ADME 1: Acute Pain and Opioid Analgesics
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Questions and Answers

Which of the following statements is true regarding oxymorphone?

  • It is less potent than oxycodone.
  • It has the same potency as oxycodone.
  • It is more potent than oxycodone. (correct)
  • It is not a metabolite of oxycodone.

N-demethylation of oxycodone is primarily facilitated by CYP3A4.

True (A)

What percentage of oxycodone is excreted unchanged?

10%

The glucuronide conjugates of oxycodone contribute to approximately _____ of its analgesic effect.

<p>83%</p> Signup and view all the answers

Match the oxycodone metabolites with their properties:

<p>Oxymorphone = 8x more potent than oxycodone Noroxycodone = 6x less potent than oxycodone Unchanged oxycodone = 10% excreted unchanged O-demethylation = CYP2D6 responsible</p> Signup and view all the answers

Which of the following is considered a key enzyme in Phase I metabolism of opioids?

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

The primary goal of metabolism is to make lipophilic molecules more hydrophilic for easier excretion.

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

Name one of the opioid analgesics that has significant active metabolites.

<p>morphine</p> Signup and view all the answers

Phase II metabolism involves the introduction of _______ species.

<p>charged/polar</p> Signup and view all the answers

Match the opioid analgesic with its characteristic:

<p>Morphine = Has significant active metabolites Codeine = Converted to morphine in the body Oxycodone = Semi-synthetic opioid Tramadol = Inhibits reuptake of serotonin and norepinephrine</p> Signup and view all the answers

What is the estimated potency ratio of morphine-6-glucuronide (M3G) compared to morphine?

<p>50:1 (C)</p> Signup and view all the answers

Morphine-3-glucuronide (M3G) is believed to have a significant contribution to analgesic activity when compared to morphine.

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

What is the risk associated with renal failure regarding the accumulation of morphine metabolites?

<p>Increased risk of inadvertent overdose</p> Signup and view all the answers

The inactive metabolite of codeine is known as codeine-6-________.

<p>glucuronide</p> Signup and view all the answers

Match the following substances with their respective characteristics:

<p>Morphine = Significant analgesic effects M3G = Limited analgesic activity Codeine = Converted to morphine in the body M6G = Active metabolite with analgesic properties</p> Signup and view all the answers

What percentage of morphine is typically converted to morphine-6-glucuronide (M6G)?

<p>50-70% (B)</p> Signup and view all the answers

Codeine-6-glucuronide is active and contributes to the analgesic effects of codeine.

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

What does UGT2B7 stand for?

<p>Uridine Diphosphate Glucuronosyltransferase 2B7</p> Signup and view all the answers

In Phase II metabolism, phenols mainly conjugate with __________ or sulfate.

<p>glucuronic acid</p> Signup and view all the answers

Match the following substances with their descriptions:

<p>M6G = More active than morphine Codeine-6-glucuronide = Inactive metabolite UGT2B7 = Enzyme responsible for glucuronidation Phenolic opioids = Compounds that undergo Phase II metabolism</p> Signup and view all the answers

Which of the following statements is true regarding Phase II conjugation in the GI tract?

<p>It can significantly increase the polarity of phenolic opioids. (B)</p> Signup and view all the answers

Morphine is primarily converted to active metabolites in Phase I metabolism.

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

What impact does Phase II conjugation have on the oral bioavailability of opioids?

<p>It can decrease oral bioavailability.</p> Signup and view all the answers

Which metabolite of tramadol has analgesic activity?

<p>M1 (D)</p> Signup and view all the answers

M3G is an active metabolite of morphine.

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

What enzymes are primarily responsible for the formation of tramadol metabolites?

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

Morphine-6-glucuronide (M6G) is ______ times more potent than morphine following intrathecal administration.

<p>70 – 360</p> Signup and view all the answers

Match the following metabolites with their properties:

<p>M3G = May cause neurotoxic side effects M6G = Active metabolite M1 = Analgesic activity (-)-M1 = Little to no analgesic activity</p> Signup and view all the answers

Which metabolite has the highest affinity for the mu-opioid receptor (MOR)?

<p>M1 (B)</p> Signup and view all the answers

M6G leads to less respiratory depression compared to morphine.

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

What is the primary function of (-)-Tramadol in the context of tramadol metabolism?

<p>Noradrenaline reuptake inhibitor</p> Signup and view all the answers

What is the verbal rating scale used for measuring pain intensity in PCA?

<p>VRS-11 (B)</p> Signup and view all the answers

A person with two non-functional alleles is considered an extensive metaboliser.

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

What is the percentage range for the metabolism of codeine by UGT2B7?

<p>0-15%</p> Signup and view all the answers

The _____ metaboliser phenotype has the highest population incidence in Ethiopians.

<p>Ultrarapid</p> Signup and view all the answers

Which of the following genotypes corresponds to a poor metaboliser phenotype?

<p>2 non-functional alleles (D)</p> Signup and view all the answers

CYP2D6-catalysed metabolism is a minor clearance mechanism for some drugs.

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

Which population has a 21% incidence of ultrarapid metaboliser phenotype?

<p>Saudi Arabian</p> Signup and view all the answers

Match the populations with their corresponding incidence rates for poor metaboliser phenotype:

<p>American White = 7.7% Ethiopian = 1.8% Colombian = 6.6% Chinese = 0.9%</p> Signup and view all the answers

Flashcards

Metabolism

The process of transforming a substance into a different form, typically to make it easier to remove from the body.

CYP450 Monooxygenases

Groups of enzymes located on the surface of a cell that catalyze metabolic reactions.

Conjugation

The process of adding a molecule (e.g., glucuronic acid) to a substance, making it more water-soluble and easier to excrete.

Active Metabolites

Substances formed during drug metabolism that can have their own pharmacological effects.

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Pharmacokinetic Profile

A measure of how quickly a drug is eliminated from the body.

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Oxycodone Metabolism

Oxycodone is metabolized primarily by CYP3A4, with CYP2D6 playing a lesser role. This leads to the formation of various metabolites such as oxymorphone, noroxycodone, and glucuronide conjugates.

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Oxymorphone Potency

Oxymorphone, a metabolite of oxycodone, is significantly more potent than oxycodone itself. It's formed through O-demethylation by CYP2D6.

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Noroxycodone Potency

Noroxycodone, another metabolite, is formed through N-demethylation by CYP3A4 and is much less potent than oxycodone.

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Glucuronide Conjugates

Glucuronide conjugates are inactive metabolites formed by a process known as glucuronidation.

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Analgesic Effect of Metabolites

Oxycodone's analgesic effect is mainly attributed to the parent drug and its active metabolites, particularly oxymorphone. This is why it's important to understand the role of these metabolites.

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Phase 2 Metabolism

The process of converting a drug to more water-soluble and excretable forms through conjugation.

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Glucuronidation

A type of Phase 2 metabolic reaction where glucuronic acid is added to a molecule. Usually makes the drug inactive.

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UGT2B7

A specific enzyme involved in glucuronidation of drugs. It plays a role in metabolizing morphine and codeine.

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Morphine-6-glucuronide (M6G)

A byproduct of morphine metabolism that is actually MORE active than morphine.

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Codeine-6-glucuronide

A byproduct of codeine metabolism that is inactive.

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Sulfation

The process of adding sulfate ions to a molecule. This is another type of Phase 2 metabolism that can alter the drug's activity.

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First-pass effect

The conversion of drugs in the gastrointestinal tract, affecting how much of the drug is absorbed into the bloodstream.

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Multicyclic

The presence of multiple metabolic pathways that may lead to different products.

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Verbal Rating Scale (VRS-11)

A measure of pain intensity on a scale of 0 to 10, where 0 represents no pain and 10 represents the worst imaginable pain.

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Patient-Controlled Analgesia (PCA)

A type of pain management where a patient controls the delivery of pain medication through a pump.

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Codeine Metabolism

A metabolic pathway where the body converts codeine to morphine, which is the active pain-relieving compound.

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CYP2D6

A gene polymorphism that influences how efficiently codeine is metabolized.

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Poor Metabolizer (PM)

A group of individuals who have specific genetic variations in CYP2D6, resulting in slower metabolism of codeine.

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Ultrarapid Metabolizer (UM)

A group of individuals who have specific genetic variations in CYP2D6, resulting in faster metabolism of codeine.

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Tramadol Metabolites

Tramadol is metabolized to produce 11 different active and inactive metabolites

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Active Tramadol Metabolite

Only one Tramadol metabolite (M1) possesses analgesic effects

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Enzyme Dependence

The formation of Tramadol metabolites depends on the activity of enzymes CYP2D6 and CYP3A4.

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Tramadol (+)-Enantiomer Action

The active enantiomer of Tramadol (+)-Tramadol acts as a weak opioid agonist and a serotonin reuptake inhibitor.

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Tramadol (-)-Enantiomer Action

The inactive enantiomer of Tramadol (-)-Tramadol acts as a noradrenaline reuptake inhibitor.

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M1 Binding Affinity

The active metabolite (+)-M1 binds to opioid receptors 700 times stronger than its parent compound (Tramadol).

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What is Morphine-6-glucuronide (M6G)?

Morphine-6-glucuronide (M6G) is a metabolite of morphine, meaning it's formed when the body breaks down morphine. It's an active metabolite, contributing significantly to morphine's pain-relieving effects.

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What happens to M6G in the body?

M6G is readily excreted from the body, but a small percentage (5-10%) can accumulate, especially in individuals with impaired kidney function, like the elderly. This accumulation can increase the risk of accidental overdose.

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What is special about M6G's lipophilicity?

M6G has a unique property called 'lipophilicity,' which means it can easily pass through cell membranes. This is unusual for a glucuronide, which are typically water-soluble. The increased lipophilicity of M6G enhances its ability to reach pain receptors in the brain.

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Is codeine-6-glucuronide active?

Codeine-6-glucuronide is a metabolite of codeine, but it doesn't have any pain-relieving effects. This means it's inactive.

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Why are M6G and codeine-6-glucuronide called 'molecular chameleons'?

Morphine-6-glucuronide (M6G) and codeine-6-glucuronide are known as 'molecular chameleons' because they can change their shape (conformation) depending on their environment. These shape changes can affect their ability to bind to receptors and influence their activity.

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Study Notes

ADME 1: Acute Pain 5 - Opioid Analgesics

  • The metabolism and pharmacogenetics of opioid analgesics are discussed in this presentation
  • Learning objectives include describing major metabolic routes and transformations, active metabolites' importance, and morphine/metabolite pharmacokinetics.
  • Another aspect is pharmacogenetics: explaining genetic variation's effect on metabolism, providing population phenotype examples, and how phenotypes influence common opioid metabolism.
  • Metabolism aims to remove xenobiotics, transforming lipophilic molecules into more hydrophilic ones for excretion.
  • Phase I modification involves adding chemical functionality (oxidation, hydrolysis, reduction) with key enzymes like CYP450 monooxygenases.
  • Phase II conjugation introduces charged/polar species (e.g., sulfation, glucuronidation, GSH conjugation) with key enzymes such as sulfotransferases and UDP glucuronosyltransferases.
  • The presentation gives main metabolic pathways and active metabolites for various opioids (buprenorphine, codeine, fentanyl, morphine, oxycodone, tramadol).
  • Morphine and Codeine phase-1 metabolism includes N-demethylation (CYP3A4) and O-demethylation (CYP2D6).
  • Nor-metabolites have limited clinical relevance, and patients deficient in CYP2D6 have reduced codeine effectiveness.
  • Morphine and Codeine phase-2 metabolism details conjugation with glucuronic acid or sulfate.
  • The conjugates are typically inactive and found in urine.
  • Phase II conjugation in the GI tract significantly impacts oral bioavailability of phenolic opioids, increasing polarity.
  • Morphine-6-glucuronide (M6G) is more active than morphine.
  • M6G can accumulate in renal impairment, increasing overdose risk.
  • Oxycodone metabolism involves oxymorphone formation through N-demethylation (CYP3A4).
  • Noroxycodone is less potent than oxycodone.
  • Tramadol has a complex metabolism with 11 metabolites, with (+)-M1 having significant analgesic activity.
  • (-)-M1 has minimal analgesic activity, and the metabolite formation depends on CYP2D6 and CYP3A4.
  • The presentation also describes various pharmacokinetic properties like oral bioavailability, protein binding, volume of distribution, half-life, and excretion of common opioids.
  • Morphine-3-glucuronide (M3G) is an inactive metabolite potentially associated with neurotoxic effects (e.g., myoclonus).
  • M3G and M6G have longer half-lives than morphine. Plasma concentrations of M3G and M6G are usually higher than morphine.
  • Metabolites accumulate in renal impairment.

Pharmacogenetics of Opioid Analgesics

  • CYP2D6 genetic variations affect opioid metabolism, categorized as extensive (EM), intermediate (IM), poor (PM), and ultrarapid (UM) metabolizers.
  • Different genotypes correspond to these phenotypes.
  • Poor metabolizers have limited codeine effectiveness due to impaired O-demethylation, leading to low morphine plasma concentrations.
  • Conversely, ultrarapid metabolizers experience extensive metabolism of codeine to morphine, potentially increasing opioid side effects.
  • Variations in CYP2D6 can affect tramadol metabolism, impacting (+)-M1 formation and increasing side effects.

Environmental Factors

  • Patient age, sex, hepatic and renal function, smoking, alcohol consumption, and concurrent medications influence opioid metabolism.

Summary

  • Active metabolites contribute to analgesic effects.
  • Pharmacogenetic differences and handling differences for analgesics, pain severity, individual response, and analgesic dose are difficult to predict.

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Explore the metabolism and pharmacogenetics of opioid analgesics in this quiz. Learn about key metabolic routes, the importance of active metabolites, and how genetic variations affect opioid metabolism. Dive into Phase I and II modifications to understand how the body processes these medications.

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