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Angioedema and ACEI-induced angioedema

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  • Pathophysiologic mechanisms of urticaria and angioedema 1.activation occur by antigen cross-linking of IgE bound to mast cell surface IgE receptors (FceRI). Histamine causes local vasodilatation and increased vascular permeability 2.Cutaneous nerve fiber stimulation produces an axonal reflex that releases substance P potent vasodilator but also stimulates the release of additional histamine from mast cells substance P(tachykinin) another peptide substrate of ACE 3.IgE cross-linking also triggers production of mast cell membrane-associated arachidonic acid metabolites, including PG D2 through action of the COX enzyme, and leukotrienes C and D through action of the lipoxygenase enzyme 4.Complement system activation generates complement fragments C3a, C4a, and especially C5a (as anaphylatoxins), which bind to mast cell surface complement receptors and trigger histamine release 5.C3a (selective for Eo) and C5a (for N, Eo, mononuclear cell) are also chemotactic for several inflammatory cells that produce histamine-releasing factors. Histamine-releasing factors contribute to the enhancement and prolongation of the inflammatory reaction in a non–IgE-dependent manner. Increased cutaneous vascular permeability leads to extravasation of plasma proteins of Hageman factor with cell surfaces, and subsequent activation of the kinin-forming system. Kallikrein is generated, which leads to conversion of high- molecular weight kininogen to bradykinin(potent mediator of vasodilatation and vascular permeability) 7.Cross-linking of mast cell–bound IgE by anti-IgE autoantibodies directed against Fc region of IgE molecule or by autoantibodies against mast cell surface IgE receptors (anti-FceRI) can trigger histamine release 8.Bradykinin is deactivated primarily by ACE located on pulmonary arterial endothelium mechanism of ACEinhibitor hypersensitivity reactions may involve interference with bradykinin degradation 9.Direct, nonimmunologic mechanisms include physical stimuli, such as thermal and mechanical; radiocontrast dyes (perhaps due to high osmolality); ethanol; medications such as vancomycin and opioids; and foods such as strawberries and shellfish 10.NSAID-induced reactions are thought to occur via inhibition of COX1, leading to shunting toward lipoxygenase pathway with resultant increased synthesis of cysteinyl leukotrienes 11.C1 esterase inhibitor controls spontaneous activation and downregulates both complement and kinin-forming pathways. C1 esterase inhibitor dysfunction can cause angioedema through inappropriate production of bradykinin 12.Indirectly, autoimmune IgG1 IgG3 antibodies produced in several autoimmune diseases can fix complement and generate anaphylatoxins LPO indicates lipoxygenase; HMW, high-molecular-weight.
  • Fig . 19.4   Mediators released from mast cells upon IgE - mediated activation . Upon cross - linking of Fc ε RI - IgE by allergen, mast cells immediately release a host of preformed mediators from storage in secretory granules via exocytosis . Concomitantly, leukotrienes and PGD 2 are generated from arachidonic acid, and cytokine and chemokine production is induced
  • Fig . 19.4   Mediators released from mast cells upon IgE - mediated activation . Upon cross - linking of Fc ε RI - IgE by allergen, mast cells immediately release a host of preformed mediators from storage in secretory granules via exocytosis . Concomitantly, leukotrienes and PGD 2 are generated from arachidonic acid, and cytokine and chemokine production is induced
  • Diagram of Hageman factor ( HF )- dependent pathways of coagulation, fibrinolysis and kinin generation Reaction 1 depicts HF autoactivation Reaction 2 describes reciprocal activation of HF and prekallikrein in which high - molecular - weight ( HMW ) kininogen functions as a cofactor HFa, activated HF .
  • HAE type III = estrogen dependent ;associated with exogenous Estrogen administration such as oral contraceptive, hormone replacement therapy
  • ปาราสิต มีชื่อว่า Trypanosoma gambiense หรือ Trypanosoma rhodesiense มีแมลง tsetse fly เป็นพาหะนำเชื้อ พยาธิตัวกลมลำไส้ Trichinella spiralis
  • -Renin = aspartic protease สร้างจาก juxtaglomerular cell in kidney -cleaves angiotensin ซึ่งสร้างจากตับได้ decapeptide angiotensin I (inactive) -ACE (known as kinase II) เป็น enzyme ชนิด non-selective dipeptidyl carboxypeptidase ซึ่งมี substrate ทั้ง angiotensin I และ bradykinin -catalyse hydrolysis of bradykinin to inactive product & A I to active A II -Chymase(non-ACE) สามารถสร้าง A II ได้ , นอกจากนี้ non-renin enzymes(tonin, cathepsin) สามารถสร้าง A II จาก angiotensiongen ได้โดยตรง
  • -Angiotensin I & II can be digested by angiotensinase(peptidase) โดยจะตัดกรดอะมิโนบริเวณ Amino terminus(aminopeptidase) or carboxyl terminus(carboxypeptidase) ได้เป็นส่วนย่อยๆ เรียก A III (2-8 peptide bind to AT1, AT2) ออกฤทธิ์คล้ายกับ A II A IV(3-8 peptide bind to AT4 receptor) stimulate release of plasminogen activator inhibitor 1 (PAI 1) ซึ่งเป็น potent antithrombolytic factor Ang (1-7 peptide bind to AT3 receptor) stimulate vasodilatation & potentiate bradykinin -signal tranduction by AT1 receptor 1.AT I receptor is member of G protein-coupled-receptor superfamily 2.part of protein close to surface(red) participate in binding to A II 3.deeper amino acid resiues(blue) binding to sartan family of ARB 4.when bind to A II  stimulate phospholipase C(PLC) & open calcium channels 5.PLC cleaves phosphoinositide(PIP2) to inositol triphosphate(IP3)  release endoplasmic calcium and to DAG 6. ทั้ง DAG & IP3 จะไป activate protein kinase C เพื่อไปเติมฟอสเฟตให้กับโปรตีนอื่นๆในเซลต่อไป
  • -AT 3 receptor ในปัจจุบัน define as Mas R ซึ่ง Ang(1-7) จะใช้ receptor ตัวนี้ในการออกฤทธิ์ Counter-regulatory กับ AT1 R -AT 2R ออกฤทธิ์ตรงข้ามกับ AT1R -AT4R purified from bovine adrenal membranes & identified as enzyme, insulin-regulated aminopeptidase(IRAP) พบใน หัวใจ , ปอด , ไต , สมอง (enhance cognitive function,Modulation of blood flow, increase natriuresis, inhibit cardiomyocyte hypertrophy)
  • BKR-1 generated in pathophysiologic conditions such as inflammation, trauma, burns, shock, and allergy. The B 1 receptor is one of two of G protein-coupled receptors that have been found which bind bradykinin and mediate responses to these pathophysiologic conditions -B 1 protein is synthesized de novo following tissue injury and receptor binding leads to an increase in the cytosolic calcium ion concentration, ultimately resulting in chronic and acute inflammatory responses B 2 receptor is a G protein-coupled receptor , coupled to G q and G i . G q stimulates phospholipase C to increase intracellular free calcium and G i inhibits adenylate cyclase it is ubiquitously and constitutively expressed in healthy tissues.
  • -bradykinin most potent vasodilators because capable to liberate 3 important endothelium-derived vasodilatory mediators -NO -PGI 2 - Endothelium-derived hyperpolizing factor(EDHF;34) -activation BKR-2 on endothelium  lead to activation of phospholipase C via tyrosine phosphorylation  Increase formation of inositol 1,4,5-triphosphate(IP3) & diacylglycerol  increase intracellular calcium By liberalization from internal stores or increase calcium influx -calcium activates Ca 2+ -sensitive endothelial nitric oxide synthase(eNOS) นอกจากนั้นยังกระตุ้น Ca 2+ -sensitive phospholipase A2 ซึ่งจะไป hydrolyses membrane phospholipids ได้เป็น arachidonic acid ซึ่งจะถูกเปลี่ยนเป็น PGI 2 ตามลำดับ - ส่วน EDHF บางตำราว่าอาจได้จากการเปลี่ยน archidonic acid โดย enzyme epoxygenase -Ju & colleagues demonstrate that bradykinin activate tyrosine kinase 2(Tyk2) of janus-activated kinase(JAK)
  • JAK - STAT signaling pathway takes part in the regulation of cellular responses to cytokines and growth factors . Employing Janus kinases (JAKs)or and Signal Transducers and Activators of Transcription (STATs), the pathway transduces the signal carried by these extracellular polypeptides to the cell nucleus , where activated STAT proteins modify gene expression . Although STATs were originally discovered as targets of Janus kinases , it has now become apparent that certain stimuli can activate them independently of JAKs. The pathway plays a central role in principal cell fate decisions, regulating the processes of cell proliferation , differentiation and apoptosis . It is particularly important in hematopoiesis - production of blood cells .
  • -Nielsen ได้สรุปว่าในภาวะ ACEI-induce AE เกิด imbalance between production & breakdown of bradykinin -C1 inhibitor favorably suppress local over-production of bradykinin
  • ในปี 2004 Cicardi & colleagues ได้ทำการ วิจัยแบบ descriptive โดยรวบรวมผู้ป่วยที่มีประวัติ AE ทั้งมี urticaria และไม่มี urticaria จำนวน 1168 คน
  • -median length of ACEI before appearance AE = 12 Mo -median duration of ACEI use after appearance of 1 st episode = 12 Mo -median length of F/U = 11 Mo
  • -8 คนที่ไม่ได้ผล ( no effect) แบ่งเป็น 6 คน เกิดจากสาเหตุอื่นๆ เช่น 1 คน พบว่ามี dental granuloma 1 คน เกิดจากการกินอาหารที่มี histamine ปนเปื้อน 4 คน unknown cause แม้หยุดยาแล้วยังเกิด AE 2 คนสุดท้าย เกิด AE ขณะ switch จาก ACEI เป็น ARB 1 คน switch to candesartan 2 Mo ยังพบ AE หายไปเมื่อเปลี่ยนยาเป็น β -blocker 1 คน หลังเริ่ม losatan พบ 2 nd AE episode จึงเปลี่ยนเป็น nifedipine หลัง F/U 8 Mo ไม่พบอาการอีกเลย
  • Angioedema

    1. 1. Angioedema นพ . สุรสฤษดิ์ ขาวละออ 2/12/52
    2. 2. Angioedema <ul><li>Outline </li></ul><ul><ul><li>Definition of angioedema </li></ul></ul><ul><ul><li>Pathophysiology mechanism </li></ul></ul><ul><ul><li>DDx of angioedema </li></ul></ul><ul><ul><li>RAE : ACEI-induced angioedema </li></ul></ul><ul><ul><ul><li>S tructure & types </li></ul></ul></ul><ul><ul><ul><li>Mechanism of action of ACEI </li></ul></ul></ul><ul><ul><ul><li>Diagnosis & treatment </li></ul></ul></ul>
    3. 3. Angioedema <ul><li>Definition </li></ul><ul><ul><li>Transient swelling of defined areas in deep dermis or subcutaneous tissue resulting from vascular leakage </li></ul></ul><ul><ul><li>Tend to be large, pale, nonpruritic </li></ul></ul><ul><ul><li>May pain or burning </li></ul></ul><ul><ul><li>Occur anywhere on the body </li></ul></ul><ul><ul><li>Typically persist for day or more </li></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 N Franklin. Middleton’s allergy 7 th edition 2009
    4. 4. Angioedema <ul><li>Outline </li></ul><ul><ul><li>Definition of angioedema </li></ul></ul><ul><ul><li>Pathophysiology mechanism </li></ul></ul><ul><ul><li>DDx of angioedema </li></ul></ul><ul><ul><li>RAE : ACEI-induced angioedema </li></ul></ul><ul><ul><ul><li>S tructure & types </li></ul></ul></ul><ul><ul><ul><li>Mechanism of action of ACEI & AE </li></ul></ul></ul><ul><ul><ul><li>Diagnosis & treatment </li></ul></ul></ul>
    5. 5. Angioedema <ul><li>Pathophysiology mechanism </li></ul><ul><ul><li>Primary effector cells : cutaneous mast cells </li></ul></ul><ul><ul><li>basophils (smaller extent) </li></ul></ul><ul><ul><li>Mast cell activation occur through both IgE-mediated and nonIgE-mediated mechanism </li></ul></ul>Clin Ped Emerg Med.2007;8:72-80 N Franklin. Middleton’s allergy 7 th edition 2009
    6. 6. Mechanism of angioedema Clin Ped Emerg Med.2007;8:72-80 1 2 3 4 5 6 7
    7. 7. N Franklin. Middleton’s allergy 7 th edition 2009
    8. 8. N Franklin. Middleton’s allergy 7 th edition 2009
    9. 9. Angioedema N Franklin. Middleton’s allergy 7 th edition 2009
    10. 10. Angioedema N Franklin. Middleton’s allergy 7 th edition 2009
    11. 11. Pathophysiology mechanism <ul><ul><li>Platelet-activating factor (PAF) </li></ul></ul><ul><ul><ul><li>Chemotactic factor secreted by mast cells </li></ul></ul></ul><ul><ul><ul><li>Greater specificity for eosinophil </li></ul></ul></ul>N Franklin. Middleton’s allergy 7 th edition 2009
    12. 12. Pathophysiology mechanism <ul><li>Hageman factor is plasma protein, can autoactivate if there is few activated HF(HFa) in plasma by HFa digest surface-bound HF to form more HFa </li></ul>N Franklin. Middleton’s allergy 7 th edition 2009 FC XII
    13. 13. Pathophysiology mechanism <ul><li>In tissue injury collagen-mucopolysac- charide complexes & vascular basement membrane serve as local activators of the pathway </li></ul><ul><li>Mucopolysaccharide (heparin, chondroitin sulfates from mast cell or basophils) initiate activation of HF </li></ul>N Franklin. Middleton’s allergy 7 th edition 2009
    14. 14. Pathophysiology mechanism <ul><li>HFa initiates coagulation(convert FC XI to FC XIa), fibrinolysis, convert prekallikrein to kallikrein </li></ul><ul><li>Kallikrein digest HMW kiniogen(15% of total plasma kininogen) to bradykinin at endothelial cell interface </li></ul><ul><li>Bradykinin interact with B2 Rc to cause vasodilatation & increase vascular permeability </li></ul>N Franklin. Middleton’s allergy 7 th edition 2009
    15. 15. Pathophysiology mechanism <ul><li>Histamine-releasing factors(HRFs) </li></ul><ul><ul><li>Product of neutrophils, platelets, alveolar mØ, human mononuclear cells(T, B cells, monocytes) </li></ul></ul><ul><ul><li>β -chemokine group, 8-10 kDa chemotactic factors </li></ul></ul><ul><ul><ul><li>Monocyte chemotactic & activating factor(MCAF) : MCP-1, MCP-2, MCP-3 </li></ul></ul></ul><ul><ul><ul><li>Macrophage inflammatory peptides(MIP-I  , MIP-I β ) </li></ul></ul></ul>N Franklin. Middleton’s allergy 7 th edition 2009
    16. 16. Pathophysiology mechanism <ul><ul><ul><li>RANTES(regulated on activation, normal T cell expressed & secreted) </li></ul></ul></ul><ul><ul><ul><li>Eotaxin 1, 2, 3 </li></ul></ul></ul><ul><ul><ul><li>Order of potency (assessed by histamine release from basophil) is </li></ul></ul></ul><ul><ul><ul><li>MCP-1 = MCP-3 > RANTES = MCP-2 > MIP-Ia </li></ul></ul></ul><ul><ul><ul><li>> MIP-Iβ </li></ul></ul></ul><ul><ul><ul><li>These substance may contribute to basophil infiltration & eosinophil accumulation associated with late-phase reaction </li></ul></ul></ul>N Franklin. Middleton’s allergy 7 th edition 2009
    17. 17. Pathophysiology mechanism <ul><li>Chemokines </li></ul><ul><ul><li>4 families </li></ul></ul><ul><ul><ul><li>CXC (  ) family </li></ul></ul></ul><ul><ul><ul><li>CC ( β ) family </li></ul></ul></ul><ul><ul><ul><li>CX3C (  ) family </li></ul></ul></ul><ul><ul><ul><li>C (  ) family </li></ul></ul></ul><ul><ul><li>RANTES (CCL5), eotaxin-1(CCL11), </li></ul></ul><ul><ul><li>eotaxin-2(CCL24), eotaxin-3(CCL26) </li></ul></ul>N Franklin. Middleton’s allergy 7 th edition 2009
    18. 21. Angioedema <ul><li>Outline </li></ul><ul><ul><li>Definition of angioedema </li></ul></ul><ul><ul><li>Pathophysiology mechanism </li></ul></ul><ul><ul><li>DDx of angioedema </li></ul></ul><ul><ul><li>RAE : ACEI-induced angioedema </li></ul></ul><ul><ul><ul><li>S tructure & types </li></ul></ul></ul><ul><ul><ul><li>Mechanism of action of ACEI & AE </li></ul></ul></ul><ul><ul><ul><li>Diagnosis & treatment </li></ul></ul></ul>
    19. 22. Angioedema <ul><li>DDx of angioedema </li></ul><ul><ul><li>Allergic angioedema </li></ul></ul><ul><ul><li>Nonallergic angioedema </li></ul></ul><ul><ul><ul><li>5 different types </li></ul></ul></ul><ul><ul><ul><ul><li>HAE(hereditary AE) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>AAE(acquired AE) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>RAE(RAAS-blocker-induced AE) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>PAE(pseudoallergic AE) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Idiopathic AE </li></ul></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    20. 23. DDx of angioedema Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    21. 24. DDx of angioedema
    22. 25. DDx of angioedema The America Journal of Medicine.2008;121(4):282-286
    23. 26. DDx of angioedema <ul><li>Masqueraders of angioedema </li></ul><ul><ul><li>Contact dermatitis </li></ul></ul><ul><ul><ul><li>Often present with angioedema of face & periorbital region </li></ul></ul></ul><ul><ul><ul><li>Angioedema-like swelling may be 1 st manifestation but reaction usually declares itself with production of vesicle or blisters </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    24. 27. DDx of angioedema <ul><ul><li>Dependent edema </li></ul></ul><ul><ul><ul><li>In lower legs of older pt. with CHF </li></ul></ul></ul><ul><ul><ul><li>Decreased plasma oncotic pressure </li></ul></ul></ul><ul><ul><ul><li>Vascular malformation </li></ul></ul></ul><ul><ul><ul><li>Superior vena cava obstruction </li></ul></ul></ul><ul><ul><ul><ul><li>Present edema at supine or prone </li></ul></ul></ul></ul><ul><ul><ul><li>Trauma or burns(esp superficial burn) </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    25. 28. DDx of angioedema <ul><ul><li>Dependent edema(cont.) </li></ul></ul><ul><ul><ul><li>Quincke’s disease : thermal injury in pt. who inhaled cocaine smoke & developed swelling of uvula </li></ul></ul></ul><ul><ul><ul><li>Infection </li></ul></ul></ul><ul><ul><ul><ul><li>Parasite infection : </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Romana’s sign : unilateral AE of one eye in American trypanosimiasis </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Trichinosis : periorbital edema with peripheral eosinophilia </li></ul></ul></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    26. 29. DDx of angioedema <ul><ul><ul><ul><li>Tropical filariasis : lymphatic obstruction(swelling of affected limb or can cause swelling of eyeball </li></ul></ul></ul></ul><ul><ul><ul><li>Bacterial infection : cellulitis, acne vulgaris </li></ul></ul></ul><ul><ul><ul><li>Viral infection : Parvovirus B19(AE in neonates), precede appearance of herpes infection </li></ul></ul></ul><ul><ul><li>Vasculitis & panniculitis </li></ul></ul><ul><ul><ul><li>Promote both urticaria & AE due to consumption of complement </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    27. 30. Quincke’s disease Romana’s sign & trypanosomiasis Trichinosis tsetse fly
    28. 31. DDx of angioedema <ul><ul><ul><li>Weber-christian disease : panniculitis with fever & swelling mimic AE </li></ul></ul></ul><ul><ul><li>Other infiltrating disorders </li></ul></ul><ul><ul><ul><li>Endocrinopathy : autoimmune thyroid dz </li></ul></ul></ul><ul><ul><ul><li>Macroglossia : mistaken AE of tongue(most ass. With systemic amylodosis), dental impressions on tongue that do not fade ;clue of infiltration </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    29. 32. DDx of angioedema <ul><ul><li>Eosinophilic dermatoses : infiltrative disorders with eosinophils </li></ul></ul><ul><ul><ul><li>Wells’syndrome : recurrent & painful plaques that resemble cellulitis, fever, peripheral eosinophilia, malaise </li></ul></ul></ul><ul><ul><ul><li>Shulman’s syndrome(eosinophilic fasciitis) : edema, pain, tenderness of affected extremities, elevated ESR, peripheral eosinophilia, elevated aldoase, hyperglobulinemia </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    30. 33. DDx of angioedema <ul><ul><li>Orofacial swelling alone </li></ul></ul><ul><ul><ul><li>Melkersson Rosenthal syndrome : persistant swelling of lips(noncaseating granulomatous infiltration of lips), fissured tongue, orofacial edema, facial nerve palsy (classic triad) </li></ul></ul></ul><ul><ul><ul><li>Crohn’s disease & sarcoidosis : cheilitis granulomatosa without facial palsy or fissure tongue </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    31. 34. DDx of angioedema <ul><ul><ul><li>Parotid gland involvement by sarcoidosis : swelling of cheek </li></ul></ul></ul><ul><ul><ul><li>Ranula mimic AE </li></ul></ul></ul><ul><ul><ul><li>Cheilitis glandularis : rare condition, old man, hypertrophy & stinging of lower lip </li></ul></ul></ul><ul><ul><ul><li>Scleredema adultorum of Buschke : rare condition, persistant periorbital edema </li></ul></ul></ul><ul><ul><ul><li>Blepharochalasis : recurrent nonpruritic swelling of both upper & lower eyelids, visual field impair </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    32. 35. DDx of angioedema <ul><ul><li>Lymphoperiferative & autoimmune </li></ul></ul><ul><ul><ul><li>Acquired C1 inhibitor deficiency as consequence of lymphoproliferative </li></ul></ul></ul><ul><ul><ul><li>Clarkson syndrome : capillary leak syndrome due to monoclonal gammopathy </li></ul></ul></ul><ul><ul><ul><li>Dermatomyositis : poikiloderma of face, persistent edema of eyelids </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:603-613 Allergy.2007;62:842-856
    33. 36. poikiloderma ranula blepharochalasis Chelitis glandularis Fissure tongue Melkersson Rosenthal syndrome
    34. 37. Angioedema <ul><li>Outline </li></ul><ul><ul><li>Definition of angioedema </li></ul></ul><ul><ul><li>Pathophysiology mechanism </li></ul></ul><ul><ul><li>DDx of angioedema </li></ul></ul><ul><ul><li>RAE : ACEI-induced angioedema </li></ul></ul><ul><ul><ul><li>S tructure & types </li></ul></ul></ul><ul><ul><ul><li>Mechanism of action of ACEI & AE </li></ul></ul></ul><ul><ul><ul><li>Diagnosis & treatment </li></ul></ul></ul>
    35. 38. DDx of angioedema Without wheals Normal C4 ACEI induced
    36. 39. Angioedema <ul><li>RAE:ACEI-induced angioedema Incidence </li></ul><ul><ul><ul><li>0.1-0.7% postmarketing surveillance </li></ul></ul></ul><ul><ul><ul><li>2.8-6% in clinical trial </li></ul></ul></ul><ul><ul><ul><li>Immunol Allergy Clin N Am.2006;26:725-737 </li></ul></ul></ul><ul><ul><ul><li>0.13% </li></ul></ul></ul><ul><ul><ul><li>J Allergy Clin Immunol.2007;1288 </li></ul></ul></ul><ul><ul><ul><li>Incidence of ARB-induced AE not known exactly </li></ul></ul></ul>
    37. 40. Angioedema <ul><li>RAE:ACEI-induced angioedema </li></ul><ul><ul><li>ACEI-induced angioedema found relative risk of 3.0 among Black compared to White people </li></ul></ul><ul><ul><li>BMJ.2006;332:1177-1181 </li></ul></ul><ul><ul><li>RAEs appears to be much more frequent than HAE </li></ul></ul><ul><ul><li>Ann Allergy Asthma Immunol.2007;98:57-63 </li></ul></ul>
    38. 41. ACEI-induced angioedema <ul><li>Structure & types </li></ul><ul><ul><li>แบ่งตามสมบัติทางเคมี และเภสัชจลนศาสตร์ ได้ 3 กลุ่ม </li></ul></ul><ul><ul><ul><li>1. Captopril-like : captopril, zofenopril </li></ul></ul></ul><ul><ul><ul><li>มี sulfhydryl (SH) ในโมเลกุล </li></ul></ul></ul><ul><ul><ul><li>ออกฤทธิ์ได้ทันที , ขับถ่ายทางไต </li></ul></ul></ul>
    39. 42. ACEI-induced angioedema <ul><ul><ul><ul><li>2.Prodrug </li></ul></ul></ul></ul><ul><ul><ul><ul><li>ถูกเปลี่ยนเป็นสารออกฤทธิ์ที่มี diacid ในตับ </li></ul></ul></ul></ul><ul><ul><ul><ul><li>แบ่งเป็น 2 กลุ่มย่อยคือ </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Dicarboxyl (CO2) group : cilazapril, enalapril, perindopril, quinapril, ramipril </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>ออกฤทธิ์ที่เนื้อเยื่อต่าง , ขับออกทางไต </li></ul></ul></ul></ul>
    40. 43. ACEI-induced angioedema <ul><ul><ul><li>Phosphinyl(PO2) group : fosinopril ละลายได้ดีในไขมัน ถูกขับออกทางน้ำดี </li></ul></ul></ul><ul><ul><ul><li>บางส่วนถูกเปลี่ยนเป็น diacid(fosinoprilat) ที่ตับ แล้วถูกขับออกทางไต </li></ul></ul></ul>
    41. 44. ACEI-induced angioedema <ul><ul><ul><li>3.Water-soluble : lisinopril </li></ul></ul></ul><ul><ul><ul><li>มี dicarboxyl เป็นส่วนประกอบ </li></ul></ul></ul><ul><ul><ul><li>ออกฤทธิ์ได้ทันที </li></ul></ul></ul><ul><ul><ul><li>ไม่สะสม , ขับถ่ายทางไต </li></ul></ul></ul><ul><ul><ul><li>ยาที่ออกฤทธิ์ได้ทันที  onset เร็ว </li></ul></ul></ul><ul><ul><ul><li>Prodrug  onset ช้า แต่ bioavailability ( การดูดซึม และความสามารถไปสู่ ตำแหน่งที่ออกฤทธิ์ ) ดีกว่า </li></ul></ul></ul><ul><ul><ul><li> duration นานกว่า </li></ul></ul></ul>
    42. 45. ACEI-induced angioedema <ul><li>Mechanism of ACE & ACEI </li></ul><ul><ul><li>Renin-angiotensin-aldosterone system </li></ul></ul>
    43. 46. 1 2 3 Nature reviews 2002
    44. 47. Nature reviews 2002
    45. 48. Nature reviews 2002
    46. 49. ACEI-induced angioedema <ul><ul><li>receptors of angiotensin </li></ul></ul><ul><ul><li> 4 types of receptors </li></ul></ul><ul><ul><ul><ul><li>1.AT 1 receptor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>2.AT 2 receptor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>3.AT 3 receptor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>4.AT 4 receptor </li></ul></ul></ul></ul>Pharmacology & therapeutic.2008;120:292-316
    47. 50. Pharmacology & therapeutic.2008;120:292-316
    48. 51. Nature reviews 2002
    49. 52. ACEI-induced angioedema <ul><ul><li>Kallikrein-kinin system </li></ul></ul><ul><ul><ul><li>Discovery at 1909 by Abelous & Bardier </li></ul></ul></ul><ul><ul><ul><li> demonstrated hypotensive effect of </li></ul></ul></ul><ul><ul><ul><li>urine </li></ul></ul></ul><ul><ul><ul><li>Kinin are family of peptide </li></ul></ul></ul><ul><ul><ul><ul><li>Bradykinin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Kallidin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Methionyl-lysyl-bradykinin </li></ul></ul></ul></ul><ul><ul><ul><li>Both kallidin & methionyl-lysyl-bradykinin </li></ul></ul></ul><ul><ul><ul><li>are converted very rapidly into bradykinin </li></ul></ul></ul>Bas M et al.Allergy.2007;62:842-856
    50. 53. <ul><ul><li>Kallikrein-kinin system antagonize </li></ul></ul><ul><ul><li> effect of RAAS </li></ul></ul><ul><ul><li>พบ kallikrein ในเนื้อเยื่อ เช่น ไต , หลอดเลือด , </li></ul></ul><ul><ul><li>ตับอ่อน , ม้าม , ต่อมน้ำลาย , ต่อมหมวกไต และใน </li></ul></ul><ul><ul><li>neutrophil, code โดยยีนบน </li></ul></ul><ul><ul><li>chromosome 19q13.2-q13.4 </li></ul></ul><ul><ul><li>Mechanism of action ของระบบนี้ดังนี้ </li></ul></ul>Bas M et al.Allergy.2007;62:842-856 ACEI-induced angioedema
    51. 54. ACEI-induced angioedema <ul><ul><li>Kinin receptor are cell surface, </li></ul></ul><ul><ul><li> G-protein-coupled receptors </li></ul></ul><ul><ul><ul><li>2 subtypes </li></ul></ul></ul><ul><ul><ul><ul><li>BKR-1 : gene locate on chromosome 14q32.1-q32.2 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>BKR-2 : gene locate on chromosome 14q32 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Both share 36% sequence homology </li></ul></ul></ul></ul>Pharmacology & therapeutic.2008;120:292-316
    52. 55. ACEI-induced angioedema Bas M et al.Allergy.2007;62:842-856
    53. 56. Angioedema
    54. 57. ACEI-induced angioedema
    55. 58. Angioedema
    56. 59. ACEI-induced angioedema <ul><ul><li>Diagnosis </li></ul></ul><ul><ul><ul><li>Character : </li></ul></ul></ul><ul><ul><ul><li>self-limited </li></ul></ul></ul><ul><ul><ul><li>nonpitting edema of vascular origin </li></ul></ul></ul><ul><ul><ul><li>most common sites </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Lips </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Tongue </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Face </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pruritus, urticaria unusual </li></ul></ul></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:725-737
    57. 60. ACEI-induced angioedema <ul><ul><ul><li>Character (cont.) : </li></ul></ul></ul><ul><ul><ul><ul><li>rarely involve bowel wall </li></ul></ul></ul></ul><ul><ul><ul><ul><li>some cases have N/V, diarrhea, abd. pain or ascites </li></ul></ul></ul></ul><ul><ul><ul><ul><li>resolution of symptoms with discontinuation of ACEI </li></ul></ul></ul></ul><ul><ul><ul><ul><li>hemioral AE associated with </li></ul></ul></ul></ul><ul><ul><ul><ul><li>tissue-type plasminogen activator administration in stroke who taking ACEI </li></ul></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:725-737
    58. 61. ACEI-induced angioedema Immunol Allergy Clin N Am.2006;26:725-737
    59. 62. ACEI-induced angioedema <ul><ul><ul><li>Onset of symptom </li></ul></ul></ul><ul><ul><ul><ul><li>Slater & colleagues รายงานไว้ว่าในสัปดาห์แรก </li></ul></ul></ul></ul><ul><ul><ul><ul><li> อุบัติการณ์จะเพิ่มขึ้นถึง 14 เท่า ( ในปี 1988) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>case report from Philip Dennis Dyer </li></ul></ul></ul></ul><ul><ul><ul><ul><li> 1994 พบผู้ป่วยหญิง อายุ 55 ปี เกิด AE หลังจาก </li></ul></ul></ul></ul><ul><ul><ul><ul><li>หยุดยาเพียง 3 วัน แม้ว่าผู้ป่วยรายนี้จะกินยาต่อเนื่องมาแล้ว </li></ul></ul></ul></ul><ul><ul><ul><ul><li> 7 เดือนโดยที่ไม่มีอาการข้างเคียงใดๆ </li></ul></ul></ul></ul><ul><ul><ul><ul><li>JACI.1994;93:947-948 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Kostis & colleagues พบว่าอุบัติการณ์เกิดขึ้นภายใน </li></ul></ul></ul></ul><ul><ul><ul><ul><li> เดือนแรกของการรักษามากถึง 9 เท่า </li></ul></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:725-737
    60. 63. ACEI-induced angioedema <ul><ul><ul><li>Onset of symptom(cont.) </li></ul></ul></ul><ul><ul><ul><ul><li>อย่างไรก็ตามแม้ว่าจะพบอุบัติการณ์มากในช่วงสัปดาห์แรก แต่พบว่าเกิด AE ถึง 27 % ที่ระยะเวลามากกว่า 6 เดือน </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Gabb GM et al. Aust N Z J Med 1996;26(6):777–82 </li></ul></ul></ul></ul><ul><ul><ul><li>Diagnostic algorithm of AE </li></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:725-737
    61. 64. The America Journal of Medicine.2008;121(4):282-286
    62. 65. The America Journal of Medicine.2008;121(4):282-286
    63. 66. ACEI-induced angioedema <ul><ul><li>Treatment </li></ul></ul><ul><ul><ul><li>early recognition & discontinuation </li></ul></ul></ul><ul><ul><ul><li>remain primary therapy </li></ul></ul></ul><ul><ul><ul><li>no other specific treatment </li></ul></ul></ul><ul><ul><ul><li>primary supportive therapy </li></ul></ul></ul><ul><ul><ul><ul><li>management of airway </li></ul></ul></ul></ul><ul><ul><ul><li>Nielsen & Gramstad administration of </li></ul></ul></ul><ul><ul><ul><li> complement 1 inhibitor (C1-INH) </li></ul></ul></ul><ul><ul><ul><li>concentrate </li></ul></ul></ul><ul><ul><ul><ul><li>decrease symptoms </li></ul></ul></ul></ul>Immunol Allergy Clin N Am.2006;26:725-737
    64. 67. ACEI-induced angioedema <ul><ul><li>Treatment (cont.) </li></ul></ul><ul><ul><ul><li>he reported that </li></ul></ul></ul><ul><ul><ul><li>61-yr-old woman </li></ul></ul></ul><ul><ul><ul><li>with COPD & past MI </li></ul></ul></ul><ul><ul><ul><li>ได้รับ ramipril 7.5 mg </li></ul></ul></ul><ul><ul><ul><li>od*7 yr, วันนี้ตื่นจากนอน </li></ul></ul></ul><ul><ul><ul><li>ด้วยอาการบวมบริเวณลิ้น ต่อ </li></ul></ul></ul><ul><ul><ul><li>มาอาการมากขึ้นบวมทั้ง oral </li></ul></ul></ul><ul><ul><ul><li>Cavity & tongue </li></ul></ul></ul><ul><ul><ul><li>Protrude ภายใน 8 ชม . </li></ul></ul></ul>Acta Anaesthesiol Scand.2006;50:120-122
    65. 68. ACEI-induced angioedema <ul><ul><li>Treatment (cont.) </li></ul></ul><ul><ul><ul><li>หลังจากได้ Berinert @ (complemaent 1 </li></ul></ul></ul><ul><ul><ul><li> inhibitor concentration) 1500 u อาการ </li></ul></ul></ul><ul><ul><ul><li> stridor ค่อยๆดีขึ้น , สามารถกลับมาพูดได้ ภายใน 20 </li></ul></ul></ul><ul><ul><ul><li> นาที </li></ul></ul></ul><ul><ul><ul><li>her C1 inhibitor: normal </li></ul></ul></ul><ul><ul><ul><li>หลังจากออกจากรพ . และหยุดยา ACEI ไม่พบอาการ </li></ul></ul></ul><ul><ul><ul><li> AE อีกเลยในระยะเวลาที่มา F/U 1 ปี </li></ul></ul></ul>Acta Anaesthesiol Scand.2006;50:120-122
    66. 69. ACEI-induced angioedema <ul><ul><li>Treatment (cont.) </li></ul></ul><ul><ul><ul><li>มีการใช้ FFP ใน resistant ACEI-induced AE รายงานโดย Karim & Masood ในปี 2002 และ Manoj R ในปี 2004 โดยให้เหตุผลว่า ใน FFP มี ACE(kinase II) อยู่ ดังนั้นเมื่อให้ FFP แก่ผู้ป่วยก็จะเป็นการลดการสะสมของ bradykinin ทำให้อาการของ AE ลดลงไปด้วย เนื่องจาก ACE เป็นตัว degrade ตามกลไกที่ได้กล่าวมาแล้วใน slide แรกๆ </li></ul></ul></ul>Ann Allergy Asthma Immunol.2004;92:573-575
    67. 70. ACEI-induced angioedema <ul><ul><li>Treatment (cont.) </li></ul></ul><ul><ul><ul><li>Cicardi & colleagues </li></ul></ul></ul><ul><ul><ul><ul><li>Pt. from january 1993 – june 2002 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>1168 pateints for symptoms of AE with & without urticaria </li></ul></ul></ul></ul><ul><ul><ul><ul><li>64 pts. were receiving treatment with </li></ul></ul></ul></ul><ul><ul><ul><ul><li> ACEI & no other obvious causes for AE </li></ul></ul></ul></ul><ul><ul><ul><ul><li>36 men, 26 women, median age 63 yrs </li></ul></ul></ul></ul>Arch Intern Med.2004;164:910-913
    68. 71. ACEI-induced angioedema 64 patients Loss F/U 10 patients 54 patients, all normal lab 26 Angiotensin receptor blocker 14 Calcium channel blocker 14 others:b-blocker, diuretic,etc Arch Intern Med.2004;164:910-913
    69. 72. ACEI-induced angioedema Arch Intern Med.2004;164:910-913
    70. 73. ACEI-induced angioedema <ul><ul><li>conclusion </li></ul></ul><ul><ul><ul><li>recommend that should immediately </li></ul></ul></ul><ul><ul><ul><li> stop drug in patients who experience </li></ul></ul></ul><ul><ul><ul><li> angioedema while taking ACEI </li></ul></ul></ul><ul><ul><ul><li>this study concerns about safety of ARBs </li></ul></ul></ul><ul><ul><ul><li> : this drug appear more obvious </li></ul></ul></ul><ul><ul><ul><li> substitutes for ACEI but there had </li></ul></ul></ul><ul><ul><ul><li> some report of AE from this drugs </li></ul></ul></ul><ul><ul><ul><li> then should reserve their use for patients </li></ul></ul></ul><ul><ul><ul><li> with ACEI-related AE </li></ul></ul></ul>Arch Intern Med.2004;164:910-913
    71. 74. ACEI-induced angioedema <ul><ul><li>Treatment (cont.) </li></ul></ul><ul><ul><ul><li>Icatibant : selective bradykinin receptor antagonist approved in only Europe, not in USA </li></ul></ul></ul><ul><ul><ul><li> effective in phase III trial </li></ul></ul></ul><ul><ul><ul><li>Ecallantide : kallikrein inhibitor </li></ul></ul></ul><ul><ul><ul><li> peptide </li></ul></ul></ul><ul><ul><ul><li> positive results in phase </li></ul></ul></ul><ul><ul><ul><li> III trial for HAE </li></ul></ul></ul>
    72. 75. conclusion <ul><ul><li>Angioedema can be devided as allergic or nonallergic </li></ul></ul><ul><ul><li>Angioedema without urticaria due to overproduction of bradykinin or impaired bradykinin degradation </li></ul></ul><ul><ul><li>Stop using ACEI : conventional </li></ul></ul><ul><ul><ul><li>therapy for ACEI-induced AE </li></ul></ul></ul>
    73. 76. conclusion <ul><ul><li>In case of ACEI-induced AE, can </li></ul></ul><ul><ul><li>substitute to ARB </li></ul></ul><ul><ul><li>ARB could have sustained AE in </li></ul></ul><ul><ul><ul><li>limited percentage which does not </li></ul></ul></ul><ul><ul><ul><li>seem a strong argument to consider </li></ul></ul></ul><ul><ul><ul><li>as contraindication in patients </li></ul></ul></ul><ul><ul><ul><li>ACEI-related AE </li></ul></ul></ul><ul><ul><li>New drugs show efficacyin </li></ul></ul><ul><ul><li>ACEI-induced angioedema but in trial </li></ul></ul>
    74. 77. Thank you