Pharmacokinetic Changes in Hepatic Dysfunction

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Pharmacokinetic Changes in Hepatic Dysfunction

• Jennifer Dugan, Pharm.D., BCPS

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Liver Physiology

• Receives blood from hepatic artery and portal
  vein
• Between cords of hepatocytes are sinusoids
• Blood is collected into hepatic vein, flows into
  inferior vena cava
• Bile flows in opposite direction of blood
• System allows for rapid exchange of drugs and
  metabolites between plasma and hepatocytes,
  hepatocytes and bile.

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Factors Affecting Movement

• Blood flow
• Protein Binding
• Mechanism of transfer
• Diffusion
• Carrier-mediated

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Biotransformation

• Phase I (nonsynthetic/functionalization)
• Oxidation
• Reduction
• Hydrolysis
• Phase II (synthetic/conjugation)
• Links to endogenous substrate (glucuronic acid,
  sulfate, glycine)
• Methylation
• Acetylation

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Oxidation

• Enzyme systems primarily in hepatocytes near
  central vein
• Enzymes
• Cytochrome P450
• NADPH-dependent P450 reductase

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Conjugation

• Frequently preserved in liver disease
• Most drugs undergoing Phase II biotransformation
  are conjugated with glucuronic acid
• Low-affinity, high capacity pathway

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Sulfation

• Occurs near portal vein
• High affinity, low capacity
• Need ATP to get cofactor to transfer inorganic
  sulfate to drug molecules
• Limited availability of inorganic sulfate
• This is reason you get nonlinear PK with
  acetaminophen

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Extrahepatic Metabolism

• Kidney
• GI
• Intestinal bacteria or enzyme systems in
  epithelial cells
• Lung
• Many pulmonary toxicities may be from local toxic
  or reactive metabolites
• Skin

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Hepatic Excretion

• Some drug molecules are not metabolized before
  excretion
• May see decreased metabolites or accumulation of
  metabolites if excretion impaired
• To be eliminated, the drug must cross sinusoidal
  membrane and return to blood as it flows toward
  central vein, or be transported into bile
• Biliary transport, like active secretion in the
  kidneys, may be inhibited competitively

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Other Liver Functions

• Protein synthesis
• Glucose homeostasis
• Lipid and lipoprotein synthesis
• Vitamin storage
• Clotting factor synthesis
• Bile acid synthesis

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Hepatic Extraction Ratio (EH)

• Extraction Ratio tells of efficiency, not extent
• EH Ca (pv ha) Cv (just venous)
• Ca
• Factors affecting EH
• Blood flow
• Protein binding
• Hepatic intrinsic clearance (ability of
  hepatocytes to remove drug from liver water when
  blood flow, protein binding, and translocation to
  the site of metabolism or elimination are not
  rate-limiting)

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Hepatic Clearance

• Volume of blood from which drug is removed
  completely per unit time
• CLH QH EH
• Hepatic clearance is not equal to systemic
  clearance

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Bioavailability

• F? 1- EH
• Fraction of the absorbed dose that reaches the
  systemic circulation
• Will approximate 1.0 for dugs that are not
  extracted efficiently
• If extracted efficiently, hepatic disease
  alterations in first pass extraction may
  significantly alter systemic availability

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Volume of Distribution

• Vd VB VT (fub/fut)
• May or may not be affected by liver disease,
  depending on extravascular distribution and
  tissue binding

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Drugs Exhibiting gt20 Decrease in Clearance in
Chronic Liver Disease

• Lidocaine
• Meperidine
• Metoprolol
• Propranolol
• Verapamil

• Caffeine
• Diazepam
• Erythromycin
• Metronidazole
• Theophylline

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Extraction Ratios

• Low Extraction Ratio
• Dosage adjustment only necessary when intrinsic
  clearance changes (ie cirrhosis)
• If total drug changes, unbound concentration
  should remain constant
• Examples- phenytoin, warfarin, diazepam,
  chlordiazepoxide, naproxen, sulindac, valproic
  acid, theophylline, bumetanide, triamterene

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Low Extraction Ratio Drugs in Normal Patients
Total
Conc
Free (unbound)
time
Drug displaced
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Low Extraction Ratio Drugs in Liver Disease
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Low Extraction Ratio Drugs in Liver Disease

• Decreased intrinisic clearance (hepatic cell mass
  and function ).
• Often increased fu ( serum albumin).
• No significant change in F.
• Overall, total Cl is generally reduced two to
  four-fold (increasing plasma levels).However,
  free (active) plasma levels may be increased by
  much more
• Therefore, highly bound drugs may need gt 2 or
  4-fold dosage reduction

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Extraction Ratios

• High Extraction Ratio
• Hepatic clearance rate-limited by liver blood
  flow
• Protein binding doesnt change clearance but
  changes amount unbound
• No change in hepatic clearance as fraction
  unbound increases

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High Extraction Ratio Drugs in Liver Disease

• Increased plasma level of drug (especially if
  taken orally)
• Decreased hepatic blood flow leads to decreased
  clearance 
• Intra-hepatic and extra-hepatic shunting of blood
  leads to decreased first pass effect, thereby
  increasing oral bioavailability

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High Extraction Ratio Drugs in Liver Disease
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PK Factors influencing clearance

• Thyroid
• Pituitary
• Pancreas
• Gender
• Pregnancy
• Race
• Nutritional Status

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Drug Interactions

• Interaction has to exceed intrapatient clearance
  variability
• Induction increases intrinsic clearance of
  unbound drug
• Inhibition decreases intrinsic clearance of
  unbound drug
• Interaction usually results in a lt50 change in
  clearance

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Drug interactions

• Total clearance has an inverse relationship to
  Css
• If drug clearance increases from 10 to 15, Css
  will decrease 33
• If drug clearance decreases from 10 to 5, Css
  will increase 100

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Drug interactions

• Magnitude of interaction based on
• Fraction of clearance due to metabolism
• Hepatic extraction ratio
• Route of administration
• For a high EH drug, cimetidine inhibits oral
  clearance by 30-50, but inhibits systemic
  clearance 15-30
• Patients with chronic liver disease are likely
  more sensitive to inhibition

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Pharmacodynamic Changes in Liver Disease

• sensitivity to oral anticoagulants
• CNS sensitivity to depressants
• risk of hypokalemia with some loop diuretics

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Chronic Liver Disease

• gt50 decrease in P450 content
• High extraction drugs are more affected in
  portosystemic shunting
• Low extraction drugs are more sensitive to
  intrinsic clearance changes
• Bioavailability may be significantly ? secondary
  to ? first pass in highly extracted drugs
• Vd increased in pts with ? albumin or ascites

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• Inflammation
• Fibroblasts secrete collagen while damaged cells
  replaced
• Collagen accumulates in sinusoidal space
• Basement membrane w/o microvilli forms
• Interferes with exchange
• Hepatocytes regenerate
• Clustered formations form nodules
• Distorted liver architecture increases portal
  pressure and promoting shunts

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Progression

• Alcohol can cause fatty infiltration
• Microsomal enzyme induction
• Increased conversion to hepatotoxic metabolites
• May be asymptomatic
• Alcoholic Hepatitis (Steatonecrosis)
• Not all alcoholics have cirrhosis

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Signs and Symptoms of Cirrhosis

• Anorexia
• Nausea
• Abdominal Discomfort
• Weakness
• Weight loss
• Fatigability

• Hepatosplenomegaly
• Jaundice
• Ascites
• Peripheral Edema
• Spider angiomas

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Portal Hypertension

• Portal vein collects blood from abdominal portion
  of digestive tract, pancreas, and spleen
  transports to liver
• Blood must pass through capillary system under
  high pressure
• Blood flow can be blocked by nodules that
  compress and distort hepatic veins, ot thrombosis
  or obstruction

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Portal Hypertension

• Portal hypertension facilitates formation of
  collateral blood vessels and intrahepatic shunts
• Low pressure veins in esophagus, anterior
  abdominal wall, splenic veins, rectum
• Esophageal and gastric varices, ascites,
  hemorrhoids, splenic enlargement

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Pharmacokinetic and Pharmacodynamic Changes

• Extraction Ratio
• Protein Binding
• Third-Spacing of fluid
• Diarrhea
• Varices
• Renal impairment

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Drug-Induced Liver Disease

• Allergic Hepatitis
• Sulfonamides
• Penicillins
• Macrolides
• Allopurinol
• Toxic Hepatitis
• Acetaminophen
• Aspirin
• Valproic Acid

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Drug-Induced Liver Disease

• Autoimmune-Mediated Disease
• Methyldopa
• Isoniazid
• Dantrolene
• Phenytoin
• Nitrofurantoin
• Toxic Cirrhosis
• Methotrexate

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Drug-Induced Liver Disease

• Liver Vascular Disorders
• Cytotoxic agents
• Azathioprine
• Androgens
• Estrogens
• Tamoxifen