Podcast
Questions and Answers
What is primarily responsible for the neuroexcitatory properties of morphine-3-glucuronide (M3G)?
What is primarily responsible for the neuroexcitatory properties of morphine-3-glucuronide (M3G)?
High-dose administration of morphine can lead to CNS excitation due to its metabolites.
High-dose administration of morphine can lead to CNS excitation due to its metabolites.
True
What is the active metabolite of morphine that has analgesic potency four to six times that of morphine?
What is the active metabolite of morphine that has analgesic potency four to six times that of morphine?
morphine-6-glucuronide (M6G)
Opioids are primarily converted to polar metabolites through a process known as _____ .
Opioids are primarily converted to polar metabolites through a process known as _____ .
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Which organ plays a key role in the excretion of opioid metabolites?
Which organ plays a key role in the excretion of opioid metabolites?
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Match the following metabolites with their effects or characteristics:
Match the following metabolites with their effects or characteristics:
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The accumulation of metabolites such as M3G and M6G is of little concern in patients with renal failure.
The accumulation of metabolites such as M3G and M6G is of little concern in patients with renal failure.
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Name one highly lipophilic opioid that can lead to accumulation if dosed frequently.
Name one highly lipophilic opioid that can lead to accumulation if dosed frequently.
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What type of opioid is morphine classified as?
What type of opioid is morphine classified as?
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Codeine is a full agonist at the u-opioid receptor.
Codeine is a full agonist at the u-opioid receptor.
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What is the general term for endogenous substances with opioid-like properties?
What is the general term for endogenous substances with opioid-like properties?
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The _______ effect may require a higher oral dose of morphine compared to parenteral doses.
The _______ effect may require a higher oral dose of morphine compared to parenteral doses.
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Match the following opioid peptides with their families:
Match the following opioid peptides with their families:
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Which of the following opioids is known for having reduced first-pass metabolism?
Which of the following opioids is known for having reduced first-pass metabolism?
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Nasal insufflation of opioids can lead to slower therapeutic blood levels due to first-pass metabolism.
Nasal insufflation of opioids can lead to slower therapeutic blood levels due to first-pass metabolism.
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What route can be used for the delivery of potent analgesics over several days?
What route can be used for the delivery of potent analgesics over several days?
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Which enzyme is primarily responsible for the metabolism of codeine, oxycodone, and hydrocodone?
Which enzyme is primarily responsible for the metabolism of codeine, oxycodone, and hydrocodone?
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Hydromorphone has been shown to form significant amounts of a 6-glucuronide metabolite.
Hydromorphone has been shown to form significant amounts of a 6-glucuronide metabolite.
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What metabolite of meperidine is known to accumulate in patients with decreased renal function?
What metabolite of meperidine is known to accumulate in patients with decreased renal function?
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The primary route of degradation for phenylpiperidine opioids is __________ metabolism.
The primary route of degradation for phenylpiperidine opioids is __________ metabolism.
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Match the opioid with its notable metabolic characteristic:
Match the opioid with its notable metabolic characteristic:
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What is a potential effect of high concentrations of normeperidine?
What is a potential effect of high concentrations of normeperidine?
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CYP3A4 is only found in the liver and has no role in first-pass metabolism.
CYP3A4 is only found in the liver and has no role in first-pass metabolism.
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What causes variation in analgesic response among patients regarding CYP2D6?
What causes variation in analgesic response among patients regarding CYP2D6?
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Study Notes
Definitions
- Opioid: Any substance, endogenous or synthetic, producing morphine-like effects. Opioid effects are blocked by antagonists like naloxone.
- Opiate: Compounds like morphine found in the opium poppy plant.
- Narcotic analgesic: An older term for opioids.
- Narcotic: Anything that induces sleep.
Introduction
- Morphine, a prototypical opioid agonist, is known for relieving severe pain.
- The opium poppy is the source of crude opium, from which morphine was isolated in 1803 by Serturner.
- Morphine was named after Morpheus, the Greek god of dreams.
- Morphine remains the standard against which other strong pain-relieving drugs are compared.
Analgesics
- Opioid analgesics include natural alkaloids, semi-synthetic alkaloid derivatives, synthetic surrogates, opioid-like drugs blocked by naloxone, and endogenous peptides interacting with opioid receptors.
Morphine and Analogues
- Morphine is a phenanthrene derivative.
- Opioid activity is possible due to free hydroxyl groups on its benzene ring.
- Variants of morphine are produced by substituting hydroxyl groups (e.g., diamorphine, codeine, oxycodone).
- Substitutions on the nitrogen atom produce antagonists like naloxone.
Synthetic Derivatives
-
Phenylpiperidine series:
- Meperidine (pethidine)
- Fentanyl, alfentanil, and sufentanil are shorter-acting but more potent.
- Remifentanyl is an analogue of fentanyl.
-
Methadone series: Methadone has no structural resemblance to morphine.
-
Benzomorphan series:
- Pentazocine
- Cyclazocine
-
Thebaine derivatives:
- Buprenorphine (very potent partial agonist)
- Etorphine (very potent full agonist, used in veterinary practice)
Relative Potencies
- A table showing potency values for various opioid drugs in relation to morphine (which equals 1).
Pharmacology of Opioid Analgesics
Source:
- Opium is derived from the poppy plant (Papaver somniferum and P album).
- After incision, a white substance from the poppy pod turns into a brown gum, crude opium.
- Opium contains alkaloids, with morphine being present at ~10% concentration.
- Codeine is synthesized commercially from morphine.
Classification
- Opioid drugs include full agonists, partial agonists, and antagonists.
- Morphine is a full agonist at the mu (μ) opioid receptor, which is the major pain-relieving opioid receptor.
- Codeine is a partial agonist at the mu receptor.
- Naloxone is a strong mu receptor antagonist.
Pharmacodynamics
- Mechanism of action: Opioid agonists relieve pain by binding to specific G protein-coupled receptors in the brain and spinal cord, involved in pain transmission and modulation.
- Receptor types: Three major classes of opioid receptors: mu (μ), delta (δ), and kappa (κ). All are G protein-coupled receptors with significant amino acid sequence homologies.
- Multiple receptor subtypes (e.g., μ₁, μ₂, δ₁, δ₂, κ₁, κ₂, κ₃) exhibit different potencies as agonists, partial agonists, or antagonists at multiple receptor classes or subtypes.
Relation of Physiologic Effects to Receptor Type
- Most opioid analgesics primarily act on the mu (μ) opioid receptor.
- Analgesia, euphoria, respiratory depression, and dependence mainly stem from μ receptor actions.
- Opioid analgesic effects are complex, also interacting with delta (δ) and kappa (κ) receptors.
Cellular Actions
- At the molecular level, opioid receptors couple with G proteins.
- This interaction affects ion channel gating, modulates intracellular Ca²⁺ levels, and alters protein phosphorylation.
Tolerance and Physical Dependence
- Repeated therapeutic doses of opioids can result in tolerance (gradual loss of effectiveness).
- Increased doses are required to maintain the original response.
- Physical dependence develops, marked by a withdrawal syndrome if the opioid is stopped or an antagonist is administered.
Organ System Effects
(These sections cover detailed effects on various organ systems: central nervous system, cardiovascular system, gastrointestinal tract, biliary tract, renal function, uterus, neuroendocrine, and others)
Clinical Applications
(This section provides specific examples of how opioids are used in clinical practice: in pain management, anesthesia, palliative care, and others).
Toxicity and Undesired Effects
- Direct toxic effects of opioid analgesics are primarily extensions of their acute pharmacological actions, resulting in respiratory depression, nausea, vomiting, constipation.
- Tolerance and dependence are notable potential issues.
Diagnosis and Treatment of Opioid Overdosage
- Intravenous naloxone is a key reversal agent for opioid overdose.
- Use of naloxone should not delay other appropriate treatments, especially respiratory support.
Contraindications and Cautions in Therapy
- Combining pure agonists with weak partial agonists (e.g. morphine with pentazocine) can diminish analgesia or induce withdrawal.
Use in Specific Patient Populations
(Detailed discussions of scenarios like pregnancy, head injuries, individuals with impaired pulmonary or renal function, and with endocrine imbalances)
Miscellaneous
Absorption, Distribution, Metabolism, Excretion
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