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AUTACOIDS : Receptor- and Non Receptor-Mediated Therapeutics 201, Learning Unit IV Semester 1, AY 2009-2010 Department of Pharmacology & Toxicology UP.

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Presentation on theme: "AUTACOIDS : Receptor- and Non Receptor-Mediated Therapeutics 201, Learning Unit IV Semester 1, AY 2009-2010 Department of Pharmacology & Toxicology UP."— Presentation transcript:

1 AUTACOIDS : Receptor- and Non Receptor-Mediated Therapeutics 201, Learning Unit IV Semester 1, AY 2009-2010 Department of Pharmacology & Toxicology UP College of Medicine July 13, 2009

2 Autacoids : Agonists, Antagonists Objectives: At the end of the session, students are expected to: Review concepts pertaining to the inflammatory process Define an autacoid Describe the different autacoids in terms of (emphasis on histamine, serotonin, eicosanoids) 1.Distribution/site in the body 2.Synthesis/storage/release/metabolism 3.Factors that stimulate synthesis, release 4.Specific receptors 5.Pharmacologic action/effect of agonists, antagonists and enzyme inhibitors 6.Clinical applications

3 Concept MAP : Maintaining/Restoring Balance in Health/Disease Sick Person Mechanisms In Disease : External/Internal milieu => Body response => S/S Management & Therapeutics Goal : Dx, Relief & Restoration, Prevention Drug & Non-Drug (Surgery, Rehab) Healthy Person Normal Tissue (Structure & Fxn)

4 Clinical illness is produced by: Direct invasion of tissue Toxic compounds liberated by the organism The body’s response to the organism



7 The manifestations of disease are usually produced by various inflammatory mediators produced by: the initiating organism or the host The resulting inflammation may be: helpful in localising the causative infection or harmful

8 Autacoids “Autacoids” : a varied group of endogenous substances occurring in minute amounts and possessing distinct chemical structure with distinct biologic/ pharmacologic activity Autos = self; Akos = medicinal agent or remedy (Greek).

9 AUTACOIDS Naturally occurring substances Localized in tissues Do not normally circulate Diverse physiological and pharmacological activities Differ from hormones and neurotransmitters Short duration of action Usually involved in response to injury Sites of action restricted to the synthesis area

10 Examples of autacoids Amines: histamine, serotonin (5HT) Polypeptides: kinins, oxytocin, angiotensin II, vasopressin, atrial natriuretic factor, endothelins. Fatty acids: prostaglandins, leukotrienes, thromboxanes, platelet activating factor (PAF). Others: endothelium-derived relaxing factor (NO), cytokines (proteins).

11 G-protein-coupled receptors (GPCRs)* Major target of drug development Signalling mechanism & potential target sites for drug action 1. Basal state (“switch off”) 2. Receptor-mediated GDP release 3. Subunit dissociation & effector regulation 4. Deactivation & return to basal state


13 Histamine (  -aminoethylimidazole): a basic amine COOH Histamine is formed from histidine by histidine decarboxylase. Small amounts of histamine formed by bacteria in the gastro- intestinal tract (GIT) is broken down in the gut wall and liver.

14 Distribution of histamine Widely distributed in: - bacteria - plants - animals - venoms and stinging fluids (stinging nettle, insect stings, bee venom).

15 Histamine Signal involved in local immune response, also a neurotransmitter synthesized by the decarboxylation of histidine Either stored or quickly inactivated by histamine-N- methyltransferase and diamine oxidase Release of histamine from mast cells is stimulated by IgE antibodies which respond to foreign antigens in the body

16 Synthesis Decarboxylation of amino acid L-histidine catalyzed by pyridoxal PO4-dependent L- histidine decarboxylase. Ingested from food or formed by bacteria in the GIT Storage sites: –perivascular tissue – mast cell –circulation – basophil (bound to chondroitin SO4) –others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues and body fluids

17 Storage of histamine ‘Slow-turnover’ histamine is stored as heparin-histamine complex in cytoplasmic granules in mast cells (lungs, GIT, skin) and basophils. ‘Fast-turnover’ histamine is stored in CNS neurons, skin and enterochromaffin-like cells (ECL) of stomach.

18 Release of ‘Slow turnover’ histamine Allergic reaction: Antigen combines with IgE antibodies on the surface of mast cells or basophils. Mechanical–induced degranulation: e.g., scratch. Non-exocytotic: displacement of histamine from storage site by a drug, e.g., tubocurarine, morphine.

19 Metabolism :

20 Histamine receptors ReceptorMecha- nism FunctionAntagonists H1H1 GqGq ileum contractionileum modulate circadian cyclecircadian cycle systemic vasodilatationsystemicvasodilatation bronchoconstriction (asthma)bronchoconstrictionasthma H 1 -receptor antagonistsH 1 -receptor antagonists Diphenhydramine Loratadine Cetirizine H2H2 G s G s ↑ Ca 2+Ca 2+ speed up sinus rhythmsinus rhythm Stimulation of gastric acid secretiongastric acid Smooth muscle relaxationSmooth muscle Inhibit antibody synthesis, T-cell proliferationantibodyT-cell and cytokine productioncytokine H 2 -receptor antagonistsH 2 -receptor antagonists Ranitidine Cimetidine H3H3 GiGi Neurotransmitter in CNSNeurotransmitterCNS Presynaptic autoreceptorsautoreceptors H 3 -receptor antagonistsH 3 -receptor antagonists ABT-239 Ciproxifan Clobenpropit H4H4 GiGi mediate mast cell chemotaxis. [2]mast cellchemotaxis [2] H 4 -receptor antagonistsH 4 -receptor antagonists Thioperamide JNJ 7777120

21 Histamine H 1 -receptors Present in endothelium, smooth muscles cells, nerve endings. Receptor activation → diacylglycerol and IP3 Contract smooth muscles: intestine, bronchi V/d: direct + NO release → flushing, headache  Vascular permeability : contract endothelial cells in venules) Triple response: flush, flare and wheal. Stimulate nerve endings: pain, itch; release epinephrine and norepinephrine from adrenal medulla; central excitation.

22 Triple response (Lewis,1927) ResponseActionEffect 1 Loczd red spot “flush” relaxation of vasc smooth m vasodilation 2 Swelling or edema “wheal” contrxn endoth cells, postcap venl increased “cap” perm or leakage 3 Brighter red halo, “flare” local axon reflxIndirect vasodi- lation

23 Pathophysiological action of histamine Mediate type 1 hypersensitivity reactions: hives and hay fever. Emesis: mediation of motion sickness Histamine shock (hypotension): systemic anaphylaxis.

24 The Allergic Reaction

25 An Allergic Reaction Early phase reaction: occurs within minutes of exposure to an allergen and lasts for 30-90 minutes Late phase reaction: begins 4-8 hours later and can last for several days, often leading to chronic inflammatory disease

26 Symptoms Allergic Rhinitis Conjunctivitis Bronchoconstriction Urticaria Atopic Dermatitis Anaphylaxis is.cfm

27 Symptoms: anaphylaxis, swelling (skin, mucosa); itching, bronchospasm, hypotension, shock, phospholipase C and A 2 activation. Liberators: large molecules (proteins – egg white, serum, venom, toxins); surface active agents, proteolytic enzymes, drugs etc. Clinical uses: diagnosis of achlorhydria, diagnosis of pheochromocytoma, and to verify integrity of axon reflexes.

28 Histamine H 2 -receptors Receptor activation: stimulation of adenylyl cyclase   cAMP. Parietal cells: H + secretion. Vascular smooth muscle cells: vasodilatation Heart:  force of contraction,  HR.

29 Histamine H 3 -receptors Largely presynaptic receptors in brain, myenteric plexus and other neurons. Autoreceptors: negative feedback inhibition of histamine synthesis and release. Heteroreceptor:  release of norepinephrine, dopamine, serotonin and acetylcholine.

30 Selected Actions of Histamine in Humans Organ TissueActionReceptor CARDIOVASCULAR Vascular Facial cutaneous Forearm Gastric mucosa Carotid artery Pulmonary artery Basilar artery Coronary artery Other pre & post cap Arterioles Postcapillary venules Heart  TPR Vasodilatation  Blood flow  Blood flow,relaxation Constriction Relaxation Constriction Vasodilatation  Permeability  SA rate  Force of contraction Atrial & vent automaticity H1, H2 H2 H1, H2 H2 (?) H1 H2 H1 H2

31 Selected Actions of Histamine in Humans Organ TissueActionReceptor RESPIRATORY Bronchiolar smooth muscleContraction (more prominent) Relaxation H1 H2 GASTROINTESTINAL Oxyntic mucosa GI smooth muscle Gallbladder smooth muscle Acid and pepsin secretion, If Relaxation & Contraction (more prominent) Relaxation (?) H2 H1 H2 (?) CUTANEOUS NERVE ENDINGS (Sensory) Pain & itching (esp to insect bites & needle stings) H1, H2 (?) ADRENAL MEDULLAEpinephrine releaseH1 BASOPHILSInhibition of IgE – dependent degranulation H2

32 Histamine & Agonists : Chemical Structure

33 Histamine Antagonists 1.Physiologic antagonism – epinephrine 2.Release inhibitors – cromolyn sodium, Beta 2 adrenoceptor agonists 3.Histamine receptor antagonists

34 Histamine H 1 -receptor antagonists Competitive; some are antimuscarinic, some block  -adrenoceptors, and receptors for bradykinin, serotonin, and some have local anesthetic properties. First generation antihistamines: lipid soluble → sedative (children may experience excitation) Second generation antihistamines: Non-sedative: loratadine

35 First Generation Antihistamines Small, lipophilic molecules that could cross the BBB Not specific to the H1 receptor Groups: –Ethylenediamines –Ethanolamines –Alkylamines –Piperazines –Tricyclics Common structural features of classical antihistamine –2 Aromatic rings –Connected to a central Carbon, Nitrogen or CO –Spacer between the central X and the amine –Usually 2-3 carbons in length –Linear, ring, branched, saturated or unsaturated –Amine is substituted with small alkyl groups eg CH3

36 Histamine Antagonists A. Ethanolamines 1.Carbinoxamine maleate 2.Clemastine fumarate 3.Diphenhydramine HCl 4.Dimenhydrinate B. Ethylenediamines 1.Pyrilamine maleate 2.Tripelennemine HCL/citrate 3.PPA C. Alkylamines 1.Chlorpheniramine maleate 2.Brompheniramine maleate D. Piperazines 1. Hydroxyzine HCl/pamoate (long acting) 2. Cyclizine HCl/lactate 3. Meclizine HCl 4. Chlorcyclizine E. Phenothiazines 1. Promethazine HCl First Generation Agents

37 Second Generation Antihistamines Modifications of the First Generation Antihistamines to eliminate side effects resulted in the Second Generation Antihistamines More selective for peripheral H1 receptors Examples: –terfenadine –loratadine –cetirizine –mizolastine –astemizole

38 Second Generation Agents A. Alkylamines Acrivastine B. Piperazines Cetirizines HCl C. Piperidines Astemizole Levocabastine Loratadine Terfenadine Fexofenadine

39 “Next” Generation Antihistamines Metabolite derivatives or active enantiomers of existing drugs Safer, faster acting or more potent than Second Generation drugs Examples: –Fexofenadine –Desloratadine –Levocetirizine

40 Therapeutic Uses: 1.Dermatosis 2.Allergic rhinitis 3.Motion sickness & emesis 4.Parkinson’s disease 5.EPS 6.Insomnia 7.Adverse reactions

41 Adverse Reactions and Side Effects First Generation Drugs: –Anticholinergic CNS interactions –Gastrointestinal reactions –Common side effects: sedation, dizziness, tinnitus, blurred vision, euphoria, lack of coordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhea, dry mouth, and dry cough Second Generation Drugs: –Common side effects: drowsiness, fatigue, headache, nausea and dry mouth Side effects are far less common in Second Generation drugs

42 Adverse Effects: 1.CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & convulsions - common in first generation antihistamines 2.GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation - dryness of mouth, throat & airway, urinary retention - first generation 3.Headache, faintness 4.Chest tightness, palpitations, hypotension 5.Visual disturbances 6.Hematological - leukopenia, agranulocytosis, HA

43 Structural ClassPrototypeCharacteristics First Gen. Agents: 1. Ethanolamine Diphenhydramine Significant antimuscarinic activity Sedation, somnolence  Incidence of GI symptoms Effective in emesis & motion sickness 2.Ethylenediamine/ Ethylamine Pyrilamine Mepyramine Pyranesamine Most specific H1 antagonist  Anticholinergic activity Feeble CNS effects Somnolence GI s/s common 3. AlkylamineChlorpheniramine Pheniramine Chlorphenamine Most potent Not so prone to develop drowsiness More suitable for older patients Sedation/CNS stimulation 4. PiperazineChlorcyclizine Oldest member More prolonged action  Incidence of drowsiness

44 Structural ClassPrototypeCharacteristics Hydroxyzine Long acting Widely used for skin allergies CNS depressant More prominent antipruritic action Cyclizine Counters motion sickness (primarily) Meclizine/Meclozine Counters motion sickness & emesis

45 Structural ClassPrototypeCharacteristics 5. Phenothiazine Promethazine Anticholinergic Prominent sedation Counters motion sickness primarily antiemetic Second Gen.Agents 1. Piperidine Terfenadine Highly selective for H1 receptor Non-sedating (-) anticholonergic action (-) pass BBB  incidence of S/E 2. AlkylamineAcrivastine Rapid onset of action (30 mins) (-) anticholinergic effects Reduce both wheal & flare response  Potential to penetrate BBB Skin allergy Allergic rhinitis 3. PiperazineCetirizine Rhinitis, urticaria (-) pass BBB

46 Histamine H 2 -receptor antagonists Competitive Cimetidine, ranitidine, famotidine.

47 Uses of h istamine H 2 -receptor antagonists  Secretion of H + and pepsin: more effective on nocturnal (due to histamine) than food-induced (due to ACh, gastrin and histamine) secretion. - Gastric ulcer: normal H +,  mucosal defense. - Duodenal ulcer:  H +, Helicobacter pylori infection? - Reflux esophagitis - Zollinger-Ellison syndrome (gastrin producing tumor)

48 Side effects of histamine H 2 -receptor antagonists Cimetidine (Tagamet) – antiandrogenic (gynecomastia in man), inhibit several cytochrome P450 drug metabolism pathways -  hepatic [O] of many drugs (e.g., propranolol, alcohol). Ranitidine (Zantac) – 5x more potent than cimetidine; reversible liver dysfunction. Famotidine (Pepcid) – 5x more potent than ranitidine.

49 BIOGENIC AMINES SEROTONIN Source : plants (banana, pineapple, plums) & animals (mollusks, arthropods, mammals (platelets, not in mast cells). Biosynthesis : Hydroxylation of tryptophan, then decarboxylation to serotonin(5-hydroxy tryptamine;5- HT). Rapidly absorbed into secretory granules. Accumulated in platelets, degradation by oxidative deamination. Uses : No therapeutic use. Antagonists are highly useful.

50 Serotonin Synthesis PCPA: inhibits TH 5-HT Precursor

51 Synthesis: Tryptophan Hydroxytryptophan 5 hydroxytryptamine (Serotonin) 5-hydroxyindole acetaldehyde 5-hydroxyindole acetic acid acid 5-hydroxytrytophol (principal metabolite) N-acetyl- 5-HT Melatonin

52 Synthesis and Metabolism Competition at the level of brain and neuronal uptake Rate limiting enzyme not saturated usually No end-product negative feedback 5-OHTr decarboxylase same as DOPA decarboxylase 5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in urine.

53 BIOGENIC AMINES SEROTONIN Actions Neurotransmitter in the CNS Precursor of melatonin Induces sleep, Intestinal motility Involved in Temperature regulation Affects mood and behavior (humans) Deficiency causes depression Hemostasis : 5-HT2 receptors → aggregation and vasoconstriction of platelets Carcinoid syndrome (tumor of serotonin producing cells) large amounts released leading to diarrhea, bronchoconstriction and edema

54 Serotonin Receptors At least 15 types and subtypes Multiple transduction mechanisms 5HT-1A: role in anxiety/depression 5HT-1D: role in migraine 5HT-2: role in CNS various behaviors, and in cardiovascular system 5-HT3: role in nausea and vomiting esp. due to Chemotherapy.

55 Serotonin Pharmacological Effects Respiratory system: bronchoconstriction if asthmatic; stimulation of aortic and carotid chemoreceptors → ↑ RR and minute vol. GI tract: small intestine very sensitive to serotonin → intense rhythmic contractions due to direct and indirect (ganglia in wall) effects. Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally).

56 Cardiovascular system: Multiple direct and indirect effects: 1.Direct vasoconstriction (large arteries) and indirect vasodilation (NO and PGI 2 – mediated) 2.Heart: direct inotropic and chronotropic effects 3.Reflex mechanisms due to change in BP 4.Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) → bradycardia and hypotension Serotonin Pharmacological Effects -2

57 Pain perception Sleep/Wakefulness Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive behavior, etc. Neuroendocrine regulation – controls hypothalamic cells involved in release of several anterior pituitary hormones. Serotonin in the Central Nervous System

58 Serotonin Agonists Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina Fluoxetine: Selective serotonin uptake inhibitors for depression and other indications Buspirone: 5-HT1A agonist for anxiety Cisapride: 5-HT4 agonist to ↑ GI motility and decrease G-E reflux (Removed from US market due to fatal arrhythmias) LSD: 5HT1A – hallucinogen Ergot alkaloids: 5-HT1 and 2 and other receptors

59 Serotonin Antagonists Methysergide and Cyproheptadine. 5HT2 antagonists. In carcinoid, migraine. Ketanserin: 5HT2 and Alpha antagonist – used as antihypertensive. Ondansetron: 5-HT3 antagonist for chemotherapy induced nausea and vomiting Clozapine: 5HT2A/2C antagonist: for schizophrenia.

60 Serotonergic Drugs: Primary Actions and Clinical Uses (Table 11-4, G&G 11 th ed) ReceptorActionPrototypeClinical dis 5-HT1AP.AgonistBuspironeAnx, dep 5-HT1DAgonistSumatriptanMigraine 5-HT2A/2CAntagonistRisperidoneMig,dep,shz 5-HT3AntagonistOndansetrnChem emes 5-HT4AgonistCisaprideGI disorder 5-HTtranspInhibitorFluox,sertDep,oc,pts

61 The Pharmacology of INFLAMMATION Cyclooxygenase Enzyme & Other Tales

62 The inflammatory reaction Complex series of integrated phenomena Cellular components & chemical mediators Events : arteriolar dilatation, increased vascular permeability, leukocyte interaction with endothelium, diapedesis and migration (chemotaxis) Symptoms : dolor, rubor, calor, tumor

63 EICOSANOIDS hormones localized to tissues where they are produced. prostaglandins, thromboxanes and leukotrienes. derived from arachidonic acid arachidonic acid from linoleic acid an essential fatty acid Table 1. Physiological functions of eicosanoids. EicosanoidFunctions prostaglandinsinflammation, fever production, prevent platelet aggregation (prevent clotting); induce labor thromboxanesproduced by platelets to promote their aggregation (blood clotting) leukotrienesallergic reactions

64 Eicosanoids: The Arachidonic Acid Derivatives All C-20 Derivatives of 5,8,11,14 Eicosatetraenoic Acid Three classes: Prostaglandins, Thromboxanes, Leukotrienes Generated by cleavage of C-2 ester of phosphatidyl inositol in membrane-associated signaling events Active at very low concentrations – regulate blood pressure, coagulation, reproduction, pain & fever Tissue-specific generation – often opposing actions

65 Eicosanoids: The Arachidonic Acid Derivatives (  5,8,11,14) Arachidonic Acid Leukotrienes: (Asthmatic Symptoms) Hydroxylation; no cyclization PGH 2 Synthase = Prostaglandin endoperoxide synthase (cyclooxygenase) COOH Prostacyclins and Prostaglandins Cyclization to 5-membered ring Thromboxanes Cyclization to 6-membered ring

66 Eicosanoids: The Arachidonic Acid Derivatives Arachidonic Acid Leukotrienes: (Asthmatic Symptoms) Prostacyclins and Prostaglandins (Pain & Fever) Thromboxanes (Clotting) *Leukotrienes are not aspirin-inhibited and are responsible for inflammatory and hypersensitivity disorders Cortisteroids- block PLA 2 to block the release of Arachidonic Acid

67 Eicosanoids: The Arachidonic Acid Derivatives Arachidonic Acid Leukotrienes: (Asthmatic Symptoms) Prostacyclins and Prostaglandins (Pain & Fever) Thromboxanes (Clotting) PGH 2 Synthase = Site of actions for aspirin (enzyme acetylation) and non-steroidal anti- inflammatory drugs including Acetominophen & Ibuprofen (noncovalent binding) *Leukotrienes are not aspirin-inhibited and are responsible for inflammatory and hypersensitivity disorders

68 Membrane Phospholipid Phospholipase A 2 Arachidonic acid Lipoxygenase Leuokotrienes Cyclooxygenase PGH 2 Thromboxanes in platelets Prostaglandins in many cells Conversion of arachidonic acid to eicosanoids. inhibited by glucocorticoids inhibited by aspirin, ibuprofen

69 Inflammatory Conditions : Drug therapy Nonsteroidal antiinflammatory drugs (NSAIDs) or aspirin-like drugs Corticosteroids Drugs modifying acute rheumatic diseases (DMARDs) Antigout therapy

70 ASA : A century hence Turn of the century drug 1971 : landmark discovery of COX (Vane) 1992 : discovery of COX-2, an inducible isoform vs COX-1 which is constitutively expressed

71 COX-1 and COX 2 : Fraternal Enzymes COX-1 : widely distributed throughout the GIT, believed to be gastroprotective (as in kidneys); “housekeeper” COX-2 : minimal amts in GIT; detectable in leukocytes, synovium, CNS (site of inflam, fever & pain); inducible, upregulated in response to growth factors & cytokines; “homewrecker”

72 COX-mediated effects of Aspirin (acetylsalicylic acid) Analgesic-antipyretic Antiinflammatory Antiplatelet Adverse Effects : gastric/duodenal ulcers, bleeding, nephropathy

73 Outline: Bringing concepts together Problem : Inflammation (eg, joints) Pathophysiology : Phases => s/s=>Dx Cellular Events : Cells, mediators ; enzymes, receptors => Targets for drug action => Drugs : Steroids, NSAIDs, DMARDs, & Biologics (basic pharmacology) Clinical Pharmacology & Therapeutics : Evidence of efficacy, safety, suitability

74 Sick Person (Inflamed Joint: s/s) Pathophysiology: cells, mediators, cytokines etc Targets for drug action THERAPY Goal: Relief & Restoration, Prevention Drugs : Symptomatic (Steroids, NSAIDs), Disease-Modifying (Gold, Mtx, Tetracyc), Biologics Surgery, Rehab/PT, Exercise Alternative therapies (Acu, Glucosamine, Chondroitin) Assessment: Proof of Efficacy & Safety Healthy Person (Normal/Fxnal Joint) CONCEPT MAP: INFLAMMATION

75 Antiinflammatory Agents : Nonsteroidal AntiinfIammatory Drugs (NSAIDs)

76 NSAIDS: Nonsteroidal Antiinflammatory Drugs Prototype: Aspirin (circa 1899) Mechanism of NSAIDS or aspirin-like drugs revolves around the enzyme prostaglandin synthase or cyclooxygenase (C0X) Shared properties: 1 antiinflammatory, analgesic, antipyretic actions 2 side effects

77 INFLAMMATION: Friend or Foe? Essential for survival versus environmental pathogens and injury (ie, beneficial effect) May be exaggerated and sustained for no apparent beneficial reason (ie, problem/ disease)

78 INFLAMMATION: Stimuli & S/S (review) Series of events elicited by numerous stimuli (infectious agent, ischemia, ag-ab interaction, thermal/other physical injury) leading to a characteristic pattern of response Accompanied by clinical signs/symptoms: erythema (rubor), pain (dolor), edema (tumor), fever (calor), tenderness (hyperalgesia)

79 3 Phases of Inflammatory Response (review) 1 Acute transient phase local vasodilation & increased capillary permeability (floodgates open) 2 Delayed, subacute phase infiltration of leukocytes & phagocytic cells (chemotaxis & diapedesis) 3 Chronic proliferative phase tissue degeneration & fibrosis (± repair)

80 Proinflammatory AUTACOIDS Histamine (early transient phase) Bradykinin & serotonin (5-HT) Leukotrienes Platelet Activating Factor (PAF) Eicosanoids : Prostaglandins Nitric oxide (NO)

81 Pharmacologic Properties : LEUKOTRIENES SITEACTIONEFFECT CVSContraction, coronary & pulm, mesent vasc Hypotension Airway Smooth m ; Bronchial glands; Bld vessels Contraction of smooth m; Stimulate secretion; Airway narrowing Inc mucus Mucosal edema Inflam & Immunity (major) Stim aggreg of pmn, neutr adhesion to endoth wall, transendoth migration; stim synth proinflam cytokines Chemotaxis

82 Functions of endogenous leukotrienes Inflammatory & Immune Response: LTs are generally proinflammatory CysLTs prob dominate during allergic constriction of the airway

83 Proinflammatory Cells & Factors (review) Endothelial Cell (EC), Leukocytes Cell Adhesion Molecules (CAMs): E-, P-, L-selectins ICAM-1, VCAM-1 Cytokines : IL-1, TNFa, chemokines) Leukocyte integrins NO synthase (iNOS vs nNOS,eNOS) Complement factor (C5a)

84 Natural Antiinflammatory factors => homeostasis IL-1 receptor antagonist (IL-1ra) Other cytokines & growth factors : transforming growth factor(TGF-ß1), IL-10, Interferon gamma Targets for novel antiinflammatory agents


86 Products of COX Pathway: Active Compounds PGD2 PGE1, PGE2 PGF2a PGI2 via prostacyclin synthase TXA2 via thromboxane synthase

87 Prostaglandin Receptor Diversity Distinct receptors for specific activity Subtypes/Agonists/G protein/2 nd mssgr DP PGD2 Gs cAMP EP1 PGE2 Gq (?) Ca 2+ ;IP 3 /DAG (?) EP2 PGE2 Gs cAMP EP3 PGE2 Gi,Gs,Gq all of above EP4 PGE2 Gs cAMP FP PGF2a Gq IP 3 /DAG/Ca 2+ IP PGI2(E2) Gs cAMP TP TXA2,H2 Gq IP 3 /DAG/Ca 2+

88 Endogenous Eicosanoids: Possible Fxns in Physiol/Pathol Processes Platelet-vessel wall interaction, hemostasis Reproduction & Parturition Vascular and pulmonary smooth muscle tone modulation Renal blood flow modulation, urine regulation, renin Inflammatory and Immune Response Malignancy (eg, colon, breast ca)

89 Therapeutic Uses of Eicosanoids Induction of labor at term : PGE2 or PGF2a Gastric cytoprotection: PGE1 analog (misoprostol) Impotence: PGE1 (alprostadil) Maintenance of PDA: PGE1 in some neonates with congenital heart disease Primary pulmonary hypertension: PGI2 (epoprostenol)

90 Outline: Bringing concepts together Problem : Inflammation (eg, joints) Pathophysiology : Phases => s/s=>Dx Cellular Events : Cells, mediators ; enzymes, receptors => Targets for drug action => Drugs : Steroids, NSAIDs, DMARDs, & Biologics (basic pharmacology) Clinical Pharmacology & Therapeutics : Evidence of efficacy, safety, suitability


92 Chemical Classification Nonselective COX Inhibitors : aspirin, paracetamol, indomethacin, diclofenac, ibuprofen,mefenamic acid, meloxicam, nabumetone Selective COX-2 Inhibitors : rofecoxib, celecoxib, nimesulide, etodolac

93 Aspirin vs tNSAIDs (How Aspirin- like are they?) Aspirin covalently modifies both COX-1 and COX-2 => irreversible inhibition of COX activity. For COX-1 => serine 530; for COX-2 => serine 516 Platelets are especially susceptible to aspirin; they cannot regenerate COX In contrast to aspirin, most NSAIDs act as reversible, competitive inhibitors of COX

94 NSAIDs: Shared Properties (THERAPEUTIC Effects) 1 antipyretic 2 analgesic, for low-to-mod intensity like dental pain, postop pain or pain from inflammatory conditions. Not visceral pain. 3 antiinflammatory, symptomatic relief in musculoskeletal disorders (eg, rheumatoid arthritis, osteo-arthritis, ankylosing spondylitis) (except paracetamol, which is effective vs brain COX only, not antiinflam in peripheral tissues)

95 Other Therapeutic Uses of NSAIDs Indomethacin for postnatal closure of PDA (not during pregnancy) Relief of cramps in primary dysmenorrhea Emerging use: prevention of colon/breast cancer, Alzheimer’s (?) with COX-2 inhibitors

96 Shared Properties of NSAIDs: SIDE EFFECTS (due to COX inhibition) 1 Gastric or intestinal ulceration due to loss of cytoprotective - PGI2 & PGE2 2 Disturbance in platelet function - TXA2 3 Prolongation of gestation/spont labor (COX2 inh) 4 Premature closure of ductus 5 Renal function changes, critical in CHF, cirrhosis, chronic renal dis, hypovolemic *(not shared/less risk with highly selective COX-2 inhibitors)

97 COXibs : Continuing Issues & Food for Thought The present coxibs (COX 2 Inhibitors) do not appear to be more efficacious than older NSAIDs They are the drugs of choice for those with gastric sensitivity;their claimed advantage seems to be in reducing ulcerogenic effect Adverse effect profile similar to other NSAIDs (even increased cardiac risk?) Emerging use: vs cancer, Alzheimer’s

98 RENIN-ANGIOTENSIN SYSTEM Angiotensin II is an 8 amino acid derived from angiotensinogen (≈ 450 amino acids), a circulating α 2 -globulin synthesized by the liver.

99 Angiotensinogen Angiotensin I (10 amino acid) Angiotensin II (8 amino acid) -- constrict arterioles and veins Angiotensin III ( 7 amino acid) Aldosterone - mineralocorticoid -- v/c arterioles/veins(retain Na + /  blood volume) Inactive products Renin  Renal arterial pressure (via intrarenal baroreceptors)  NaCl flux in macula densa cells (in thick ascending limb) Renal sympathetic nerve (  1) Angiotensin converting enzyme ( ACE or kininase II) in vascular endothelium and blood

100 ACTIONS OF ANGIOTENSIN II (t½ < 1min) Activates AT 1 and AT 2 receptors;  IP3 1. Constrict arterioles (renal efferent > renal afferent) and veins. 2.  Sympathetic activity (  release and response to norepinephrine). 3.  Aldosterone (Na + retention/K + and H + excretion at renal distal tubule and collecting duct). 4.  Na + reabsorption directly at the renal proximal tubule. 5.  Drinking. 6.  Cell growth: blood vessel (cell # and size) and heart (size). 7.  Renin release [ANG II  (-) feed-back inhibition of renin release from juxtaglomerular cells]

101 Blockers of the renin-angiotensin system Angiotensin converting enzyme (ACE) inhibitors. Non-peptide angiotensin AT 1 receptor antagonists. Blockers of sympathetic nervous system.

102 BLOCKERS OF THE RENIN-ANGIOTENSIN SYSTEM Angiotensin converting enzyme (ACE) inhibitor: captopril (2 amino acid), enalapril (3 amino acid) Vasodilatation and decrease in blood pressure via:  ANG II (  concentrations of renin and ANG I)  Bradykinin (vasodilator)  Activity of sympathetic nervous system  Blood volume (  Na+ reabsorption at renal tubules) Dilate arterioles:  renal blood flow --  glomerular filtration rate (GFR)   blood volume Dilate capacitance vessels (venodilation,  venous return and cardiac work) Patients with high plasma renin activity are particularly sensitive to ACE inhibitors

103 Therapeutic use of ACE inhibitors Hypertension:  total peripheral resistance (TPR), blood pressure and mortality Left ventricular contractile dysfunction: -  Afterload (  TPR) -  Left ventricular hypertrophy (preload,  cell growth) and wall tension -  Cardiac contractility and output - Delays progression of heart failure;  mortality - First line drug for management of heart failure Myocardial infarction (  mortality) Chronic renal failure (  renal blood flow/GFR,  proteinuria)

104 Side effects of ACE inhibitors Dry cough (>10%, due to  bradykinin) Angioedema (0.2%, due to  bradykinin) Foetal hypotension/malformation (2nd/3rd trimester)  GFR and may cause acute renal failure in patients with renal artery stenosis (due to  renal glomerular capillary pressure) Hyperkalemia (why?)

105 Non-peptide angiotensin AT 1 receptor antagonists: losartan Block effect of ANG II on AT 1 receptors;  level of ANG II ANG AT 2 receptors in injured tissues: implications unclear. As efficacious as ACE inhibitors in decreasing blood pressure and improving cardiac function in heart failure. Slow progressive renal damage in patients with chronic renal failure due to type 2 diabetes. Similar side effects as ACE inhibitors; ↓↓ cough and angioedema. May be used concurrently with ACE inhibitors for the prevention of heart failure.

106 Blockers of sympathetic nerve activities  -Adrenoceptor antagonist: propranolol  2 -Adrenoceptor agonists: clonidine,  - methyldopa

107 ENDOTHELIUM-DERIVED AGENTS Nitric Oxide (NO) A lipid soluble gas, slowly reactive radical, short half-life NOS deaminates L-arginine to L-citrulline & NO NO Breaks down to nitrates and nitrites Known as endothelium derived relaxing factor (EDRF) Organic nitrates (amyl nitrate, nitroglycerin, nitroprusside) release NO Nitric Oxide Synthase (NOS) antagonists counteracts vascular relaxation

108 ENDOTHELIUM-DERIVED AGENTS NITRIC OXIDE Nitric Oxide Synthase (NOS) NOS-1 (nNOS, bNOS): constitutive, low output form NOS-2 (MacNOS, iNOS): inducible, high output immune/inflammatory isoform that is found principally in monocytes and macrophages NOS-3 (eNOS): constitutive, low output form, vascular tone Control of constitutive forms of NOS (nNOS and eNOS) is mediated by intracellular calcium and calmodulin. Pulsatile flow and shear stress stimulate eNOS synthesis iNOS can be induced in macrophages, Kupffer cells, neutrophils, fibroblasts, vascular smooth muscle & endothelial cells.

109 ENDOTHELIUM-DERIVED AGENTS EFFECTS OF NO Physiological vasodilator, influences vascular resistance and BP Homeostasis of vascular beds(cerebral, pulmonary, coronary) eNOS blockers increase BP by vasoconstriction Basal NO production in these beds regulates vascular tone NO mediates NANC neurotransmission It causes: relaxation of stomach & internal anal sphincter, and involved in penile erection

110 ENDOTHELIUM DERIVED AGENTS EFFECTS OF NO Induction of iNOS in neutrophils and monocytes  NO Antiviral effect of interferon (IFN  ) is due to NO TNF  and LT (pro-inflammatory agents) also induce NOS Macrophages kill microorganisms by NO Cytotoxic and/or cytostatic effects of non-specific host defense nNOS derived NO influences neuronal development, memory, vision and nociception

111 ENDOTHELIUM-DERIVED AGENTS Endothelin Introduction The most potent vasoconstrictor discovered to date First identified (1988) from the porcine aortic endothelial cells Endothelin family has 3 isopeptides (ET-1, ET-2, ET-3) Each isopeptide is encoded by separate genes All ETs have 21 amino acids and 2 intra molecular disulfide bonds Biologically & structurally ET is similar to sarafotoxin (snake venom) ET is a vessel mitogen & causes myocardial cell hypertrophy ET has positive inotropic and antiarrhythmic effects ET can interact with inflammatory cytokines

112 ENDOTHELIUM-DERIVED AGENTS Endothelin Biosynthesis Preproendothelin (203 amino acids) is the precursor in plasma Converted by dibasic endopeptidase to big ET (39 amino acids) ET converting isoenzyme cleaves Big ET to active ET By cleaving, the C terminal is removed These enzymes are membrane bound metallopeptidases Metalloendopeptidases enzymatically degrade ET Norepi, angiotensin II, vasopressin, bradykinin, thrombin, LPS, TNF , and IL-1 stimulate ET precursor expression

113 ENDOTHELIUM-DERIVED AGENTS Endothelin Pharmacological effects Type I reaction: (ET-1 and ET-2) vasoconstriction, bronchoconstriction, uterine contraction, stimulation of aldosterone synthesis Type II reaction: (ET-1, ET-2 & ET-3) all are equally effective vasorelaxation inhibition of platelet aggregation

114 ENDOTHELIUM-DERIVED AGENTS Endothelin ET receptors Two types have been identified (ET A and ET B ) ET A is responsible for type I responses ET B is responsible for type II responses ET B1 produces vasodilatation by releasing NO and PGI 2 ET B2 produces nonvascular smooth muscle contraction.

115 ENDOTHELIUM-DERIVED AGENTS Endothelin Physiological functions ET is involved in the closure of the ductus arteriousus Glucocorticoid induced cytochrome P- 450 stimulates production of ET Carbon monoxide inhibits cytochrome P-450 NO inhibits vasoconstriction due to ET and ET synthesis

116 ENDOTHELIUM-DERIVED AGENTS Endothelin Diseases Hypertension (laminitis is associated with hypertension) Cardiac myopathy, heart failure, pulmonary Hypertension COPD, Systemic Inflammatory Response Syndrome (SIRS) SIRS: sepsis, adult respiratory distress syndrome (ARDS), multiple organ failure, hemorrhagic shock, anaphylaxis High plasma ET in hypertrophy, cardiomyopathy, chronic heart failure, and asthma (BAL fluids) ET-1 probably mediates cardiac myopathy after hypoxia (ischemia) and pressure overload

117 ENDOTHELIUM-DERIVED AGENTS Endothelin Therapeutic uses Inhibitors of ET converting enzyme ET receptor antagonists Problems ET is involved in complex reactions with several other mediators ET has anti-arrhythmic effects Antagonists of ET have potential to predispose to arrhythmia These effects are under investigation now

118 Summary 1. Autacoids are part of a heterogenous group of substances that participate in homeostasis. 2. Autacoids have different sources, fates, and biologic activities. 3. Autacoids play an important role in health and disease. 4. Understanding the pharmacologic properties of these agonists, antagonists & inhibitors using prototype drugs is important to effectively utilize these agents in the clinical setting.

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