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Pharmacology - VAP844 > Pharmacokinetics 3 > Flashcards

Pharmacokinetics 3 Flashcards

1
Q

Metabolism

A

Rid the body of endogenous compounds as well as xenobiotics (foreign compounds)

Lipophilic and unionized compounds are poorly excreted in urine

Metabolism typically alters the compound to be more hydrophilic

Two main types of metabolism pathways

Phase 1 reactions

Phase 2 reactions

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2
Q

Phase 1 reactions

A
  • Metabolic reactions
    • oxidation, reduction, hydrolysis
    • Net effect - increased hydrophilicity/ decreased lipiphilicity
      • addition of a polar group
      • Removal of non-popar groups
    • The metabolites are then excreted or provide functional groups for phase 2 reactions
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3
Q

Phase 1 metabolic reactions

A
  • Cytrochrome P450 (CYP) Mixed-function oxidase (MFO) system
    • primarily in liver, but also in intestines, kidneys, skin
    • One of the primary enzyme families for drug metabolism (Phase 1)
    • Iron-containing heme-oxidase
    • Dozens to hundreds of different types of CYP
      • plants, some bacteria, fungi, insects, mammals
    • The cytochrome P450 enzyme is the rate limiting step in this metabolic pathway
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4
Q

CYP Isoforms

A
  • isoforms have minor structural variations, but huge impact on specificity
  • Result:
    • Different CYP specificities for substrates, inducers, and inhibitors
  • For example
    • Methadone is metabolized primarily by CYP2B11 in dogs
    • Ketaconazole pirmarily inhibits CYP3A12 in dogs
    • Fluconazole is a CYP2B11 inhibitor
    • Fluconazole inhibits methadone metabolism, but ketaconazole does not
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5
Q

Cytochrome P450 (CYP)

A

Enzyme induction:

  • Increased Synthesis of CYP
  • Decreased degradation of CYP
  • Activation of per-existing CYP components

Enzyme Inhibition:

  • Reversible inhibition of CYP
  • Destruction of CYP
  • Inhibiting CYP synthesis
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6
Q

CYP Induction

A
  • Phenobarbital:
    • CYP2B11 inducer and substrate
    • Induces its own metabolism by 300%

A. predicted plasma concentration

B. actual plasma concentration

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7
Q

Phase 2 reactions

A
  • Conjugation reactions:
    • Always adds something that makes it larger
    • Addition of a polar endogenous substance to the drug or metabolite
      • Glucuronic acid, Acetic acid, Amino acid, sulfate
    • A functional group must be present
      • -OH, -SH, -NH2
      • Phase 1 metabolites or directly on the drug
    • Products of phase 2 are larger and more polar
    • Metabolites then excreted in bile, urine, feces
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8
Q

Phase 2 conjugation Reactions

A

Glucuronidation

Acetylation

Sulfate conjugation

Amino Acid conjugation

Others

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9
Q

Glucuronidation

A

Phase 2 reaction

  • Drug substrate + Glucuronic Acid
  • Species differences
    • Cats are deficient in some glucuronide conjugation enzyme subtypes
      • Decresed clearance after aspirin
      • Acetaminophen toxicity
        • Most species produce acetaminophen glucuronides as metabolites
        • Cats are dedicient and produce CYP metaboites which are toxic
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10
Q

Acetylation

A

Drug substrate + Acetyl CoA

  • Species Differences
    • Dogs are deficient
      • increased adverse effects of sulfonamide antimicrobials
        • Hepatotoxicity, polyathropathy, blood dyscrasias, death
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11
Q

Sulfate Conjugation

A

Substrate + Phosphoadenosyl Phosphosulfate

  • Species Differences
    • Swine are deficient
      • Clinical relevance?
      • Research relevance
      • National Board Exam
    • Primary means cats eliminate morphine
      • other species make glucuronide conjugates
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12
Q

Amino Acid Conjugation

A
  • Substrate:
    • Primarily glycine
  • Species Differences:
    • Some avian species deficient
    • Benzoic acid metabolized to hippuric acid by glycine conjugation
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13
Q

Biliary Secretions

A
  • Carrier mediated:
    • saturation and competition
  • Large molecules weight drugs and metabolites
  • Polar drugs
    • products of phase 2 metabolism
    • Drug
  • Specific Transporters
    • Weak acids (OATs)
    • Weak bases (OCTs)
    • Neutral
    • Inorganic metals
    • P-glycoprotein
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14
Q

Hepatic Drug metabolism / elimination

A
  • Phase 1 metabolism
    • Cytochrome P450
  • Phase 2 metabolism
    • glucuronidation
    • Acetylation
    • Sulfate conjugation
    • Amino Acid conjugation
  • Biliary Secretion:
    • Active transporters
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15
Q

Enterohepatic Recycling

A
  • Bile duct empties into duodenum
  • Bile contains drug metabolite, excreted as a conjugate
  • Intestinal bacterial flora de-conjugate dome drug-conjugate complexes; free drug can then be reabsorbed
  • Therefore a single drug molecule may be secreted and absorbed numerous times increasing the drug exposure
  • Reasoning for multiple dosing of activated charcoal for certain toxicities
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16
Q

Metabolites

A
  • generally metabolites have less pharmacologic activity
  • Occasionally metabolites are more active
    • Tramadol - analgesic, metabolized to o-desmethyltramadol 200x activity in cats
  • Pro-drug:
    • inactive drug metabolized to active form
      • Enalapril - metabolized to enalaprilat
  • Lethal synthesis
    • Acetaminophen - cats
    • Ethylene Glycol (Antifreeze) - any species
17
Q

Extrahepatic Metabolism

A
  • GI tract, skin, Kidneus, spleen, lung
    • contain metabolizing enzymes
    • May be substantial contribution
  • Morphine in Dogs
    • ~50% of morphine metabolism in dogs is hepatic, 50% dut to extrahepatic metabolism
    • Clinical conswquence:
      • prodound liver disease only decreases morphine elimination by ~50% in dogs
18
Q

Renal Drug Elimination

A

Renal elimination is determind by

  1. Glomerular filtration
  2. Tubular secretion
  3. Tubular reabsorption (Decreases elimination)
19
Q

Glomerular Filtration

A
  • ~25% of cardiac output goes to the kidneys
  • Essentially a mechanism of ultrafiltration
  • Cells, proteins excluded
    • protein bound drugs do NOT get filtered, only free drugs
  • Epithelial processes are changes
    • restricts large charged compounds from being filtered
  • Glomerular filtration is not saturable
  • Glomerular filtration Rate *GFR) dependent to:
    • Renal blood pressure
    • Plasma oncotic pressure
    • Number of Glomeruli
20
Q

Active Tubular Secretion

A

Proximal Renal Tubule

  • Carrier mediated - depends on what it has a greater affinity fot
    • May not be affected by plasma protein binding
  • Secretion:
    • Acid Transporters (OAT3)
    • Base Transporters (OCT2)
    • P-glycoprotein
    • others
  • Can be saturated
    • competition between drugs
21
Q

Passive Tubular Reabsorption

A

Proximal and Distal Renal tubules

  • Only lipophilic unionized drug is reabsorbed
    • Alkaline Urine:
      • weak acid - excretion favored
      • Ion trapping in urine
    • Acidic Urine
      • Weak bases - excretion favored
      • Ion Trapping in urine
  • Reabsorption decreases renal eliminations
  • Renal elimination - GFR + Tubular secretion - tubular reabsorption
22
Q

Renal Elinimaiton

A
  • Special Circumstances
    • Metabolism
      • Phase 1 and Phase 2 metabolism
      • Directly or secondarily after liver “relay metabolism”
      • Cilastatin:
        • inhibits brush border metabolism of imipenem
        • Therefore imipenem remains active in urine
    • Pinocytosis
      • Aminoglycoside antimicrobials
      • Accumulates primarily in proximal tubular cells
        • Resulting in nephrotoxicty
        • Prolonged slaughter withdrawal time in food animals
23
Q
A

Pharmacology - VAP844 (14 decks)

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