02.06.12(a): Drugs and the Liver


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02.06.12(a): Drugs and the Liver

  1. 1. Author(s): Rebecca W. Van Dyke, M.D., 2012License: Unless otherwise noted, this material is made available under the terms of theCreative Commons Attribution – Share Alike 3.0 License:http://creativecommons.org/licenses/by-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, andadapt it. The citation key on the following slide provides information about how you may share and adapt this material.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections, orclarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medicalevaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about yourmedical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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  3. 3. M2 GI Sequence Drugs and the Liver Rebecca W. Van Dyke, MDWinter 2012
  4. 4. Learning Objectives• At the end of this lecture the students should be able to:•• 1. Describe the barrier function of the liver (and gut) with respect to drugs and xenobiotics.• 2. Describe the hepatic pathways for handling and disposing of• drugs and xenobiotics.• 3. Describe the pathophysiologic basis for drug-drug interactions at the level• of cytochrome P450 (CYP) enzymes.• 4. Predict drug-drug interactions based on knowledge of relevant• P450 enzymes and inhibitors/inducers.• 5. Describe the principals of drug-induced liver disease and be able to give• some representative examples.• 6. Describe how alcohol consumption and/or poor nutritional status may• enhance susceptibility to acetaminophen-induced liver injury.• 7. Describe an approach to drug-induced liver disease.• 8. Describe the potential consequences of liver disease on drug metabolism• and the clinical effect of medications.•
  5. 5. Industry Relationship Disclosures Industry Supported Research and Outside Relationships• None
  6. 6. Drugs and the Liver Liver Disease Drug-DrugDrugs Interactions LIVER Drug Elimination Drug Metabolites (the good, the bad and the ugly)
  7. 7. Why Study Drugs and the Liver?• Liver is a major biotransforming and elimination organ – Barrier and “Garbage Disposal”• Drug-drug interactions occur in liver – May increase toxicity or reduce effect• Drugs cause liver damage – Mechanism and can it be predicted?• Liver disease in turn alters drug disposal (remember renal disease and drug excretion?)
  8. 8. D r u g A b s o r p tio nBarriers to uptake G u t/L iv e r B a r r ie r F u n c tio nof potentially undesirablechemicals/xenobiotics(an eternal problem): Taken up M e ta b o liz e d C o n ju g a te d R e tu r n e d to b lo o d E x c r e te d in b ile1. Gut mucosa2. LiverBarrier consists of multiple A b s o rb e dsteps. In ta c t N o t A b s o rb e dNot all xenobiotics are affected A b s o rb e d a n d E x c r e te dby each step. A b s o rb e d a n d M e ta b o liz e d
  9. 9. Hepatic Clearance of Drugs• 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 – Liver blood flow – Liver intrinsic clearance – Fraction of drug not bound to albumin
  10. 10. Hepatic Clearance of Drugs Q (fx unbound drug) (ClINT)ClH = Q + (fx unbound)(ClINT) Q = liver blood flow ClINT = rate of ability of liver to clear blood of drug if blood flow not limiting
  11. 11. Hepatic Drug Clearance• For High Extraction Drugs:• Equation reduces to simple form:• ClH = Q
  12. 12. Effect of Efficient Extraction by Hepatocytes in SeriesPortal HepaticVein VeinInput Output100% 5%
  13. 13. High Extraction Drugs/Xenobiotics/ Endogenous Compounds • Nitroglycerine • Lidocaine • Propranolol • Bile Acids
  14. 14. D r u g A b s o r p tio nHigh Extraction Drugs: F ir s t P a s s C le a r a n c e L o w s y s te m ic b io a v a ila b ilityDrugs/xenobiotics rapidly o f r a p id c le a r a n c e d r u g scleared in a single passthrough the liver. R a p id u p ta k e a n d e lim in a tio n b y h e p a to c y t e sConsequences can begood or bad:Oral administration of drugs/xenobiotics is inefficient –must administer IV/IM.However, enterohepaticcirculation of bile acids isefficient.
  15. 15. Hepatic Drug Clearance• For Low Extraction Drugs:• Equation reduces to simple form:• ClH = fx unbound x ClINT
  16. 16. Effect of Low Extraction Efficiency by Hepatocytes in SeriesPortal HepaticVein VeinInput Output100% 80%
  17. 17. Low Extraction Drugs/ Endogenous Compounds • Diazepam • Phenytoin • Theophylline • Bilirubin1. 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.
  18. 18. Steps in Liver Biotransformation and Elimination of Drugs - I • Transport of drugs/xenobiotics from blood – Liver has unique access to blood – Versatile transporters in liver membrane • Biotransformation in the liver – Phase I (cytochromes P450) – Phase II (conjugation)
  19. 19. Steps in Liver Biotransformation and Elimination of Drugs - II• Biliary excretion• Efflux to blood for eventual renal excretion
  20. 20. Liver Biotransformation and Elimination of Drugs - III• These processes exist for endogenous compounds, not just for drugs and xenobiotics
  21. 21. Phase 1 and Phase 2 Biotransformation in Liver O Sugar OH OH Glucuronyl CYP transferase ER ER Phase 1 Phase 2 Oxidative Conjugation to polar ligand reactions Glucuronyl transferases CYP-mediated Sulfotransferases Glutathione-S- transferases
  22. 22. Phase 1: Biotransformation• 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)
  23. 23. Anatomy of theCytochromesP450, a.k.a. CYP Fe
  24. 24. Contributions of SpecificP450s to Drug Metabolism CYP3A4 CYP2E1 CYP2D6 CYP2D6 CYP2C* CYP2C* CYP1A2 unknown * multiple subfamily members exist
  25. 25. CYPs: Role in breakdown of active drug Genetic variations: Desipramine Kinetics Due to Polymorphisms in CYP 2D6 fast Extensive slow Extensive Poor Metabolizer Metabolizer Metabolizer (most common)log plasmaDesipramineconcentration TIME since administration Implications for other drugs metabolized by CYP2D6: ??? Codeine
  26. 26. Role: Production of an active drug:Biotransformation of an inactive pro-drug) to an active drug pro-drug active drug Glucuronyl OH transferase CYP3A4 ER ER
  27. 27. Phase 2: Conjugation• 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
  28. 28. Conjugation of acetaminophen to UDP-glucuronic acid NH-CO-CH3 NH-CO-CH3 UDP + Glucuronic acid O Glucuronic acid OH UDP-glucuronyl transferase ER CYP ER
  29. 29. Phase II Conjugation• Endogenous examples: – Conjugation of bilirubin to glucuronide – Conjugation of bile acids to glycine/taurine• Genetic polymorphisms of conjugating enzymes poorly understood.• Inducibility of conjugating enzymes poorly understood.
  30. 30. Drug/Xenobiotic Elimination• Once drugs have been altered by Phase I and Phase II enzymes, they may be excreted by:• Biliary Excretion• Renal Excretion
  31. 31. C analicular O rganic C om pound E fflux Pum ps AD H epatocyteOrganic molecules P P - g lyco p ro te in cytosol AT MDR) ( P(especially once mademore hydrophilic by Bile C analiculusPhase I and Phase IIreactions) are often B ile a cid D aunom ycin V erapam ilrapidly excreted in bile. AD P tra n sp o rte r C yclosporine Bile acids AT P Examples: bilirubin C onjugated bilirubin G lutathione S -conjugates bile acids other conjugated organic anionsSome drugs/xenobiotics M R P -2are transported without o rg a n ic a n io n tra n s p o rte rany biotransformation P AD P ATstep.
  32. 32. Common Theme• Liver uses similar mechanisms to handle endogenous and xenobiotic compounds• FYI: these enzymes and transporters appear to be coordinately regulated by orphan nuclear receptors
  33. 33. Liver and Intestine Handling of Drugs/XenobioticsNot exclusive to liver: Gut may also handle drugs/xenobiotics Drug Drug MDR (P-gp) Drug MDR Metabolite (P-gp) Metabolite Drug Drug Drug CYP CYP ER ER Hepatocyte Enterocyte Both liver and gut can eliminate drugs by metabolism and/or apical excretion. Reduce any or all and blood concentration will rise.
  34. 34. Drug-Drug Interactions: Various Issues• 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
  35. 35. Case Presentation• 23 year old man underwent cardiac transplantation.• Begun on usual doses of cyclosporin A (6 mg/kg/day) and levels were therapeutic for 2 days.• Then developed renal failure and seizures consistent with acute cyclosporin A toxicity - blood levels of CsA were high.
  36. 36. Case Continued• Dose was reduced and therapeutic blood levels were re-established• However, 6 weeks after surgery his blood levels had fallen to subtherapeutic levels and dose had to be increased again.• WHY?
  37. 37. Cytochrome P450Metabolism/Competition B D A C CYP1A2 CYP2D6 CYP3A4 ENDOPLASMIC RETICULUM
  38. 38. Drug Interactions and CYP3A4Absence of competition - CYP3A4Drug: Unaltered CyclosporinCyclosporin A Cyclosporin Metabolites
  39. 39. Cytochrome P450 Metabolism A B CsA Keto CYP1A2 CYP2D6 CYP3A4 ENDOPLASMIC RETICULUM
  40. 40. Drug Interactions and CYP3A4 Ketoconazole Nicardipine CYP3A4 UnalteredDrug Cyclosporin ACyclosporin A Metabolites
  41. 41. Our Case• Patient has Cyclosporin A toxicity and high blood levels 2 days after transplant.• Not likely due to genetically low levels of CYP3A4 as six weeks later his blood levels were low.• More likely high levels due to simultaneous administration of a competing drug - ketoconazole for suspected fungal infection.
  42. 42. Not Just a Problem with Conventional Drugs Drug-Drug Interactions Leading to Toxicity Coumadin Result: Increased blood coumadin Increased prothrombin time Spontaneous bleeding St John’s B Wort A CYP1A2 CYP2D6 CYP3A4 ENDOPLASM I C RET I CULUM
  43. 43. Induction of CYP Enzymes• CYP substrates can induce CYP gene transcription, increasing liver capacity for drug metabolism.• Induction is usually specific for one or only a few CYPs.• Induction likely occurs through broad- specificity orphan nuclear receptors.
  44. 44. Example:CYP3A4 Induction by rifampin pre pre 1 day 7 days post (6 mo) (3 days) Rifampin
  45. 45. Drug Interactions and CYP3A4: Induction of CYP Enzymes Antiseizure drugs Rifampin St. John’s Wort CYP3A4Drug Drug Metabolites
  46. 46. Our Case: Subtherapeutic cyclosporin levels 6 weeks after discharge Antiseizure drugs: Phenobarbital Dilantin CYP3A4Cyclosporin Unaltered Cyclosporin Metabolites
  47. 47. Approach to Drug-Drug Interactions• Be aware of the problem• Look up potential interactions – computer databases• Monitor blood levels of drug• Monitor biologic action• Monitor for known toxicities
  48. 48. Effects of Drugs on the Liver: Drug-Induced Liver Disease• Many types of injury• Some predictable – drug-drug interactions• Most rare and not easily predictable – idiosyncratic/metabolic/genetic• Therapeutic misadventure
  49. 49. Drug-Induced Liver Disease• Hepatocellular injury – toxic metabolite: isoniazid, acetaminophen• Autoimmune hepatocellular injury – halothane hepatitis• Cholestatic liver injury – estrogen
  50. 50. Acetaminophen Metabolism Glucuronidation SulfationAcetaminophen Stable Excretion Metabolites CYP2E1 Glutathione(CYP3A4, CYP1A2) conjugation Toxic metabolites (NAPQI) Covalent binding oxidative stress Hepatocyte damage
  51. 51. Safe, useful andwidely available,but……….. Andy Melton, Flickr
  52. 52. A little may be good,however a lot maybe bad.
  53. 53. Acetaminophen Metabolism: High Dose GlucuronidationAcetaminophen Sulfation StableOverdose Saturated Metabolites Excretion d ate ur Glutathione t Sa CYP2E1 conjugation Toxic metabolites (NAPQI) N-acetylcysteine Covalent binding (antidote to overdose) oxidative stress Hepatocyte damage
  54. 54. Liver Damage Due to Toxic Doses of Acetaminophen• What part of the liver will be affected?• Hepatocellular versus cholestatic disease?
  55. 55. Acetominophen HepatotoxicityPortalTract Pericentral Hepatocyte necrosis
  56. 56. Mechanism of Drug-Induced Autoimmune Liver Disease Halothane Hepatitis F Hapten = [ F--C--C=O Tolerent [ [ Autoimmunity F O [ Cyp Cyp <5% 2E1 2E1Plasma Membrane F F [ F Cl [ F--C--C=O [ [ [ [ F--C--C--H F--C--C=O [ [ [ [ F O Neoantigen F OH [ F Br Cyp Cyp >95% 2E1 2E1 ER ER
  57. 57. Drug-induced Cholestatic Liver Disease• Estrogen – specific effect on bilirubin and bile acid transport – discussed earlier in the week
  58. 58. Drug-Induced Liver Injury• Bile duct injury• Steatosis and steatohepatitis• Vascular injury/veno-occlusive disease• Neoplasms• Other rare types of liver disease
  59. 59. Therapeutic Misadventure• Patient uses a drug at a “safe” dose.• In the presence of an environmental change, toxicity develops.• Example: acetaminophen and alcohol
  60. 60. Drug-Induced Liver Disease: Case47 year old known alcoholic admitted through ER with jaundice and disorientation.1 week ago he developed abdominal pain, he thought this was due to alcohol so stopped drinking.Took over-the-counter pain reliever for several days and abdominal pain subsided.Labs: Bilirubin 5.7 mg/dl Alk Phos 210 IU/l AST 10,310 IU/l ALT 12,308 IU/l PT 41 secondsWhat type of liver problem does he have?
  61. 61. Acetaminophen Metabolism Glucuronidation SulfationAcetaminophen Stable Excretion Metabolites CYP2E1 Glutathione(CYP3A4, CYP1A2) conjugation Toxic metabolites (NAPQI) Covalent binding oxidative stress Hepatocyte damage
  62. 62. A Potentially Lethal Combination Andy Melton, Flickr Jerry Lai, Flickr
  63. 63. Effects of Alcohol on Acetaminophen:Drugs that Induce CYP2E1 • Isoniazid (INH) • Phenobarbital • Ethanol !!!
  64. 64. Acetaminophen Metabolism After Chronic EtOH Use and with Fasting Glucuronidation Sulfation StableAcetaminophen Excretion Metabolites CYP2E1 Glutathione conjugation Toxic metabolites (NAPQI) EtOH Covalent binding Fasting oxidative stress Hepatocyte damage
  65. 65. Second Case• Patient was a chronic alcoholic• Chronically induced CYP 2E1• Poorly nourished with low glutathione levels• Developed mild pancreatitis and took acetaminophen while fasting• Developed acute massive hepatic necrosis
  66. 66. Approach to Drug-Induced Liver Disease• Always consider drugs/herbs/toxins in the differential diagnosis of ALL liver diseases• Stop all drugs/agents immediately• Look it up - check computer databases and textbooks
  67. 67. Approach to Prevention of Drug-Induced Liver Disease• Be aware of problem and check databases for known interactions• Screen for initial mild liver damage before it becomes severe - AST/ALT most used• Holy Grail: tailor drugs to patient’s genetic/environmental/drug profile
  68. 68. Effect of Liver Failure or Cirrhosis on Drug Disposition• 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?)• Low clearance drugs – often relatively little effect until end stage liver failure/cirrhosis as drug metabolism is relatively well preserved
  69. 69. Effect of Liver Failure or Cirrhosis on Drug Disposition• Specifically: High clearance drugs – affected by portosystemic shunts - markedly increased systemic bioavailability of oral drugs – drug levels in blood may get very high
  70. 70. Cirrhotic patients with D r u g A b s o r p tio n E ffe c t o f C ir r h o s isportosystemic shunts: L a rg e in c r e a s e in s y s te m ic b io a v a ila b ility - e s p e c ia lly fo r r a p id c le a r a n c e d r u g sBlood from intestinesbypasses the liver, L e s s e ffic ie n t:delivering much more U p ta k e M e ta b o lis m C o n ju g a tio nof orally administered B ilia r y e x c re tio ndrugs to the systemiccirculation.Thus, systemic bioavailabilityof orally administered highclearance drugs is muchgreater.
  71. 71. Effect of Liver Failure or Cirrhosis on Drug Disposition• Cirrhosis does not: – increase susceptibility to idiosyncratic drug reactions – increase likelihood of autoimmune-mediated drug reactions
  72. 72. Approach to Drug Use in Patients with Significant Liver Dysfunction• 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
  73. 73. Summary• Drugs/xenobiotics and liver intersect in many ways• Suspect problem(s)• Look up data
  74. 74. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 51: Andy Melton, Flickr, http://www.flickr.com/photos/trekkyandy/216437482/, CC:BY-SA, http://creativecommons.org/licenses/by-sa/2.0/deed.enSlide 62: Andy Melton, Flickr, http://www.flickr.com/photos/trekkyandy/216437482/, CC:BY-SA, http://creativecommons.org/licenses/by-sa/2.0/deed.en; Jerry Lai,http://www.flickr.com/photos/jerrylai0208/6127164522/, CC:BY-SA, http://creativecommons.org/licenses/by-sa/2.0/deed.en