Pain Relievers, NSAIDS, and Gout

Here are the study notes:

Salicylates and Respiratory Center

• Salicylates directly stimulate the respiratory center in the medulla, leading to hyperventilation (increased rate and depth) and respiratory alkalosis
• Respiratory alkalosis is compensated in the kidney by loss of HCO3-, Na+, and K+ plasma pH is lowered to normal with a loss of fixed anion
• In children, respiratory alkalosis is followed by a decrease in plasma pH, low plasma HCO3- with near normal pCO2

Salicylate Toxicity

• Salicylate toxicity (overdose or poisoning with > 5g/d of aspirin or salicylate) in adults is characterized by tinnitus, hearing loss, and vertigo as initial signs of toxicity
• In children, common signs of toxicity include acidosis, hyperventilation, and lethargy
• Rescue: i.v. NaHCO3, alkalization of urine with bicarbonate to reduce salicylate reabsorption, promote excretion, correction of acid-base disturbances, replacement of electrolytes and fluids, cooling, forced diuresis, and hemodialysis

NSAIDS (Non-Selective Reversible COX Inhibitors)

• Common agents: Ibuprofen, Naproxen, Ketorolac, Meloxicam, Piroxicam, Sulindac
• Activity profile: Analgesic, antipyretic, anti-inflammatory, and anti-platelet effects (aspirin)
• Side effects: GI (gastric, intestinal ulcers, bleeding), renal (acute renal failure, analgesic nephropathy), CV (worsen hypertension, increased risk of heart attack and stroke, except aspirin/naproxen)

Selective COX-2 Inhibitors

• Common agents: Celeboxib (Celebrex)
• Indications: Pain, inflammation, effective in rheumatoid arthritis and osteoarthritis
• Side effects: CV (increased risk of heart attack and stroke), less risk of GI ulcers/bleeding, lacks anti-platelet effects, can be combined with aspirin, renal (deterioration of chronic renal failure, increase in blood pressure)

Acetaminophen (Paracetamol)

• Mechanism of action: Inhibits COX-1 and COX-2, crosses the blood-brain-barrier
• Indications: Analgesic, antipyretic, poor anti-inflammatory activity in the periphery
• Side effects: Hepatotoxicity due to acetaminophen overdose, treatment is N-acetylcysteine (NAC) to replenish glutathione stores in the liver

COX-2 Inhibitors

• Mechanism of action: Inhibits COX-2, reducing production of prostaglandins
• Indications: Pain, inflammation, effective in rheumatoid arthritis and osteoarthritis
• Side effects: CV (increased risk of heart attack and stroke), less risk of GI ulcers/bleeding, lacks anti-platelet effects, can be combined with aspirin, renal (deterioration of chronic renal failure, increase in blood pressure)

Pharmacotherapy for Gout

• Indications: Acute gouty arthritis, urate lowering therapy for chronic gout
• Mechanism of action: Binds and stabilizes tubulin subunits, inhibiting microtubule polymerization, inhibiting urate crystal phagocytosis, neutrophil activation, migration, and degranulation
• Adverse effects: Severe diarrhea, GI symptoms, rhabdomyolysis, polyneuropathy
• Contraindications: Uric acid stones, GI symptoms, infusion reactions

Rheumatoid Arthritis

• Definition: Long-term, progressive, and disabling autoimmune disease causing inflammation, swelling, and pain in and around the joints and organs
• Treatment: NSAIDs, disease-modifying anti-rheumatic agents (DMARDs), including chemotherapeutics like methotrexate and biologics### Eicosanoid Metabolism Overview
• Eicosanoids are essential signaling molecules derived from polyunsaturated fatty acids, particularly arachidonic acid, which is abundant in cell membrane phospholipids.
• They play crucial roles in regulating various physiological processes such as inflammation, immune response, blood clotting, and smooth muscle contraction.

Arachidonic Acid Pathways

• Arachidonic acid serves as a precursor for all four classes of eicosanoids: prostanoids, lipoxygenase products, cyclooxygenase products, and hydroxyeicosatetraenoic acids.
• The pathways involve two main enzymatic reactions: cyclooxygenase (COX) mediating the production of prostaglandin H2 (PGH2), and lipoxygenase (LOX) responsible for the generation of hydroperoxyeicosatetraenoic acids (HPETE).
• Both PGH2 and HPETE serve as substrates for subsequent transformations into different classes of eicosanoids.

Prostaglandins

• Prostaglandins are one class of eicosanoids with various biological actions depending on the specific prostaglandin type.
• Prostaglandin E2 (PGE2) has anti-inflammatory effects while prostaglandin F2α (PGF2α) participates in inflammation and uterine contractions.
• Prostacyclin (PGI2) acts as a potent vasodilator and inhibits platelet aggregation.

Leukotrienes

• Leukotrienes are another group of eicosanoids synthesized through LOX activity, specifically 5-lipoxygenase (5-LOX).
• They are involved in allergies, asthma, and other inflammatory conditions due to their ability to recruit neutrophils and increase vascular permeability.
• Cysteinyl leukotrienes, including LTC4, LTD4, and LTE4, are the primary active forms responsible for these effects.

Thromboxanes

• Thromboxanes arise from COX action, mainly COX-1 and COX-2, and are named after their ability to stimulate aggregation of human platelets, causing blood clots to form.
• Thromboxane A2 (TXA2) is particularly significant because it induces platelet aggregation and contributes to vasoconstriction.

Lipoxins

• Lipoxins are unique among eicosanoids since they are formed via sequential interactions between 5-LOX and 12-LOX at sites of tissue damage.
• Their formation depends upon the availability of free cis linolenic acid and involves both enzymes simultaneously acting on the AA substrate.
• Lipoxins create a balance between resolution and persistence of inflammation and allow them to modulate the inflammatory process.

Pharmacotherapy for Gout

• Colchicine is used to treat acute gouty arthritis, binding and stabilizing tubulin subunits to inhibit microtubule polymerization, urate crystal phagocytosis, neutrophil activation, migration, and degranulation.
• Xanthine Oxidase Inhibitors (XOI) reduce the production of uric acid, and are used as an alternative or addition to XOI.
• Probenecid inhibits uric acid reabsorption in proximal tubules to increase renal elimination.
• Pegloticase is a recombinant uricase that catalyzes the breakdown of uric acid to allantoin.

Rheumatoid Arthritis

• Rheumatoid arthritis is a long-term, progressive, and disabling autoimmune disease causing inflammation, swelling, and pain in and around the joints and organs.
• NSAIDs, such as aspirin, were once the drug of choice, but DMARDs, disease modifying anti-rheumatic agents, are now the preferred treatment.
• DMARDs include chemotherapeutics such as methotrexate and biologics.

NSAIDs

• NSAIDs have analgesic, antipyretic, anti-inflammatory, and anti-platelet effects (aspirin).
• Common NSAIDs include ibuprofen, diclofenac, indomethacin, naproxen, ketorolac, meloxicam, and piroxicam.
• Side effects of NSAIDs include GI, renal, and CV effects.

COX-2 Inhibitors

• Celecoxib is a selective COX-2 inhibitor, effective in rheumatoid arthritis and osteoarthritis, with a lower risk of GI ulcers/bleeding.
• COX-2 inhibitors have CV effects, but lack antiplatelet effects, and can be combined with aspirin.
• Sulfa drugs, such as celecoxib, should not be used with allergies.

Pharmacotherapy for Gout and Rheumatoid Arthritis

• Indomethacin is used to treat rheumatoid arthritis, musculoskeletal pain, and to treat patent ductus arteriosus.
• Sulindac is metabolized to a sulfide which is the active drug, with less GI toxicity.
• NSAIDs are used to treat pain, inflammation, and to reduce inflammation during an acute gout attack.