Peripheral Analgesics & NSAIDs Summary

Types of Pain

• Nociceptive pain: Normal response to stimuli (e.g., pinprick).
• Inflammatory pain: Tissue injury or infection (e.g., sunburn).
• Neuropathic pain: Damage to the nervous system; serves no useful purpose.

Definitions

• Hyperalgesia: Increased pain from supra-threshold stimuli.
• Allodynia: Pain from normally non-painful stimuli.
• Analgesia: Painlessness.

Nociception

• Physiological response to injury.
• Tissue injury leads to chemical release, activating nerve terminals.

Modulation of Nociceptive Pathway

• Mediators: Prostaglandins, bradykinin, serotonin, etc.
• Peripheral analgesics (e.g., NSAIDs) attenuate mediators affecting C-fiber activity.

Transduction at Nociceptive Afferents

• Modulators: Voltage-gated ion channels, ligand-gated ion channels, GPCRs, TrkA receptors.
• TRPV1 receptor: Key receptor activated by heat.

Analgesic Drugs

• Classic drugs: Opioids (centrally-acting), NSAIDs.
• NSAIDs and anti-inflammatory drugs have major overlap.

Peripheral vs Central Analgesics

• NSAIDs have some CNS effects.
• Opioids have effects in the periphery.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Treat pain and inflammatory conditions.
• Inhibit cyclo-oxygenase (COX) enzymes, reducing prostaglandin synthesis.

Cyclo-oxygenase Pathway

• Arachidonic acid (AA) liberated from membrane by PLA2.
• Synthesis of prostaglandins, prostacyclin, and thromboxane.

Cyclo-oxygenase Enzymes

• COX1: Constitutive, produces prostanoids for homeostatic regulation.
• COX2: Inducible, observed at sites of inflammation and relevant to hyperalgesia.
• NSAIDs target COX enzymes.

Aspirin

• Irreversibly inhibits COX enzymes.
• Non-selective, greater affinity for COX1.
• Used at low doses for antiplatelet effect.

Mechanisms of NSAID Action

• Therapeutic effects occur via COX2 inhibition.
• Adverse effects occur via COX1 inhibition.

Cyclo-oxygenase Binding Sites

• NSAIDs enter hydrophobic channel, preventing fatty acids from reaching catalytic domain.
• Aspirin acetylates Ser-530, causing irreversible inhibition.
• Amino acid Iso523Val produces side pocket in COX2.

Catalytic Activity of Cyclo-oxygenases

• COX enzymes are bifunctional.
• Most NSAIDs inhibit the dioxygenase step.

COX2 Inhibitors

• Selective for COX2 inhibition.
• Fewer GI effects but cardiovascular concerns.

Other Actions of NSAIDs

• Some NSAIDs scavenge free oxygen radicals.
• Aspirin inhibits expression of transcription factor NF-κB.

Paracetamol

• Analgesic and anti-pyretic but not anti-inflammatory.
• No GI bleeding or effects on platelets.

Paracetamol – Mechanism of Action

• Mechanism unclear.
• Weak COX inhibitor.
• May be mediated by active metabolite NAPQI.

Transient Receptor Potential A1 (TRPA1)

• Co-expressed with TRPV1 on nociceptive primary afferents.
• Responds to pain, itch, and cold.
• Leads to allodynia.

Paracetamol - Toxicity

• High doses can cause fatal liver damage.
• Antidote: N-acetyl cysteine.

Paracetamol Metabolism

• NAPQI is a toxic metabolite formed during paracetamol metabolism.
• Glutathione S-transferase detoxifies NAPQI; depletion leads to hepatotoxicity.