Allergy

In defence against infecting organisms, the body produces antibodies which combine with protein in the organisms to neutralize any effects which they may have upon the body. By means of this defence mechanism the body develops resistance or immunity. This often gives protection against reinfection by the same organism (e.g. you never get chickenpox twice). An antibody is a protein (globulin) which reacts only with the protein of the infecting organism (usually called an antigen) responsible for its formation. There is no cross antibody formation to other organisms (cross immunity), for example, between measles and polio. Sometimes renewed exposure to an infection produces a different or altered response – this is called allergy, which is the result of the body having been sensitized to that organism. Allergy to organisms is rare and most allergy is to a foreign protein (i.e. a protein not made by your body and not known to your own defence systems).

Foreign proteins (allergens) include drugs, house dust, pollens, certain foods and all sorts of things. These are usually grouped under the general term allergens. The reason why some people become sensitized and not others is not understood – we are all, for example, exposed to pollen grains and yet some of us will develop hayfever and others will not. Nor is the nature of allergic reactions fully understood; it may be a fault in the immunity mechanisms resulting in faulty antibody production or it may be due to an inherited defect in the tissues concerned.

The features of the allergic reaction are largely due to the release locally or into the blood-stream of a chemical called histamine and several other chemicals. A single allergen may cause reactions at several sites; thus a patient allergic to a certain food may develop stomach symptoms, a rash and wheezing. Allergens may affect the body through the skin (e.g. contact dermatitis due to cosmetics), in the food (e.g. allergy to strawberries), by inhalation (e.g. hayfever and asthma due to grass pollens), and by injections (e.g. insect bites and allergy to anti-tetanus serum). The resulting reactions may appear as skin rashes; swelling of the eyelids, face, lips and throat (angioedema); as abdominal symptoms (vomiting, diarrhoea and colic); or commonly as hayfever (itching eyes, running nose and sore throat), or as wheezing (asthma). Allergic reactions may be sudden and transient, e.g. sneezing, or last for years, e.g. eczema. They may be trivial, or so serious as to cause sudden death from what is called anaphylactic shock – collapse of the circulation, fall in blood pressure and acute asthma. This usually occurs in patients given an injection which contains a protein to which they have already been made sensitive by a previous injection (e.g. anti-tetanus serum; bee stings). It is rare.

One of the chemicals mainly responsible for allergic reactions is histamine; it is present in most tissues of the body and is released when cells are injured. It causes the small vessels of the body (capillaries) to dilate, particularly those in the skin, making it hot and red. It also makes the vessels more permeable so that plasma flows from inside the blood vessels into the surrounding tissues to produce swelling (oedema). When histamine is injected into the human skin it produces what is called a triple response: (i) a localized red spot which extends within a few seconds, reaches a maximum in about a minute and then becomes bluish; (ii) a bright red ‘flame’ spreads out from this spot and (iii) local swelling occurs forming a weal. (This reaction is often associated with itching and pain.) Histamine also causes the blood vessels in the brain to dilate, which produces a headache. It causes a fall in blood pressure and may increase the heart rate. Large doses may produce shock (collapse). It stimulates the muscles of the small bronchial tubes to produce constriction resulting in asthma and it stimulates the production of acid in the stomach. It is released in anaphylactic shock, allergy and injury. Its concentration is particularly high in the skin, stomach lining and in the lungs.

Any chemical that causes tissue damage will cause the release of histamine but some drugs may do this with little sign of tissue damage. The allergic effects produced by drugs may vary from an itchy skin rash to death from anaphylactic shock. The release of histamine may be caused by a physical process – e.g. sunburn, cold, light and friction – as well as by drugs. Pressure on the skin may release histamine and some people can write their name on their skin (dermatographia). The juice of the stinging nettle contains histamine which produces a skin rash called urticaria (nettle-rash).

Antihistamines

The conventional antihistamines block the action of histamine at peripheral (H₁) receptor sites. They stop, in varying degrees, most, but not all, of the effects produced by histamine. They may also reduce the intensity of allergic and anaphylactic reactions. They act, not by preventing the release of histamine, but by occupying its sites of action. They block its action on the muscles of the intestine and bronchial tubes, they reduce the weal produced by histamine and they reduce hayfever symptoms, itching skin rashes and swelling. They have no effect upon stomach secretions because they do not block H₂ receptors. Those antihistamines that block H₂ receptors are called H₂ receptor blockers (or H₂ antihistamines) and are used to treat patients suffering from peptic ulcers (see p. 83).

In addition to their actions in blocking the effects of histamine, some H₁ antihistamines produce drowsiness and they are referred to as sedative antihistamines. Others produce much less drowsiness because they do not enter the brain as easily. These are referred to as non-sedative antihistamines. Sedative antihistamines may also be used to prevent nausea, vomiting and dizziness (see Chapter 18).

In effective dosage all antihistamines produce adverse effects, but these vary from individual to individual and from drug to drug. For adverse effects and precautions see A–Z of Medicines.

Antihistamines can increase the effects of alcohol and impair driving skills, particularly the sedative ones.

Antihistamines Used to Treat Allergy

*acrivastine (Benadryl Allergy Relief, Semprex)

azatadine (Optimine)

brompheniramine (Dimotane)

*cetirizine (Zirtek)

chlorphenamine(chlorpheniramine) (in Haymine, in Galpseud Plus, Piriton)

clemastine (Tavegil)

cyproheptadine (Periactin)

desloratadine (Neoclarityn)

*fexofenadine (Telfast)

hydroxyzine (Atarax, Ucerax)

*loratadine (Clarityn)

mequitazine (Primalan)

*mizolastine (Mistamine, Mizollen)

pheniramine (Daneral SA)

promethazine (Phenergan)

*terfenadine

alimemazine(trimeprazine) (Vallergan)

triprolidine (in Actifed preparations, in Sudafed Plus)

Those antihistamines marked with an * in the above list do not enter the brain as easily as the other antihistamines and therefore produce fewer harmful effects on the brain. In particular, they produce less drowsiness. They are referred to as non-sedative antihistamines. The others enter the brain and may produce drowsiness, and are referred to as sedative antihistamines.

Use of H₁ Antihistamines

There are numerous antihistamines to choose from and, bearing in mind individual variations in response, it is often a matter of trial and error before you find one that will relieve your particular allergic symptoms and produce a minimum of adverse effects. The ones that produce less drowsiness are the ones to use in the daytime. For night-time, one that produces drowsiness may be helpful, e.g. promethazine or alimemazine(trimeprazine).

1. Antihistamines are useful in relieving the symptoms of seasonal hayfever, but they have no effect upon the cause.

2. They are of little benefit in treating asthma.

3. They are used intravenously to treat angioedema (see later).

4. They are used intravenously to treat severe allergic reactions (see later).

5. Some skin rashes, such as allergic nettle-rash (urticaria), respond well to antihistamines by mouth. Long-standing rashes are little affected. Antihistamines by mouth may be         used to relieve itching. When applied to the skin, there is a danger of producing allergic dermatitis. Given by mouth or injection they relieve the itching and swelling produced by     insect bites.

6. They are of use in relieving the rash in serum sickness (an allergic reaction following the injection of a serum), but they do little to help the fever and joint pains.

7. They are of benefit in treating blood transfusion reactions.

8. They are of no value in treating allergic reactions affecting the stomach or intestine – nausea, vomiting, diarrhoea.

9. Many drug reactions respond well to antihistamines – but do not forget to stop the drug that caused the reaction.

10. Some antihistamines are effective in preventing motion sickness.

11. Some are useful sedatives.

Warnings: Antihistamine drugs are complex chemicals which have many actions in the body and produce numerous effects including adverse effects ranging from loss of appetite to serious blood disorders. They may increase the effects produced by alcohol and sedative drugs and interfere with your mental function. If they make you drowsy you should not drive a motor vehicle or operate moving machinery. Overdose with these drugs is serious and difficult to treat.

Sedative antihistamines may produce alarming reactions in some children (stimulation, fever and convulsions).

Because of the variations in response between individuals taking antihistamines it is often necessary to try different ones. If a drug does not relieve your symptoms within about three days it is unlikely to do so at all. If it produces drowsiness take it at bedtime. Always take antihistamines with food, because they can irritate the stomach. If you are just starting a course, try taking the first dose on a Friday and then you have the weekend to overcome or become accustomed to the adverse effects. Avoid prolonged-release preparations until you know the nature and intensity of the adverse effects caused by the antihistamine drug in question. Prolonged-release preparations are most useful taken at bedtime in order to reduce early-morning symptoms.

Sodium Cromoglycate

This is a non-steroidal anti-inflammatory drug that works on the surface of certain cells (mast cells) to prevent the release of histamine and other chemicals that produce the allergic reaction and trigger inflammation. It may be inhaled to prevent asthma (Aerocrom, Cromogen, Intal, Intal Compound), applied to the eyes to prevent allergic reactions in the eyes (Hay-Crom, Opticrom, Vividrin) and applied up the nose to prevent hayfever (Rynacrom, Rynacrom Compound, Vividrin) and by mouth to treat food allergy (Nalcrom).

Ketotifen

Ketotifen (Zaditen) produces similar effects to sodium cromoglycate but also possesses some antihistamine activity. It is taken by mouth.

Desensitization (Hyposensitization or Immunotherapy)

Hayfever, urticaria, allergic asthma, contact dermatitis and other allergic disorders are due to allergy to certain agents, e.g. foods, pollens, fur, feathers, dust, hair, mites and cosmetics. Contact dermatitis of the skin may occur to drugs (e.g. streptomycin), metals (e.g. nickel buttons on jeans), plants

(e.g. primula), paint, resins and cosmetics. Most people get to know what they are sensitive to and can avoid that substance in future. In some cases it is not possible to identify or to avoid a particular substance, e.g. hayfever. Therefore, skin tests to certain allergens may be carried out, although the results of these tests are often difficult to assess.

Desensitization (injections of an allergen under the skin at intervals using gradually increasing strengths) may be beneficial to patients who have suffered a severe allergic reaction to a wasp or bee sting. Desensitization to grass pollen may occasionally help some people who suffer from hayfever providing they do not suffer from asthma. Multiple desensitization is not recommended since it may precipitate an acute allergic reaction, particularly in children.

Patients undergoing desensitization are at risk of developing a severe allergic reaction and therefore treatment should only be given where there are adequate facilities to provide resuscitation. People with asthma are at particular risk.

Allergic Emergencies*

In addition to securing the airway and giving oxygen the following drugs are used in an allergic emergency (anaphylactic shock) and to treat angioedema (swelling of the mouth and throat):

1. Adrenaline(epinephrine) – intramuscularly in a dose of 0.5–1.0 mg (0.5–1 ml of 1 in 1,000 adrenaline(epinephrine) solution). Repeat every ten minutes according to pulse rate, blood pressure and improvement. If the patient is taking non-selective beta-blockers salbutamol should be given by slow intravenous injection.

*Individuals at risk of allergic shock (e.g. allergy to bee or wasp stings or to peanuts) should carry adrenaline(epinephrine) with them at all times. Special kits are available containing a pre-filled syringe of adrenaline(epinephrine) (e.g. Anapen, Ana-Guard, Epi-Pen, Min-I-Jet). Ana-Kit contains a pre-filled syringe of adrenaline(epinephrine) plus chewable tablets of chlorphenamine(chlorpheniramine) (an antihistamine).

2. Chlorphenamine(chlorpheniramine) – 10–20 mg by slow intravenous infusion for 24–48 hours to prevent relapse.

3. Hydrocortisone (sodium succinate or sodium phosphate) 100–300 mg by slow intravenous injection – slow to work, but may prevent deterioration.

Drugs Used to Treat Hayfever

Hayfever (allergic rhinitis) is either seasonal, caused by allergy to, for example, grass pollen, or perennial (all the year round) and caused by allergy to, for example, house-dust mites or animal fur.

The most effective treatment of hayfever is to try to avoid or reduce contact with the allergen. Drug treatment aimed at preventing or relieving hayfever includes the use of:

• Antihistamines by mouth (see earlier).
• Antihistamine nose drops or sprays, e.g. azelastine (Rhinolast), levocabastine (Livostin).
• Corticosteroid nasal applications, e.g. beclometasone (Beconase preparations, Beclo-aqua, Nasobec, Zonivent), betamethasone (Betnesol, Vista-Methasone drops), budesonide (Rhinocort Aqua), dexamethasone (in Dexa-Rhinaspray Duo), flunisolide (Syntaris), fluticasone (Flixonase Nasule), mometasone (Nasonex) and triamcinolone (Nasacort).
• Corticosteroids by mouth or injection (see Chapter 37) may be used if the symptoms of seasonal hayfever are severe.
• Sodium cromoglycate nasal applications (Rynacrom, Vividrin) to relieve inflammation.
• Anti-allergy eye drop preparations include azelastine (Optilast), emedastine (Emadine), lodoxamide (Alomide) and levocabastine (Livostin).
• Anti-inflammatory eye drops include sodium cromoglycate (Clariteyes, Hay-Crom, Opticrom, Viz-on, Vividrin) or nedocromil (Rapitil) may help.
• A combined antihistamine/decongestant eye preparation may help allergy affecting the eyes, e.g. Otrivine-Antistin (antazoline and xylometazoline).
• Ipratropium (Rinatec spray) is an anticholinergic drug (p. 33) that may be beneficial to people suffering from a runny nose caused by perennial hayfever.

Treatment plan for allergic rhinitis

If watery nose Use local anticholinergic e.g. ipratropium (Rinatec). Nose blocked Use local sympathomimetic decongestants e.g. xylometazoline (Afrazine, Dristan, Otradrops, Otraspray, Otrivine, Vicks Sinex).

Drugs that Suppress the Immune System

In certain medical conditions it is necessary to dampen down (suppress) the activities of the immune system by using drugs. The drugs used for this purpose are referred to as immunosuppressive drugs. Immunosuppression is needed in treating auto-immune diseases in which the immune system attacks normal body tissues. This attack may be local as in Hashimoto’s disease of the thyroid gland, or it may be general and affect many organs and tissues, for example lupus erythematosus. Suppression of the immune system is also necessary in treating patients who have had an organ transplant, otherwise the immune system would cause rejection of the transplanted organ.

The production of antibodies and the cells involved in the immune system are dependent upon the production and multiplication of lymphocytes. Therefore any drug that interferes with the production or multiplication of lymphocytes will suppress the immune system.

The risk of immunosuppressive drugs is that by suppressing immunity (the body’s resistance to infection) they throw the patient open to the risk of infection from various bacteria, fungi and viruses. Also, because lymphocytes prevent the multiplication of abnormal cells there is an increased risk of developing certain types of cancer.

Immunosuppressive Drugs

Azathioprine (Azamune, Immunoprin, Imuran, Oprisine) is an anti-cancer drug that helps the survival and functions of transplanted organs. It is also of benefit to some patients suffering from rheumatoid arthritis and other auto-immune disorders, usually when corticosteroids have failed to control the symptoms.

Mycophenolate mofetil (Cellcept) is an immunosuppressive used to prevent kidney transplant rejection. It is used in combination with ciclosporin and corticosteroids.

Chlorambucil (Leukeran) and cyclophosphamide (Endoxana) are used to treat certain cancers. They are also used to reduce the immune response in patients suffering from rheumatoid arthritis and other auto-immune disorders.

Corticosteroids suppress the immune reaction. They are used to prevent transplant rejection.

Ciclosporin (Neoral, Sandimmun, SangCya) is a powerful immunosuppressive drug and is the principal drug used to reduce the risk of rejection of transplanted organs.

Tacrolimus (Prograf) produces similar effects to ciclosporin although it is not related to it.

Sirolimus (Rapamune), etanercept (Enbrel) and infliximab (Remicade) are selective immunosuppressants which inhibit the activity of tumour necrosis factor. They are used for the treatment of rheumatoid arthritis.

Basiliximab (Simulect) and daclizumab (Zenapax) are monoclonal antibodies that are used for the prophylaxis of acute rejection in renal transplantation.