Metabolism of Opioid Analgesics
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Questions and Answers

What is the primary aim of metabolism in the context of opioid analgesics?

  • To remove xenobiotics from the body (correct)
  • To increase the lipophilicity of molecules
  • To convert the analgesics into inactive forms
  • To enhance the potency of the analgesics

Which phase of metabolism primarily involves the introduction of chemical functionality?

  • Phase IV - detoxification
  • Phase II - conjugation
  • Phase III - excretion
  • Phase I - modification (correct)

What determines if a person is classified as a Poor Metaboliser (PM)?

  • Having two non-functional alleles (correct)
  • Having one reduced functional allele
  • Possessing multiple copies of a gene
  • Having at least one functional allele

Which enzyme class is primarily involved in Phase I metabolism?

<p>CYP450 monooxygenases (C)</p> Signup and view all the answers

Which allele variant is associated with an Ultrarapid Metaboliser (UM) phenotype?

<p>Multiple copies of a functional allele (D)</p> Signup and view all the answers

What is a characteristic of Phase II metabolism?

<p>Involves the introduction of charged or polar species (D)</p> Signup and view all the answers

Which of the following populations has the highest incidence of Ultrarapid Metaboliser (UM) phenotype?

<p>Ethiopian (A)</p> Signup and view all the answers

What is the main metabolic pathway for codeine?

<p>CYP 2D6, CYP 3A4, CYP 3A5 (A)</p> Signup and view all the answers

How does genetic variation affect the metabolism of opioid analgesics?

<p>It can result in different metabolic phenotypes (D)</p> Signup and view all the answers

What percentage of American Whites are classified as Poor Metabolisers (PM)?

<p>7.7% (B)</p> Signup and view all the answers

Which opioid has no active metabolites?

<p>Fentanyl (A)</p> Signup and view all the answers

What is the role of the CYP2D6 enzyme in drug metabolism?

<p>It catalyzes the metabolism for some drugs. (D)</p> Signup and view all the answers

What enzyme is primarily responsible for dealkylation in many μ-receptor agonists?

<p>CYP 3A4 (B)</p> Signup and view all the answers

What is the outcome of being deficient in CYP 2D6 for codeine metabolism?

<p>Minimal or no response to codeine (C)</p> Signup and view all the answers

Which active metabolite is produced from oxycodone?

<p>Oxymorphone (A)</p> Signup and view all the answers

What is a significant advantage of M6G over morphine as an analgesic?

<p>Reduced occurrences of nausea and anti-emetic use (C)</p> Signup and view all the answers

In which time frame does M6G show less sedation compared to morphine?

<p>During the first 4 hours post-operative (A)</p> Signup and view all the answers

Which of the following is NOT a characteristic of M6G based on its analgesic properties?

<p>Higher likelihood of nausea (A)</p> Signup and view all the answers

What measure is used to assess pain intensity during PCA in the mentioned groups?

<p>11-point verbal rating scale (VRS-11) (A)</p> Signup and view all the answers

What aspect of M6G contributes to potentially lower overall costs compared to morphine?

<p>Significant reductions in nausea and anti-emetic requirements (B)</p> Signup and view all the answers

What is the primary conjugation process for phenolic opioids in Phase II metabolism?

<p>Glucuronidation or sulfation (C)</p> Signup and view all the answers

Which metabolite of morphine is considered to be more active than morphine itself?

<p>Morphine-6-glucuronide (M6G) (C)</p> Signup and view all the answers

What is one consequence of Phase II conjugation on the oral bioavailability of phenolic opioids?

<p>Increased polarity (A)</p> Signup and view all the answers

How is morphine-3-glucuronide (M3G) disposed of from the body?

<p>Excreted in urine (B)</p> Signup and view all the answers

What risk increases due to the accumulation of glucuronide metabolites in individuals with poor renal function?

<p>Inadvertent overdose (A)</p> Signup and view all the answers

What role does UGT2B7 play in the metabolism of opioids?

<p>It contributes to glucuronidation (D)</p> Signup and view all the answers

Why might elderly patients be at a higher risk for opioid-related complications?

<p>They often experience renal failure or poor function (D)</p> Signup and view all the answers

Which feature is characteristic of morphine and codeine metabolites?

<p>They often exist in an inactive form (C)</p> Signup and view all the answers

What is the potency of M1 compared to the parent compound of tramadol?

<p>700 times greater (A)</p> Signup and view all the answers

Which metabolite of morphine is known to be active?

<p>Morphine-6-glucuronide (M6G) (D)</p> Signup and view all the answers

How does the potency of M6G vary with the route of administration?

<p>It is more potent with subcutaneous administration (C), It is more potent with intravenous administration (D)</p> Signup and view all the answers

What is the relative potency of M3G compared to morphine?

<p>Inactive metabolite with no significant potency (B)</p> Signup and view all the answers

Which liver enzymes are primarily responsible for tramadol's complex metabolism?

<p>CYP2D6 and CYP3A4 (B)</p> Signup and view all the answers

What is a key characteristic of (-)-M1 in the context of analgesic activity?

<p>It has little to no analgesic activity (B)</p> Signup and view all the answers

Which statement regarding the metabolites of morphine is correct?

<p>M6G can accumulate in renal impairment. (D)</p> Signup and view all the answers

What describes the overall potency and metabolic activity of oxycodone compared to its active metabolites?

<p>Metabolites account for the majority of oxycodone's analgesic effects. (B)</p> Signup and view all the answers

Flashcards

Metabolism's Goal

To remove foreign substances (xenobiotics) from the body.

Lipophilic to Hydrophilic

Metabolism transforms fat-soluble molecules into water-soluble molecules for easier excretion.

Phase I Metabolism

Introduction of functional groups (e.g., oxidation, reduction) to make molecules more reactive.

CYP450 Enzyme

A major enzyme involved in Phase I metabolism, responsible for many drug reactions.

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Phase II Metabolism

Attachment of polar groups (conjugation) to increase water solubility for excretion.

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N-dealkylation

A common Phase I metabolic reaction where an alkyl group is removed from a nitrogen atom. This can affect the drug's activity by altering its lipophilicity and ability to bind to its receptor.

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'Nor' metabolite

A drug metabolite formed after N-dealkylation, often resulting in reduced potency and activity compared to the parent drug.

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CYP 2D6

A major enzyme responsible for codeine's metabolism to morphine. Individuals with genetic deficiencies in CYP 2D6 may not convert codeine efficiently, leading to poor pain relief.

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Codeine and CYP 2D6 deficiency

Patients deficient in the CYP 2D6 enzyme cannot efficiently O-dealkylate codeine, leading to decreased conversion to morphine and a minimal analgesic effect. Thus, these individuals are unable to benefit significantly from codeine-based analgesics.

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Morphine-6-glucuronide (M6G)

A metabolite of morphine that is more potent than morphine itself, contributing significantly to its analgesic effects.

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Codeine-6-glucuronide

A metabolite of codeine that is inactive, meaning it does not contribute to the analgesic effects.

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Morphine-3-glucuronide (M3G)

A metabolite of morphine that is less active than morphine, contributing to its analgesic effects but to a lesser extent than M6G.

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UGT2B7

An enzyme crucial for the Phase II metabolism of opioids, specifically morphine and codeine.

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Lipophilicity

The tendency of a substance to dissolve in fats or lipids. It influences how easily a drug can cross cell membranes.

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Molecular Chameleon

A term used to describe morphine-6-glucuronide, whose structure changes, impacting how it interacts with the body. This change influences its lipophilicity, making it able to cross cell membranes more easily.

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Renal Failure

When the kidneys are not functioning properly, leading to a buildup of substances in the body, including M6G, which can increase overdose risk.

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How does Phase II metabolism affect oral bioavailability of opioids?

The conjugation process in the GI tract increases the polarity of phenolic opioids, making them less likely to be absorbed into the bloodstream and decreasing their oral bioavailability.

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Codeine Metabolism

The process of converting codeine into morphine by the enzyme CYP2D6. This conversion is essential for codeine's pain-relieving effects.

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CYP2D6 Deficiency

A genetic condition where individuals have reduced or no activity of the CYP2D6 enzyme, leading to poor conversion of codeine to morphine.

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Poor Metabolizer

An individual with CYP2D6 deficiency who cannot efficiently convert codeine to morphine, resulting in minimal pain relief.

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Ultra-Rapid Metabolizer

An individual with multiple copies of the functional CYP2D6 gene, leading to faster and more efficient codeine metabolism.

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Codeine and Pain Relief

Individuals with CYP2D6 deficiency may experience less effective pain relief from codeine due to insufficient morphine production.

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M6G Analgesic Effect

M6G provides similar pain relief as morphine but with fewer side effects, such as less respiratory depression, nausea, and sedation.

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M6G vs. Morphine: Respiratory Depression

M6G causes significantly less respiratory depression compared to morphine, making it a safer option for patients with breathing difficulties.

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M6G: Nausea Reduction

M6G leads to a significant decrease in nausea compared to morphine, reducing the need for anti-nausea medication.

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M6G: Less Sedation

Patients experience less sedation in the initial hours after surgery when using M6G, allowing for faster recovery.

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M6G: Cost Factor

M6G's cost is a consideration when comparing it to other analgesic options, potentially affecting its accessibility.

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Oxycodone's Metabolite: Oxymorphone

Oxymorphone is a major metabolite of oxycodone, formed by the liver. It's a potent analgesic, significantly stronger than oxycodone itself.

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Oxymorphone's Potency

Oxymorphone is about 8 times more potent than oxycodone in laboratory studies. This highlights its significant contribution to oxycodone's overall pain-relieving effect.

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Tramadol's Metabolism: Complex?

Tramadol undergoes a complex metabolic process, involving multiple enzymes and producing numerous metabolites. Only one metabolite, M1, is responsible for pain relief.

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Tramadol's Active Metabolite

M1 is the main active metabolite of tramadol. It's responsible for the majority of tramadol's analgesic effects.

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Morphine-6-Glucuronide (M6G): Active?

M6G is an active metabolite of morphine. Its potency can vary depending on how it's administered.

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Morphine-3-Glucuronide (M3G): Potency?

M3G does not provide pain relief like morphine or M6G. Instead, this metabolite might contribute to some side effects, like muscle spasms.

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Morphine Metabolites: Accumulation?

M3G and M6G last longer in the body than morphine itself. In people with kidney problems, these metabolites may build up.

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Morphine Pharmacokinetics: Key Fact?

The levels of M3G and M6G in the blood are often higher than the levels of morphine itself.

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Study Notes

The study of ADME in acute pain examines how various opioid analgesics are metabolized during short-term management.

  • The presentation covers the metabolism and pharmacogenetics of opioid analgesics.

Learning Objectives

  • Opioid Analgesic Metabolism:
    • Describe metabolic pathways for different opioids (e.g., morphine, codeine, oxycodone, tramadol).
    • Understand the significance of active metabolites in opioid potency.
    • Learn the pharmacokinetic profile of morphine and its metabolites.
  • Pharmacogenetics:
    • Explain how genetic variation influences individual metabolic responses to opioids.
    • Identify populations with prevalent metabolic phenotypes.
    • Analyze the effect of phenotypic differences on opioid metabolism.

Metabolism - Revision

  • Metabolism's role is to eliminate foreign substances (xenobiotics).
  • Lipophilic molecules are transformed into hydrophilic ones for excretion.
  • Phase I Modification: Chemical modifications (oxidation, hydrolysis, reduction) via enzymes like CYP450 monooxygenases, monoamine oxidase, peroxidases, reductases, esterases, and amidases.
  • Phase II Conjugation: Adding charged/polar species (sulfation, glucuronidation, GSH conjugation) with enzymes like sulfotransferases, UDP glucuronosyltransferases, and glutathione S-transferases.

Opioid Metabolism Summary Table

OpioidMain Metabolic PathwayActive MetabolitesBuprenorphineCYP 3A4, CYP 3A5, UGT1A1, UGT2B7MorphineCodeineCYP 2D6, CYP 3A4, CYP 3A5Morphine-6-Glucuronide (M6G)FentanylCYP 3A4, CYP 3A5NoneMorphineUGT2B7M6GOxycodoneCYP 2D6, CYP 3A4, CYP 3A5OxymorphoneTramadolCYP 2D6, CYP 3A4, CYP 3A5M1

Morphine and Codeine - Phase 1 Metabolism

  • Many µ-receptor agonists have an N-methyl group readily dealkylated by CYP 3A4, forming less active 'nor' metabolites.
  • This deactivation leads to decreased lipophilicity and reduced agonist properties.
  • Individuals with CYP2D6 deficiencies cannot effectively O-dealkylate codeine, resulting in decreased analgesic efficacy.

Morphine and Codeine - Phase 2 Metabolism

  • Important aspects of morphine metabolism include conjugation with glucuronic acid or sulfate
  • These conjugates are primarily inactive and excreted in urine.
  • Phase II conjugation in the GI tract affects oral bioavailability, increasing polarity.
  • Morphine-6-glucuronide (M6G) is often more potent than morphine, particularly following intravenous administration.
  • Morphine-3-glucuronide (M3G) is typically inactive but can sometimes cause neurotoxic effects.

Oxycodone Metabolism

  • Oxycodone's active metabolite, oxymorphone, is ~8x more potent than oxycodone.
  • O- and N-demethylation are key metabolic pathways, with CYP2D6 and CYP3A4 playing significant roles.
  • Over 80% of oxycodone's analgesic effect comes from its metabolites.

Tramadol Metabolism

  • Tramadol is metabolized via phase I and II pathways, generating 11 active metabolites.
  • (+)-Tramadol acts as a weak opioid agonist and serotonin reuptake inhibitor.
  • (-)-Tramadol inhibits norepinephrine reuptake.
  • The active metabolite (+)-M1 has much greater affinity for the opioid receptor than the parent molecule.

Pharmacogenetics of Opioid Analgesics

  • Genetic variations in CYP isoforms (e.g., CYP2D6) influence drug metabolism, causing different metabolic phenotypes.
  • Poor metabolizers (PM) have reduced activity of CYP2D6, potentially leading to lower plasma concentrations of active metabolites and reduced analgesic efficacy.
  • Ultrarapid metabolizers (UM) have increased activity of CYP2D6, leading to higher levels of active metabolites and a potential for greater opioid-related side effects.
  • Populations show varying frequency of PM and UM phenotypes.
  • Genetic variation influences patient outcomes with respect to drug responses, adverse effects, and dosages.

Important Takeaways

  • Environmental factors (age, sex, liver/kidney function, smoking, alcohol consumption, concurrent medications) influence opioid metabolism and analgesic responses.

Is Codeine Still Appropriate?

  • Concerns exist about codeine's safety due to its pro-drug nature, unpredictable pharmacokinetics, and genetic influences.
  • Reports of fatalities, specifically in neonates and children, highlight risks.

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Description

This quiz explores the complexities of drug metabolism with a focus on opioid analgesics. It covers key concepts such as metabolic phases, enzyme interactions, genetic variations affecting metabolism, and specific alleles related to metabolizer phenotypes. Test your knowledge on how these factors influence the effectiveness of opioid medications.

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