Commonly used ANALGESICS & NSAIDs:

  Analgesics/NSAIDS Mechanism Uses Side Effects
  AcetaminophenClass: nonopioid analgesic Weakly inhibits COX compared to salicylates (selective COX3 inhibition?)° dose-dependent (0 order) elimination ° Excretion: CYP450 metabolism ???? sulfate and glucuronide conjugation by GSH ° analgesic (=aspirin)° antipyretic (=aspirin)° (NO anti-inflam.)° use in children w/ viral illness ° no prolonged bleeding° no GI effects° no uric acid inhibition° no Na retention° no hypersensitivity° analgesic nephropathy (papilla and interstitium)° ↑ warfarin anticoagulation° Toxicity: hepatic centrilobular necrosis caused by formation of reactive quinone metabolite ???? binding to hepatic protein ???? toxicity. (Risk ↑ in alcoholics, CYP3A inducers, glutathione depletion) Antidote: acetylcysteine to replenish glutathione and bind toxic intermediate (administered asap)
  AspirinClass: salicylate Irreversible inhibition of COX via acetylation of active site; ° May inhibit NF-kB (↓ exp’n of inflammatory mediators, ↓ COX 1&2 exp’n)° Excretion: rapid deacetylation to salicylic acid ???? pH dep. renal excretion and hepatic conjugation ° Dose-dependent (0 order) excretion ° analgesic° antipyretic° ↑ ED50 for anti-inflam. b/c of ↑ COX??° Thromboembolic disorders (TIA, MI) ° prolonged bleeding due to irreversible TXA2 block in platelets (doubles bleeding time for 4-7 days); contraindicated before surgery and w/ bleeding disorders° inhibits uric acid excretion/ antagonism of uricosuric drugs° Renal effects: Na retention and edema ° NEVER give to children with varicella or influenza ???? Reye’s (encephalopathy)° Toxicity: ↑ depth and rate of respiration (resp. alkalosis);depression of resp. center in medulla (resp. acidosis); inhibition of enzymes in CBH, protein, and fat metabolism (metabolic acidosis); tinnitus, coma, CNS effects
  Aspirin, IbuprofenClass: NSAIDs Inhibition of COX (more selective for COX2)
° Also includes salicylates, ibuprofen and congeners, diclofenac, ketorolac (iv for pain), indomethacin, NOT acetaminophen° Alternatives: DMARDs, immunosuppressants, biological response modifiers		 ° Anti-inflam.° Joints: RA, psoriatic, IBD-related arthritis; osteoarthritis° IBD: ulcerative colitis, Crohn’s disease(treat w/ prodrugs)° Acute rheumatic fever ° Dose-dependent GI effects (esp. in elderly and alcoholics) due to ↓PG in GI mucosa: blood loss/ hemorrhage, gastric and duodenal ulcers, dyspepsia (Treat w/acet., COX2, DMARD; PGE analog (misoprostol) or acid inhibitor (omeprazole))° ↓ risk of colon cancer due to anti-inflam.° Renal effects: Na retention and edema ° analgesic nephropathy (papilla and interstitium)° aspirin insensitivity: bronchospasm, rhinorrhea, urticaria due to leukotrienes; esp. in asthmatics
  Ibuprofen,naproxenClass: propionic acids   ° analgesic° antipyretic° anti-inflam. ° safer than aspirin or acetaminophen in acute overdose
  CelecoxibClass: COX2 inhibitor
° 5-50x more selective		   ° ↑ therapeutic index due to ↓ GI effects° May ↑ risk of atherosclerosis° Renal toxicity: Na retention and edema (COX2 inhibition in macula densa ???? ↑ renin)° analgesic nephropathy (papilla and interstitium)
  MethotrexateClass: DMARDs Disease Modifying Antirheumatoid Drugs° gold compounds, penicillamine, antimalarials, sulfasalazine, IL-1 receptor antagonist, immunosuppressants, glucocorticoids, leflunomide, methotrexate    
  InfliximabClass: TNF-α inhibitor(biological response modifier)      
 
  • COX1
    • Constituitive
    • GI integrity
    • Platelet aggregation
  • COX1 Inhibition
    • Channel block
    • Reversible
  • COX2
    • Inducible by cytokines, GFs, and tumor promoters
    • Ovarian function
    • Renal function
  • COX2 Inhibition
    • Channel side pocket confers selectivity
    • Time-dependent inhibition

Analgesia: inhibition of PGE synthesis in periphery (dorsal horn of SC); limited CNS effects

  • treats headache, dysmenorrhea, and pain (joints, skeletal m., and teeth)
  • Combination Preparations: caffeine, opioids, decongestants, and sedative antihistamines

Antipyresis: ↓ fever (but not normal temperature)

  • acts on hypothalamic nuclei (inhibits PGE produced by endogenous pyrogens IL-1, TNF-α, and IFN-α)
  • ↑ peripheral Q
  • ↑ sweating

 

 

HISTAMINE ANTAGONISTS

       
  Receptor Mechanism & Side effects Uses
Diphenhydramine, ChlorpheniramineClass: 1st H1 antagonist ↑ IP3/DAG(agonist – 2-methylhistamine)
° dilation of arterioles and venules (EC ???? NO), but constriction of large vessels° ↑ capillary permeability (wheal) ° constriction of bronchial smooth m.° * sensory nerve endings (itch & flare)° CNS arousal		 ° relatively non-selective:° local anesthetic° muscarinic blockade (resembles atropine poisoning w/CNS stim.)° weak α-adrenergic blockade° sedation ° allergic dermatitis ° allergies (rhinitis, conjunctivitis, urticaria)° anti-emetic, motion sickness, sedative-hypnotic
Loratidine, Fexofenadine (Allegra)Class: 2nd H1 antagonist ° more polar – less entry into CNS° arrhythmia due to K channel block (ventricle = torsades de pointes)° interaxn w/ drugs affecting CYP3A (erythromycin) ° allergies (rhinitis, conjuctivitis, urticaria)° mastocytosis
RaniditineClass: H2 antagonist ↑ cAMP° agonist – 4-methylhistamine, impromidine° ↑ gastric acid secretion° vasodilation (longer-acting than H1)° β1-like effects on heart ° contains imidazole-like group (~ histamine)° low incidence, mild° small amt crosses BBB° metabolite inhibits CYP450° cimetidine is an anti-androgen ° ↓ gastric acid secretion:GI ulcersZollinger-Ellison syndrome (gastrin tumor)Acid reflux
Cromolyn sodiumClass: Cromones Inhibit histamine release @ level of degranulation° administer by inhalation ° irritation from inhalation ° prophylaxis against allergic rhinitis and asthma° allergic conjunctivitis (inhibits mast cell degranulation and H1 receptors)
  • Histamine is made from histidine via histidine decarboxylase and stored in mast cells and basophils.
  • Degranulation is triggered by bradykinin, C3a and C5a, interaction w/ IgE, and some basic drugs (morphine)
  • Fast turnover in enterochromaffin-like cells of gastric mucosa, histaminergic neurons of CNS, and epidermis

H3 is a presynaptic inhibitor that ↓Ca influx. Ag: methylhistamine. Ant: thioperamideGOUT & HYPERURICEMIA

       
  Mechanism Uses Side Effects
Colchicine, NSAIDs (indomethacin)Class: Anti-inflammatory Suppression of inflammation° inhibits microtubules° suppresses leukocyte motility and phagocytosis ° prophylaxis ° Chronic: bone marrow suppression, myopathy° Toxicity: GI damage° DO NOT use salicylates (↓ renal clearance of uric acid and antagonize uricosurics)
ProbenecidClass: Uricosuric ° ↑ renal clearance of uric acid by blocking tubular reabsorption @ oatp   ° prevent secretion of organic acids° alkaline urine protects against renal urate ppt° DO NOT use w/ nephrolithiasis° loses effectiveness w/renal failure
AllopurinolClass: Xanthine Oxidase Inhibitor ° inhibits xanthine oxidase (catalyzes hydroxylation of xanthine and hypoxanthine); precursors are more soluble and are cleared more rapidly by the kidneys ° long-lasting metabolite° converted to a ribonucleotide ???? feedback inhibition of de novo purine synthesis° can be combined w/ other classes ° hyperuricemia due to overproduction ° patients w/ impaired renal fxn° preexisting renal urate stones ° hypersensitivity (rash)

Uric acid is the end product of purine metabolism

  • overproduction: primary familial gout, myeloproliferative disorders, cytotoxic drugs
  • impaired excretion: renal disease, drugs that ↓ tubular secretion (diuretics)

Low solubility or uric acid ???? ppt in joints and kidneys ???? pain and inflammation