Allergy

Allergy

This chapter is prepared for PharmD students in accordance with the officially endorsed curriculum in Pakistan.

October 23, 2024

Chapter outline
» Introduction
» Types of allergens
› Inhalant allergens
› Ingestant allergens
› Injectant allergens
› Contactant allergens
› Infectant allergens
› Infestant allergens
» Case History
» Skin tests
» Mechanism of allergy
» Treatment of allergy

Introduction
» Allergy is a disorder of the immune system
› Allergy is a condition in which the immune system reacts abnormally to a foreign substance
» Definition: Allergy is a damaging overreaction of an individual’s immune system in response to a foreign or non-self substance (called an allergen) that is perceived as harmless to most people
» When an individual is hypersensitive and develops allergic symptoms, the individual is said to be allergic
» Allergens are antigenic substances that can trigger an allergic reaction in hypersensitive individuals
› Almost any substance, whether of biological, chemical, or synthetic origin, may prove to be allergenic, e.g., a particular food, pollen, dust, fur, etc.
» In addition, numerous other factors are allergy producing
› Such as emotional factors, atmospheric factors, psychosomatic factors, and chronic types of infection
› However, because most allergens are composed of plant or animal matter, we will study them in Pharmacognosy
» The exact cause of allergy is still undetermined
› Based on genetic studies, medical and immunologic investigators generally agree that the tendency to be allergic is hereditary
› However, at the present time, it is impossible to predict whether a newborn infant will be allergic or not
› Perhaps future research into the pathophysiology of allergy will reveal the answers
» Predisposing factors that may make some persons susceptible to allergy are;
› Hereditary tendency to allergic response
› Dysfunction of the endocrine glands
› Increased excitability of sympathetic and parasympathetic nervous systems
› Absorption of toxic metabolic and catabolic substances
› Hepatic dysfunction
› Psychic influences
» Symptoms of an allergic reaction are;
› Itchy, watery eyes
› Itchy nose
› Sneezing
› Runny nose
› Rashes
› Hives (a rash with raised red patches)
› Stomach cramps
› Vomiting
› Diarrhea
› Bloating
› Swelling
› Redness
› Pain
› Tongue swelling
› Cough
› Throat closing
› Wheezing (a whistling sound when you breathe)
› Chest tightness and loss of breath
› Feeling faint
› Can lead to anaphylaxis (a serious allergic reaction that is rapid in onset and may cause death)

Types of allergens
» Allergens are antigenic substances that can trigger an allergic reaction in hypersensitive individuals
› Almost any substance, whether of biological, chemical, or synthetic origin, may prove to be allergenic, e.g., a particular food, pollen, dust, fur, etc.

i. Inhalant allergens
» Airborne substances that cause allergy when they come in contact with nasal or buccal mucosa during respiration are called inhalant allergens
› Examples: Pollen, animal dander, etc.

ii. Ingestant allergens
» Allergens which are present in foodstuff and swallowed are termed ingestant allergens
› Examples: Allergy caused by milk and coffee

iii. Injectant allergens
» Substances that cause allergy when they are injected are called injectant allergens
› Examples: Penicillin allergy, bee sting, etc.

iv. Contactant allergens
» Allergens that produce allergy when they come into direct contact with the epithelium are called contactant allergens
› Examples: Cosmetics, wool, etc.

v. Infectant allergens
» Metabolic wastes and growth products of pathogenic microorganisms that cause allergy are called infectant allergens
› Examples: Constant presence of bacterial wastes in bronchiectasis (chronic bacterial infection of the bronchioles) may act as infectant allergens

vi. Infestant allergens
» Metabolic wastes and growth products of parasitic organisms that cause allergy are called Infestant allergens
› Examples: Growth products and metabolic wastes of hookworms, tapeworms, pinworms, threadworms, dermatophytes, etc.

i. Inhalant allergens
» Airborne substances that cause allergy when they come in contact with nasal or buccal mucosa during respiration are called inhalant allergens
› Inhalant allergens produce a condition called ‘hay fever’

Hay fever
» Hay fever is an allergic reaction manifested by sneezing, lacrimation, itching, and swelling of nose and eyes
› The term ‘hayfever’ was originated in England over a century ago because it was believed that the odor emanating from new-mown hay (a type of grass) was responsible for the ‘fever’ or stuffiness of the nasal passages

Seasonal hay fever
» If symptoms of hay fever occur during certain months of the year, it is called seasonal hay fever
› Seasonal hay fever is also called ‘pollinosis’ because this condition is usually associated with the release of pollen grains from certain plants
» In the case of seasonal hayfever, determination of the exact dates within which symptoms occur frequently gives a clue to the type of pollen grains responsible for the allergy
› For example, in Islamabad pollen season starts in the first week of March and ends in mid of April
» Pollens from different plants can be distinguished and identified without difficulty because of their heterogeneous nature
› Pollen grains may be round, oval, angular, square, rectangular, or of other shape, depending on whether they are contracted or fully expanded
› Most pollen grains are single entities, but some may be 2-compound, 3-compound, tetrads, and so forth
» The outer wall of pollens is known as the ‘exine’ and the inner wall as the ‘intine’
› The surface appearance of the exine is characteristic and is a determining factor in the identification
» Atmospheric pollens are liberated chiefly by anemophilous (wind-pollinated) plants
› Pollens of anemophilous plants are usually small, light, nonadhesive, and relatively smooth
› Trees (oak and walnut), grasses (Bermuda grass and timothy), and weeds (ragweed and plantain) are examples of plants having anemophilous flowers
› Wind-pollinated flowers are rarely colored and are generally not fragrant because they do not need to attract insects for the pollination process
» In contrast, pollens of entomophilous (insect-pollinated) plants are usually larger, heavier, adhesive, and may be somewhat spiny
› Plants with scented, colored flowers (clover, hollyhock, honeysuckle, rose, etc) are entomophilous

Nonseasonal hayfever
» Nonseasonal hayfever, more commonly called ‘perennial rhinitis’, is not related to any specific month or season and may be caused by inhalants other than pollens
› Nonseasonal hayfever may be caused by mold spores, dust, animal epidermis or dander, feathers, cotton linters, volatile oils, and countless other factors
» Inhalant allergens responsible for nonseasonal hay fever may occur in the home, at the place of employment, or in some particular locality frequently visited by the patient
› In the home, cotton pillowcases, sheets, and blankets usually shed ‘linters’ or fragments of cotton fibers that are light enough to float in the air and act as inhalant allergens
› The pillows, if made of feathers, may be a source of the allergen, particularly if the pillows are old and the feathers are disintegrating
› If a person has a sensitivity to feathers, he should use a foam rubber pillow or should cover the feather pillow with a plastic, dust-free cover
› Sometimes pet birds may cause a feather sensitivity
» Odors and perfumes are a major factor in nonseasonal allergy
› The increased desire for unusual scents in toiletries and cosmetics has led manufacturers to use volatile oils from many new plant sources as ingredients in their formulations
› For example, sandalwood oil is an ingredient in some men’s toiletries; however, photoallergy to sandalwood oil has been reported in the medical literature
› Many other volatile oils are allergenic
› Removal of the allergens by substituting nonscented cosmetics brings relief
» Another cause of inhalant allergy (nonseasonal hay fever) is animal epidermis or animal dander (epithelial scales)
› Cats, dogs, guinea pigs, and other pets are occasionally responsible for a patient’s cough, wheeze, or asthmatic attack
› Sometimes patients are affected by the odors of the animals rather than by the dander
› Any type of furniture stuffed with horsehair or other animal material should also be investigated as a cause of nonseasonal hay fever
» Another cause of nonseasonal hay fever is the allergen present in castor beans
› The allergen is not removed with the oil when the seeds are expressed
› Because this allergen is air-borne and windborne, persons living in the vicinity of industrial factories that make or use castor bean pomace may exhibit allergic reactions
» Much of the nonseasonal hayfever is thought to be caused by fungus spores, especially of such molds as Alternaria, Helminthosporium, Hormodendrum (Cladosporium), and Aspergillus
› Mold spores are almost constantly present in the atmosphere, even during winter, and have been traced as the contributing factors to many cases of nonseasonal hay fever
› Aspergillus, Penicillium, and other molds abound in moist places and occur in cellars and damp cupboards
» Persons allergic to mold spores are usually allergic to dust as well
› Dust is almost indefinable because it differs from one place to the next, but it probably is composed of mold spores, cotton linters, animal danders, sizing from rugs and carpets, and innumerable other allergenic particles
› Various types of mites have also proved to be major allergens in house dust, particularly the acarine mite, Dermatophagoidcs, and specifically its species, D. pteronyssinus

ii. Ingestant allergens
» Allergens which are present in food stuff and swallowed are termed ingestant allergens
» Food allergens ordinarily cause gastrointestinal symptoms, but they may also cause skin rash, puffed lips and tongue, eczema of the hands, migraine, rhinitis, or other more serious effects, such as bronchial asthma
» In food allergy, the activity of the allergen is not localized in one organ or area of the body but is transferred to other organs by the blood
› Thus, ingestant allergens can cause an ‘atopic dermatitis’
» Some of the most common allergens ingested by children are foods considered essential to proper diet and growth, such as cow’s milk, orange juice, cod liver oil, or other vitamin-containing fish liver oils
» The most satisfactory method of combating food allergies is the elimination of the offending substance from the diet
» Milk allergy is caused by a lactalbumin
› Heating or boiling alters this protein, so evaporated milk may be used as an effective substitute for cow’s milk
› Milk allergy may result in severe dermatitis, recurrent rhinorrhea (runny nose), bronchitis, and asthma
› Various commercial milk substitutes that are prepared from soybean isolates offer a milk-free formula claimed to be devoid of antigenicity
» Coffee can also produce an allergic response
› The principal allergenic component of green coffee is chlorogenic acid
› However, the coffee roasting process alters the structure of chlorogenic acid
› Symptoms of coffee allergy include severe migraine, gastroenteritis, and widespread hives
» Gluten is also an ingestant allergen
› Gluten is a structural protein naturally found in certain cereal grains, especially wheat
› Glutin is responsible for the elastic texture of the dough
› Symptoms of gluten allergy include abdominal pain, anxiety, bloating, and diarrhea or constipation
› Gluten-free products are available for people suffering from gluten allergy

♦ What do you know about ‘lactose intolerance’?

iii. Injectant allergens
» Substances that cause allergy when they are injected are called injectant allergens
» The most common example is the allergic reactions to penicillin injections
› It is estimated that anaphylactic reactions to penicillin occur with a frequency of 1 to 5 per 10,000 patient-courses of penicillin
› Once a patient has suffered a penicillin reaction, he is keenly concerned about the next injection he may receive
› Skin testing for penicillin allergy can be done but under controlled conditions
› 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid) (7-ACA), as well as the semisynthetic penicillins and cephalosporins cause positive intracutaneous reactions in most susceptible patients
› For this reason, antibiotics such as cephalosporins and semisynthetic penicillins should be used with caution by physicians treating patients who are sensitive to penicillin G
» In addition to penicillin products, other injectables may cause allergies; liver extract, antitoxins, and the glandular products
› The symptoms in such cases include itching of the palms of the hands and the soles of the feet, erythema, and peeling of the skin
» Because bees, hornets, and wasps actually ‘sting’ instead of ‘bite’, such insects are considered a source of injectant allergens
› Stings of such insects can induce severe local and constitutional reactions, sometimes causing death
› In fact, it has been estimated that more people die annually from bee stings and wasp stings than from snakebites
› Such patients can be immunized by using injections of antigens because one antigen is common to all bees and wasps, however, each species has its own additional distinct antigen(s)
› Immunologic comparisons of the effects of insect venoms, venom sac extracts, and whole insect extracts have been made to determine the optimal method of treatment

♦ What do you know about ‘anaphylactic shock’?

iv. Contactant allergens
» Allergens that produce allergy when they come into direct contact with the epithelium are called contactant allergens
» Plants acting as contactant allergens include Toxicodendron radicans (poison ivy), T. diversilobum (known as western poison oak), T. quercifolium (known as eastern poison oak), and T. vernix (known as poison sumac, poison elder, or poison dogwood)
› All of these contain the same nonvolatile phenolic principle ‘urushiol’
› Watery blisters associated with pruritus are found in this allergic reaction which can become quite distressing if not properly treated
› The blisters break open, and the exuding fluid forms new blisters that spread quite rapidly
› Urushiol is not a single compound but, instead, a mixture of closely related C₁₅ and C₁₇ catechols, varying from one another by the number and position of double bonds in their side chains
› Urushiol occurs in the sticky sap of the plant that exudes when the plant is injured
› Urushiol causes dermatitis on penetration of the epidermis of the skin
› Urushiol may be conveyed by hands or clothing from one person to another
› Urushiol can be transmitted readily from place to place by different carriers, both animate and inanimate
› Shoes, gloves, and clothing can retain the toxicity of urushiol for months
› Dogs, cats, and farm animals frequently become contaminated, and their hairs may be the source of human contamination
» Other plant contactant allergens causing contact dermatitis are asparagus, buckwheat, buttercups, catalpa leaves, chrysanthemums, daffodils, English ivy, ginkgo leaves, lobelia, marigolds, mayapple, osage orange, flowering spurge, snow-on-the-mountain, smartweeds, and dozens of others
» Occasionally contact dermatitis has been caused by aeroallergens, such as the various pollen grains that contain oils, hairs from different kinds of leaves and flowers, and even small fragments of plant tissue carried by smoke emanating from brush fires, grass fires, and burning leaves
» A number of cosmetic manufacturing companies have removed certain known irritants and allergens from their beauty products and consequently use the term ‘hypoallergenic cosmetics’ to denote this fact
» ‘Orris root’, an ingredient in ‘violet’ talcum powders, is a chief contact allergen
› Another example of contactant allergen is ‘dibromofluorescein’, commonly used in indelible lipsticks
» Because perfumes can be allergenic, many hypoallergenic products are unscented
› In others, the perfuming agents are carefully screened to eliminate possible allergens
» Frequently, individuals cannot tolerate wool in clothing, blankets, or even in the form of wool fat (lanolin) in cosmetics
» Soaps and soap powders, plain and enzyme detergents, nail polishes and nail polish removers, and hair dyes and hair sprays are listed among the numerous major causes of contact dermatitis

♦ Name five plants in your area that may act as ‘contact allergens’.

v. Infectant allergens
» Metabolic wastes and growth products of pathogenic microorganisms that cause allergy are called infectant allergens
» Numerous living organisms may cause allergy through the products they release during their metabolism in the human body
› Some individuals harbor certain types of bacteria, protozoans, molds, helminths, and other parasitic forms which, by their continual presence in the body, are responsible for chronic illness
› The patient may or may not be aware of this infection because it may or may not manifest recognizable symptoms
› Metabolic products of growth of these organisms may be of such nature that the individual becomes sensitized
» For example, during bronchiectasis (chronic bacterial infection of the bronchioles), the constant presence of bacterial wastes may sensitize the allergic individual
› In this case, the bacterial metabolic wastes are considered infectant allergens

vi. Infestant allergens
» Metabolic wastes and growth products of parasitic organisms that cause allergy are called infectant allergens
» Invasions of hookworms, tapeworms, pinworms, threadworms, dermatophytes, and other forms have caused allergic responses in susceptible individuals
» Growth products and metabolic wastes of these parasites are constantly present in the body and are referred to as infestant allergens

♦ What is the difference between ‘infectant allergens’ and ‘infestant allergens’?

Case History
» To determine the circumstances surrounding the patient’s allergy, the allergist must record all details regarding the allergic attacks, including data on the type of occupation and the familial background
» Information concerning the place, time, and mode of onset of past symptoms, as well as those causing the most recent attack, is recorded in the case history or allergic history of the individual
» As stated on a typical case history report, the entries include;
» Name and sex; Marital status; Occupation; Chief complaint
» Present illness [Age of onset; Date of first attack; Place, time, and mode of onset; Seasonal Variation; Duration; What relieves attacks]
» Present attack [Date of onset; Place of onset; Mode of onset; Sneezing; Nasal discharge; Wheeze; Cough; Headache]
» Symptoms affected by [Meals; Drugs; Exertion; Excitement; Weather changes; Wind; Smoke or fumes; Time of day; Mowing lawn; Rain; Working in the garden; Automobile rides; Playing golf; Riding horse; Feeding stock; Cleaning house; Change of season; Change of environment; Change of occupation]
» Other points of information include the types of medication the patient may be taking and the conditions of the home environment (heating system, type of floor covering, presence of household pets, kinds of cosmetics used, nature of bed covers and pillows, and numerous other details)
» A past medical history may be requested
» Allergic symptoms of the paternal and maternal relatives are frequently a clue
» A complete case history includes both a physical and a laboratory examination, the latter to include reports on urine, blood, sputum, and nasal smears
» In addition, results of a radiograph and an electrocardiogram are customary
» Following or concurrent with the laboratory examination, the allergist makes his diagnosis and attempts to confirm it by the use of skin tests

Skin tests
» For diagnosis of allergens, skin tests are conducted in 3 principal ways;
i. Scratch test
ii. Intradermal (intracutaneous) test
iii. Patch test
» Skin tests are quite useful in determining sensitivity to inhalants, injectants, contactants, and some ingestants
› The reactions with the ingestants are less reliable than those with the other allergens

i. Scratch test
» Scratch test, also called ‘skin prick test’ or ‘puncture test’, checks for immediate allergic reactions to different substances
» This type of testing uses needles (lancets) that barely penetrate the skin’s surface
» You will not bleed or feel pain, except a mild momentary discomfort
» After cleaning the test site with alcohol, the nurse draws small marks on your skin and applies a drop of allergen extract next to each mark
› Allergenic extracts are stable preparations of various antigenic substances and are used for diagnosis, preseasonal prophylaxis, and treatment of allergies (except food allergies)
› She then uses a lancet to prick the extracts into the skin’s surface
› A new lancet is used for each allergen
› To see if your skin is reacting normally, histamine is also scratched into your skin’s surface
› About 15 minutes after the skin pricks, the nurse observes your skin for signs of allergic reactions
› Next, the nurse will clean your skin with alcohol to remove the marks
» In adults, the test is usually done on the forearm
» Children may be tested on the upper back

ii. Intradermal (intracutaneous) test
» In the intradermal (intracutaneous) test, a small quantity of the allergenic extract is injected between the layers of the skin
» The injection site is examined after about 15 minutes for signs of an allergic reaction (Table 1)
» This test is mostly used to find injectant allergens
› This test may also be used if the skin scratch test was negative and the doctor still thinks that you are allergic to the allergen

iii. Patch test
» Patch test is mostly used for contactant allergens
» In this test, the material is applied directly to the skin, which is neither scratched nor penetrated with a needle
› You wear the patches on your arm or back for 48 hours
› During this time, you should avoid bathing and activities that cause heavy sweating
› The patches are removed when you return to your doctor’s office
› Irritated skin at the patch site may indicate an allergy
» As a general rule, patch tests require a much longer time for the reaction to occur, at least 48 hours but sometimes 4 to 5 days
» The allergen need not be extracted for applications to the skin in this type of test
» Patch tests can detect delayed allergic reactions, which can take several days to develop

» Other tests, such as the ophthalmic test, passive transfer (Prausnitz–Küstner) test, and microscopic examination of nasal secretions, may be employed by the physician as occasion demands

Mechanism of allergy
» The mechanism of allergy is very complicated and not fully understood
› Major outline is described below

Primary / first exposure
» Allergens are antigenic, i.e., they are capable of eliciting the body to produce specific antibodies against these antigens
» When a person comes into contact with an allergen for the first time, no allergic reaction occurs
› Instead, the immune system undergoes the process of ‘sensitization’
› This is primary/first exposure (Figure 2)
» In sensitization, the body prepares itself for future encounters with the foreign invader
› In this stage, the immune system presents the antigens to immune cells (B cells also called plasma cells)
› B cells produce an antibody that is specific to that antigen
› This antibody is called immunoglobulin E (IgE)
› A person who has created IgE antibodies, specific to an antigen, is referred to as having become ‘sensitized’ to that antigen
› For example, ragweed pollen, causes a susceptible person’s body to produce antibodies
› These particular antibodies have a special affinity for the chemical components of ragweed pollen and related pollens in the ragweed family
› But these antibodies cannot combine with the antigenic molecules in unrelated pollens, in foods, or other allergenic substances
» In the next step, allergen-specific IgE antibodies attach to the surface of mast cells
› Mast cells are a type of granular white blood cell
› Mast cells can be found in most tissues of the body
› Mast cells are strategically placed in locations that are in close contact with the external environment, such as skin, airways, and intestines, to aid in early recognition of allergens
» No symptoms of the allergy are produced during the primary exposure and sensitization phase

Second exposure
» When a person is re-exposed (second exposure) to a substance that he or she is allergic to
› Allergen-specific IgE antibodies, attached to mast cells, recognize and bind to that allergen
› Mast cells are stimulated/activated
» Activation of mast cells results in the rapid release of histamine, bradykinin, and other inflammatory substances, called ‘inflammatory mediators’
» Histamine and other inflammatory mediators bind to their specific receptors on target cells leading to;
› Dilation of blood vessels
› Constriction of bronchioles
› Excessive mucus secretion
› Other symptoms of allergy
» Symptoms of allergy begin to appear within 1 hour after being exposed to an allergen, such as;
› Sneezing
› Wheezing
› Itchy eyes
› Runny nose
› Cough
› Hives

♦ What do you know about the ‘hygiene hypothesis’?

Treatment of allergy
» There is no treatment for allergy
» Some techniques and therapies to overcome the symptoms are described below

Avoid allergen exposure
» It is a lifestyle modification approach which involves avoiding the allergens
» For example;
› Avoid the food that causes allergy
› Change the environment to avoid inhalant allergies
› Replace wool pillows and blankets

Hyposensitization method
» In this method, at regular intervals, a measured amount of the greatly diluted extract is injected subcutaneously (like vaccination)
› The dose is gradually increased so your body gradually gets used to it and does not react so badly
› The hyposensitization treatment is particularly useful for counteracting allergies caused by inhalant allergens and some contactant allergens
» If the treatment is conducted before the time of pollination of the plants, it is termed ‘preseasonal’
› If the treatment is maintained throughout the year for some allergies, it is called ‘perennial’
› If the treatment is instituted during the symptomatic period, it is known as ‘coseasonal’ (the lease satisfactory method)

Use of anti-histamines
» Anti-histamine drugs are competitive antagonists of histamine to histamine receptors (H₁ receptors)
› H₂ receptor antihistamines typically treat GIT symptoms
» Antihistamines cannot prevent the antigen-antibody reactions
› Rather they prevent the damage caused by the release of histamine
» There are two main groups of antihistamines (first generation and second generation)
› Both are H₁ receptor antagonists
» First generation anti-histamines
› They can cross the blood-brain barrier
› That is why cause sleepiness
› Examples are;
Chlorpheniramine (Piriton^®, GSK)
Pheniramine (Avil^®, Sanofi-aventis)
» Second generation anti-histamines
› They cannot cross the blood-brain barrier
› That is why do not cause sleepiness
› Examples are;
Loratadine (Xylor^®, Atco)
Desloratadine (Destina^®, Hilton)
Fexofenadine (Fexet^®, Getz)

Use of corticosteroids
» Corticosteroids in the form of creams, tablets, and injections can also be used to get quick relief from severe symptoms
» Examples are;
› Dexamethasone
› Hydrocortisone
› Prednisolone
› Betamethasone
» Steroids are never recommended for long-term use because of their severe side effects

Use of adrenaline
» Allergic reaction may lead to anaphylactic shock
› In such scenarios, epinephrine (adrenaline) is used

Anaphylaxis is a severe, potentially life-threatening condition. It can occur within seconds or minutes of exposure to something you are allergic to, such as bee stings. Anaphylaxis can cause sudden blood pressure drop, narrowing airways, and block breathing. It can be fatal

♦ Do Arinac^® tablets and Panadol CF^® tablets contain the same drugs?

Arinac^®: Ibuprofen + Pseudoephedrine
Panadol CF^®: Paracetamol + Pseudoephedrine + Chlorpheniramine

Ibuprofen: Anti-inflammatory
Paracetamol: Antipyretic
Pseudoephedrine: Nasal decongestants (provides short-term relief for a blocked or stuffy nose)
Chlorpheniramine: Anti-histamine

So, to relieve which condition(s), these tablets are supposed to be used?

♦ What is the difference between Panadol^®, Panadol Extra^®, and Panadol CF^® tablets?
♦ Why Panadol CF^® is used to treat seasonal flue?
♦ Which type of allergens are there in Islamabad?

Reading References

» Tyler VE, Brady LR, Robbers JE. Pharmacognosy. Lea & Febiger, 9^th edition, 2003.
» www.fda.gov

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