Nonsteroidal Antiinflammatory Drugs

NSAIDs are used to treat symptoms not diseases – three effects related to prostaglandin synthesis:

Aspirin – oldest and safest of the NSAIDs

Aspirin is acetosalicylic acid; it irreversibly inhibits COX (acetylation of active site; most NSAIDs reversibly inhibit COX)

after acetyl group is donated, aspirin becomes salicylic acid, which inhibits a promoter of COX-II
because of very short T_½ of acetylated form (10-15 min), most is converted to salicylic while in portal circulation

acetylsalicylic acid never reaches the synovium – all joint effects are probably due to salicylic acid

anti-inflammatory effects also occur through alteration of CT metabolism and antigen-antibody interactions

Aspirin is relatively safe; Americans consume 300 tons per year (1-2 tablets per person per day)

can safely tolerate many grams per day – some RA patients take 20 grams per day or more without serious problems
one problem is acid-base imbalance – alkalosis (CO₂ metabolism derangement), acidosis (salicylate is an acid)
at high doses, salicylic acid inhibits respiration, a medical emergency – common cause of child poisoning

Other Nonsteroidal Anti-inflammatory Agents – ibuprofen, naproxin, etc.

NSAIDs act only by blocking COX. All therapeutic effects and side effects arise from this.

NSAIDs have a longer T_½ than aspirin, so that lower doses reach poorly-perfused areas (like joints); also higher toxicity

Note: Acetaminophen is not an NSAID. Since it only blocks COX in the CNS, it has no anti-inflammatory effects.

Glucocorticoids

mimic the action of cortisol (an essential endogenous protein)

Cortisol is released only from the glomurosa fasciculata of the adrenal cortex

stimulated by ACTH (adrenocorticotrophic hormone) from anterior pituitary; ACTH also maintains adrenal cortex
ACTH release stimulated in turn by CRF (corticotrophin releasing factor) from the hypothalamus
stress (physical, emotional, infection) starts the whole process

What does cortisol do? – as a steroid, cortisol binds cytosolic receptors and alters transcription of many proteins

one of these proteins (lipocortin) inhibits phospholipase A₂ causing decrease in arachadonic acid and prostaglandins

Side Effects – more prevalent with long-term use of glucocorticoids

Atrophy of Adrenal Cortex – due to inhibition of ACTH (trophic for the adrenal glands)

cortisol provides negative feedback on its own production by inhibiting ACTH and CRF release

Derangement of Energy Metabolism – cortisol is a major regulator of energy metabolism (with insulin and glucagon)

increases muscle breakdown for gluconeogenesis and inhibits utilization of glucose; muscle atrophy

Suppression of Immune System – induces apoptosis of lymphocytes causing leukopenia

Suppression of Other Pituitary Hormones – e.g., growth hormone; causes growth suppression

Alteration of Calcium Metabolism in Bone – causes severe osteoporosis with chronic use

Suppression of Menstruation, Vascular Necrosis, Cataracts, Euphoria or Dysphoria – uncertain mechanisms

Therapeutic considerations – glucocorticoids are unparalleled in their effectiveness as anti-inflammatory drugs

single dose of any size is safe; <2 weeks requires reasonable dosing; >2 weeks requires weaning from the drug
local injection is benign and very effective

Other Drugs for Inflammatory Disease

methotrexate – folate acid antagonist – impairs one-carbon transfer step used in DNA synthesis

inhibits proliferation of lymphocytes that mediate destruction of the joint, so may actually slow joint erosion

side effects: anorexia, GI irritation (bleeding), teratogenesis (not for pregnant women)

gold – injections are somehow anti-inflammatory, and may slow progression of disease

however, it takes several weeks to work, only works in half of patients, and has many unpleasant side effects

leflunomide (arava) – inhibits dihydroorotate dehydrogenase (required for UMP synthesis)

action and side effects similar to methotrexate, but activates p53 and so may predispose to neoplasia

etanercept (enbrec) – soluble TNF receptor bound to Ig that soaks up TNFa – long T_½ (115 hours!)

matrix metalloproteases inhibitors – at least 100 possible targets for inhibition – drugs not yet available