Pharmacology of allergy

Allergy, types, mechanism and treatment

1. By Gurubarath M M. Pharm 2 nd sem Dept. of Pharmacology PSG College of Pharmacy 1 JUNE 2020 PHARMACOLOGY OF ALLERGY

2. PSG College of Pharmacy 2 ALLERGY An allergy is an adverse reaction that results from previous sensitization to a particular chemical or to one that is structurally similar. Such reactions are mediated by immune system Drug allergy It is an immunologically mediated reaction producing stereotype symptoms which are unrelated to the pharmacodynamic profile of the drug, generally occur even with much smaller doses and have a different time course of onset and duration. This is also called Drug Hypersensitivity. JUNE 2020

3. PSG College of Pharmacy 3 For a chemical to cause an allergic reaction, it or its metabolic product usually acts as an hapten , combining with endogenous protein to form an antigenic complex . ALLERGIC REACTION - MECHANISM A contact with an Allergen such as ragweed pollen may cause an allergic reaction The course of drug allergy is variable ; an individual previously sensitive to a drug may subsequently tolerate it without a reaction and vice versa. Allergens cause the B cells to get activated B cells form the Plasma cells that produce large amounts of IgE antibodies IgE Abs firmly attach themselves to mast cells On re-exposure to allergen mast cells will then release granules rich in mediators Histamines Leukotrienes Other mediators JUNE 2020

4. PSG College of Pharmacy 4 TYPES Mediated by both IgG and IgM antibodies Major targets are cells in the circulatory system Complement is activated and Cytolysis occurs Auto immune reactions subside within several months Type 2 : Cytolytic reactions Mediated by T-lymphocytes and macrophages T cells produce Lymphokines – attract granulocytes – inflammatory response Reaction takes more than 12 hrs to develop Type 4 : Delayed Hypersensitivity reactions Mediated by IgE antibodies Ag:Ab reaction takes place on mast cell surface Various mediators are released Immediate Hypersensitivity Type 1: Anaphylactic reactions Mediated by IgG antibodies Ag:Ab complexes – deposited in vascular endothelium Serum sickness occurs Abs directed against tissue antigens Reactions last 6-12 days and subside Type 3 : Arthrus reactions Humoral B. Cell mediated JUNE 2020

5. PSG College of Pharmacy 5 ANAPHYLACTIC SHOCK Also known as Anaphylaxis It is an allergic reaction that is severe enough to cause Shock SHOCK Decreased tissue perfusion i.e., Decreased oxygenation of tissues How does allergy cause shock? 2 types of Anaphylaxis Immunogenic Non immunogenic JUNE 2020

6. PSG College of Pharmacy 6 ANAPHYLACTIC SHOCK IMMUNOGENIC Sensitization Allergen – interact with B cells – create antibodies ( IgE ) – IgE docks onto the Mast cells – Mediators of immune system Immune system sensitized to Allergen Allergic response Allergen creates immediate allergic response – allergen activates mast cells Release immune molecules Cytokines Communicate with WBCs and recruit more WBCs- and activated in response to these allergens Activation of Mast cell and immune cells cause release of Histamine - Vasodilator Decrease in BP and loose function of circulatory system and no longer able to distribute oxygen - Shock Histamine cause blood vessels leaky – fluid escapes the vascular space which causes swelling to occur all throughout the body NON -IMMUNOGENIC Antigen specifically targets receptors on the Mast cells Histamine release Cytokine release SHOCK JUNE 2020

7. PSG College of Pharmacy 7 ANAPHYLACTIC SHOCK SYMPTOMS Classified according to the actions of Histamine Drop in blood pressure Flushing of skin Swelling Itchiness Rhinorrhea (runny nose) Vessels dilates in nasal vasculature Overactive release of fluid Lungs Bronchospasms Swelling in throat JUNE 2020

8. PSG College of Pharmacy 8 ANAPHYLACTIC SHOCK TREATMENT Airway Circulation Breathing A C B Provide 100% of oxygen supply with bag mask ventilation – to push through lung Blood pressure is maintained with Epinephrine ADRENALINE Strong Sympathetic activity Constrict blood vessels Maintain blood pressure Also Counteracts Histamine Adrenaline also causes Bronchodilation IV fluids help fill up vascular space ANTIHISTAMINES Directly counteracts effects but not immediate JUNE 2020

9. HISTAMINE PSG College of Pharmacy 9 HISTAMINE Histamine exerts its effects by binding to various receptors found throughout the body Receptor H 1 receptors mediate inflammatory and allergic reactions H 1 H 1 receptors – expressed primarily on Vascular endothelial cells Smooth muscle cells Brain Peripheral nerve endings Binds to vascular endothelial receptor and causes blood vessels to dilate – leading to edema and redness Binds to smooth muscle receptor (bronchioles) causes Bronchoconstriction Binds to H 1 receptors in brain – promotes Wakefulness and appetite suppression Stimulates peripheral nerve endings – pain and itching sensations JUNE 2020

10. PSG College of Pharmacy 10 ANTI-HISTAMINES (H 1 ) Anti-Histamines bind to H 1 receptor as inverse agonists on target tissue and stabilize its inactive conformation They lead to inhibition of histaminic actions and gradual relief of allergy related symptoms such as inflammation, itching, running nose and sneezing H 1 receptor blockers 1 st generation 2 nd generation Edema formation and itch are effectively suppressed. Other effects, such as hypotension, are less well antagonized INACTIVE Anti-Histamines are ineffective in bronchial asthma , reasons include; 1) Leukotrienes (C 4 ,D 4 ) and PAF are more important mediators than histamines 2) Conc. Of Anti-histamines attained at site may not be sufficient to block Histamine released in bronchi JUNE 2020

11. PSG College of Pharmacy 11 ANTI-HISTAMINES (H 1 ) 1 ST GENERATION 2 ND GENERATION Due to lipophilic structure cross BBB and cause sedation and impair cognitive function Poor H 1 receptor selectivity – capable of occupying other receptors Cholinergic blockade α -adrenergic blockade Serotonin blockade Dry mouth, blurred vision, urinary retention Hypotension, reflex tachycardia Increased appetite SIDE EFFECTS Have bulkier and less lipophilic structure – they do not cross BBB Much more selective for peripheral H 1 receptor involved in allergies Same allergy symptom relief with less side effects such as sedation STOP Some also inhibit late phase allergic reaction by acting on leukotrienes or by antiplatelet activating factor effect. Brompheniramine, Chlorpheniramine, Clemastine, Cyproheptadine, Diphenhydramine, Doxylamine, hydroxyzine, Meclizine, Promethazine Cetirizine, Desloratadine, Fexofenadine, Loratadine, Levocetirizine, Ketotifen, Azelastine, Olopatadine DRUGS DRUGS JUNE 2020

12. PSG College of Pharmacy 12 PENICILLIN-HYPERSENSITIVITY Incidence of 1 to 10% is reported Penicillin G is the most common drug implicated in drug allergy. Rash, Itching, Urticaria and Hay fever are common. Wheezing, Angioneurotic edema, Serum sickness and Exfoliative dermatitis are less common Anaphylaxis is rare (1-4 per 10,000 patients) but may be fatal Penicillin hypersensitivity is unpredictable History of penicillin allergy must be elicited before injecting it A scratch test or Intra dermal test maybe performed first. Testing with Benzoyl penicilloyl-polylysine is safer. JUNE 2020

13. JUNE 2020 PSG College of Pharmacy 13 PLATELET ACTIVATING FACTORS Important mediator of Anaphylaxis Serum level of factor correlates with severity of systemic reactions PAF also involved in asthmatic patients cause Bronchoconstriction, Mucous hyper secretion and Inflammation of bronchi Human vascular smooth muscle cells ( HVSMC ) stimulated with PAF release PGE 2 – relax smooth muscle

14. PSG College of Pharmacy 14 KININS In addition to the ability to produce vasodilation and edema, Bradykinin stimulate fluid production from Airway submucosal glands via a reflex action Bradykinin can function to increase mucous production and cause Rhinorrhea Stimulate PGE 2 by epithelial cells through increasing Cl - transport in the airway Bradykinin is considered important mediator in the pathogenesis of human allergic diseases MECHANISM JUNE 2020

15. JUNE 2020 PSG College of Pharmacy 15 REFERENCE Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12 th edition; Page no. 76,914,922,931,54,302-303. Essentials of Medical Pharmacology 7 th edition by K D Tripathi; Page no.85-87, 167, 719. Role of Kinins in Human Allergic Disease. N Engl Reg Allergy Proc. 1986;7(3):213-218.