4. Nonsteroidal anti-inflammatory drugs (NSAIDs), opioids and their mechanism of action

NSAIDs exhibit their analgesic effect due to the inhibition of prostaglandin synthesis at the peripheral nerve endings, while opioids demonstrate their effect in central nervous system through its depression [41]. NSAIDs mechanism of action is through the inhibition of prostaglandin and thromboxane (eicosanoids) biosynthesis by inhibition of cyclooxygenase activity (COX-1 discovered by John Vane or COX-2 from Daniel Simmons) in reversible or irreversible fashion and dose-dependent manner competition of arachidonic acid. In the past four decades, many new drugs such as piroxicam, flurbiprofen, diclofenac, naproxen, ibuprofen, etoricoxib and celecoxib were introduced based on their COX activity. Their mechanism of action depends on whether they inhibit COX-1, COX-2, or both, which are responsible for the synthesis of different prostaglandins found in pathological situations (COX-2 is more expressed in inflammatory conditions). However, this inhibition also results in the loss of some protective effects of prostaglandins with respect to the gastrointestinal (COX-1), cardiovascular, platelet and renal function [42]. Taking this into consideration, COX-1 inhibitors are more prone to cause gastrointestinal bleeding, which can be prevented by a switch to COX-2 inhibitors. However, short-term use of the latter is recommended based on their cardiovascular side effects which results from the imbalance of PGI2 as antithrombic mediator and as one of the most important prostanoid in regulating homeostasis of the cardiovascular system and also TXA2 as prothrombic mediator [43–45]. Recently, there has been an increasing interest in their effects extended beyond COX enzymes and fascinating results have been shown in different pathologies such as cancer through major cellular signaling pathways, which mediate inflammatory response [46, 47].

Opioid mechanism of action is mediated via their affinity for μ, κ, δ and opioid receptor like-1 (ORL-1) which are G-protein-coupled opioid receptors acting on GABAergic neurotransmission, in CNS and throughout the body, by acting as agonists, weak agonists and partial agonists. These responses are mainly mediated from Gi proteins by closing N-type voltageoperated calcium channels and opening calcium-dependent inwardly rectifying potassium channels, which result in hyperpolarization and reduction in neuronal excitability. Another mediated effect is the decrease of intracellular cAMP, which modulates the release of substance P, a nociceptive neurotransmitter [48].

These receptors are activated also by endogenous ligands such as endorphins. It is shown that their action is also dose mediated by showing better efficacy when the dose increased. However, side effects should be taken into consideration. Most significant opioid effects are mediated through μ and κ receptors including for morphine and other semisynthetic and synthetic drugs such as meperidine, methadone, hydrocodone, oxycodone, fentanyl, buprenorphine, pentazocine and tramadol.
