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CH3(CH2)18COOH ... WITH "Z" FORM DOUBLE BONDS
EICOSANOIC ACID [ARACHADONIC ACID]
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Precursor for Leukotrienes, Lipoxins, & Hydroxyeicosatetraneoic acids
Arachadonic Acid
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Precursor for prostaglandins, thromboxanes, and prostacyclins
Arachadonic Acid
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Arachadonic acid is converted to Epoxyeicostatreinoic acids (EETS) by this enzyme
Epoxygenase (CYP450)
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•Constantly present in low levels in
many organs
–Kidney
–GIT
–Platelets
Cox-1
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•PGS produced by this enzyme are important
for many normal physiologic reactions
–Renal
•Vasodilation
in kidney
•Maintenance
of normal function
–Platelets
•Thromboxane
formation
–Gastric
mucosa
•Mucosal
protectants against HCl
Cox-1
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•Present in fewer tissues under basal conditions
–Brain
–Renal cortex
•Inflammatory
cytokines produced as a result of tissue damage induce PG generation
–Pain
–Inflammation
Cox-2
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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)
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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
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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
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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)
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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
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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
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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
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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
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List the 6 NSAID classes
- –Aspirin and the salicylates
- –3,5-Pyrazolidinediones
- –Arylalkanoic acids – “Classical”
- –Fenamates (N-Arylanthranilic acids)
- –Oxicams
- –COX-2 inhibitors
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3 Major Therapeutic Applications of NSAIDS
- •Analgesics
- –Pain
- •Anti-inflammatory agents
- –Inflammation
- •Antipyretics
- –Fever
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ASA and NSAID Mechanism of Action
- •inhibit the cyclooxygenase system
- (COX-1 and COX-2) reducing the production of
- –Prostacyclin
- –Prostaglandins
- –Thromboxane
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Most NSAIDS inhibit Cox 1 or Cox 2 more?
Cox 1 [depletes prostaglandins]
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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
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2 Major differences between and among NSAIDs
–Therapeutic half-lives
–Safety profiles
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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
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Arylalkanoic Acid Derivatives
•Arylacetates –Arylacetic acids & Heteroarylacetic acids
•Arylpropionates [“Profens”] –Arylpropionates & Heteroarylpropionates
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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
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Arylalkanoic Acids (Pharmacokinetics)
Absorption
–Rapid and complete for most compounds
–Food may delay, but not effect the total absorption
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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
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Arylalkanoic Acids (Pharmacokinetics)
Bioavailability
High Bioavailability (80-95%)
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Arylalkanoic Acids (Pharmacokinetics)
Excretion
–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
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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)
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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
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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
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Examples of Arylalkanoic Acid Derivatives
(Generic Drug Names for Eye Solutions)
- Flurbiprofen Sodium
- Bromfenac Sodium
- Diclofenac Sodium
- Ketorolac Tromethamine
- Nepafenac
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Arylalkanoic Acids (Adverse Effects)
- Gastrointestinal upset
- –Nausea, vomiting, diarrhea, constipation – (3-12%)
- –Dyspepsia (3-13%)
- –Cramping (3-10%)
- –Anorexia (1-3%)
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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%)
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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
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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
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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
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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
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Arylalkanoic Acids Contraindications
- •Hypersensitivity to
- –Particular NSAID
- –Any component of the formulation
- –ASA
- –Patients with “aspirin triad”
- •Bronchial asthma
- •Aspirin intolerance
- •Rhinitis
- –Other NSAIDs
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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
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•Ortho- or para- placement of the phenoxy greatly decreases activity
•Replace oxygen bridge with carbonyl group -> Ketoprofen
•Indications (p.o.)
–RA/OA
–Migraine
Fenoprofen
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•Indications (p.o.)(Ansaid®)
–RA/OA
•Indications (ophthalmic)(Ocufen®)
–Inhibition
of intraoperative miosis during cataract extraction surgery
Flurbiprofen
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•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
action
Ibuprofen
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•Indications (p.o.)
–RA/OA
–Analgesia
–Fever
–Primary
dysmenorrhea
•Other
–Sept, 2010 – Ketoprofen
+ Omeprazole marketed in UK as Axorid®
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Ketoprofen
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•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®
Naproxen
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•New NSAID - NicOx
(French Co.)
•Naproxen derivative
–A
nitrooxybutyl
ester
–This
esterification permits drug to also function as nitric oxide donator
–New class –
Cyclooxygenase-Inhibiting
Nitric Oxide
Donator (CINOD)
–Developed
to increase safety (myocardial, GI) but retain NSAID efficacy
Naproxcinod
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•Indications (ophth.)
–Post-operative
inflammation and pain following cataract surgery
–First
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
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Bromfenac
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•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
site
•More likely to produce hepatotoxicities than other NSAIDS
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Diclofenac
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•N-4 chlorobenzoyl moiety orients away from C-2
methyl; noncoplanar with indole
•Indications (p.o., rectal)
–RA/OA/Gout
–Bursitis/tendinitis
Indomethacin
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•Indications
(IM, IV, p.o.)
–Analgesia
•Short
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
analgesia
Ketorolac
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•A unique NSAID, as it is a NONACIDIC
p.o.
PRODRUG – MINIMAL GI UPSET
•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.)
–RA/OA
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Nambutone
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•A NOVEL NONACIDIC PRODRUG
•NDA approved Alcon product – August
25, 2005
•Penetrates ocular tissues and
converts to the active arylalkanoic acetic acid Amfenac (2-amino-3-benzoyl-benzeneacetic
acid)
–Amfenac
= Debromobromfenac
Nepafenac
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•Indications (p.o.)
–RA/OA/Gout
•Special adverse effect potential
–Stevens-Johnson Syndrome with Toxic
Epidermal Necrolysis
•Potentially
fatal
•Reported to have the highest incidence of SJS-TEN of any NSAID
•Recent
settlement - $21 million to blinded and scarred patient in Concord, NH
Sulindac
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