1. CH3(CH2)18CH3
  3. Precursor for Leukotrienes, Lipoxins, & Hydroxyeicosatetraneoic acids
    Arachadonic Acid
  4. Precursor for prostaglandins, thromboxanes, and prostacyclins
    Arachadonic Acid
  5. Arachadonic acid is converted to Epoxyeicostatreinoic acids (EETS) by this enzyme
    Epoxygenase (CYP450)
  6. •Constantly present in low levels in
    many organs
  7. •PGS produced by this enzyme are important
    for many normal physiologic reactions
    in kidney
    of normal function


    protectants against HCl
  8. •Present in fewer tissues under basal conditions
    –Renal cortex

    cytokines produced as a result of tissue damage induce PG generation
  9. COX-1 vs COX-2
    Two Crucial Variables:
    •The chemical topography of COX enzymes at sites where NSAIDs bind

    • •The chemical similarity between NSAIDs and arachidonic acid (the endogenous COX
    • substrate)
  10. COX-1 vs COX-2
    Three Key Elements

    What is Key Element #1?
    The amino acid residues comprising the binding domain the active site cavity in COX-1 and COX-2 are identical
  11. Key Element #1 of Cox 1 vs Cox 2

    These binding site residues include a trio of :
    • •aromatic and/or lipophilic amino acid active site residues (VAL349, TYR385, TRP387) that augment receptor affinity through
    • –Hydrophobic or Π electron-requiring van der Waals interactions
    • –Lipophilicity that propels the NSAID across biomembranes to reach receptors
  12. Key Element #1 of Cox 1 vs Cox 2

    Arginine (ARG120) is critical upstream from the active site cavity because:
    –the acidic functional group of arachidonic acid and of the NSAIDS assumes an anionic character (negative charge) at physiologic pH

    –It can then be anchored via electrostatic forces to the cationic (positively charged) guanidinyl group of Arginine (ARG120)
  13. COX-1 vs COX-2 Three Key Elements

    What is Key Element #2?
    • •The key SER (serine) residue at the edge of the active site of the two COX isoforms is vulnerable to irreversible acetylation by aspirin (ASA)
    • –SER530 - COX-1 – Acetylation to a great degree
    • –SER516 - COX-2 – Acetylation to a lesser degree
  14. ASA Acetylation of COX
    •The oxygen atom of serine launches a nucelophilic attack on the electrophilic carbonyl carbon of ASA

    •Acetylated COX results in distorted docking site for arachidonic acid, with subsequent loss of function
  15. COX-1 vs COX-2 Three Key Elements

    What is Key Element #3?
    •Key structural differences between the allosteric binding area of COX-1 and COX-2 is reflected particularly in the “gatekeeper” residues that determine access to residues in the allosteric pocket
  16. Crucial difference between Cox 1 & 2 that influences drug design
    A Gap in the side pocket on Cox-2

    • –Valine (smaller) in place of isoleucine (larger) leaves a gap in the channel, thus allowing access to the “side pocket”
    • –Gap is binding site for COX-2 inhibitors
  17. List the 6 NSAID classes
    • –Aspirin and the salicylates
    • –3,5-Pyrazolidinediones
    • –Arylalkanoic acids – “Classical”
    • –Fenamates (N-Arylanthranilic acids)
    • –Oxicams
    • –COX-2 inhibitors
  18. 3 Major Therapeutic Applications of NSAIDS
    • •Analgesics
    • –Pain
    • •Anti-inflammatory agents
    • –Inflammation
    • •Antipyretics
    • –Fever
  19. ASA and NSAID Mechanism of Action
    • •inhibit the cyclooxygenase system
    • (COX-1 and COX-2) reducing the production of
    • –Prostacyclin
    • –Prostaglandins
    • –Thromboxane
  20. Most NSAIDS inhibit Cox 1 or Cox 2 more?
    Cox 1 [depletes prostaglandins]
  21. Major difference between ASA and typical NSAID mechanisms
    • –ASA (but not active metabolite salicylate) acetylates and irreversibly inhibits the COX system
    • –NSAIDS reversibly inhibit the COX system
    • –ASA has a longer duration of antiplatelet action
  22. 2 Major differences between and among NSAIDs
    –Therapeutic half-lives

    –Safety profiles
  23. Arylalkanoic Acid Properties
    • •Very low water solubility
    • –Water soluble salts may be formed at the carboxylate functionality
    • •Center of acidity (carboxylate) is one carbon adjacent to a flat surface (aromatic or heteroaromatic ring)
    • –Two or more carbons distant results in diminished activity
  24. Arylalkanoic Acid Derivatives
    •Arylacetates –Arylacetic acids & Heteroarylacetic acids

    •Arylpropionates [“Profens”] –Arylpropionates & Heteroarylpropionates
  25. 4 Properties of Profens
    • 1) Substitution of a methyl group on the carbon atom that separates the Ar ring from the acidic center increases anti-inflammatory activity
    • 2) Groups larger than methyl decrease anti-inflammatory activity – Methyl group in alicyclic rings results in minimal changes
    • 3) Introduction of a second lipophilic area that is noncoplanar with the Ar/HeteroAr ring enhances activity
    • 4) S-(+)-isomer is consistently active –If administered as a racemate, the inactive R-enantiomers tend to be converted to the bioactive S-enantiomers
  26. Arylalkanoic Acids (Pharmacokinetics)

    –Rapid and complete for most compounds

    –Food may delay, but not effect the total absorption
  27. Arylalkanoic Acids (Pharmacokinetics)

    Protein Binding
    •High protein binding (>90%)

    –May displace other drugs from protein binding sites with enhanced activity and/or toxicity of displaced drugs
  28. Arylalkanoic Acids (Pharmacokinetics)

    High Bioavailability (80-95%)
  29. Arylalkanoic Acids (Pharmacokinetics)

    –Unchanged renally

    –Hepatic metabolism

    •Phase I – Aromatic ring hydroxylation; reduction of keto functions to alcohols

    •Phase II – Glucuronide and sulfate conjugation of parent and/or drug metabolite
  30. Arylalkanoic Acids (Indications)
    • •Anti-inflammatory
    • –Rheumatoid arthritis (RA)
    • –Osteoarthritis (OA)
    • –Gout
    • •Primary dysmenorrhea
    • •Analgesia
    • –Mild-to-moderate pain (including symptoms of common cold)
    • •Antipyresis (fever)
  31. Arylalkanoic Acids (Indications)
    •Aids in closure of patent ductus arteriosus in premature infants – A fetal vessel connecting the left pulmonary artery with descending aorta which normally closes after birth
  32. Arylalkanoic Acids (Indications)
    • •Ophthalmic
    • –Inhibition of intraoperative miosis
    • •Constricts iris sphincter independent of cholinergic mechanisms
    • •Inhibits miosis during cataract extraction surgery
    • –Therapy of post-operative inflammation following (MAJOR APPLICATIONS)
    • •Cataract removal
    • •Corneal refractive surgery
    • –Relief of ocular itching caused by seasonal allergic conjunctivitis
  33. Examples of Arylalkanoic Acid Derivatives

    (Generic Drug Names for Eye Solutions)
    • Flurbiprofen Sodium
    • Bromfenac Sodium
    • Diclofenac Sodium
    • Ketorolac Tromethamine
    • Nepafenac
  34. Arylalkanoic Acids (Adverse Effects)
    • Gastrointestinal upset
    • Nausea, vomiting, diarrhea, constipation – (3-12%)
    • –Dyspepsia (3-13%)
    • –Cramping (3-10%)
    • –Anorexia (1-3%)
  35. Arylalkanoic Acids (Adverse Effects)
    • Gastric or duodenal ulcer
    • –Hemorrhage and perforation possible
    • –Endoscopic confirmation (5-35%)
    • –Variable by compound and dose
    • –4,000 cases/year with 700 deaths
    • •Central Nervous System
    • –Dizziness (1-17%)
  36. Arylalkanoic Acids (Adverse Effects)
    • Cardiovascular risks
    • –Meta-analyses
    • –All NSAIDs have CV risks (MI, stroke)
    • –Variable by compound and dose
    • •Naproxen appears to be the least
    • –Magnitude is small in absolute terms
    • •About 1 CV event/100 patient years
    • •July, 2011 – Older adults with hypertension and CV disease using NSAIDs for chronic pain are at significantly increased risk of CV events
  37. Arylalkanoic Acids Pregnancy Risk Factor
    • •Category B/C (depending on lit source)
    • –Phenylpropionic acid dvts (“Profens”)
    • •Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen Sodium, Oxaprozin
    • –Phenylacetic acid dvts (“Fenacs”)
    • •Diclofenac, Etodolac, Indomethacin, Ketorolac, Nabumetone, Sulindac
    • –Fenamates
    • •Meclofenamate, Mefenamic Acid
  38. Arylalkanoic Acids Pregnancy Risk Factor
    • •Category B/C (depending on lit source)
    • –Oxicams
    • •Meloxicam, Piroxicam
    • –COX-2 inhibitors
    • •Celecoxib
    • •Safety in pregnancy not established; use not recommended
    • –Sep, 2011 – Use early in pregnancy is linked to twice the risk of miscarriage
  39. Arylalkanoic Acids Pregnancy Risk Factor
    • •Category D
    • –Pregnant women in the third trimester
    • •May cause closure of the ductus arteriosus in the
    • fetus, tricuspid incompetence, pulmonary hypertension
    • –Ductus arteriosus normally changes into a fibrous cord, the ligamentum arteriosum, in the first two months after birth
    • •Intracranial bleeding
    • •Renal dysfunction, dysgenesis, injury
    • •GI bleeding
  40. Arylalkanoic Acids Contraindications
    • •Hypersensitivity to
    • –Particular NSAID
    • –Any component of the formulation
    • –ASA
    • –Patients with “aspirin triad”
    • •Bronchial asthma
    • •Aspirin intolerance
    • •Rhinitis
    • –Other NSAIDs
  41. Arylalkanoic Acids Contraindications
    • •Third trimester pregnancy
    • –May produce closure of the ductus arteriosus in the fetus
    • •Active GI bleeding and/or ulcer disease
    • •Others
    • –Impaired renal/hepatic function – drug dependent
  42. •Ortho- or para- placement of the phenoxy greatly decreases activity

    •Replace oxygen bridge with carbonyl group -> Ketoprofen

    •Indications (p.o.)


  43. •Indications (p.o.)(Ansaid®)


    •Indications (ophthalmic)(Ocufen®)

    of intraoperative miosis during cataract extraction surgery
  44. •First NSAID since indomethacin to reach
    the U.S. market

    •First arylpropionic acid in the U.S.A.

    •First Rx NSAID to achieve OTC status

    –Dr. Juhl
    (Dean, School of Pharmacy, 1986-2002) chaired FDA Panel that recommended this
  45. •Indications (p.o.)






    –Sept, 2010 – Ketoprofen
    + Omeprazole marketed in UK as Axorid®

  46. •C-6 substitution on naphthalene
    ring with small lipophilic groups produced maximal activity

    •2-naphthylpropionic acids >>
    than 2-naphthylacetic acids

    •S-(+)- isomer more potent but R(-)- isomer is marketed as Anaprox®
  47. •New NSAID - NicOx
    (French Co.)

    •Naproxen derivative


    esterification permits drug to also function as nitric oxide donator

    –New class –
    Nitric Oxide
    Donator (CINOD)

    to increase safety (myocardial, GI) but retain NSAID efficacy
  48. •Indications (ophth.)

    inflammation and pain following cataract surgery

    NSAID ophthalmic to be post-operatively dosed b.i.d., as others are q.i.d.

    –October, 2010 – FDA approves ISTA Pharm. XibromQD® (once
    daily dosing) in ophthalmic post-surgical patients

    •b.i.d. formulation – discontinued Mar, 2011

  49. •Function of the ortho-chloro groups is to force the anilino-phenyl group out of the plane of
    the phenylacetic acid – important for binding to

    •More likely to produce hepatotoxicities than other NSAIDS

  50. •N-4 chlorobenzoyl moiety orients away from C-2
    methyl; noncoplanar with indole

    •Indications (p.o., rectal)


  51. •Indications
    (IM, IV, p.o.)


    term (up to 5 days) management of moderately severe ACUTE pain requiring analgesia at the
    opioid level

    •Not for
    chronic pain

    •Produces analgesia equivalent to about 12
    mg of morphine

    •A widely accepted alternative to narcotic
  52. •A unique NSAID, as it is a NONACIDIC

    •The lack of an acidic carboxylic
    acid functional group while in the gut
    decreases the risk of GI mucosal irritation – VERY IMPORTANT

    •t1/2 = 22.5-30 h (ACTIVE METABOLITE)

    •Indications (p.o.)



    •NDA approved Alcon product – August
    25, 2005

    •Penetrates ocular tissues and
    converts to the active arylalkanoic acetic acid Amfenac (2-amino-3-benzoyl-benzeneacetic

    = Debromobromfenac
  54. •Indications (p.o.)


    •Special adverse effect potential

    –Stevens-Johnson Syndrome with Toxic
    Epidermal Necrolysis


    •Reported to have the highest incidence of SJS-TEN of any NSAID

    settlement - $21 million to blinded and scarred patient in Concord, NH
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