Principles of therapy for allergies

1. Principles of therapy for allergies Bader Al-qannass

2. 2 Definitions: Allergy: is an inappropriate and often harmful response of the immune system to normally harmless substances (Allergen). Hypersensitivity Reactions: reactions that are mediated by immunologic mechanisms leading to tissue damage (4 types). Allergen: agent (antigen) that triggers an IgE specific response. Antigen: a protein that invade and the body's defenses recognize as foreign, a series of events occurs in an attempt to render the invader harmless, destroy it, and remove it from the body. Antibodies: (protein substances that protect against antigens).

3. 3 Why is this important? Allergies are very common in America, 50 million people suffer from them (about 1 in 4 people) Allergies are the 6th leading cause of chronic disease and they cause the health care system $18 billion annually Over 60% of people with allergies develop asthma as well Keeping them under control is very important!!

4. 4 Hypersensitivity

5. 5 Four types of hypersensitivity reaction mediated by immunological mechanisms that cause tissue damage Types I - III are antibody-mediated and Type IV are T cell mediated (and divided into 3 groups) Types I - III are distinguished by the different types of antigens recognized and the different classes of antibody involved. Type I are mediated by IgE, which induced mast cell activation Types II & III are mediated by IgG, which can engage complement-mediated and phagocytic effector mechanisms to varying degrees Type II are directed against cell-surface or matrix antigens Type III are directed against soluble antigens and the tissue damage involved is caused by responses triggered by immune complexes A special category of type II responses involves IgG antibodies against cell-surface receptors that disrupt the normal functions of the receptor, either by causing uncontrollable activation or by blocking receptor function Type IV are T cell mediated and subdivided into 3 groups Group 1 = tissue damage is caused by the activation of macrophages by TH1 cells, which results in inflammatory response Group 2 = damage is caused by the activation of TH2 cells of the inflammatory responses in which eosinophils predominate Group 3 = damage is caused directly by cytotoxic T cells (CTL) Four types of hypersensitivity reaction mediated by immunological mechanisms that cause tissue damage Types I - III are antibody-mediated and Type IV are T cell mediated (and divided into 3 groups) Types I - III are distinguished by the different types of antigens recognized and the different classes of antibody involved. Type I are mediated by IgE, which induced mast cell activation Types II & III are mediated by IgG, which can engage complement-mediated and phagocytic effector mechanisms to varying degrees Type II are directed against cell-surface or matrix antigens Type III are directed against soluble antigens and the tissue damage involved is caused by responses triggered by immune complexes A special category of type II responses involves IgG antibodies against cell-surface receptors that disrupt the normal functions of the receptor, either by causing uncontrollable activation or by blocking receptor function Type IV are T cell mediated and subdivided into 3 groups Group 1 = tissue damage is caused by the activation of macrophages by TH1 cells, which results in inflammatory response Group 2 = damage is caused by the activation of TH2 cells of the inflammatory responses in which eosinophils predominate Group 3 = damage is caused directly by cytotoxic T cells (CTL)

6. 6 IgE-mediated reactions can have multiple effects

7. 7 Important points� Allergic reactions : result of the production of specific IgE antibody against common, innocuous antigens. Allergens are small, highly soluble protein antigens that typically enter the body at very low doses by diffusion across mucosal surfaces and trigger a TH2 response Allergen-specific TH2 cells produce IL-4 and IL-13, which drive allergen-specific B cells to produce IgE IgE binds to high-affinity receptor for IgE on mast cells, basophils and activated eosinophils Reexposure to the allergen triggers an allergic response

8. 8 Type I Mediators and Effects

9. 9 Types of Allergy Classified according to symptoms they produce i.e. skin, nose and lungs etc and causes: Skin allergy Food allergy Allergen inhalation (Allergic rhinitis, Allergic asthma ) Allergy to medicine

10. 10 Risk factors of Allergy Family history of allergy Exposure to allergens:

11. 11 Symptoms Allergy is a local or systemic ,Local symptoms are: Nose: swelling of the nasal mucosa) Allergic Rhinitis) Eyes: redness and itching of the conjunctiva ) Allergic Conjunctivitis) Airways : Bronchoconstriction, Wheezing and Dyspnoea. -Sometimes outright attacks of asthma -In severe cases the airway constricts due to swelling known as anaphylaxis Ears: feeling of fullness, possibly pain, and impaired hearing due to the lack of eustachian tube drainage. Skin: rashes;such as eczema, hives (urticaria) and contact dermatitis. Headaches .

12. 12 Systemic allergy - Response is also called anaphylaxis; multiple systems can be affected including the: Digestive System, the Respiratory System, and the Circulatory System . - Depending of the rate of severity, it can cause Cutaneous Reactions, Bronchoconstriction, Edema, Hypotension, Coma, and even Death. - This type of reaction can be triggered suddenly or the onset can be delayed. -The severity of this type of allergic response often requires injections of epinephrine.

13. 13 Therapy

14. 14 Therapy for Allergy Antihistamine. ? -Adrenergic agonists (Decongestants) Corticosteroids. Mast cell stabilizers. Antileukotriene drugs. Mast cell stabilizers. Immunosuprissive. Direct Inhibitors -Theophyllines, Xanthines -Epinephrine

15. Antihistamines

16. 16 Histamine Receptors H1 Bronchial constriction Musous secretion Intestinal smooth muscle contraction Itching and pain at sensory nerve endings H1 and H2 Reduces BP Increase permeability in skin H2 - Gastric secretion in stomach

17. 17 The different Histamine receptors

18. 18 Clinical Uses of Antihistamines Allergic rhinitis (common cold) Allergic conjunctivitis (pink eye) Allergic dermatological conditions Urticaria (hives) Angioedema (Swelling of the skin) Puritus (Atopic Dermatitis, insect bites) Anaphylactic reactions (severe allergies) Nausea and vomiting (first generation H1-antihistamines) Sedation (first generation H1-antihistamines)

19. 19 Adverse side effects Associated with the first generation H1-antihistamines and due to their lack of selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS depression: Sedation Dizziness Tinnitus Blurred vision Euphoria Uncoordination Anxiety Insomnia Tremor Nausea/Vomitting Dry Mouth/Dry Cough Can also infrequently cause: urinary retention, palpitations, hypotension, headache, hallucinations, psychosis The reasons for these side effects is the lack of selectivity of the H1-antihistamines. These drugs in addition to being H1-receptor inverse agonists, they are muscarinic acetycholine receptor antagonists (anticholinergic agents), and may also have action at alpha-adrenergic receptors and 5-HT receptorsCan also infrequently cause: urinary retention, palpitations, hypotension, headache, hallucinations, psychosis The reasons for these side effects is the lack of selectivity of the H1-antihistamines. These drugs in addition to being H1-receptor inverse agonists, they are muscarinic acetycholine receptor antagonists (anticholinergic agents), and may also have action at alpha-adrenergic receptors and 5-HT receptors

20. 20 Adverse side effects Newer second generation H1-antihistamines are more selective for the peripheral histamine receptors and have far less side effects (drowsiness, fatigue, headache, nausea and dry mouth)

21. 21 First antihistamine Piperoxan Discovered in 1933 by Jeff Forneau and Daniel Bovent while developing a guinea pig animal model of anaphylaxis They received the Nobel Prize in 1957

22. 22 Classes of first generation H1 receptor antagonist antihistamines Ethylenediamines Ethanolamines Alkylamines Piperazines Tricyclics

23. 23 Ethanolamines This class has significant anticholinergic side effects and sedation, however reduced the gastroinestnal side effects The anticholinergic side effects may include: motor impairment, dry mouth/throat, flushed skin, rapid or irregular heart beat, blurred vision, sensitivity to light, pupil dilation, urinary retention, constipation, difficulty concintrating, short term memory loss, visual disturbances, hallucinations, confusion, erectile dysfunction, and delirium The anticholinergic side effects may include: motor impairment, dry mouth/throat, flushed skin, rapid or irregular heart beat, blurred vision, sensitivity to light, pupil dilation, urinary retention, constipation, difficulty concintrating, short term memory loss, visual disturbances, hallucinations, confusion, erectile dysfunction, and delirium

24. 24 Ethanolamines Clemastine (Tavegyl) Dimenhydrinate (Dramamine) Dramamine is actually a combination of two drugs: diphenhydramine (Benadryl) and 8-chlorotheophillinate (similar to caffeine and is a mild CNS stimulator) They thought that adding the 8-chlorotheophillinate would counteract the affects of the diphenhydramine, however that is not that case and sedation still occursDramamine is actually a combination of two drugs: diphenhydramine (Benadryl) and 8-chlorotheophillinate (similar to caffeine and is a mild CNS stimulator) They thought that adding the 8-chlorotheophillinate would counteract the affects of the diphenhydramine, however that is not that case and sedation still occurs

25. 25 Alkylamines An important factor in this class of drugs, which is selectivity to the H1-receptor binding site These drugs have fewer sedative and GI adverse effects, but a greater incidence of CNS stimulation

26. 26 Akylamines Chlorphenamine

27. 27 Akylamines Triprolidine hydrochloride Pheniramine (Avil)

28. 28 Piperazines Structurally related to the ethylenediamines and the ethanolamines and thus produce significant anti-cholinergic effects Used most often to treat motion sickness, vertigo, nausea and vomiting

29. 29 Piperazines Hydroxyzine

30. 30 Piperazines Meclizine Cetirizine (Zyrtec)

31. 31 Tricyclics These drugs are structurally related to tricyclic antidepressants, which explains why they have cholinergic side effects

32. 32 Tricyclics Ketotifen (Zaditor)

33. 33 Second generation H1-receptor antagonists These are the newer drugs and they are much more selective for the peripheral H1-receptors involved in allergies as opposed to the H1-receptors in the CNS. They are however bulkier and less lipophilic than the first generation drugs, therefore they do not cross the BBB as readily. Recent studies have also showed that these drugs also have anti-inflammatory activity and therefore, would be helpful in the management of inflammation in allergic airways disease .

34. 34 Second generation H1-receptor antagonists Loratadine (Claritin) Terfenadine (Seldane)

35. 35 Second generation H1-receptor antagonists Levocabastine(Livostin)

36. 36 Third generation H1-receptor antagonists These drugs are derived from second generation antihistamines They are either the active metabolite of the second generation drug designed to have increased efficacy and fewer side effects

37. 37 Third generation H1-receptor antagonists Deslortadine (Clarinex)

38. 38 The Future of Antihistamines An effective alternative to corticosteriods in the treatment of allergic airways conditions (The anti-inflammatory activity of second generation antihistamines). The action of the H4 receptor will also continue to be researched and will possibly lead to effective treatment of autoimmune diseases. Creating antihistamines with higher selectivity and less adverse side effects will continue to be the goal

39. 39 ? -Adrenergic agonists (Decongestants) Phenylephrine, Oxymetazoline (long acting),Pseudophedrine Reduce air way resistant by constrict dilated arterioles in the nasal mucosa. Side effect: -Systemic effect (Tachycardia, palpitations, arrhythmias. -Rebound nasal congestion. -Nasal bleeding. Use in combination with Antihistamines.

40. 40 Combination of Antihistamine and Pseudoephedrine, Dihydrocodeine, and Chlorpheniramine (Hydro-Tussin). Triprolidine and Pseudoephedrine (Actifed) Loratidine and Pseudoephedrine (Clarinase) Chlorpheniramine and Pseudoephedrine ) Allerest) Diphenhydramine and Pseudoephedrine (Benadryl)

41. Glucocorticoid

42. 42 Glucocorticoid Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger similar effects.

43. 43 Effects Glucocorticoids have potent Anti-Inflammatory and Immunosuppressive properties. Widely used as drugs to treat inflammatory conditions such as arthritis or dermatitis, and as adjunction therapy for conditions such as autoimmune diseases. Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extra uterine. Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticis have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to osteoporosis), delayed wound healing, muscle weakness and increased risk of infection.

44. 44 Mode Of Action Glucocorticoids bind to the cytosolic glucocorticoid receptor. This type of receptor gets activated upon ligand binding. After a hormone binds to the corresponding receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The opposite mechanism is called transrepression. The activated hormone receptor interacts with specific transcription factors and prevents the transcription of targeted genes. Glucocorticoids are able to prevent the transcription of any of immune genes ,including the IL-2 gene.

45. 45 Pharmacologic properties A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in the - Pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) - And in pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water. Absorb well through the intestines (by mouth ), but also by other ways like topically on skin. Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. Hydrocortisone cream or ointment is available nonprescription up to 1% strength. Stronger forms generally require prescription.

46. 46 Data refer to oral dosing, except when mentioned. Note that oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Note that fludrocortisone, DOCA, and aldosterone are not considered glucocorticoids and are included in this table to provide perspective on mineralocorticoid potency.Data refer to oral dosing, except when mentioned. Note that oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Note that fludrocortisone, DOCA, and aldosterone are not considered glucocorticoids and are included in this table to provide perspective on mineralocorticoid potency.

47. 47 Medical uses and effects of high dose glucocorticoids Allergic disorders. Inflammatory disorders. Autoimmune disorders. posttransplantory immunosuppressants: to prevent the Acute Transplant Rejection and the Graft-Versus-Host disease.

48. 48 Side effects In the long run they may impair many healthy anabolic processes (selectivity). These are the side effects that could be prevented: Immunosuppression. Hyperglycemia (increased gluconeogenesis, insulin resistance and impaired glucose tolerance ("steroid diabetes"). Bruising of skin. Osteoporosis (reduced bone density) Weight gain . Adrenal insufficiency (if used for long time and stopped suddenly without a taper) . Anovulation. Irregularity of menstrual periods. growth failure, pubertal delay. increased plasma amino acids, increased urea formation. excitatory effect on central nervous system Hyperglycemia (increased gluconeogenesis, insulin resistance and impaired glucose tolerance ("steroid diabetes"). Hyperglycemia (increased gluconeogenesis, insulin resistance and impaired glucose tolerance ("steroid diabetes").

49. 49 Adrenal suppression and withdrawal The use of high dose steroids for more than a week begins to produce suppression of the patient's adrenal glands because the exogenous glucocorticoids suppress hypothalamic corticotropin releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH). With prolonged suppression the adrenal glands atrophy (physically shrink) and can take months to recover full function after discontinuation of the exogenous glucocorticoid.

50. 50 Mast cell stabilizers: These agents appear to stabilise the mast cells to prevent degranulation and mediator release. Cromoglicate (Cromolyn) Nedocromil Uses: - As prophylaxis in exercise-induced bronchoconstrection. - Or in pregnant and children as initially in case of asthma or allergic rhinitis. - They are used when other drugs (eg, antihistamines, topical corticosteroids) are ineffective or not well tolerated. Ocular forms are also available. Side effect: Bitter taste and irritation of pharynx and larynx.

51. 51 Antileukotriene drugs Montelukast ,Zafirlukast, Zileuton Selective, reversible inhibitors of cysteinyl Leukotriene-1 receptor. Use: in prophylaxis of asthma. Not effective as �2 agonist or corticosteroids. Taken orally (Zafirlukast absorption impaired by the food). Side effects: -Increase LFTs (D/C if 3 fold). -Headache -Dyspepsia

52. 52 Anti-IgE Antibody (Omalizumab) Xolair Recombinant DNA-derived monoclonal Antibody (selectively bind to IgE antibodies which lead to decrease the affinity of the IgE to bind to the mast cells and basophils. Use: in moderate to severely allergic asthmatic patients with elevated IgE levels . Dose is determined by a dosing chart based on the patient's weight and IgE levels. The drug is administered sc every 2 wk. Have a limited role because less expensive, effective alternatives are available. 

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