Anti-allergies 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
HISTAMINE RECEPTORS
H1, H2, H3, H4
Receptor distribution
–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
• Receptor Distribution
–Eyes, glandular cells, nerves, lungs, skin, duodenum, nasal
mucosa, stomach, vascular smooth muscle, endothelium, immune cells
1st Generation antihistamines
Classic antihistamines aka 1st generation antihistamines are highly lipophilic and therefore enter the CNS and other tissues readily
1st generation antihistamines as a class are poorly selective for H1, showing non- specific binding with muscarinic, serotonergic, and adrenergic receptors as well as cardiac potassium channels
2nd and 3rd generation antihistamines are much less capable of crossing the BBB of the CNS and therefore have less associated adverse FX
Innate vs adaptive immune response
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
HYPERSENSITIVITY RESPONSES
Type 1-4
An exaggerated immune response specifically involving an innate or foreign innocuous or toxic antigen classified as an allergen
MNEMONIC: ACID
• Type I: (Allergic or Immediate) <1hour
Systemic Anaphylaxis, atopy, conjunctivitis, asthma, latex, insect venom, angioedema, urticaria, food allergies, rhinitis, atopic dermatitis, environmental allergens
• Type II: (Cytotoxic / IgG and IgM Mediated) minutes to several hours
Graves disease, myasthenia gravis, hyperacute graft rejection, hemolytic rxns
• Type III: (Immune Complex) 3-10 hours
Arthritis, nephritis, vasculitis, rheumatoid arthritis, systemic lupus
• Type IV: (Delayed or Cell-Mediated) 48-72 hours (non-granulomatous) Conjunctivitis medicamentosa, contact dermatitis, SJS, TEN, chronic graft rejection, Type-1 diabetes, multiple sclerosis, PPD test, latex, fungal infection, TB skin test, allergy testing
MAST CELLS
- The Type I Hypersensitivity Reaction employs mast cells as its effector cells; wheal and flare are hallmark signs of degranulation
1. 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
Type 1 hypersensitivity
De novo mediator synthesis by PLA2 (minutes)
Responds to antihistamines
Hypersensitivity reaction therapies
Antihistamines are :
- Histamine receptor antagonists
or
- Inverse agonists
Inverse agonists
- inverse agonists represent a unique class of agonists that 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 21
ANTIHISTAMINE USE IN EYE CARE
Besides allergic conjunctivitis, antihistamines have a broader pattern of use:
§ Myokymia
§ Allergic rhinitis
§ Intra-operative anti-miotic
ORAL vs TOPICAL ALLERGY THERAPY
Oral
- Better for deeper ocular involvement
- Better for moderate → severe eyelid edema & conjunctival chemosis
- Better for sinus allergies that are retroactively affecting the eyes by way of the nasolacrimal drainage pathway
Topical
- Required dosing may be more frequent than oral therapy
- Dosing may range from q2h to qd; see manufacturer’s recommendations
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®]
Moderately Sedating
• Clemastine [Tavist®]
Strongly Sedating
• Diphenhydramine [Benadryl®]
2nd generation antihistamines
- Notably less lipophilic; negligible CNS effects
- 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
3rd generation antihistamines
- Notably the least lipophilic; negligible CNS effects
- 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
ORAL ANTIHISTAMINE ADVERSE EFFECTS
- Drowsiness, dizziness, impaired coordination, headache, epigastric discomfort, thickened bronchial secretions, dry mucous membranes, constipation, urinary retention, hypotension, blurred vision, diplopia, tachycardia, diaphoresis
- Cardiotoxicity involving a prolonged QT interval led to d/c 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
Topical antihistamines
prescription only
2nd generation
Topical antihistamines adverse reactions
Emadine Serious Adverse Reactions
• Keratitis, corneal infiltrates
Emadine(Emedastine) Common Adverse Reactions
- Headache
- Abnormal dreams
- Bitter taste
- Blurred, dry eyes
- Foreign body sensation
- Hyperemia, pruritus, lacrimation
Zerviate(Cetirizine) Common Adverse Reactions
- Reduced visual acuity
- Hyperemia
concernsTopical antihistamines & decongestants
§Over-the-counter (OTC) ophthalmic products are subject to oversight by the FDA under the OTC Code of Federal Regulations
§In the code it is recommended that first-generation vasoconstrictors be used no more than 4 times daily due to theoretical safety concerns
Adverse reactions of topical antihistamines and decongestants
Adverse Reactions
- Mydriasis, anisocoria, medicamentosa, reactive hyperemia, lacrimation or dry eye, irritation, pain, photophobia, IOP fluctuation, conjunctival vasoconstriction, headache
- Chronic use may initially impair accommodation
Drug Interactions
• MAOI’s, alcohol
Contraindications
- Hypersensitivity (topical > oral)
- Cardiovascular disease, uncontrolled diabetes
- Narrow anterior chamber angles
- Precautionary use with dry eye
Pharmacology and clinical uses of mast cell stabilizers
Pharmacology
§Oral agents are believed to block Ca++ influx that stimulates degranulation; this effects not only mast cells but other immune cells
Clinical Uses
§Halt Type I Hypersensitivity Reaction
§Routinely used for chronic allergies
§Commonly used for allergy season prophylaxis
§Vernal keratoconjunctivitis & giant papillary conjunctivitis are well-suited conditions for MCS therapy
Topical mast cell stabilizers
(prescription only)
Adverse effects of topical mast cell stabilizers
