Pharmacology - Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are highlighted as widely used drugs that alleviate pain through specific pharmacological actions. The explanation connects their effectiveness to the fundamental workings of the pain pathway, emphasizing the role of the somatic sensory cortex in perceiving sensations. This concise overview bridges the clinical use of NSAIDs with the underlying neural mechanisms of pain.

The somatosensory cortex distinguishes touch and pain by mapping different body regions. The brainstem, consisting of the midbrain, pons, and medulla, extends into the spinal cord where sensory neurons enter from the dorsal side. Tissue damage triggers immune cells to release inflammatory mediators such as prostaglandins, bradykinin, serotonin, and histamine, stimulating these sensory neurons. This cascade further amplifies the response by prompting the release of substances like substance P and CGRP along the neural pathways.

Prostaglandin E2 triggers cell depolarization, generating an action potential that initiates pain signal transmission. The signal travels to the spinal cord’s dorsal horn where a first-order neuron synapses with a second-order neuron. This second-order neuron crosses over to the opposite side and ascends through the spinothalamic tract to reach the thalamus. In the thalamus, the relay of the signal continues to a third-order neuron, which directs the pain information to the somatosensory cortex for precise localization.

Injury triggers cells to convert membrane phospholipids into arachidonic acid, which is subsequently transformed into prostaglandin H2 and then into prostaglandins E2 and F2. These prostaglandins play a pivotal role in triggering pain, fever, and inflammation. The process is mediated by two distinct enzymes: COX-1, which maintains homeostasis, and COX-2, which is activated during trauma. In platelets, a slightly different pathway converts prostaglandin H2 into thromboxane A2, essential for blood clotting.

NSAIDs reduce inflammation, relieve pain, and lower fever by inhibiting the cyclooxygenase enzyme. They are classified as non-selective drugs, like aspirin, ibuprofen, and naproxen, which block both COX-1 and COX-2, or as selective agents that specifically target COX-2. The non-selective inhibitors reduce platelet aggregation, potentially increasing bleeding risk, and may also trigger allergic reactions and bronchospasm.

Aspirin thins the blood by inhibiting COX in platelets, preventing thromboxane A2 formation and platelet aggregation. In the stomach, blocking COX-1 reduces protective prostaglandins, allowing increased acid production that can lead to dyspepsia, ulcers, and hemorrhage. In the kidneys, the inhibition of prostaglandin synthesis impairs blood flow and may result in injury. The combination of NSAIDs, diuretics, and ACE inhibitors creates a 'triple whammy' that heightens the risk of renal damage.

Selective NSAIDs were developed to mitigate the side effects seen with non-selective versions. Paracetamol acts as a potent analgesic and antipyretic, potentially by inhibiting a Cox enzyme isoform, though its exact mechanism remains unclear. Despite its effectiveness in relieving pain and fever, paracetamol lacks anti-inflammatory properties and carries a risk of liver toxicity at high doses.