Treatment Strategies of Allergic Disease

Question 1

Define allergic sensitisation

Answer 1

Process where B cells produce specific-antibodies against an allergen

Question 2

Define atopy

Answer 2

Tendency to develop an exaggerated IgE response - often have a triad of: eczema (atopic dermatitis), Allergic rhinitis (hayfever) or allergic asthma

Question 3

Outline the development of allergy towards an allergen

Answer 3

Allergen exposure

Sensitsation

Re-exposure

Allergic Inflammation

Acute or Chronic

Question 4

Describe some ways in which sensitisation to an allergen can be affected

Answer 4

1. Timing of exposure
   
   1. in utero
   2. Infancy
2. Route of exposure
   
   1. Oral
   2. Cutaneous
3. Dose of allergen
4. Other
   
   1. Pollution
   2. Infection
   3. Diet

Question 5

Describe ways in which allergic sensitisation can be prevented

Answer 5

Pregnant and breast-feeding mothers are adviced to be cautious with introduction of commonly allergenic food

HOWEVER,

needs updating:

1. Du Toit, JACI, 2008
   
   1. _​_Study suggests early introduction of ellergen (peanut) leads to better toleration of the allergen
2. LEAP study: Du Toit NEJM, 2015
   
   1. ​Early consumption rather than avoidance, effecitve at primary and secondary prevention of peanut allergy in at risk individuals

Question 6

Outline the aims of the TRACE study

Answer 6

Aimed to identify the lowest dose of peanut allergen that allergic people can tolerate

Also looked at the effects of exercise and sleep deprivation on the induction of an allergic response

Question 7

Describe the benefit and limitation of allergen avoidance to prevent an allergic reaction

Answer 7

Benefit: No allergen = no symptoms

Limitation: Not all foods are labelled sufficienty enough

Question 8

Severe Asthma with Fungal Sensitisation (SAFS) is aspergillus sensitisation associated with imparied lung function (Fairs et al AJRCCM, 2010). This is treated with anti-fungals. Name an example, briefly descibe its MOA and describe how its effects may amplify other medications in asthmatics

Answer 8

Itraconazole

Cytochrome P450 inhibitor (inhibitis production of ergosterol)

Prednisolone metabolised by CP450, therefore, itraconazole can increase the effects of prednisolone by extending its half-life

Question 9

Differentiate between an agonist and an inverse agonist

Answer 9

Agonist acts on a receptor to cause an effect.

Inverse agonist works on the same receptor but causes the opposite effet

E.g. Histamine receptors = Cetirizine (H1), Ranitidine (H2)

GABA receptors = BZD, hypnotics, BARBs

Beta-adrenergic receptors = propanolol

Question 10

Outline the pathway for allergic iflammation

Answer 10

Early phase:

1. Allergen binds IgE
2. Binds to Mast cell (CD23/FcεI)
3. Degranulation

Late phase:

1. Allergen presented to T cells by dendritic cells
2. Release of chemokines (eotaxin)
3. Present to B cell -> affinity maturation
4. IgE antibodies made
5. Allergic inflammation

Question 11

Describe some immediate symptoms after allergen exposure

Answer 11

Urticaria (vasodilation)

Itching

Watery discharge

Nasal congestion

Bronchospasm

Anaphylaxis

Question 12

Describe some late symptoms after allergen exposure

Answer 12

AHR

Nasal blockade

Loss of smell

Niphasic anaphylaxis

Nasal Hyperreactivity

Question 13

Name the secretions of mast cells when activated by IgE-allergen complex

Answer 13

Histamine (main)

Eicosanoids (PGD2)

Tryptase

TNF-a, IL-33

Bradykinin

Question 14

Describe the main effects of histamine

Answer 14

Vasodilation

↑vascular permeability

Smooth muscle contraction

Nerve-end stimulation

Question 15

Describe the difference between first and second generation anti-histamines and give examples

Answer 15

1st = sedating: chlorphenamine - also have anti-muscarinic effects

2nd = non-sedating: cetirizine, loratidine

Sedating because they cross the blood brain barrrier

Question 16

List some pharmacotherapy for allergies (7)

Answer 16

Anti-histamines

Lekotriene Antagonists

Mast Cell Stabilisers

Adrenline

Bronchodilators

Corticosteroids

Cell/Biologics Therapy

Question 17

Describe the mechanisms of Leukotriene antagonists (2) and give two examples of drugs

Answer 17

1. 5-Lipoxygenase inhbitors
   
   1. Zileuton
      
      1. could cause hepatitis
2. CystLT receptor antagonists
   
   1. Monetlukast

Heterogeneous response in patients (add-on therapy in asthma and 2nd line for allergic rhinitis)

Question 18

Describe the effects of Leukotrienes.

Answer 18

Smooth muscle contraction

Eosinophilic inflammation

Musuc prooduction

Question 19

Describe the pros and cons of mast cell stabilisers (sodium cromoglicate, INTAL)

Inhaled, eyedrops, intranasal

Answer 19

Pros: Well tolerated

Cons: short duration of action, needs frequent administration

Question 20

Name the dosage, route, and effects of adrenaline in anaphylaxis

Answer 20

Dosage

• Adrenaline, 1 in 1,000, 0.5mg, i.m.
• Cardiac rescucitatin: 1 in 10,000 i.v. 0.01mg/kg every 4 min

Effects

• Vasoconstriction
• ↑CO
• bronchodilation
• Inhibits mast cell degranulation

Question 21

Name three types of bronchodilators and describe their moa

Answer 21

1. Beta-adrenoceptor agonists
   
   1. ↑adenylate cyclase -> ↑cAMP -> inhibition of Ca cytosolic influx -> SM relaxation
      
      1. Salbutamol, formoterol
2. Methylxanthines
   
   1. Inhibit cAMP phosphodiesterases -> ↑cAMP
3. Anti-cholinergics
   
   1. competitve inhibition of M3 receptors on bronchial SMCs

Question 22

Describe the mechanisms of action of glucocorticosteroids

Answer 22

1. Trans-activation
   
   1. Binding to GRE to ↑transcription of anti-inflammatory genes (SLPI-I, annexin-1, IκB-α)
   2. Through ↑HDAC2?
2. Trans-repression
   
   1. GC ↓HAT -> ↓Histone acetylation -> ↓pro-inflmmatory gene expression

Question 23

Describe the effects of GC on inflmmatory and structural cells

Answer 23

1. Inflammatory Cells
   
   1. ↓Eos, mast cell, DC numbers
   2. ↓inflammatory cytokines
2. Structural Cells
   
   1. ↓Cytokine mediators
   2. ↓vascular permeability
   3. ↓mucus secretion
   4. ↑B2-receptors in ASMC

Question 24

Describe the adverse effects of glucocorticosteroids

Answer 24

1. Weight gain
2. T2DM
3. Muscle wasting
4. Cataracts/glaucoma
5. Immunosuppression
6. Osteopenia/osteoporosis
7. Skin (bruising, thining)
8. Psychosis
9. Suppression of HPA (instant wihdrawal leads to insufficiency as steroids inhibit adrenal production)