Pharmacology of COX Inhibitors and Prostaglandins

COX Inhibitors

• Can reduce renal function
• Can worsen hypertension and congestive heart failure (CHF)

Reproductive Organs

• Female
  • Uterus
    • Prostaglandins stimulate and initiate labor and can induce abortion
    • Cause uterine contractions during menstruation causing pain (dysmenorrhea)
      • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) help reduce pain
• Ductus Arteriosus
  • Prostaglandins maintain a patent ductus arteriosus in utero
    • NSAIDs given late in pregnancy can cause premature closure, leading to pulmonary hypertension in the newborn
    • NSAIDs can help close the ductus arteriosus in premature babies
      • High doses of indomethacin and ibuprofen are used for this

Central and Peripheral Nervous System Actions

• Prostaglandin E1 (PGE1) and Prostaglandin E2 (PGE2) increase body temperature at the hypothalamus
• Prostaglandin D2 (PGD2) can induce natural sleep
• PGE1 and PGE2 inhibit norepinephrine (NE) release from postganglionic sympathetic nerve endings
  • NSAIDs block this effect, causing vasoconstriction
  • PGE2 can cause hyperalgesia by reducing the threshold of nociceptor neurons and increasing leukocyte recruitment, causing inflammation
• The analgesic effects of NSAIDs are mostly due to their central action of preventing PGE2-induced reduction of glycinergic inhibition

Pharmacology of NSAIDs

• Most are organic acids (except Nabumetone) and act reversibly (except aspirin)
• Some are short-acting, with a half-life of 10 hours
• Aspirin is irreversible, resulting in longer-lasting effects than predicted by its half-life
  • COX enzyme must be re-synthesized for normal function
• Organic acids accumulate at sites of inflammation, targeting the desired site of action
• Most are well absorbed orally, metabolized by the liver, renally excreted, and highly bound to albumin (>98%)

Therapeutic Effects

• Antipyretic, analgesic, anti-inflammatory
  • Acetaminophen (Tylenol) lacks anti-inflammatory action

Adverse Effects

• Can cause acute bronchoconstriction in patients with asthma
• Can worsen gout
  • Low-dose aspirin (81mg) is generally safe, while therapeutic doses (325mg) decrease urate excretion
    • Very high doses increase urate excretion
• Reye's syndrome linked to aspirin given to children with viral infections and fever
• Avoid in gastrointestinal (GI) disease
• Avoid in head trauma due to risk of bleeding
• Caution in renal failure
• Use with caution during pregnancy, as it is excreted in breast milk

Indomethacin (Indocin)

• Available orally, intravenously, as a suppository, and as an ophthalmic preparation
• Similar anti-inflammatory, analgesic, and antipyretic actions as salicylates, but more potent than aspirin
• Non-selective COX-1 and COX-2 inhibitor
• Indications
  • Primarily for rheumatoid arthritis, osteoarthritis, acute gouty arthritis, and eye pain
  • Used to facilitate closure of patent ductus arteriosus in premature babies
• Adverse Effects
  • Up to 33% of patients discontinue due to adverse effects
    • GI pain, hemorrhage, diarrhea, pancreatitis, headache, rarely psychosis, hallucinations, and some renal problems can occur

Propionic Acid Derivatives

• Better tolerated than aspirin and indomethacin
• Similar efficacy to aspirin, but aspirin is cheaper
• Indications
  • Alleviation of pain and inflammation in many disorders including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, tendonitis, bursitis, and dysmenorrhea
• All are relatively equal, but naproxen may have an advantage in analgesia and tolerability

Ibuprofen (Motrin, Advil)

• Dose range: 1200mg-3200mg/day
• Can be given with food to reduce GI effects
• Half-life: 2 hours
• 5-15% of patients discontinue due to GI problems
• Not recommended during pregnancy or breastfeeding
• Toxicity is similar to salicylism
• Less anti-inflammatory action than other NSAIDs
• Alternative to indomethacin for patent ductus arteriosus
• Injectable formulation for pain and fever in patients unable to take oral medication

Naproxen (Aleve, Naprosyn)

• Fully absorbed, peak plasma concentration reached in 2-4 hours
• Antipyretic Effects
  • Reduces elevated temperature, minimally affecting normal temperatures
  • Through the inhibition of COX in the hypothalamus
• Antiplatelet Effects
  • Irreversible acetylation of COX-1 blocks thromboxane A2 (TXA2) formation
  • Also blocks prostacyclin, but clinically the TXA2 effect predominates
  • Irreversible inhibition in platelets is long (8-11 days, lifespan of the platelet)
    • Platelets need to be replaced, so patients are advised not to take NSAIDs within 7 days of surgery
      • Can be problematic with coronary disease, increasing the risk of myocardial infarction (MI)
      • Prolonged bleeding time usually returns to normal within 36 hours, but 7 days is recommended

Clinical Uses of Aspirin

• Analgesia, antipyresis, anti-inflammatory
• Mild to moderate pain (not visceral)
  • Headache, arthritis, dysmenorrhea
  • Combined with opioids, like oxycodone (Percodan), for moderately severe pain (dentistry)
• Rheumatoid arthritis, osteoarthritis, etc. (lowest effective dose ~ 3g/day)
• Prophylactic use for coronary artery disease, etc.
  • Selective blocking of TXA2 in platelets
    • Low dose of 40-80mg/day

Aspirin Intoxication (Salicylism)

• Can occur and be fatal if high amounts are ingested (10-30gms; 300-350µg/ml)
• Mild, Chronic Symptoms
  • Headache, dizziness, tinnitus, hearing loss, dimness of vision, mental confusion, lassitude, sweating, thirst, hyperventilation, and nausea
• More Severe Symptoms
  • Convulsions, coma, skin eruptions, acid-base disruptions, fever, and dehydration
• CNS depression, cardiovascular collapse, and respiratory failure can lead to death
• Treatment
  • Cardiovascular and respiratory support
  • Removal of agent from the stomach with activated charcoal
  • Correction of acid-base abnormalities
  • Alkalinization of urine to facilitate excretion