NONNARCOTIC ANALGESIC-ANTIPYRETICS AND NSAIDS

NONNARCOTIC ANALGESIC-ANTIPYRETICS AND NSAIDS

A. Salicylates

1. Chemistry

a. Salicylates are derivatives of salicylic acid, which is found as the glycoside salicin in willow bark. The prototypical drug is aspirin, the acetylester of salicylic acid. A simple ester, aspirin hydrolyzes easily, is unstable in aqueous media, and is affected by moisture.

b. Morestable salicylates include diflunisal (Dolobid) and the topical agent methyl salicylate (wintergreen oil). Other salicylates are salsalate (Disalcid); sodium thiosalicylate (Resolute; injectable); choline salicylate (Trilisate; oral liquid); and the salicylate derivatives mesalamine (Asacol), olsalazine (Dipentum), and sulfasalazine (Azulfidine).

c. Most salicylates are weak acids. Their excretion is influenced by changes in urinary pH.

Pharmacology

a. Salicylates inhibit the enzyme cyclooxygenase and thus inhibit local prostaglandin synthesis. As a result, they are analgesic for low intensity integumental pain, antipyretic, and anti- inflammatory. Note that aspirin is the only salicylate that irreversibly inhibits cyclooxygenase by covalent acetylation of the enzyme.

b. Salicylates also block platelet cyclooxygenase and subsequent formation of thromboxane A2. As a result, they inhibit platelet aggregation and eventual thrombus formation.

B. p-Aminophenol derivat ives

1. Chemistry. The prototypical p-aminophenol derivative is acetaminophen (Tylenol), an active metabolite of phenacetin and acetanilid.

2. Pharmacology

a. p-Aminophenol derivatives inhibit central prostaglandin synthesis, presumably through a selectivity for COX-3 with relatively little or no activity on COX-1 or COX-2. They are analgesic for low- intensity pain and are antipyretic.

b. Because they are less effective than salicylates in blocking peripheral prostaglandin synthesis, they have no anti-inflammatory activity and do not affect platelet function.

C. Pyrazolone derivatives

1. Chemistry. The most important pyrazolone derivatives are phenylbutazone, its metabolite oxyphenbutazone, and the uricosuric agent sulfinpyrazone (Anturane). Phenylbutazone is the prototypical agent.

2. Pharmacology

a. Phenylbutazone, oxyphenbutazone, and azapropazone inhibit prostaglandin synthesis and stabilize lysosomal membranes. As a result, they have analgesic, antipyretic, and anti-inflammatory effects. They also have good uricosuric activity.

b. Sulfinpyrazone inhibits proximal tubular absorption of urate and has a uricosuric effect. However, it is devoid of analgesic, antipyretic, or anti-inflammatory effects.

D. Agents used for the treatment of gout

1. Chemistry

a. Acute attacks of gout result from an inflammatory response to joint depositions of sodium urate crystals. Therapeutic agents counter this response by reducing plasma uric acid concentrations or inhibiting the inflammatory response.

b. Agents used for the treatment of gout have widely varying structures and include the pyrazolone derivative sulfinpyrazone; the alkaloid colchicine; isopurines, such as allopurinol (Zyloprim); and benzoic acid derivatives, such as probenecid (Benemid).

2. Pharmacology

a. Colchicine's mechanism of action is presumed to be related to its antimitotic activity. It inhibits tubul in synthesis, which is required for the movement of inflammatory cells. Through its ability to prevent tubul in polymerization, colchicine appears to inhibit chemotaxis of leukocytes and other inflammatory cells in the affected joint, thus reducing the inflammatory response to deposited urate crystals by inhibiting leukocyte migration and phagocytosis. It also interferes with kinin formation and reduces leukocyte lactic acid production.

b. Allopurinol reduces serum urate levels by blocking uric acid production. It competitively inhibits the enzyme xanthine oxidase, which converts xanthine and hypoxanthine to uric acid.

c. Probenecid, a uricosuric agent, inhibits the proximal tubular reabsorption of uric acid, increasing uric acid excretion, thus reducing plasma uric acid concent rations.

E. NSAIDs

1. Chemistry

a. The classic NSAIDs consist of many structurally diverse acids. These include propionic acid derivatives (fenoprofen [Nalfon], flurbiprofen [Ocufen], ibuprofen [Motrin], ketoprofen [Orudis], naproxen [Anaprox, Naprosyn], and oxaprozin[Daypro]), acetic acid derivatives (diclofenac [Voltaren], etodolac [Lodine], indomethacin [Indocin], ketorolac [Toradol], sulindac [Clinoril], and tolmetin [Tolectin] and the subclass of the fenamates or anthranilic acid derivatives meclofenamate and mefenamic acid [Ponstel]), and the enolic acid derivatives (piroxicam [Feldene], meloxicam [Mobic], and nabumetone [Relafen]).

b. Selective COX 2 inhibi tors celecoxib (Celebrex) and rofecoxib (Vioxx), and valdecoxib (Bextra) are pyrazole derivatives.

2. Pharmacology

a. Nonspecific NSAIDs have anti-inflammatory effects, resulting from their ability to inhibit the cyclooxygenase enzyme system and thus reduce local prostaglandin synthesis.

b. NSAIDs also have analgesic and antipyretic effects. In addition, some NSAIDs have mild uricosuric activity. Some agents also have weak inhibitory activity for lipoxygenase, mild selectivity for COX-2, and weak to moderate ability to inhibit leukocyte proliferation and migration and to stabilize lysosomal membranes. The clinical relevance of these secondary actions has not been elucidated.

c. COX-2 inhibitors exert anti-inflammatory effects by specifically inhibiting prostaglandin synthesis associated with the inflammatory response. Their ability to decrease pain and inflammation associated with arthritic diseases is approximately equal to that produced by the nonselective NSAIDs. Moreover, by virtue of their selectivity, thei ractions on gastric mucosa and platelet aggregation are theorized to be less than the nonselective NSAIDs.