Opioid Analgesics Metabolism Quiz

ADME 1: Acute Pain 5

• This presentation focuses on the metabolism and pharmacogenetics of opioid analgesics.
• It covers major metabolic routes and transformations of relevance to opioid analgesics.

Learning Objectives

• Opioid Analgesic Metabolism:
  • Describe major metabolic routes and transformations.
  • Explain the importance of active metabolites in analgesic potency (e.g., morphine, codeine, oxycodone, tramadol).
  • Describe the pharmacokinetic profile of morphine and its metabolites.
• Pharmacogenetics:
  • Explain how genetic variation leads to different metabolic phenotypes.
  • Provide examples of populations with prevalent phenotypes.
  • Describe the impact of phenotypic differences on the metabolism of common opioid analgesics.

Metabolism - Revision

• Metabolism aims to remove xenobiotics (foreign substances) from the body.
• Lipophilic molecules are transformed into more hydrophilic molecules to facilitate excretion.
• Phase I Modification:
  • Introduces chemical functionality (e.g., oxidation, hydrolysis, reduction).
  • Key enzymes include CYP450 monooxygenases, monoamine oxidases, peroxidases, reductases, esterases, and amidases.
• Phase II Conjugation:
  • Introduces charged/polar species (e.g., sulfation, glucuronidation, GSH conjugation).
  • Key enzymes include sulfotransferases, UDP glucoronosyltransferases, and glutathione S-transferases.

Opioid Metabolism

• Shows the main metabolic pathways and active metabolites for various opioids (buprenorphine, codeine, fentanyl, morphine, oxycodone, tramadol).
  • Example: Codeine's active metabolite is Morphine-6-Glucuronide (M6G).
  • Example: Oxycodone's active metabolite is Oxymorphone.

Morphine and Codeine - Phase 1 Metabolism

• Many µ-receptor agonists have an N-methyl group easily dealkylated by CYP 3A4, creating a "nor" metabolite.
• Nor-metabolites have limited clinical relevance due to decreased distribution, loss of agonist-promoting properties, and reduced receptor interaction.
• Patients deficient in CYP2D6 cannot effectively O-dealkylate codeine, resulting in a reduced or absent analgesic response to codeine-based analgesics.

Morphine and Codeine - Phase 2 Metabolism

• Phenols in opioids can conjugate with glucuronic acid or sulfate.
• Both conjugates are frequently found in the urine of patients taking multicyclic opioids.
• Mostly inactive.
• Phase II conjugation in the GI tract significantly increases the polarity of phenolic opioids and impacts oral bioavailability.

Morphine and Codeine - Phase 2 Metabolism

• Morphine-6-glucuronide (M6G) is generally more active than morphine.
• M6G is readily excreted, but can accumulate in individuals with renal impairment or poor renal function.
• Increased risk of overdose in susceptible individuals.
• "Molecular chameleon" behavior of morphine metabolites.

Oxycodone Metabolism

• Oxycodone is about 8 times more potent than codeine in vitro.
• Oxymorphone is a key active metabolite of oxycodone, formed through O-demethylation.
• N-demethylation leads to noroxycodone (which is substantially less potent than oxycodon).
• Approximately 83% or 95% (oral and IV, respectively) of analgesic effect is from these metabolites.

Tramadol Metabolism

• Tramadol undergoes complex metabolism involving both phase I and II.
• Eleven metabolites have been identified.
• Only M1 has significant analgesic activity.
• (+)-Tramadol is a weak opioid agonist and serotonin reuptake inhibitor.
• (-)-Tramadol is a norepinephrine reuptake inhibitor.
• (+)-M1 has a higher affinity for μ-opioid receptors than its parent compound.
• (-)-M1 shows negligible analgesic activity.

Pharmacokinetics of opioid analgesics

• A table outlining various opioid pharmacokinetic properties: Log D, oral bioavailability, protein binding, V, T½, duration, excretion, onset, and maximum analgesic effect time.

Pharmacogenetics of Opioid Analgesics

• Focus on pharmacogenetics of opioid analgesics.
• Presents different possible drug metabolism phenotypes in humans associated with CYP isoforms and their corresponding genotypes.

CYP2D6 single nucleotide polymorphisms

• Describes how CYP2D6 polymorphisms affect outcomes by comparing poor and ultra-rapid metabolizers.
  • Poor metabolizers have less morphine formation and minimal analgesic response to codeine.
  • Ultra-rapid metabolizers generally metabolize codeine and other drugs faster, increasing risk of side effects and needing higher doses to achieve therapeutic effects.

Is It Still Appropriate to Use Codeine?

• Questions if codeine should still be used as it has poor analgesic properties, unpredictable pharmacokinetics, and genetic influences may contribute to fatalities, particularly in neonates and children.

M6G as an Analgesic

• Similar analgesic effects to morphine, with fewer side effects (less respiratory depression, nausea, and anti-emetic, less sedation in first 4 h post-op).
• Cost-effective.

Environmental Factors

• Factors such as patient age, sex, hepatic and renal function, lifestyle choices (smoking, alcohol consumption), and concurrent medications can impact opioid metabolism.

Summary

• Active metabolites contribute significantly to the analgesic effects of most opioids.
• Pharmacogenetic differences impact drug handling and predict unpredictable outcomes.
• Difficulties in predicting pain severity, analgesic dose, and individual responses to analgesics stem from these issues.

Test your knowledge on the metabolism of opioid analgesics with this quiz. Explore key concepts such as metabolic phases, active metabolites, and the impact of genetic variation on drug metabolism. Perfect for students studying pharmacology or related fields.