenytoin
Theophylline
Bilirubin |
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Term
| Biotransformation in the liver |
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Definition
Phase I (cytochromes P450)
Phase II (conjugation) |
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Term
| phase 1 vs phase 2 Biotransformation in Liver |
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Definition
Phase 1: oxidative rxn, CYP-mediated
Phase 2: conj to polar ligand, glucuronyl transferases, sulfotransferases, glutathione-S-transferases |
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Term
| Phase 1: Biotransformation (which enzyme, where?, purpose, AE, consistent or variable?) |
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Definition
Direct modification of primary structure
Cytochromes P450
Oxidative reactions
Add reactive/hydrophilic groups (-OH)
Often rate-limiting, located in ER
May eliminate or generate toxic molecules
Account for many drug-drug interactions
HIGHLY VARIABLE (genetic polymorphisms, inhibitable, inducible) |
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Term
| Polymorphisms affecting CYP 2D6 cause variations in metab of which 2 drugs? |
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Definition
: Desipramine
Codeine=> overactive 2D6 => toxic levels of morphine! |
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Term
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Definition
Catalyze covalent binding of drugs to polar ligands (“transferases”)
glucuronic acid, sulfate, glutathione, amino acids
Increase water solubility
Enzymes generally in ER, some cytosolic
Often follow Phase I biotransformation reactions
frequently use -OH or other group added by CYPs |
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Term
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Definition
Endogenous examples:
Conjugation of bilirubin to glucuronide
Conjugation of bile acids to glycine/taurine
Conj of acetaminophen to glucuronic acid
Genetic polymorphisms of conjugating enzymes poorly understood.
Inducibility of conjugating enzymes poorly understood. |
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Term
Some drugs/xenobiotics
are transported without
any biotransformation
step.
Organic molecules
(especially once made
more hydrophilic by
Phase I and Phase II
reactions) are often
rapidly excreted in bile.
Which transporters do these? |
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Definition
P-glycoprotein MDR - for no biotransformation step
Bile acid transporter: ATP
MRP-2: for modified molecules
ALL ATP-dependent |
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Term
| T/F: Both liver and gut can eliminate drugs by metabolism and/or apical excretion. |
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Definition
| T: Reduce any or all and blood concentration will rise. |
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Term
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Definition
Competitive inhibition of CYP
drug A increases toxicity of drug B
Induction of CYP
increased elimination of drug
increased production of toxic metabolites
Applicable to environmental and “natural” products as well as drugs |
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Term
| Cyclosporin A can => AEs? due to concurrent administration of _____? |
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Definition
renal failure and seizures consistent with acute cyclosporin A toxicity
ketoconazole
due to competition of 3A4 |
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Term
1. Coumadin and _______ =>
2. Rifampin => ? |
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Definition
1. St. John's Wort
2. CYP3A4 Induction occurs through broad-specificity orphan nuclear receptors, increasing liver capacity for drug metabolism, usually specific for one or only a few CYPs. |
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Term
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Definition
Antiseizure drugs (Phenobarbital, Dilantin)
Rifampin
St. John’s Wort |
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Term
Drug induced liver disease mechanisms/prototypes:
Hepatocellular injury
Autoimmune hepatocellular injury
Cholestatic liver injury |
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Definition
Hepatocellular injury
toxic metabolite: isoniazid, acetaminophen
Autoimmune hepatocellular injury
halothane hepatitis
Cholestatic liver injury
estrogen |
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Term
| How does acetaminophen toxicity occur? |
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Definition
normally it undergoes glucuronidation sulfation to produce stable metabolites.
some of it undergoes CYP2E1 (3A4/1A2) => Toxic metabolites (NAPQI) => which can undergo 1) covalent binding/oxid stress => hepatocyte. and 2) glutathion conjugation to => stable metabolites => excretion |
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Term
Isoniazid (INH)
Phenobarbital
Ethanol !!!
are bad combos w/ acetaminophen why? |
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Definition
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Term
| Liver Damage Due to Toxic Doses of Acetaminophen...What part of the liver will be affected? |
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Definition
| PERICENTRAL hepatocyte necrosis! |
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Term
| How does autoimmunity develop against a particular drug? (name the prototype) |
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Definition
halothane hepatitis:
the drug is mistranslocated ONTO the CYP2E1 at the site of the ER and the 2E1 is transferred out of the cell before being cleaved of the hapten. |
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Term
| Drug-induced cholestatic liver disease: prototype? |
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Definition
Estrogen
specific effect on bilirubin and bile acid transport |
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Term
| what can result form d-induced liver injury? |
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Definition
Bile duct injury
Steatosis and steatohepatitis
Vascular injury/veno-occlusive disease
Neoplasms
Other rare types of liver disease |
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Term
| What exactly does having acetaminophen with EtOH and fasting do? |
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Definition
EtOH => induces 2E1, dec glutathione conjugation
Fasting => dec glucuronidation and dec glutathione conj |
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Term
| T/F: Always consider drugs/herbs/toxins in the differential diagnosis of ALL liver diseases |
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Definition
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Term
| acetaminophen + alc toxicity leads to what labs? |
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Definition
Labs: Bilirubin 5.7 mg/dl
Alk Phos 210 IU/l
AST 10,310 IU/l
ALT 12,308 IU/l
PT 41 seconds |
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Term
| Effect of Liver Failure or Cirrhosis on Drug Disposition with high clearance vs. low clearance. |
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Definition
Low clearance drugs
often relatively little effect until end stage liver failure/cirrhosis as drug metabolism is relatively well preserved
Don’t really have to change drug dosese too much until end of liver failure! b/c keep on making CYPs…
Specifically: High clearance drugs
affected by portosystemic shunts - markedly increased systemic bioavailability of oral drugs
drug levels in blood may get very high
Drug biotransformation and elimination is a liver function
Drug elimination may be reduced in patients with significant liver dysfunction - thus blood levels may be higher for longer (toxicity vs effectiveness?) |
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Term
| The development of what in cirrhotic patients => high levels of orally administered but high clearance drugs? |
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Definition
Cirrhotic patients with
portosystemic shunts:
Blood from intestines
bypasses the liver,
delivering much more
of orally administered
drugs to the systemic
circulation.
Thus, systemic bioavailability
of orally administered high
clearance drugs is much
greater. |
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Term
| Cirrhosis increases susceptibility to idiosyncratic drug reactions and increases the likelihood of autoimmune-mediated drug reactions |
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Definition
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Term
| Drug Use in Patients with Significant Liver Dysfunction |
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Definition
Reduce oral doses of high extraction drugs such as propranolol
Monitor the biologic effect of the drug (heart rate)
Monitor blood levels (if possible)
Start with low dose and titrate up to biologic effect or blood level |
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