NSAIDs and Acetaminophen Overview

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Acetaminophen

NSAIDs are a group of drugs with analgesic and antipyretic effects. Specific preparations also have anti-platelet and anti-inflammatory effects (at specific dosages).
Analgesic: Drug relieving pain
Antipyretic: Drug lowering elevated body temperature to normal.
Anti-inflammatory: Refers to the property of a substance or treatment that reduces inflammation or swelling.
Anti-platelet: A class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation.

Classification of NSAIDs

Non-selective COX inhibitors: Inhibit COX-1 and COX-2. Examples include aspirin, and most analgesics. Further breakdown of subtypes:
Salicylic acid derivatives: Aspirin, aloxiprine, amino salicylic acid, diflunisal, methyl salicylate.
Acetic acid derivatives: indomethacin, sulindac, etodolac; diclofenac
Propionic acid derivatives: Ibuprofen, ketoprofen, fenoprofen, naproxen.
Fenamic acid derivatives: mefenamic acid, fulfenamic acid.
Pyrazalone derivatives: phenylbutazone, azapropazone
Oxicams: piroxicam, tenoxicam
Selective COX-2 inhibitors: Examples include celecoxib, etoricoxib, and meloxicam.

Types of Cyclo-Oxygenase Enzymes (COX)

COX-1: Constitutive (physiological)
Stomach: Decreases HCl (prevents peptic ulcers, through forming PGE2)
CVS: Vasoconstriction & ↑ coagulation (through TXA2 that enhances platelet aggregation)
Kidney: Renal vasodilation (through PGE2)
COX-2: Inducible (stimulated by inflammation)
Pathological Infection: Toxins, inflammation and IL-1 & TNF stimulate COX-II increases PG.
CVS: Vasodilatation and coagulation (PGI2 decreases platelet aggregation)
Kidney: Renal vasodilation (through PGI2)
COX-3: Mainly in the brain (hypothalamus: Fever, Thalamus: Pain)

Arachidonic Acid

NSAIDs impact Arachidonic Acid, affecting various bodily systems through different COX pathways.
COX-1 inhibition can lead to peptic ulcers and GI bleeding.
COX-2 inhibition shows varying effects.

Pharmacokinetics of NSAIDs

Absorption: Oral administration; good absorption in acidic stomach and intestinal mucosa.
Metabolism: Primarily in the liver (oxidation and conjugation)
Plasma Protein Binding: High binding to plasma proteins leads to high bioavailability.

Mechanism of Action of NSAIDs

NSAIDs inhibit cyclooxygenase (COX) enzymes, reducing prostaglandins and thromboxane synthesis.
Corticosteroids mainly inhibit Phospholipase A2

Acetyl Salicylic Acid (Aspirin) Pharmacokinetics

Source: Willow tree bark
Salicylic acid is acetylated to form aspirin.
Absorption: Better absorbed in the stomach and intestines. Higher absorption in the intestines due to larger surface area and prolonged contact time. pH of stomach increases absorption.
Distribution: Throughout the body, including the blood-brain barrier and placenta. Use in pregnancy should be avoided in later stages due to possible complications.
Metabolism: Hepatic microsomal enzymes are involved with mainly renal excretion (Dual route of elimination). First order elimination for therapeutic doses, zero order elimination for toxic doses.
Excretion: Urine, increased by urine alkalinization.
Action: Small doses (1-2g) are analgesic and antipyretic. Large doses (5g) are mainly anti-inflammatory.
Important Note: Aspirin's irreversible inhibition of platelet COX-1 enzyme is critical for its antiplatelet effects. A notable difference from other NSAIDs.

Pharmacological Actions of Aspirin

Analgesic: Mild to moderate pain relief (not severe pain due to peripheral and central actions)
Antipyretic: Reduces fever (by decreasing PGE2 synthesis in the hypothalamus).
Anti-inflammatory: Decreases PG synthesis, inflammatory cell activation and chemotaxis. Decreases capillary permeability.
Cardiovascular Effects: Low doses (cardioprotective effects) inhibits COX and decreases TXA2 production, leading to antiplatelet effect (lower risk of cardiovascular problems). High doses inhibit prothrombin, prolong bleeding time.
GIT Effects: Causes gastric ulcers (acute and chronic) due to salicylate ingestion.
Uterine Effect: Affects uterine contractions via PGE inhibition.
Renal Effects: (Analgesic Nephropathy) Inhibits PGE2 and PGI2, reducing renal blood flow and potentially causing edema due to salt and water retention. Possibly increasing blood pressure and leading to acute kidney injury due to hypoperfusion.

Therapeutic Uses of Salicylates

Anti-inflammatory in osteoarthritis, gout, and rheumatic arthritis
Analgesic in common conditions (headache, arthralgia, myalgia, dysmenorrhea)
Antipyretic for fever treatment
CVS protective (Low dose aspirin) for cardioprotection by lowering risk of cardiovascular events.
Keratolytic, counter-irritant in removing warts, and relieving local rheumatic pain

Adverse Effects of Salicylates

Gastrointestinal: Increased risk of gastric ulcers and bleeding due to COX-1 inhibition.
Bleeding: Aspirin's irreversible COX-1 inhibition differentiates it, causing more bleeding-related complications.
Renal: Analgesic nephropathy (kidney damage), salt and water retention.
Hypersensitivity: Bronchospasm (aspirin asthma) in patients with asthma or allergic rhinitis. Reye's Syndrome (encephalopathy and liver damage in children with viral infections).
Teratogenicity: Avoid use in late pregnancy.
Idiosyncrasy: Hemolysis in patients with Favism.

Precautions and Contraindications for Aspirin Use

GIT disorders: peptic ulcer, gastritis, and hemorrhagic pancreatitis
Hemorrhagic disorders (hemophilia, thrombocytopenia)
Chronic renal diseases (aggravation of renal failure)
Chronic liver diseases and uncontrolled hypertension.
Gout (small to moderate doses can inhibit uric acid excretion.)
Surgical procedures (stop aspirin at least 7 days before).
Children with viral infections (avoid use due to risk of Reye's syndrome)

Other Non-selective COX Inhibitors

Diclofenac: Less gastric irritant than other NSAIDs but nephrotoxic. Topical gels for local pain and arthritis.
Ibuprofen: Good alternative for aspirin in children with flu fevers but long-term use can increase hypertension in women.
Indomethacin and Piroxicam: Indomethacin speeds ductus arteriosus closure in premature infants. Piroxicam has a longer half-life and increased bleeding and ulceration risks compared to other NSAIDs.

Case Study: Aspirin and Surgery

Patients taking aspirin should discontinue use 7-10 days before surgery to avoid complications. Aspirin's irreversible inhibition of platelets interferes with blood clotting mechanisms.

Selective COX-2 Inhibitors

Celecoxib and Rofecoxib inhibit COX-2 and reduce the risk of peptic ulcers but may have associated cardiovascular risks.

Mechanism of Action of Selective COX-2 Inhibitors

Selectively inhibit COX-2, the inflammation and pain-causing enzyme.
Reduced risk of peptic ulcers, but sometimes may cause renal issues

Advantages and Adverse Effects of Selective COX-2 Inhibitors

Advantages: Low incidence of serious gastrointestinal issues, less risk of bleeding.
Disadvantages: High risk of cardiovascular issues (some were removed from the market). Avoid use in those with unstable angina or ischemic strokes. Kidney involvement is also possible, though less severe than with non-selective COX inhibitors.

Non-selective vs. Selective COX-2 Inhibitors

Comparison table of varied effects including mechanism, pharmacological effects, gastric and renal side effects, thrombotic complications, and hypersensitivity.

N-Acetyl-p-Aminophenol (APAP) / Acetaminophen

Structure, and chemical properties.
Pharmacokinetics: Absorbed orally and intravenously, passes the blood-brain barrier and placenta. 85% metabolized in the liver into mostly inactive glucuronide and sulfate conjugates. Small amount broken down by CYP450 to toxic N-acetyl-p-benzoquinoneimine (NAPQI) potentially leading to cell death.
Mechanism of Action: Inhibits prostaglandin synthesis primarily in the central nervous system (CNS). Less effect on peripheral tissues and has little, if any, antiplatelet effect; no effect on the cardiovascular system or gastric mucosa.
Therapeutic Action: Antipyretic in reducing fevers, analgesic for managing mild to moderate pain conditions.
Adverse Effects: Generally safe. High doses or predispositions are associated with hepatotoxicity, especially in susceptible patients. Intravenous acetylcysteine is an antidote.