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Aspirin and Antiinflammatory Agents

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1 Aspirin and Antiinflammatory Agents
Chapter 17

2 History of Aspirin Hippocrates (~ B.C.): historical records of pain relief treatments, including powder made from willow tree bark, leaves to help heal headaches, pains and fevers 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

3 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 bark

4 1838: Raffaele Piria (Italian chemist) purified salicylic acid
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


6 1899: Felix Hoffmann (German chemist; worked for Bayer) rediscovered Gerhardt's formula
Admin’d to his father who was suffering from arthritis w/ good results Convinced Bayer to market the new wonder drug Aspirin patented March 6, 1889

7 Aspirin first sold as powder
“Aspirin”: “A" in acetyl chloride, "spir" in spiraea ulmaria (plant from which salicylic acid derived), “in” familiar name ending for medicines 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


9 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

10 Acute Inflammatory Rxn
Response of mammalian host to invading pathogen or noxious agent If deficient, suppressed  opportunistic infections If inappropriate  autoimmune dysfunctions Many, varied biochem mediators Interactions w/ each other, immune response biochem’s/cells

11 Eicosanoids Generated de novo from membr phospholipids
From esterified fa Eicosa=20 C; tetraenoic=4 db’s History: 1930s – substance in semen  uterine contractions Believed originated in prostate (so prostaglandin) Now recognize family of mol’s in most tissues, der’d from arachidonic acid

12 Biosynthesis PLA2 cleaves arachidonic acid from membr phospholipid
Also cleaves lyso-PAF – precursor of another mediation of inflamm’n (PAF) Rang 15.6

13 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

14 Brody 17-1 flowchart

15 Cyclooxygenase (COX) Two forms: COX-1, COX-2 COX-1
Exploited by drug designers COX-1 Constitutive enz (always present) in most cells “Housekeeping protein” Prostanoids prod’d impt to normal homeostasis (ex: regulation vascular responses)

16 Arach acid further metab’d differently in diff cells
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, TXA2


18 Prostanoid Receptors Five main classes
Typical G-protein coupled receptors DP-receptors FP- IP- TP- EP-, based on 5 classes prostanoids + TXA2

19 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

20 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)

21 PGI2  vasodilation; inhib’n platelet aggreg’n
TXA2  vasoconstriction; platelet aggreg’n 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)

22 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

23 Sensitize afferent neurons to bradykinin  pain PGE’s impt to fever
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

24 Leukotrienes Prod’d from membr phospholipids by 5-lipoxygenase
Adds hydroperoxy grp to C5 of arach acid ( HPETE) Further metab  LTA4  LT’s B4-F4 LTC4,D4,E4 = Slow Reacting Substance of Anaphylaxis “Cysteinyl-leukotrienes”


26 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]

27 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

28 Drugs Inhibiting Prostanoid Prod’n
Two main types Glucocorticoids Non-steroidal antiinflammatories (NSAIDs) 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)

29 Commonly Used NSAIDs Aspirin Ibuprofen Diflunisal Fenbufen Diclofenac
Mefenamic Acid Nabumetone Acetaminophen Naproxen Sulindac Indomethacin Tolmetin Piroxicam Tenoxicam

30 ibuprofen Fenbufen Indomethacin Sulindac

31 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

32 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 acid Rxn: insertion 2 O, extraction free radical  5C ring


34 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


36 Celecoxib (Celebrex) Rofecoxib (Vioxx)

37 COX-1 inhib’n instantaneous, competitively reversible
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

38 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 inflamm’n

39 COX-1 vs COX-2 COX-2 most responsible for prod’n prostanoids impt to inflammation COX-2 inhib’n predicts best antiinflamm response Most NSAIDs inhibit both COX enz’s (diff extent inhib’n) COX-1 inhib’n predicts unwanted gi tract side-effects (irritation) Selective COX-2 inhibitors marketed Celecoxib (“Drug Side Effect Lawyers”; incr’d risk heart attack) Rofecoxib (Vioxx withdrawal)


41 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

42 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

43 Skin Reactions Renal Effects 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 necrosis Impt w/ paracetamol (now withdrawn)

44 Aspirin Acetylsalicylic acid Among most commonly consumed world-wide
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

45 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


47 Acetaminophen One of most common non-narcotic analgesic/antipyretic
Rel weak (?) antiinflammatory activity Selective for COX-3 (recently described) Given orally; well absorbed Peak plasma concent’s min’s Plasma ½ life 2-4 h Glucuronidated or sulfated in liver

48 Unwanted effects few at therapeutic doses
Large doses over long period increases renal damage risk Toxic doses (2-3x max therapeutic)  hepatotoxicity 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


50 Init symptoms poisoning nausea, vomiting
Hepatotoxicity occurs 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

51 Drugs that Inhibit Leukotriene Synthesis/Activity
Zileuton – inhibits 5-lipoxygenase Antiasthmatic Zyflo Zarfirlukast, Montelukast Cys-LT receptor antagonists Accolate, Singulair

52 (Zyflo) Montelukast (Singulair) Zafirlukast (Accolate)


54 Glucocorticoids For antiinflammatory activity, work through both innate and adaptive responses Through induction/inhib’n transcription of modulator proteins Innate via cyclooxygenase modulation, leukocyte mediators Adaptive via cytokines and pathogen-assoc’d prot’s

55 Innate Responses via Leukocytes
Mediators gen’d from both cells and plasma Modify, regulate vascular and cellular events Tissue macrophages recognize pathogen-assoc’d molec patterns on invading microorganisms Interaction triggers release cytokines (esp IL-1, TNF-a, chemokines)

56 IL-1, TNF-a  vasc dilation, fluid exudation
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 surfaces Draw leukocytes toward pathogen  phagocytosis

57 Adaptive Responses via Leukocytes
Lymphocytes: T cells, B cells Cloned for specific attack on partic invader 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 adaptive)


59 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 CNS input Opioid peptides inhibitory Psych factors inhibitory or stimulatory Injury, infection


61 Basal glucocorticoids in blood
Highest 8 a.m. Lowest midnight Metabolic actions Carbohydrate: decr’d uptake, utilization glu; incr’d gluconeogenesis;  hyperglycemia Proteins: incr’d catab; decr’d anab Fat: permissive lipolysis; fat redist’n Regulation of inflammatory response

62 Mechanism of Antiinflammatory Action
Glucocorticoid receptors cytoplasmic Steroid hormones lipophilic Control gene transcr’n Found in most cells 3000 to 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


64 Glucocorticoids Repress Transcr’n
Through inhib’n transcr’n factors AP-1, NF-kB  Repression genes for COX-2 So no prostanoids, leukotrienes  Repression genes for cytokines, adhesion factors So lessens macrophage activity Others

65 Glucocorticoids Induce Transcr’n
Annexin-1 (= lipocortin-1) Impt to neg faeedback control at hypothal/ant pit Antiinflammatory (inhibits PLA2?) Others Take sev hours

66 Antiinflammatory Actions of Glucocorticoids
Red’d vasodilation, decr’d fluid exudation At acute inflamm’n  decr’d influx, activity of leukocytes 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 responses

67 Decr’d redness, heat, pain, swelling Decr’d wound healing, repair
Regardless of cause of inflamm’n Invaders, chem/phys stimuli, hypersensitivity/autoimmunity Used to suppress graft rejection May prevent “overshoot” of endogenous responses

68 Unwanted Effects Occur w/ large doses, prolonged admin
Suppression of response to infection, injury Sudden withdrawal  suppression ability synthesize endogenous hormones Metabolic, water/electrolyte effects w/ endogenous hormones Swelling, Cushing’s syndrome

69 Calcium, phosphate regulation by endogenous hormones
So osteoporosis Metabolic effects of endogenous hormones So growth inhib’n in children

70 Pharmacokinetics Various routes of admin
Active orally IM/IV 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)

71 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

72 Corticosteroid Agents
Hydrocortisone Cortisone Corticosterone Prednisolone Prednisone Methylprednisolone Triamcinolone Dexamethasone Betamethasone Beclometasone dipropionate Budesonide Deoxycortone Fludrocortisone Aldosterone

73 Hydrocortisone Corticosterone


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