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									NSAIA’s or NSAID’s
   Major market
       Aspirin 3rd in use to caffeine and alcohol
       70-100 million prescriptions anually
       OTC use up to 7x prescriptions
       15% of Americans suffer from an
        inflammatory disorder
       > 80% of those over 55 have a detectable
        joint abnormality
Inflammation Summary
1. Initial injury causes release of inflammatory
      Histamine, serotonin, leukokinins, lymphokinins,
       prostaglandins, etc.
2. Vasodilation
3. Increased vascular permeability
4. Leukocyte migration, chemotaxis,
5. Proliferation of connective tissue cells
      Neutrophils, basophils, mast cells, platelets,
       macrophages, and lymphocytes
   Non-Steroidal Anti-Inflammatory Drugs
   Inflammation
       Acute inflammation
            Initial response to injury
            Mediated by autocoid release – chemical messenger
            Precedes immune response
       Immune response
            Immune cells actived in response to foreign bodies or antigenic
             substances released during acute inflammation.
            Beneficial when it leads to phagocytosis/neutralization
            Detrimental when it leads to chronic problems
       Chronic inflammation
            Release of a number of mediators not prominent in the acute response
            Most common: Rheumatoid Arthritis
   Why does this matter???
       Cell damage associated with inflammation acts on cell membranes
       Release of lysosomal enzymes
       Liberation of arachadonic acid – eicosanoid synthesis
            Prostaglandins, prostacyclins, leukotrienes, thromboxanes
Prostaglandins (PGH)

          Hormone release
          - Temp. elevation
          - pain
          - inflammation
Cyclooxygenase - COX
   Arachidonate  Prostaglandins (PGH) & Thromboxanes (TXA)
       Smooth muscle
            Vascular – vasodilation (PGE2 PGI2)
            GI – cramping
            Airways – relaxed (PGE1 PGE2 PGI2)
       Blood – inhibit platelet aggregation
       Kidney – increase excretion (vasodilation)
       Nervous system
            Fever
            Sleepiness
            Neurotransmission – decrease in norepi release
   COX-1
       Constitutively expressed – always present
       Homeostasis (i.e. gastric cytoprotection)
   COX-2
       Immediate, early response gene product in inflammatory response
       Stimulated by growth factors, tumor promoters, & cytokines
Warning: children/teens should NOT use any salicylates for chicken pox (varicella) or
     flu symptoms without consulting an MD  Reye’s syndrome: vomiting, lethargy,
     belligerence, delirium, coma, brain damage with a 20-30% mortality

Indications: mild to moderate pain, inflammatory conditions including rheumatic
     fever, rheumatoid arthritis and osteoarthritis; prophylactic prevention of TIA due
     to fibrin platelet emboli, reduce the risk of MI and unstable angina pectoris, a
     number of unlabeled experimental uses

MOA: all analogs are hydrolyzed to salicylic acid with the exception of salicyamide
     and diflunisal. Salicylic Acid lowers body temperature via vasodilation
1.   ASA is a potent inhibitor of prostaglandin synthase: acetylates primarily COX-1.
     Cyclooxygenase is the first enzyme in the prostaglandin synthesis pathway
2.   ASA and only aspirin: Irreversible inhibitor of platelet aggregation (7-10 days) by
     preventing COX mediated synthesis of thromboxane A2 – a mediator of platelet
     aggregation and a potent vasoconstrictor
3.   ASA in large doses inhibits COX in arterial walls preventing synthesis of
     prostacyclin (PGI2) – a potent vasoconstrictor and inhibitor of platelet
     aggregation - this is why low doses are best in antiplatelet applications
                                                   O         Conversion to amide or
Substitution at the                                          ester eliminates anti-
5 – position increases                                       inflammatory activity while
anti-inflammatory                                            maintaining analgesia
activity                           6
                              5          1

                              4          2
                                                              Halogen (Cl, F, Br, I)
                                                              at 3 – 6 enhances
                                                              potency & tox

            OH at these locations kills activity
     Many drug interactions!                                              OH
     Salicylic acid approximate lethal dose is 10-30 grams                   O
          (4g in children)
          OH                                                       Salicylic Acid
                                                                   Salicyclic Acid

          O              Chewable tablets, gum tablets, tablets,enteric coated
      O       CH3
                         tablets, extended release tablets, delayed release
                         tablets, suppositories included buffered products
Acetylsalicylic acid
aka: Aspirin, ASA                                                  CH3
                                                       O             +
                                                             H3C   N
                                                             O     CH3
Liquid product
Fewer GI side effects than aspirin
                                               Choline Salicylate - Arthropan®
                                               Choline salicyclate - Arthropan
                                250 and 500 mg tablets-swallow whole do not chew
 F                         OH
                                Indications: mild to moderate pain, osteoarthritis
           F                    and rheumatoid arthritis (all on this page)
     Diflunisal - Dolobid®      MOA: Non-selective COX inhibitor
                                Extra Strength Doan’s Pills®
                       Mg+ 2    Sodium-free salicylate derivative with low GI upset
                                Magnesium toxicity is possible in patients with renal
 Magnesium Salicylate
Magnesium salicyclate

           O                    Disalcid® – 500 and 750 mg capsules and tablets
               O                Insoluble in gastric secretions and is NOT
           OH                   absorbed until it reaches the small intestine

 Salicylsalicyclic acid         Also Pamprin® for menstrual cramps
 aka: Salsalate
                          Enteric coated tablets
           O-Na+          Less effective in relieving pain and fever than
             O            an equal dose of ASA

           OH             Patients hypersensitive to ASA may tolerate
                          this drug
Sodium Salicylate
 Sodium salicyclate       Platelet function is not affected although
                          prothrombin time is increased

           S-Na+          Rexolate® injection
                S         IM injection is preferred
           OH             Indications: acute gout, muscular pain and
                          musculoskeletal disturbances, rheumatic fever
Sodium Thiosalicylate
 Sodium thiosalicyclate
     NSAID’s - other
Indications: No clear guidelines to selecting the best agent  selection based on
     MD experience, patient convenience, side effects and cost.
1.   Arthritis
•    Rheumatoid arthritis – except for ketorolac, mefenamic acid, meloxicam, and
•    Osteoarthritis – except for ketorolac, mefenamic acid
•    Concomitant therapy with second-line agents such as gold salts or corticosteroids
•    Juvenile arthritis - tolmetin and naproxen are used for treatment
2.   Mild to moderate pain: Post-extraction dental pain, postsurgical episiotomy pain,
     soft tissue athletic injuries (diclofenac potassium, etodolac, fenoprofen, ibuprofen,
     ketoprofen, ketorolac, meclofenamate, mefenamic acid, naproxen, naproxen sodium,
3.   Primary dysmenorrhea – diclofenac potassium, ibuprofen, ketoprofen, mefenamic
     acid, naproxen, naproxen sodium, rofecoxib
4.   Idiopathic heavy menstrual blood loss: meclofenamate (not included in slides)
5.   Unlabeled uses: sunburn, migraine headaches, others
         NSAID’s - other
MOA: these drugs exhibit antipyretic, analgesic and anti-inflammatory activity
   primarily by inhibition of prostaglandin synthase (COX – cyclooxygenase)
•   COX enzymes catalyze the conversion of arachodonic acid into a variety of
    endoperoxides that are converted into prostaglandins, thromboxanes, etc.
•   Two COX isoenzymes exist:
    1.   COX-1: In all tissues and cell types most notably in platelets (aggregation
         ability), endothelial cells, GI tract (regulates gastric acid secretion), renal
         microvasculature (maintains blood flow), glomerulus and collecting ducts
         •    Inhibition of COX-1 is a major contributing factor to GI side-effects exerted
              by these drugs – loss of GI protective effects of prostaglandins
         •    Drugs that inhibit primarily COX-1: ASA, ketoprofen, indomethacin,
              piroxicam, sulindac
         •    Slighty selective in COX-1 inhibition: ibuprofen, naproxen, diclofenac
    2.   COX-2: An inducible enzyme with some constitutive expression in kidney, brain,
         bone, female reproductive system, neoplasias, and GI tract
         •    Drugs with slight COX-2 selectivity: etodolac, nabumetone, meloxicam
         •    Drugs with selective inhibition of COX-2: celecoxib, refecoxib
COX Selectivity
 NSAID’s - other
  Na+-O     O                             HO     O
                H                                    H
                N                                    N

               H3C                               H3C
                      CH3                                    CH3

Mefenamate Sodium - Generics             Mefenamic Acid - Ponstel®

           O        CH3
                    N                           O                  CO2H
                            CO2-Na+                      N


    Tolmetin Sodium - Telectin®       Ketorolac Tromethamine - Toradol®

                                           Injectable NSAID
                                           Long acting, immediate
        NSAID’s - other
                                Propionic acid derivatives

                                                                            H3C       CO2H
  H3C     CO2-                          H3C     CO2H


                         2                           O
Fenoprofen Calcium -   Nalfon®     Ketoprofen -     Orudis®,   Oruvail®
                                                                          Naproxen - Aleve®,
                                                                          Anaprox®, Naprosyn®
    H3C    CO2H                     H3C       CO2H

                                                                             O              CO2H
              F                                                                   N
                                                                             Oxaprozin - Daypro®

Flurbiprofen - Ansaid®           Ibuprofen - Motrin®, Advil®
NSAID’s - other
          O       O
              S       CH3                  HO                    Cl
                  N                                         H
                        H                                   N

              OH      O       N                         Cl

      Piroxicam - Feldene®               Diclofenac - Voltaren®
                                         Combo with Misoprostol -
H3C                                      MeO
                          H                                       O
                                                        N       CH3
      F                           CO2H                                Cl

      Sulindac - Clinoril®               Indomethacin - Indocin®
NSAID’s - other
                                                   O       O
H3C         CH3
                                                       S       CH3
        H             CO2H                                 N
        N                                                        H
                  O                                              N       S   CH3

                                                       OH      O     N

  Etodolac - Lodine®                            Meloxicam - Mobic®




                             Nabumetone - Relafen®
        NSAID’s - other
Products available: COX-2 Selective agents

                      N N                                                   N
                             CF3                     O                          O

          H3C                                                                 CH3
                                   CH3SO2                 NH2SO2

         Celecoxib - Celebrex®       Rofecoxib - Vioxx®    Valdecoxib - Bextra®

     At therapeutic concentrations inhibition of COX-1 does not occur:
     Advantageous when one does not want to inhibit COX-1: GI problems are
     apparently less due to continued COX-1 prostaglandin protection of the GI
     Use linked to increased risk of MI event rate (JAMA 2001; 286: 954-959)
     and a worsening of hypertension (
    Migraine Headaches
Clinical Presentations:
   Often accompanied by brief aura (visual scotomas, hemianopia)
   Severe throbbing, usually unilateral headache (few hours to a few days in duration)
   Familial disease:
        more common in women
        onset: early adolescence; less common in older patients
        Migraine associated with stress
        Headache frequency: Range -- two or more per week to once a year
Migraine Pathophysiology:
   Vasomotor mechanism - inferred from:
        increased temporal artery pulsation magnitude
        pain relief (by ergotamine) occurs with decreased artery pulsations
   Migraine attack associated with (based on histological studies):
        sterile neurogenic perivascular edema
        inflammation (effective antimigraine medication reduces perivascular inflammation)
   Serotonin involvement (evidence for):
        Throbbing headache: associated with decreased serum and platelet serotonin
        Presence of serotonergic nerve terminals at meningeal blood vessels
        Antimigraine drugs influence serotonergic neurotransmitter
        Some chemical triggers may work through serotonin pathways, i.e. decreasing estrogen
         (associated with the menstrual cycle) and increased prostaglandin E1.
   Seven receptor subtypes
       5-HT1, 2 & 5-HT4-7: G-protein coupled
            Inhibit adenylate cyclase
       5-HT3: gated ion channel
   Major role in GI motility
       Enterochromaffin cells
   Stored in platelets
       Acts as a vasoconstrictor - hemostasis
       Binds to 5-HT2, provides some aggregation effects
   CV: think of 5-HT as a vasoconstrictor
   CNS
       Sleep, cognition, senses, motor, temperature, pain, appetite,
        sexual behavior, hormone secretion, etc.
  Serotonergic Drugs
Receptor        Action          Drug             Disorder

  5-HT1A     Partial Agonist Buspirone    Anxiety, depression

  5-HT1D     Agonist        Sumatriptan   Migraine

 5-HT2A/2C   Antagonist     Methysergide Migraine, depression

  5-HT3      Antagonist     Ondansetron Chemo-induced emesis

  5-HT4      Agonist        Cisapride     GI disorders

   5-HT     Inhibitor       Fluoxetine,   Depression, O/C, panic,
transporter                 sertraline    PTSD (Post traumatic)
     Agents for Migraine
1.   Serotonin 5-HT1 Receptor Agonists – Ergot Alkaloid Alternatives
Indications: acute treatment of migraine with or without aura, cluster headaches
     (sumatriptan injection only)
MOA: Selective competitive agonists of 5-HT1 receptors with no affinity for 5-HT2
   and 5-HT3 receptors, a- or b-adrenergic, dopamine, muscarininc, histamine
   or benzodiazepine receptors
     •   The 5-HT1 receptor is present on the human basilar artery and in the
         vasculature of human dura mater
     •   The etiology of migraine is theorized to be caused by the release of
         sensory inflammatory neuropeptides such as vasoactive intestinal
         peptide, substance P, and others which cause localized vasodilation
     •   Use of agonists produces vasoconstriction and inhibition of pro-
         inflammatory substance release

Serotonin – 5-HT                                      NH2

   Tryptophan is hydroxylated and N H
    decarboxylated to form 5-HT 5-hydroxytryptamine
   In Neurons 5-HT is:
       Stored in vesicles
       Released
       Taken up by pre-synaptic neurons
       Recycled or metabolized
   5-HT released by inhibitory neurons
   Stimulates 5-HT1, 5-HT2, or 5-HT3
   Antagonists: Depression, Attention Deficit
    Disorder (ADD), headaches, and nausea
    Agents for Migraine
     Available products: Serotonin 5-HT1 Receptor Agonists

                                         25 and 50 mg tablets, injection and 5
                     H                   and 20 mg nasal spray
CH3NHSO2                           CH3   Injection is SC as a 6 mg dose, also
                                N        available in an auto-injection pen
                                         Nasal spray is one spray per nostril (5
    Sumatriptan succinate - Imitrex ®    mg), 20 mg dose has higher side
                                         effects, do not increase dosage with
                                         MD consultation – Not for patients with
                                         CV disease!
                    N                    5 and 10 mg tablets and orally
         N                        CH3
                                         disintegrating tablets – more rapid
     N                          N
                                         NOT intended for prophylactic therapy
                                         Dosing must be no more often than
    Rizatriptan Benzoate -   Maxalt®     every two hours
       Agents for Migraine
       Available products: Serotonin 5-HT1 Receptor Agonists
                        H                  2.5 and 5 mg tablets
O                                    CH3   Use extreme caution in hepatic failure
       N                           N       which can result in large BP elevation
                                           More rapid onset than P.O. Sumatriptan
           Zolmitriptan - Zomig®

                                           NEW for late 2001
              CO2H                         More selective for the different subtypes
           OH           H                  of Serotonin 5-HT1 Receptors
                                           Metabolized by MAO and CYP3A4 and
    N SO2                            CH3
                                   N       2D6
                                           40% excreted unchange in the kidney
    Almotriptan malate - Axert®
                Agents for Migraine
                Available products: Serotonin 5-HT1 Receptor Agonists

                                                         1 and 2.5 mg tablets
        S                                                Contraindicated in patients with severe
    O       O                                            renal or hepatic failure

                                                         Slower onset, longer half-life
                Naratriptan -   Amerge®
                          H                             2.5 mg tablets

                                                        Indicated for acute treatment of migraine
                                                        attacks with or without aura

                                                        26 hour half-life allows better compliance
                                                        since attacks usually last 4-72 hours
                                          O             Usually one tablet treatment
        Frovatriptan succinate - Frova®
Agents for Migraine - 2003
Available products: Serotonin 5-HT1 Receptor Agonists






            Eletriptan Hydrobromide - Relpax®

  NEW for 2003 – Similar to sumatriptan in effectiveness
    Agents for Migraine
    Opioid Partial agonists/antagonists

                                 Indications: Nasal spray – treatment of
               N                 migraine headaches, Injection – pain
                   OH            management post-operatively and during
                                 labor, preoperative/ preanesthesia
                                 Antagonistic activity 1/40th of naloxone, onset
Butorphanol tartrate - Stadol®   <10 minutes, 2-3 mg = 10 mg morphine
    Agents for Migraine
2.   Ergot Alkaloids
Indications: prevention or reduction of vascular headache that occur in
     patients suffering from 1 or more headaches per week
MOA: Non-selective 5-HT1 & 2 agents. Also binds adrenergic and
   dopaminergic receptors. Partial agonist of 5-HT1 with activity similar
   to Sumatriptan. As 5-HT2 antagonist, it blocks the vasopressive
   effects of serotonin as well as effects on extravascular smooth muscle
•    Continuation of therapy past 6 months is not recommended due to
     fibrosis effects
•    Do not stop the drug suddenly. Reduce dosage slowly over 2-3 weeks
     to prevent headache rebound.
•    Beta blockers and these drugs should not be used concurrently since
     peripheral ischemia will occur - gangrene possible
•    Contraindicated in pregnancy due to ototoxic properties
•    It takes 1-2 days for protective effects to develop
      Agents for Migraine
     2.   Ergot Alkaloids – products available

                        CH3                                     H
                                                           O    N
               O    N                                                     CH3

                        CH3                                           OH
                    N                                               CH3

         N                                       H3C
 d-Lysergic Acid Diethylamide: LSD               Methysergide maleate - Sansert ®

MOST famous of the ergot alkaloids         Can be used for migraine prophylaxis

Hallucinogen with no anti-migraine         Long term treatment can lead to
                                           retroperitoneal fibrosis, pleuropulmonary
activity                                   fibrosis and fibrotic thickening of the
                                           cardiac valves
       Agents for Migraine
       2.   Ergot amine derivatives– products available
                    CH3                                             CH3
                H                                               H           OH
            O   N       O   OH                            O     N       O

                        N H N                                           N H N
                    O                                               O
                N                                               N            O
                    CH3      O                                      CH3

      N                                              N
      H                                              H

     Hihydroergotamine mesylate -                  Ergotamine Tartrate - Ergomar®
     Migranal®, DHE 45®

3.     Misc agents: Isometheptene mucate, dichloralphenazone, APAP –
       Isocom®, Midrin®
MOA: acts by constricting dilated cranial and cerebral arterioles, thus reducing the
   stimuli that lead to vascular headaches. APAP: Raises pain threashold,
   Dichloralphenazone: sedative to help with emotional stress caused by migraine
Drug Interactions
   A triptan should not be used within one-day following
    another triptan or any ergotamine-containing drug
    (vasoconstriction may be additive)
   Ergot derivatives should not be taken or until 24
    hours or more following a triptan
   "Serotonin Syndrome": weakness, hyperreflexia,
    incoordination following use of a selective serotonin
    reuptake inhibitor (SSRIs) with a triptan
   All triptans except naratriptan are contraindicated in
    patients taking MAO inhibitors (or within two weeks
    of discontinuation of MAO inhibitors)

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