Pharmacology of NSAIDs and COX Inhibitors

Non Steroidal Anti-inflammatory Drugs (NSAIDs)

• NSAIDs are analgesic, antipyretic, and anti-inflammatory
• Their effects are from inhibiting prostaglandin synthesis by blocking the cyclo-oxygenase (COX) enzyme.
• Two COX isoenzymes exist: COX-1 (constitutive in cells) and COX-2 (induced during inflammation).
• Corticosteroids are powerful anti-inflammatory agents but have chronic toxicity limitations.

Classification of Analgesic Antipyretic Drugs

• Non-selective COX inhibitors:
  • Salicylates (aspirin, sodium salicylate, diflunisal)
  • Indol derivatives (indomethacin)
  • Anthranilic acid derivatives (mefenamic acid)
  • Propionic acid derivatives (ibuprofen, ketoprofen, naproxen)
  • Aryl acetic acid derivatives (diclofenac, ketorolac)
  • Oxicams (piroxicam)
  • Alkanones (nabumetone)
  • Pyrazolone derivatives (phenylbutazone, oxyphenylbutazone, azapropazone)
  • Aniline derivatives (phenacetin, paracetamol)
• Selective COX-2 inhibitors:
  • Celecoxib
  • Meloxicam

Salicylates (1)

• Derived from salicylic acid (highly irritant)
• Include aspirin, sodium salicylate, diflunisal
• Local actions: antifungal, antiseptic, and counter-irritant (methyl salicylate)
• Systemic actions:
  • CNS: inhibits prostaglandin synthesis, increases pain threshold, increases heat loss through cutaneous vasodilation and sweating
  • High doses can lead to hyperthermia through oxidative phosphorylation uncoupling

Anti-inflammatory, Anti-rheumatic Action (2)

• Inhibit cyclooxygenase enzyme, preventing prostaglandin synthesis (important for inflammation)
• Aspirin irreversibly inhibits the enzyme.
• Inhibit platelet aggregation
• Inhibit kallikrein system (reducing pain, redness, and edema)
• Stabilize lysosomal membranes (reducing tissue damage)
• Inhibit leukocyte and macrophage migration (inhibiting chemotaxis)

Respiration and Acid/Base Balance (3)

• Ordinary dose: little effect
• Large dose: increased respiratory rate, CO2 loss, respiratory alkalosis, reduced plasma bicarbonate
• High doses: produce metabolic acidosis and respiratory acidosis (in children)
• Cardiovascular System (CVS): little effect. Large doses can lead to peripheral vasodilation (VD) and reduced vascular resistance (VMC).
• Uric Acid: filtered through glomeruli, reabsorbed and secreted in tubules. Salicylates in large doses increase uric acid excretion (uricosuric), and in small doses reduce uric acid secretion causing retention in the blood.

Blood (4)

• Small doses (75-150 mg/day) of aspirin inhibit platelet aggregation (acetylation of cyclooxygenase).
• Larger doses compete with vitamin K, inhibiting prothrombin formation (leading to hypoprothrombinemia).
• G6PD deficiency can cause hemolytic anemia

Gastrointestinal Tract (GIT) (5)

• Inhibition of prostaglandins (PGs) can lead to gastric ulceration and bleeding, inhibiting acid secretion, and impacting gastric blood flow.
• Reduced mucus secretion.
• Nausea and vomiting (central and peripheral effects).

Metabolic Actions (6)

• Uncoupling of oxidative phosphorylation and increased cellular metabolism leads to increased oxygen and CO2 consumption.
• High doses cause hyperglycemia from increased cortisone and adrenaline levels

Other Actions (7)

• Inhibiting antigen-antibody reaction
• Release of adrenaline with larger doses
• Displacement of thyroxine from protein binding sites.
• Delay in labor onset (in larger doses)

Administration (8)

• Taken after meals to minimize gastric irritation
• Sodium salicylate should be administered in an enteric-coated tablet.

Therapeutic Uses (9)

• Local: salicylic acid as an antifungal and antiseptic; methyl salicylate as a counter-irritant
• Systemic:
  • Analgesic/antipyretic (0.6-0.65 g/day)
  • Anti-inflammatory (50-75 mg/kg/day)
  • Acute rheumatic fever (10 g/day)
  • Rheumatoid arthritis (8 g/day)
  • Preventing intravascular thrombosis (aspirin 75-150 mg/day)
  • Gout (>5 g/day)

Side Effects and Toxicity (10)

• Gastric irritation (increased occult blood in stools)
• Hypersensitivity (asthma, rash)
• Idiosyncratic reactions (G6PD deficiency)
• Prolonged use: hypoprothrombinemia, salicylism (headache, mental confusion, vertigo, tinnitus, sweating, nausea, vomiting)
• Renal irritation (albuminuria)
• Reye's syndrome (severe hepatic damage)
• Acute salicylate poisoning (restlessness, tremors, convulsions, vomiting, dehydration)

Treatment (11)

• Gastric lavage with sodium bicarbonate
• Correction of hyperpyrexia (cold fomentation or ethyl alcohol evaporation)
• Correction of dehydration and acid-base balance (IV fluids with electrolytes)
• Alkalinization of urine with NaHCO3
• Vitamin K administration

Contraindications (12)

• Peptic ulcer
• Bronchial asthma
• Idiosyncratic reactions
• Allergies
• Bleeding tendencies

Indole Derivatives (Indomethacin, Sulindac) (2)

• Indomethacin: potent prostaglandin synthesis inhibitor, oral (6hr t1/2)
  • Effective in rheumatoid arthritis, gout
  • Adverse effects: GIT disturbances, pancreatitis, headache, thrombocytopenia, aplastic anemia, hyperkalemia, skin rash, asthma. (Contraindicated in pregnancy, children, peptic ulcer)
• Sulindac: similar to indomethacin, but less potent and has less gastric irritation (prodrug)

Anthranilic Acid Derivatives (Mefenamic Acid) (3)

• Mefenamic Acid inhibits COX and phospholipase A2: Less effective than aspirin as an anti-inflammatory agent
  • GI disturbances, avoid pregnancy

Propionic Acid Derivatives (Ibuprofen, Ketoprofen, Naproxen) (4)

• Analgesic, antipyretic, and anti-inflammatory (inhibit cyclooxygenase, prostaglandin synthesis).
• Potent uricosuric, displace other drugs, decrease diuretic & beta-blocker effects.
• 20 times more potent than aspirin.

Arylacetic Acid Derivatives (Diclofenac) (5)

• Similar actions as other NSAIDs.

Oxicams (Piroxicam) (6)

• Long plasma half-life (45 hours), enterohepatic cycling
• Adverse effects: GI disturbances

Pyrazolone Derivatives (Dipyrone, Phenylbutazone, Oxyphenbutazone, Azapropazone) (8)

• Dipyrone: rarely used due to bone marrow depression
• Phenylbutazone/Oxyphenbutazone/Azapropazone: strong anti-inflammatory, potent uricosuric agent, useful in acute gout attacks, absorbed quickly from GIT, high binding to plasma proteins, enzyme inducer, displaces other drugs from binding sites
• Adverse effects: nausea, vomiting, peptic ulcer, GIT bleeding, water retention, rash, urticaria, edema, hypertension, bone marrow depression, liver and renal toxicity, and bronchospasm.

COX-2 Inhibitors (Selective) (15)

• Selectively inhibit COX-2 (induced at inflammation sites)
• Less GI disturbance than nonselective NSAIDs
• COX-2 is active in kidney, so COX-2 inhibitors can cause renal toxicity.
• Rofecoxib & Etoricoxib: Rheumatoid arthritis, osteoarthritis, and acute gouty arthritis.

Aniline Derivatives (Acetaminophen/Paracetamol) (16)

• Pharmacokinetics: Oral absorption, bound to a lesser extent to plasma proteins, metabolized by conjugation (glucuronic and sulfuric acids) in the liver
• Minor toxic metabolite (N-acetyl-p-benzoquinoneimine): formed by cytochrome P450; detoxified by glutathione. Hepatic and kidney damage possible.

Acetaminophen (Paracetamol) (16, 17)

• Action: COX enzyme inhibition
• Uses: Analgesic, antipyretic
• Side effects: hepatotoxicity

Aniline Derivatives (Phenacetin) (17)

• Action: COX enzyme inhibition
• Uses: Analgesic, antipyretic
• Side effects: severe toxicity

Acute Paracetamol Poisoning (18)

• Ingestion of 15g or more.
• Hepatotoxicity and acute renal tubular necrosis.
• Treatment: N-acetylcysteine within 8 hours of ingestion

Sedative, Hypnotic & Anxiolytic Drugs (19–22)

• Used for anxiety and insomnia
• Classification:
• GABA-facilitating drugs (benzodiazepines, barbiturates, zolpidem)
• 5-HT1A agonists (buspirone)
  • GABA: Ionotropic (ligand-gated ion channels) and metabotropic (G protein coupled receptors).
• GABA bind to its receptor, opening Cl− channels causing hyperpolarization (inhibiting neuronal firing).
• Benzodiazepines act on γ subunit receptors and enhance GABA effect
• Zolpidem & Zaleplon bind to BZ₁ receptors.
• Barbiturates increase GABA-gated chloride channel opening duration.

Benzodiazepines (23)

• Classification:
  • Long-acting (diazepam, prazepam, flurazepam, clorazepate, chlordiazepoxide)
  • Intermediate-acting (temazepam, oxazepam, lorazepam, alprazolam)
  • Short-acting (triazolam, midazolam)
• Actions: Anti-anxiety, anterograde amnesia, sedation, hypnosis, muscle relaxant, anti-convulsant, anesthesia adjunct
• Uses: Anxiety, insomnia, status epilepticus, pre-operative sedation
• Side effects: Confusion, drowsiness, anterograde amnesia, ataxia, nausea, vomiting, diarrhea, dry mouth, bitter taste, allergy, and bone marrow depression, abuse & dependence

Flumazenil (27)

• Benzodiazepine receptor antagonist
• Used to reverse benzodiazepine overdose and improve mental status in hepatic encephalopathy
• Side effects: agitation, confusion, dizziness, nausea.

Zolpidem and Zaleplon (28)

• Non-benzodiazepine hypnotics
• Bind to BZ₁ receptors to facilitate GABA effects
• Minimal muscle relaxation and anticonvulsant effects
• High doses: amnestic effect
• Zaleplon: rebound insomnia potential

Buspirone (29)

• Partial agonist at 5-HT₁A presynaptic receptors
• Affinity for dopamine D₂ receptors
• No hypnotic, sedative, anticonvulsant, or muscle relaxant effects
• No rebound anxiety or withdrawal if stopped suddenly
• Side effects: tachycardia, palpitations, nervousness, paresthesia, gastrointestinal upset, miosis, and hypertension (with MAOIs)

Barbiturates (30, 31)

• Classification: Long-acting, intermediate-acting, short-acting, ultrashort-acting
• Uses: Sedation, hypnosis, pre-anaesthesia, potentiate other analgesics
• Toxicity: Tolerance, hypersensitivity, automatism, chronic use: habituation & addiction, acute overdose: hypotension, hypothermia, hyporeflexia, coma, respiratory failure
• Treatment: gradual withdrawal

Test your knowledge on anti-inflammatory drugs, including their classifications and mechanisms of action. This quiz covers key characteristics of selective COX-2 inhibitors, propionic acid derivatives, and more. Understand the implications of using these medications in clinical practice.