Aspirin and Antiinflammatory Agents

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Transcript Aspirin and Antiinflammatory Agents

Aspirin and Antiinflammatory
Chapter 17
History of Aspirin
• Hippocrates (~ 460 - 377 B.C.): historical
records of pain relief treatments, including
powder made from willow tree bark,
leaves to help heal headaches, pains and
• The Royal Society of London publishes an
article by the Rev. Edward Stone, "Account
of the success of the Bark of the Willow in
the Cure of Agues," officially reporting
what had been folklore for centuries
• 1826: Brugnatelli and Fontana (Italians)
obtained salicin in impure form
• 1828: Johann Buchner, University of
Munich professor of pharmacy, isolated tiny
amount of bitter tasting yellow, needle-like
crystals, which he called salicin from willow
• 1829: Henri Leroux (French chemist)
improved extraction procedure  30g
from 1.5kg of bark
• 1838: Raffaele Piria (Italian chemist)
purified salicylic acid
– BUT salicylic acid “tough on stomachs” so
searched for 'buffering‘
• 1853: Charles Frederic Gerhardt (French
chemist) neutralized salicylic acid by
buffering w/ sodium (sodium salicylate)
and acetyl chloride  acetylsalicylic acid
– Worked, but Gerhardt did not market it and
abandoned his discovery
• 1899: Felix Hoffmann
(German chemist;
worked for Bayer)
rediscovered Gerhardt's
– Admin’d to his father
who was suffering from
arthritis w/ good results
– Convinced Bayer to
market the new wonder
– Aspirin patented March
6, 1889
• “Aspirin”: “A" in acetyl chloride, "spir" in
spiraea ulmaria (plant from which salicylic
acid derived), “in” familiar name ending for
– Aspirin ® and Heroin ® were once trademarks
belonging to Bayer
• Aspirin first sold as powder
– First Aspirin tablets made in 1915
• After Germany lost World War I, Bayer
forced to give up both trademarks as part of
the Treaty of Versailles in 1919
– Reduces "aspirin" to generic word for any brand
of acetylsalicylic acid
• 1950: Dr. Lawrence L. Craven (US) describes
aspirin's action as a blood-thinner, begins
prescribing daily doses to his patients as a means of
preventing heart attacks
• 1971: John R. Vane (British pharmacologist)
discovers aspirin's mechanism of action —inhibits
prod’n prostaglandins -- hormone-like substances in
the body
– 1982: Sir John R. Vane is co-winner of the Nobel Prize in
Medicine for his discoveries concerning prostaglandins
• 1990s: Studies show regular use of aspirin may
reduce risk of colon cancer.
• 2005: Research shows aspirin reduces risk of stroke
in healthy women, although no clear benefit is seen
for prevention of heart attack
Acute Inflammatory Rxn
• Response of mammalian host to
invading pathogen or noxious agent
– If deficient, suppressed  opportunistic
– If inappropriate  autoimmune
• Many, varied biochem mediators
– Interactions w/ each other, immune
response biochem’s/cells
• Generated de novo from membr
– From esterified fa
• Eicosa=20 C; tetraenoic=4 db’s
• History: 1930s – substance in semen 
uterine contractions
– Believed originated in prostate (so
• Now recognize family of mol’s in most
tissues, der’d from arachidonic acid
• Biosynthesis
– PLA2 cleaves arachidonic acid from membr
• Also cleaves lyso-PAF – precursor of another
mediation of inflamm’n (PAF)
Rang 15.6
• Not stored, but synth’d when needed
– Stimuli for PLA2 activity vary w/ tissue
• Ag-Ab rxns on mast cells
• Bradykinin binding on fibroblasts
• Thrombin binding on platelets
– Free fa further metab’d by
• Fatty acid cylooxygenases 1 and 2
• Lipoxygenases
• CYPs
• Primarily locally-active
– Commonly work at cell/tissue/structure from
which synth’d (autocoids)
– Blood concent very low
• Efficient pulmonary degradation
Brody 17-1 flowchart
Cyclooxygenase (COX)
• Two forms: COX-1, COX-2
– Exploited by drug designers
• COX-1
– Constitutive enz (always present) in most
– “Housekeeping protein”
– Prostanoids prod’d impt to normal
homeostasis (ex: regulation vascular
• COX-2
– Induced in inflammatory cells by
inflammation stimuli
– Inhibited by NSAIDs
• Arach acid further metab’d differently in
diff cells
– Platelets  TXA2
– Vasc endothelium, macrophages  PGI2
– Most impt: PGE2, PGI2, PGD2, PGF2a,
Prostanoid Receptors
• Five main classes
• Typical G-protein coupled receptors
FPIPTPEP-, based on 5 classes prostanoids + TXA2
• Modulate adenylyl cyclase
– Stimulators: DP, EP2, EP4, IP
– Inhibitors: EP2
• Modulate phosphlipase C  DAG/IP3
and Ca+2 mobilization
• Many cells have >1 PG receptor subtype
• Eicosanoids do not enter cells except w/
transport system intake
– Lung, renal prox tubules, thyroid plexus,
ciliary body
Actions of Prostanoids
• PGD2  vasodilation, inhib’n platelet
aggreg’n, relaxation gi muscle, uterine
relaxation, mod’n release hypothl/
pituitary hormones
• PGF2a  contraction myometrium
(humans); luteolysis (cattle);
vasoconstriction (dogs, cats)
• PGI2  vasodilation; inhib’n platelet
• TXA2  vasoconstriction; platelet
• PGE2  contraction bronchial & gi
smooth muscle (EP1 receptor); relaxation
bronchial, vascular, gi smooth muscle
(EP2); contract’n intest smooth muscle
and pregnant human uterus, inhib’n
gastric acid secr’n, inhib’n lipolysis and
autonomic neurotransmitter release (EP3)
Prostanoids and Inflamm’n
• PGE2 -- Predom prostanoid w/ inflamm
response; PGI2 also generated
– Prod’d by local tissues, blood vessels w/
acute inflamm’n
• PGD2 released by mast cells
– With chronic inflamm’n, PGE2 and TXA2
released by monocytes/macrophages
• Powerful vasodilators
– Synergize w/ histamine, bradykinin
• Redness w/ inflamm’n due to dilation
precapillary arterioles by prostaglandins
–  Incr’d blood flow
– Histamine + bradykinin also required
• Sensitize afferent neurons to bradykinin
 pain
• PGE’s impt to fever
– Found in high concent in csf
– Prod’d in hypothalamus in response to
pyrogen (IL1) rel’d by bacteria
–  Elevation temp set-point
• Prod’d from membr phospholipids by 5lipoxygenase
– Adds hydroperoxy grp to C5 of arach acid
• Further metab  LTA4  LT’s B4-F4
– LTC4,D4,E4 = Slow Reacting Substance of
– “Cysteinyl-leukotrienes”
Actions of Leukotrienes
• LTB4 powerful chemotactic for
neutrophils, macrophages
– On neutrophils  upreg’n membrane
adhesion mol’s; incr’d prod toxic O2
prod’s; release granule enz’s
– On macrophages  stim’n prolif’n;
cytokine release
– Receptor of phosphatidylinositol/DAG type
 incr’d cell [Ca]
• LTD4 impt to respiratory system
– Spasmogens
– Incr’d mucous secr’n
– Red’d airway conductance
• LTD4 impt to cardiovascular system
– Decr bp (constrict’n small coronary vessels)
– Wheal/flare w/ subcu dose
• LTB4 impt to bronchial hyperreactivity
in asthmatics; role in cardiovascular
changes w/ acute anaphylaxis
Drugs Inhibiting Prostanoid Prod’n
• Two main types
– Glucocorticoids
– Non-steroidal antiinflammatories (NSAIDs)
– Used worldwide
• > 50 on market
• Many have unwanted effects
– Three major types of effects
• Mod’n inflammatory rxn (antiinflamm)
• Red’n pain (analgesic)
• Lower body temp (antipyretic)
Commonly Used NSAIDs
Mefenamic Acid
• Most traditional NSAIDs have sim
antiinflammatory activity except
– Indomethacin, piroxicam may be stronger
– Aspirin has diff pharmacological actions
• Antipyresis activity relieves fever
• Analgesia effective against arthritis, bursitis,
muscular/vascular pain, toothache,
dysmenorrhea, postpartum pain
– Headache pain relieved by blocking cerebral
vascular dilation w/ prostanoid decr
NSAID Mechanism of Action:
COX Inhib’n
• COX enz’s bifunctional
– Main activity  PGG2
– Peroxidase activity converts PGG2PGH2
• Inhibitors block only main rxn
• COX enz’s assoc’d w/ cell membr
– Active site hydrophobic, accepts arachidonic
– Rxn: insertion 2 O, extraction free radical
 5C ring
COX-1 vs COX-2
• COX-2 active site slightly wider
• Aa523 differs
– COX-1 has leucine
• Rel bulky
– COX-2 has valine
• Smaller; leaves gap
• Allows access to side-pocket
– COX-2 selective agents have side chain, interacts w/ pocket
– May be too large to fit COX-1 active site channel
Celecoxib (Celebrex)
Rofecoxib (Vioxx)
• Traditional NSAIDs
– H-bond polar arginine (120) half-way down
channel  blockage of channel
• COX-1 inhib’n instantaneous,
competitively reversible
• COX-2 inhib’n incr’s w/ time
– Also reversible (by competitively excluding
arach acid)
• Aspirin
– Binds, acetylates serine530  irrev inact’n
of both enz’s
• NSAIDs may inhibit inflammation by
other mech’s also
– Some scavenge oxygen radiacls prod’d by
neutrophils, macrophages (ex: sulindac)
– Aspirin inhbits expr’n transcr’n factor NF-kB
• Impt to transcr’n genes for mediators of
COX-1 vs COX-2
• COX-2 most responsible for prod’n
prostanoids impt to inflammation
– COX-2 inhib’n predicts best antiinflamm
• Most NSAIDs inhibit both COX enz’s (diff
extent inhib’n)
– COX-1 inhib’n predicts unwanted gi tract sideeffects (irritation)
• Selective COX-2 inhibitors marketed
• Celecoxib (“Drug Side Effect Lawyers”; incr’d risk
heart attack)
• Rofecoxib (Vioxx withdrawal)
NSAID Adverse Reactions
• Numerous; may cause death
• Elderly w/ joint diseases need fairly large
doses, long-continued use
– High incidence side effects: gi, liver, skin,
kidney, spleen, blood, bone marrow
• Gastrointestinal disturbances commonest
– Due to COX-1 inhib’n
• Impt for PGS that inhibit acid secr’n, protective
of mucosa
• Side-effects include dyspepsia, diarrhea
(or constipation), nausea, vomiting,
gastric bleeding, ulceration
– May  hemorrhage, perforation
– Can admin PGs to relieve
– Selective COX-2 inhib’s  decr’d gi effects
• Skin Reactions
– Second most common side-effect
– Mild rashes, urticaria, photosensitivity
• May be fatal
– Most frequently w/ mefenamic acid, sulindac
• Renal Effects
– Some pts susceptible
• Reversible w/ stopping drug
– PGs synth’d here impt to vasodilation at
kidney w/ angiotensin II, noradrenaline
– Can  chronic nephritis, renal papillary
– Impt w/ paracetamol (now withdrawn)
• Acetylsalicylic acid
• Among most commonly consumed
• Rel insoluble; Na+ and Ca+2 salts
readily soluble
• Many effects beyond antiinflammatory
– Antiplatelet for cardiovascular disorders
– Decr’d colon, rectal cancer
– Decr’d risk, later onset of Alzheimer’s
• Weak acid, unionized in stomach
–  good abs’n
– Most abs’n in ileium (more surface area)
• Metab by ox’n (25%); glucuronide or sulfate
conjugation (50%); excr’d unchanged (25%)
– Rate excr’n incr’d in alkaline urine
• Irreversible inhibitor of COX enz’s
• Toxicity may be local or systemic
– Same side-effects as NSAIDs
– Salicylism: tinnitis, vertigo, decr’d hearing w/ large,
repeated doses
– Reye’s syndrome in children: liver and CNS disturbances
– May alter acid-base balanceby uncoupling ox’ve
phosph’n  incr’d blood [O2]  alteration breathing 
resp alkalosis
• One of most common non-narcotic
– Rel weak (?) antiinflammatory activity
– Selective for COX-3 (recently described)
• Given orally; well absorbed
– Peak plasma concent’s 30-60 min’s
• Plasma ½ life 2-4 h
– Glucuronidated or sulfated in liver
• Unwanted effects few at therapeutic doses
– Large doses over long period increases renal
damage risk
• Toxic doses (2-3x max therapeutic) 
– Potentially fatal
– Phase II enz’s sat’d  products of mfo’s (Phase
I enz’s) in incr’d concent
• N-acetyl-p-benzoquinone imine
– Usually metab’d by conjugation glutathione
– Depletion glutathione  suff imine to react w/ cellular
nucleophiles  necrosis liver, kidney tubules
• Init symptoms poisoning nausea,
• Hepatotoxicity occurs 24-48 h later
• Treatment
– Gastric lavage, then
– Oral activated charcoal
– If early, acetylcysteine IV or methionine
orally  incr’d glutathione in liver 
enhanced metab/excr’n
Drugs that Inhibit Leukotriene
• Zileuton – inhibits 5-lipoxygenase
– Antiasthmatic
– Zyflo
• Zarfirlukast, Montelukast
– Cys-LT receptor antagonists
– Antiasthmatic
– Accolate, Singulair
• For antiinflammatory activity, work
through both innate and adaptive
– Through induction/inhib’n transcription of
modulator proteins
• Innate via cyclooxygenase modulation,
leukocyte mediators
• Adaptive via cytokines and pathogen-assoc’d
Innate Responses via Leukocytes
• Mediators gen’d from both cells and
– Modify, regulate vascular and cellular
• Tissue macrophages recognize pathogenassoc’d molec patterns on invading
– Interaction triggers release cytokines (esp IL1, TNF-a, chemokines)
• IL-1, TNF-a  vasc dilation, fluid
– Exudate has enz cascade mol’s  kinin
system, complement system
•  release histamine from mast cells  local
dilation arterioles
• W/ local tissue damage  cytokines rel’d 
eicosanoids synth’d (PGI2, PGE2 
vasodilation, leukotrienes  chemotaxis prot’s)
• Expression of adhesion mol’s on cell
– Draw leukocytes toward pathogen 
Adaptive Responses via
• Lymphocytes: T cells, B cells
• Cloned for specific attack on partic
– Humoral response via B cells, Ab’s
– Cell mediated response via T cells
• Produce various prot’s to modulate, coordinate
responses of other leukocytes (innate and
Endogenous Glucocorticoids
• Steroids secr’d by adrenal cortex
• Synth’d, rel’d w/ ACTH from ant pit
– ACTH secr’n regulated
• Corticotropin Releasing Factor from hypothal
• Blood [glucocorticoid]
– CRF secr’n regulated
• Blood [glucocorticoid]
• CNS input
– Opioid peptides inhibitory
– Psych factors inhibitory or stimulatory
– Injury, infection
• Basal glucocorticoids in blood
– Highest 8 a.m.
– Lowest midnight
• Metabolic actions
– Carbohydrate: decr’d uptake, utilization
glu; incr’d gluconeogenesis; 
– Proteins: incr’d catab; decr’d anab
– Fat: permissive lipolysis; fat redist’n
• Regulation of inflammatory response
Mechanism of Antiinflammatory
• Glucocorticoid receptors cytoplasmic
Steroid hormones lipophilic
Control gene transcr’n
Found in most cells
3000 to 10000 per cell, depending on tissue
• Receptor binding  conform’l change 
exposure DNA-binding domain and dimerization
• Bound dimer  nucleus
• Bind steroid response elements on DNA
•  Repression or induction partic genes
Glucocorticoids Repress Transcr’n
• Through inhib’n transcr’n factors AP-1,
•  Repression genes for COX-2
– So no prostanoids, leukotrienes
•  Repression genes for cytokines,
adhesion factors
– So lessens macrophage activity
• Others
Glucocorticoids Induce Transcr’n
• Annexin-1 (= lipocortin-1)
– Impt to neg faeedback control at
hypothal/ant pit
– Antiinflammatory (inhibits PLA2?)
• Others
• Take sev hours
Antiinflammatory Actions of
• Red’d vasodilation, decr’d fluid exudation
• At acute inflamm’n  decr’d influx, activity of
• At chronic inflamm’n  decr’d activity
macrophages, decr’d angiogenesis
• Decr’d prod’n, action of cytokines (IL’s, TNF),
eicosanoids, IgG, complement components
• Overall: red’n chronic inflamm’n, autoimmune
rxns BUT decr’d healing, protections of inflamm
• Decr’d redness, heat, pain, swelling
• Decr’d wound healing, repair
• Regardless of cause of inflamm’n
– Invaders, chem/phys stimuli,
• Used to suppress graft rejection
• May prevent “overshoot” of
endogenous responses
Unwanted Effects
• Occur w/ large doses, prolonged admin
• Suppression of response to infection,
• Sudden withdrawal  suppression
ability synthesize endogenous hormones
• Metabolic, water/electrolyte effects w/
endogenous hormones
– Swelling, Cushing’s syndrome
• Calcium, phosphate regulation by
endogenous hormones
– So osteoporosis
• Metabolic effects of endogenous
– So growth inhib’n in children
• Various routes of admin
– Active orally
– Topically
• Fewer side effects
• Binding to corticosteroid-binding
globulin and albumin
– Bound forms inactive
• Hydrocortisone ½ life 90 mins (main
biol effects in 2-8 h)
Clinical Uses
• Replacement in adrenal failure
(Addison’s disease)
• Antiinflammatory for asthma; skin/ear/
eye inflamm’n; hypersensitivity
disorders; autoimmune disorders;
transplant pts
• Neoplastic disease for red’n cerebral
edema; in combination w/ cytotoxic
drugs; antiemesis w/ chemotherapy
Corticosteroid Agents
• Dexamethasone
• Betamethasone
• Beclometasone
• Budesonide
• Deoxycortone
• Fludrocortisone
• Aldosterone