Chapter: Modern Pharmacology with Clinical Applications: Opioid and Nonopioid Analgesics

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COX-2 Inhibitors

Celecoxib (Celebrex) and rofecoxib (Vioxx) are the two available COX-2 inhibitors.

COX-2 Inhibitors

Chemistry

Celecoxib (Celebrex) and rofecoxib (Vioxx) are the two available COX-2 inhibitors. Both lack a carboxylic group present in most NSAIDs and therefore are able to orient into the COX-2 enzyme in a selective manner that differs from that of other NSAIDs. They have low aque-ous solubility that prevents parenteral administration.

Mechanism of Action

As previously discussed, the COX-2 inhibitors have se-lectivity for inhibition of the COX-2 enzyme, which has low constitutive activity but is highly inducible at sites of tissue injury. In addition to the peripheral role of COX-2 in inflammation, COX-2 may play an important role in the CNS. COX-2 is expressed constitutively in some excitatory neurons in the brain and spinal cord and is induced in traumatic brain injury such as that in-duced by ischemia and seizures. It has been hypothe-sized that COX-2 may also be involved in neurodegen-erative diseases, since COX-2 inhibitors have shown some positive effects in Alzheimer’s disease. Thus, the mechanism of action of COX-2 inhibitors may involve brain and spinal cord sites as well as local sites of injury.

Pharmacological Effects and Clinical Uses

Celecoxib has been approved for the treatment of os-teoarthritis and rheumatoid arthritis, and rofecoxib has been approved for the treatment of osteoarthritis, acute pain and primary dysmenorrhea. Celecoxib and rofe-coxib do not appear to differ in efficacy for the treat-ment of osteoarthritis. However, neither drug has effi-cacy greater than that of the non-selective NSAIDs. Since the COX-2 enzyme appears to play an important role in colon cancer the COX-2 inhibitors may find fu-ture uses in the treatment or prevention of colorectal cancer.

Adverse Effects, Contraindications

The major advantage of the COX-2 inhibitors is their decreased GI effects and formation of gastric ulcera-tions compared with the COX nonselective agents. However, once an ulcer is present, COX-2 is induced in response, and the COX-2 enzyme is essential for wound healing. Therefore, celecoxib and rofecoxib can delay in wound healing and increase the time for ulcer repair and tissue regeneration. Patients with gastric ulcers should be switched if possible to another antiinflamma-tory to allow ulcers to heal.

Celecoxib is contraindicated during pregnancy, since COX-2 levels must be maintained for ovulation and on-set of labor. COX-2 seems to be involved into the regu-lation of the renin–angiotensin system, and both cele-coxib and rofecoxib use are associated with transient sodium retention.

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