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Questions and Answers
Which of the following classes of analgesics is specifically designed for the acute treatment of migraine and cluster headaches?
Which of the following classes of analgesics is specifically designed for the acute treatment of migraine and cluster headaches?
What is the primary type of pain caused by an injury to body organs or tissues?
What is the primary type of pain caused by an injury to body organs or tissues?
Which opioid receptor subtype is primarily located in the brainstem and medial thalamus?
Which opioid receptor subtype is primarily located in the brainstem and medial thalamus?
What is the effect of activating opioid receptors on adenylate cyclase activity?
What is the effect of activating opioid receptors on adenylate cyclase activity?
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Which of the following is NOT considered an analgesic adjuvant?
Which of the following is NOT considered an analgesic adjuvant?
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What is the primary neurotransmitter whose release is decreased due to hyperpolarization of nerve cells following opioid receptor activation?
What is the primary neurotransmitter whose release is decreased due to hyperpolarization of nerve cells following opioid receptor activation?
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Which opioid receptor subtype is associated with endogenous peptides such as endomorphin-1 and β-endorphin?
Which opioid receptor subtype is associated with endogenous peptides such as endomorphin-1 and β-endorphin?
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Which type of pain is caused by an infection or inflammation as a result of tissue damage?
Which type of pain is caused by an infection or inflammation as a result of tissue damage?
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What is the equianalgesic oral dose of meperidine compared to morphine?
What is the equianalgesic oral dose of meperidine compared to morphine?
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Which structural change to meperidine increases its analgesic potency?
Which structural change to meperidine increases its analgesic potency?
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What is the primary risk factor for developing normeperidine toxicity?
What is the primary risk factor for developing normeperidine toxicity?
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Which statement about methadone is accurate?
Which statement about methadone is accurate?
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How does the metabolism of methadone primarily occur?
How does the metabolism of methadone primarily occur?
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Which of the following is NOT an adverse effect of methadone?
Which of the following is NOT an adverse effect of methadone?
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What is a potential side effect of normeperidine?
What is a potential side effect of normeperidine?
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Which modification to the N-group of meperidine does NOT produce an antagonist?
Which modification to the N-group of meperidine does NOT produce an antagonist?
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Which drug class is NOT considered an exogenous agonist for the μ-receptor?
Which drug class is NOT considered an exogenous agonist for the μ-receptor?
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What is a primary characteristic of δ-receptor activity in humans?
What is a primary characteristic of δ-receptor activity in humans?
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Which of the following is true regarding kappa (κ) agonists?
Which of the following is true regarding kappa (κ) agonists?
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Regarding the structure of morphine, how many chiral centers does it possess?
Regarding the structure of morphine, how many chiral centers does it possess?
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What must be taken into account when administrating morphine orally compared to intravenously?
What must be taken into account when administrating morphine orally compared to intravenously?
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How does meperidine compare to morphine in terms of potency and brain penetration?
How does meperidine compare to morphine in terms of potency and brain penetration?
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Which of the following effects is NOT associated with agonist activity at the μ-receptor?
Which of the following effects is NOT associated with agonist activity at the μ-receptor?
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What specific characteristic limits the use of potential δ-receptor targeting ligands?
What specific characteristic limits the use of potential δ-receptor targeting ligands?
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Study Notes
Opioid Receptors and Analgesics
- Analgesics are categorized by their therapeutic use into classes
- Opioids (narcotic analgesics) are major for acute and moderate-severe chronic pain relief
- NSAIDs and acetaminophen are commonly used for mild to moderate pain and fever reduction.
- Triptans (antimigraine medications) target migraine and cluster headaches.
- Analgesic adjuvants include tricyclic antidepressants (amitriptyline), anticonvulsants (gabapentin, pregabalin), and topical analgesics (lidocaine patches) for neuropathic pain.
Origin of Pain
- Pain is classified into physiological (nociceptive), inflammatory, and neuropathic types.
- Physiological pain results from injury to body organs or tissues.
- Inflammatory pain arises from infection or inflammation following tissue damage.
- Neuropathic pain is a chronic pain from nervous system injury.
WHO 3-Step Analgesic Ladder
- A step-wise approach to pain management
- Step 1: Non-opioid analgesics (acetaminophen or NSAIDs) with or without adjuvants.
- Step 2: Less potent opioids (hydrocodone, codeine, tramadol) with or without non-opioid analgesics and adjuvants.
- Step 3: Potent opioids (morphine, oxycodone) with or without non-opioid analgesics and adjuvants.
Opioid Receptors
- Opioid receptors are distributed throughout the brain, spinal cord, and peripheral tissues.
- These receptors (μ, δ, κ) often overlap.
- All opioid receptors are G-protein-coupled.
- Receptor activation inhibits adenylate cyclase, decreasing cyclic AMP (cAMP).
- This inhibits voltage-gated calcium channels, decreasing firing and release of pain neurotransmitters (e.g., glutamate, substance P).
The μ-Receptor
- Primarily located in the brainstem and medial thalamus.
- Endogenous peptides include endomorphin-1, endomorphin-2, and β-endorphin.
- Exogenous agonists include drug classes: 4,5-epoxymorphinan, morphinan, benzomorphan, 4-phenyl/4-anilido piperidines, and diphenylheptanes.
- Agonists produce analgesia, respiratory depression, decreased gastrointestinal motility, euphoria, and hormone release. Addictive effects are also linked to these receptors.
- Most clinically used opioid drugs act on the µ-opioid receptor.
The δ-Receptor
- Targeting these receptors is thought to lead to new treatments for schizophrenia, bipolar disorder, and depression.
- In humans, proconvulsive activity is reported,potentially limiting use.
The κ-Receptor
- Primarily found in the limbic, brainstem, and spinal cord.
- In clinical trials, most к-agonists produce dysphoria. This limits psychological addiction but is acceptable for patients.
- Some available compounds with к-agonist activity include pentazocine, nalbuphine.
- Clinical trials in humans show spiradoline (к-agonist), did not produce analgesia, but also did not produce dysphoria, diuresis, or sedation
SAR of Morphine
- Morphine is the prototype ligand for the µ-opioid receptor.
- It has 5 chiral centers and potentially 16 optical isomers.
- The naturally occurring and active form is the levorotatory enantiomorph.
- The X-ray structure is described as a "T" shape with defined rings formation.
SAR of Meperidine
- Meperidine has low potency at the μ-receptor vs. morphine (0.2% compared to morphine) but higher brain penetration (10% potency compared to morphine).
- Meperidine is a μ receptor agonist.
- Dose equivalence with morphine is described.
- Metabolism to normeperidine is described.
- The 4-ethyl ester is optimal length for analgesic potency.
- Structural changes that increase potency include the introduction of m-hydroxyl on the phenyl ring, replacing the methyl at N with a phenylethyl or p-aminophenyl group.
- Replacing the N-methyl with N-allyl/N-cyclopropylmethyl does not result in an antagonist.
- Analgesia duration may be shorter than the half-life, requiring frequent dosing to reduce pain.
- Normeperidine can cause CNS excitation, including tremors, twitches, and multifocal myoclonus, followed by grand mal seizures.
- Risk factors for normeperidine toxicity include high doses, long duration of treatment, renal dysfunction, or CYP inducers
SAR of Methadone
- Methadone (Dolophine) is a synthetic opioid for analgesia and opioid addiction treatment and maintenance.
- It is a racemic mixture, with R-enantiomer having about 7-50 times higher opioid activity than the S-enantiomer.
- Methadone is a μ-receptor agonist.
- The major metabolic pathway involves N-demethylation to EDDP, an inactive product.
- Adverse effects include standard opioid effects (pupil constriction, respiratory depression, physical dependence, extreme somnolence, coma, cardiac arrest, death), as well as QT interval prolongation and torsades de pointes.
Benzomorphans
- Structural simplification of morphine (removing the C ring of the morphinan structure) yields benzomorphans, also called benzazocines.
- Active benzomorphans have similar bridgehead carbons to morphine (carbons 9, 13 and 14 of morphine).
- Pentazocine is the only clinically used benzomorphan, and is prepared as the 2(R), 6(R), 11(R) enantiomer.
Pentazocine
- Pentazocine is a mixed agonist/antagonist opioid receptor. It is a partial agonist at the µ-receptor and a weak antagonist at the μ receptor.
- Pentazocine is also an agonist at the κ-receptor .
- This specific activity impacts higher rates of dysphoria in patients compared with morphine.
- It is available as a 50-mg tablet that also includes a low dose (0.5 mg) of naloxone (antagonist).
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Description
Explore the classifications of analgesics, including opioids, NSAIDs, and adjuvants for pain relief. Understand the origins of pain, differentiating between physiological, inflammatory, and neuropathic pain. Additionally, learn about the WHO 3-Step Analgesic Ladder for effective pain management.
