Analgesics and Pain Management Overview

Analgesics

• Analgesics are compounds with varied mechanisms, relieving a wide range of pain causes.
• They're categorized based on therapeutic use:
  • Opioids (narcotic analgesics) play a key role in managing acute and moderate-to-severe chronic pain.
  • NSAIDs and acetaminophen are commonly used to relieve mild-to-moderate pain and reduce fever.
  • Other classes include triptans (antimigraine), analgesic adjuvants (tricyclic antidepressants, anticonvulsants, topical analgesics).

Pain

• Pain is a frequent medical complaint with diverse underlying causes, symptoms, and neurobiological mechanisms.
  • Physiological (nociceptive) pain, the most common type, often originates from injuries to body organs or tissues. It's further classified into cutaneous, somatic, and visceral pain.
  • Inflammatory pain results from infection or tissue damage.
  • Neuropathic pain is complex and chronic, often stemming from nervous system injury (e.g., limb amputation, spinal surgery, shingles).

Opioid Receptor Discovery and Endogenous Ligands

• Enkephalin, the first endogenous peptide, is a mixture of Met-enkephalin and Leu-enkephalin, differing only in their terminal amino acids.
• The actions of enkephalins are transient, correlating with rapid degradation of the Tyr-Gly bond by aminopeptidases.

SARs of Enkephalins

• The first amino acid, tyrosine (Tyr¹), shows preference for this residue.
• Changes in this residue, whether by substitution or masking of hydroxyl, often result in inactive or weakly active peptides.

GLY2

• Replacing naturally occurring L-glycine with various D-amino acids leads to peptides resistant to aminopeptidase cleavage.
• This substitution is the most effective replacement, while L-amino acid analogs show limited activity.

MET5/LEU5

• Position 5 tolerates more residue changes compared to other positions.
• Many amino acid substitutions at this position retain peptide activity.

Opioid Receptors

• Opioid receptors are widely distributed throughout the brain, spinal cord, and peripheral tissues (μ, δ, and κ).
• Activation triggers inhibition of adenylate cyclase, decreasing cAMP production and affecting various cellular processes, including nociceptive C-fiber calcium influx.
• Endogenous opioid peptides for the μ-receptor include endomorphin-1, endomorphin-2, and β-endorphin.
• Exogenous agonists bind to the μ-receptor, producing analgesia, respiratory depression, decreased gastrointestinal motility, and euphoria, contributing to opioid addiction.

8-Receptor

• Endogenous opioid peptides for the δ-receptor include Met-enkephalin and Leu-enkephalin, and some synthetic peptides have high receptor affinity, although low bioavailability.

κ-Receptor

• Kappa receptors are primarily found in the limbic system, brainstem, and spinal cord.
• TRK-820 exhibits substantial selectivity for κ-receptors, compared to μ-receptors.
• Methyl-substituted nitrogen amides, with a methylene spacer, are crucial for κ-receptor activity.

Other Analgesics (Examples)

• Morphine: Prototype μ-receptor ligand, commonly used for severe and postoperative pain, however, it has many side effects.
• Codeine: Morphine derivative metabolized to morphine, acting as a cough suppressant, with some analgesic properties.
• Heroin: Morphine derivative exhibiting quicker blood-brain barrier penetration & higher potency, but also significantly increased toxicity & addiction potential.
• Hydromorphone: Morphine derivative with slightly enhanced binding and potency.
• Hydrocodone: Morphine derivative with better brain penetration & increased κ-receptor binding.
• Oxycodone: Hydrocodone derivative, exhibiting greater potency and receptor affinity.
• Oxymorphone: Hydromorphone derivative with increased receptor binding affinity, but lower bioavailability.
• Dextromethorphan: Two-ring morphinan; OTC cough/cold preparation used to treat symptoms, but potentially abused.
• Pentazocine: Benzomorphan acting as a partial agonist/antagonist at μ-receptors; also an agonist at κ-receptors.
• Meperidine: μ-receptor agonist with some potency gains by structural changes like m-hydroxyl addition on the phenyl ring; metabolized to normeperidine.
• Diphenoxylate: Weak opioid agonist, combined with atropine in OTC antidiarrheal preparations.
• Loperamide: 4-phenylpiperidine used as an antidiarrheal, showing increased potency after substituting the 4-phenyl group with a 4-anilide.
• Fentanyl: High lipophilicity and rapid metabolism contribute to rapid onset & short duration of action; highly potent derivative.
• Remifentanil: Designed for rapid metabolism; ester group is metabolized by esterases, resulting in a very short duration of action.
• Methadone: Synthetic opioid for analgesic therapy and opioid addiction maintenance; a μ-receptor agonist.
• Tramadol: Weak μ-agonist with analgesic effects, somewhat antagonized by naloxone.
• Naltrexone: Pure opioid antagonist at all opioid subtypes acting as a treatment of opioid dependence.
• Naloxone: Pure opioid antagonist reversing opioid-induced respiratory depression from overdose

This quiz covers the various types of analgesics, including opioids, NSAIDs, and their uses in pain management. It also examines different types of pain, such as nociceptive, inflammatory, and neuropathic pain, providing insights into their causes and treatment options.