*Allergy Flashcards
ALLERGY PATHOPHYSIOLOGY
- Allergies and autoimmune disease are hypersensitivity
reactions of an over-reactive immune system to exogenous
and endogenous antigens, respectively - Itch is a pathognomonic symptom of allergy
- Histamine is a principal mediator of itching
- Itch along with symptoms of dryness (burning, gritty, scratchy)
may be resolved with dry eye therapy - When present, clinical signs & symptoms of inflammation
(redness, warmth or heat, swelling, pain or notable discomfort)
may call for combination anti-inflammatory therapy
HISTAMINE PHARMACOLOGY
- Histamine is expressed throughout the body by a large variety of
cells and neurons, in the latter case acting as a neurotransmitter - For allergies, histamine predominantly acts through the H1 receptor,
resulting in:- Vascular permeability
- Runny nose, watery eyes, swollen lids, papillae
- Vasodilation
- Redness, headache, hypotension, reflex tachycardia
- Smooth muscle contraction
- Bronchoconstriction
- Sensory nerve stimulation
- Pain & itching, sneezing, coughing
EXOGENOUS AGONISTS OF THE IMMUNE RESPONSE
Apart from endogenous pathways, many foreign substances (antigens),
as well as physical processes, have the capacity to evoke an
immunological response
Physical Activators
• Temperature, pressure
Environmental Antigens
• Animal dander, ragweed, pollen, dust, insect bites, venoms
Biological Antigens
• Bacteria, viruses, fungi, parasites
Chemical Antigens
• Vaccines, drugs, proteins, carbohydrates, metals, food additives
*ANTIHISTAMINE PHARMACOLOGY
- Classic antihistamines aka 1st generation antihistamines are highly lipophilic and therefore enter the CNS and other tissues readily
- 2nd generation antihistamines do not readily enter the CNS and therefore have less associated adverse FX
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INNATE IMMUNE RESPONSE
A non-specific generic acute response
- A first-line defense lacking immunologic memory
- Acts near entry-points of infection or injury
- Humoral
- Activation of the non-classical (alternative) complement cascade in response to microbe surface interaction
- Release of cytokines by first-responder TH-2 cells
- Cell-mediated
- Phagocytes ingest foreign proteins, fungi, pathogens viruses, bacteria, and parasites and NK cells secrete cytokines to recruit monocytes (premature macrophages) and neutrophils
ADAPTIVE IMMUNE RESPONSE
An acquired specific response
- Requires prior exposure to the antigen
- Evasion of the innate response may occur
- Features both specificity & memory
- Humoral
- Activation of the classical complement cascade in response to Ag-Ab complexes
- Exposed dendritic cells (APC’s) stimulate T cells to mature into Helper T’s which cause B-cells to transform into antibody-producing plasma cells
- Memory B-cells secrete antibodies upon re-exposure
- Cell-mediated
- Exposed dendritic cells (APC’s) stimulate T cells to mature into Helper T’s which facilitate sensitization of Killer T’s
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ANTIGENS
Foreign substances having the capacity to
evoke an immunological response
- Environmental Antigens
- Animal dander, Ragweed, Pollen, Dust, Insect stings
- Biological Antigens
- Bacteria, viruses, fungi, parasites
- Chemical Antigens
- Vaccines, drugs, proteins, carbohydrates, metals, food additives
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MAST CELLS
- The Type I Hypersensitivity Reaction employs mast cells as its
effector cells; wheal and flare are hallmark signs of degranulation - Mast cells, found throughout the body, play a key role in the
development and maintenance of allergic reactions, thereby rendering them as attractive therapeutic targets - Mast cells release mediators from 3 major sources:
- Preformed (seconds): histamine, proteases, serotonin, heparin
- De novo synthesis (minutes): eicosanoids (leukotrienes and
prostaglandins); products of the arachidonic acid cascade - Induced transcription (hours): gene expression of chemokines,
cytokines, TNF-a, growth factors
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ANAPHYLAXIS
An acute, systemic hypersensitivity reaction to a previously sensitized allergen
- Ige in the bloodstream reacts with the antigen leading to a robust release of chemical mediators resulting in impaired respiration (bronchoconstriction), dramatically reduced blood pressure (vasodilation), and swelling
- Monitor respiration
- Place patient in supine position to maximize blood flow to CNS
- Monitor blood pressure
- Avoid any oral hydration; smelling salts may be considered prn
- Serious anaphylactic reactions develop within minutes (up to 2 hours) and require immediate emergency treatment with epinephrine (epipen)
- O2, IV steroids, and airway management, including intubation, should also be considered as indicated; be prepared to call for medical support
Cautions for use of epipens
Caution in patients with heart disease or high blood pressure,
Parkinson’s disease, diabetes, or a thyroid disorder
TYPE IV DELAYED HYPERSENSITIVITY
- Re-exposure (memory) response
- E.g. TB testing, MS, chronic transplant rejection
- T-cell based unlike Types I-III; antibody independent
- NOT responsive to antihistamines
- Most responsive to steroid therapy
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PRESCRIPTION ORAL MAST CELL STABILIZERS
- Disodium cromoglycate (the gold standard)
- Cromolyn℞: indicated for food allergies, asthma, IBD
(also anti-inflammatory)
ANTIHISTAMINES
- In contrast to the widely held notion that H1 & H2 antihistamines were histamine receptor antagonists, it’s interesting to note that they are actually inverse agonists which uniquely act on receptors that possess constitutive activity
- Constitutive receptors resonate between inactive and active states, the latter being able to trigger downstream events even in the absence of ligand binding
- Antihistamines shift the equilibrium toward the inactive state
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HISTAMINE RECEPTORS
- Receptor Types
- H1: classic receptor involved in immediate hypersensitivity
reaction - H2: promotes gastric acid production, immune cell activation
- H3: pre-synaptic feedback inhibition
- H4: immuno-modulation, inflammation & nociception roles
- H1: classic receptor involved in immediate hypersensitivity
- Receptor Distribution
- Eyes, glandular cells, nerves, lungs, skin, duodenum, nasal mucosa, stomach, vascular smooth muscle, endothelium, immune cells
ORAL ANTIHISTAMINE GENERATIONS
1st Generation
• Highly lipophilic, these drugs are well recognized for their
propensity to readily cross the BBB resulting in adverse reactions
affecting the CNS, heart, vasculature, and parasympathetic tone
• In fact, their lack of H1 receptor selectivity accounts for
interactions with muscarinic, serotonergic, and adrenergic
receptors as well as cardiac potassium channels
2nd Generation
• Owing to the lack of safety and efficacy studies that were
performed on 1st generation antihistamines when they began to
enter the market in the 1940’s, the 2nd generation of H1
antihistamines is largely agreed to represent the antihistamine of
choice in the treatment of allergic rhinitis, allergic conjunctivitis, and
chronic urticaria
3rd Generation
• The recent introduction of 3rd generation antihistamines offers
promise of even greater safety
1st Generation antihistamines
These drugs have a notably lipophilic structure which readily promotes access to the CNS across the BBB
Mildly Sedating
• Chlorpheniramine [Chlor-Trimeton®] (allergex)
Moderately Sedating
• Clemastine [Tavist®]
Strongly Sedating
• Diphenhydramine [Benadryl®]
ORAL ANTIHISTAMINE ADVERSE EFFECTS
Ocular
• Oral antihistamines are noted for drying mucosal membranes to a much greater degree than topical antihistamines
• Blurred vision, diplopia
CNS
• Drowsiness, dizziness, impaired coordination
CV
• Headache, hypotension, tachycardia
GI/GU
• Epigastric discomfort, constipation, urinary retention
Respiratory
• Thickened bronchial secretions
Glandular
• Diaphoresis
ORAL ANTIHISTAMINES: THE BACK STORY
- Cardiotoxicity involving a prolonged QT interval led to discontinuation of 2nd generation astemizole and terfenadine, though 1st generation
promethazine, brompheniramine and diphenhydramine drugs carry this same risk -
Respiratory depression, coma and death are serious adverse effects of 1st generation antihistamines which remain on the market due to name
recognition, longevity and OTC status - In recent years, the 2nd generation of H1 antihistamines has come to
represent the antihistamine of choice in the treatment of allergic rhinitis,
allergic conjunctivitis, and chronic urticaria - The recent introduction of 3rd generation antihistamines is evidence of
ongoing efforts to arrive at a much safer drug profile
Drug interactions with 1st generation antihistamines
- Potassium supplements
- Codeine & Opioids
- Anticholinergics
Contraindications of 1st generation antihistamines (Chlorpheniramine, diphenhydramine)
- Peptic ulcer
- Prostatic hypertrophy
- Bladder obstruction
- Angle closure glaucoma
2nd Generation antihistamines (Cetirizine, loratadine)
- Cetirizine is most potent 2nd gen, albeit the most sedating as well
- 2nd gen agents have a longer elimination profile, allowing for qd
dosing in some cases; they also have some potential to decrease
histamine RELEASE
Adverse effects of Cetirizine (2nd generation antihistamine)
- Drowsiness,
- dizziness,
- fatigue,
- abdominal pain,
- headache,
- dry mucous membranes,
- diarrhea,
- nausea
- vomiting
Contraindications and cautions of Cetirizine (2nd generation antihistamine)
Contraindications
• Hydroxyzine allergy
Caution
• Avoid combining with CNS depressants
In an August 2019 lawsuit, plaintiffs claim that withdrawal of the drug
produces an itch that has been described as being more severe than
the original itch for which the drug was being taken
3rd generation antihistamines
- Desloratadine
- Levocetirizine
- Fexofenadine
- Fexofenadine has least CNS effects; it’s a metabolite of terfenadine (Seldane: removed from market due to cardiotoxicity)
- Desloratadine is a metabolite of Loratadine
- Among these three 3rd gen agents, levocetirizine is most sedating, fexofenadine has a short DOA, and desloratadine, although less potent and rarely causing somnolence, has a longer DOA
