Allergy and Classification of Anti-allergic drugs

Allergy: What is it? 

Allergy is a hypersensitivity (hyperreactivity) of the body’s immune system against a xenobiotic substance that can act as an allergen or antigen. This type of reaction by our immune system is undesirable since it predisposes the affected tissue to damage.

The allergic response is mediated by different mechanisms that may be due to an antigen-antibody reaction, or cell-mediated. The predisposition of an individual to different allergens is not predictable; hence, antiallergic drugs become essential. The drugs are used to decrease the reactivity of the cells to allergens.

If not taken proper care, the allergic response may become fatal.  

• How do they work?

The reaction of cells to an allergen can be classified into four broad categories –

1. Type 1 reaction – this allergic reaction is the IgE antibody-mediated. The response is immediate (within seconds – minutes). IgE sensitizes basophils in the peripheral blood or mast cells and causes them to produce anaphylactic mediators like histamine, serotonin, intestinal peptides, prostaglandins, leukotrienes upon degranulation. These mediators get released in high amounts that show the pharmacological effect.
2. Type 2 reaction – this reaction is cytotoxic, i.e., causes cell death. The result of such a response is tissue damage due to the binding of antibody (IgM, IgG) to the antigen. The damage is caused by cell membrane lysis, phagocytic action of macrophages on the target cell, and direct damage to the affected cell.
3. Type 3 reaction – this reaction results from the antigen-antibody complex, causing an immune complex formation. The complement system gets activated, and complex-mediated tissue injury by exogenous antigens (microbes), or endogenous antigens (blood components).
4. Type 4 reaction – it is a cell-mediated reaction, involving T cells, antigens, and macrophages. The macrophages present an antigen to T cells, by which cell-mediated immune memory develops. Upon subsequent exposure, T cells cause direct cytotoxicity, lymphokine, and inflammatory mediator recruitment.

The drugs, therefore, are used to inhibit these types of responses. The treatment initially begins with allergen elimination or avoidance, followed by drug interventions to prevent mediators’ exaggerated release.

• Different classes of these drugs

The major types of antiallergic drugs are –

1. Antihistaminic – dimedrol, diprazine, loratadine, cetirizine, levocetirizine, fexofenadine 
2. Mast cell stabilizers – cromolyn, nedocromil, lodoxamide, pemirolast
3. NSAIDs – ketorolac, flurbiprofen, tromethamine
4. Corticosteroids – fluoromethanol, betamethasone, hydrocortisone, prednisolone

Drugs used to relieve generalized symptoms of immediate allergic response –

1. Adrenomimetics – adrenaline
2. Methylxanthines – euphylline, theophylline
3. Ca+2 preparations – calcium chloride, calcium gluconate

• Indications in which they are preferred

1. Antihistaminic used in histamine-mediated allergic reactions – allergic rhinitis, allergic conjunctivitis
2. Mast cell stabilizers used in vernal keratoconjunctivitis, keratitis, allergic keratoconjunctivitis, and giant papillary conjunctivitis, itching
3. NSAIDs are used to inhibit inflammatory response mediated by prostaglandins and in seasonal allergic reactions
4. Corticosteroids are used in extreme allergic reactions, to suppress the overall immune response and inflammatory response throughout the body.
5. Combinations of drugs used to treat drug-mediated allergic response (e.g., penicillin)

• Side effects

1. Antihistaminic – sedation, peripheral anti-secretory effects, CNS dysregulation, palpitations
2. Mast cell stabilizers – burning and stinging pain at the site of administration, watery, puffy eyes (ophthalmic preparations)
3. NSAID – transient stinging and burning sensation, allergic reaction & keratitis in rare conditions
4. Corticosteroids – overall decrease in immune response, secondary infection, anti-prostaglandin effects
5. Adrenomimetics – increased sympathetic effects
6. Methylxanthines – hypotension, arrhythmias, tremors, insomnia, GI disturbances
7. Ca+2 preparations – bradycardia, vasodilation, GI disturbance, hypercalcemia, arrhythmias

• Contraindications

v Antihistaminic – Sensitivity to specific antiallergic drugs, pregnancy, and lactation

v Mast cell stabilizers – sensitivity of the patient to drug, and formulation

v NSAIDs – sensitivity to NSAID, corneal epithelial defect (ophthalmic preparation), pregnancy

v Corticosteroids – pregnancy, immunodeficient patients

v Adrenomimetics – pheochromocytoma, patients on sympathomimetic therapy

v Methylxanthines – sensitivity to specific drugs

v Ca+2 preparations – patients with the risk of cardiovascular events

Drugs used in anaphylaxis

• What are they

Anaphylaxis can be explained as a severe allergic reaction that has a rapid onset and may be fatal. The hyperactivation of mast cells and basophils in the blood involved crosslinking IgE and aggregation of other mediators. Activation of mast cells or basophils rapidly respond and release preformed mediators like histamine, peptides, and proteoglycans. This is further accompanied by phospholipase A2 activation, followed by prostaglandins, leukotrienes, and PAF (platelet-activating factor).

A release of inflammatory cytokine and chemokines is also mediated that include tumor necrosis factor (TNF), interleukins. Many of these mediators are thus believed to be responsible for the pathophysiology of anaphylaxis. Anaphylaxis can thus be a response to multiple mechanisms of allergic responses. The drugs used to suppress such an exaggerated body response are known as anaphylactic drugs.

• How do they work

Several mediators have variable effects on different organs that precipitate serious implications. The table below comprises the key mediators and their multiple effects on organs.

Table 1 – Mediators and their physiological effect

The drugs that are used for management, either act on the chemical mediator release, or they are used to relieve the physiological effects elicited by these mediators.

• Different classes of these drugs

Since anaphylaxis is a life-threatening condition, the management is focused on emergency stabilization, followed by a combination of drug therapy.

First-line therapy

v Emergency management – Airway, breathing, and circulation resuscitation to ensure the survival

v Vital stats monitoring – oxygen administration with cardiac monitoring and oxygen saturation.

v Airway management: in case of severe respiratory distress, tracheal intubation should be immediately performed. Investigation for angioedema and following fluid removal should be done immediately to reduce the chance of respiratory failure.

v Decontamination: the patient should be physically examined for any causative agent, and removed if found, followed by removal of the endogenous agents by chelation or mechanical removal.

Drug of choice – Epinephrine – 0.3 to 0.5 mg (0.3 to 0.5 mL of the 1:1000 dilutions) I.M. repeated every 5 to 10 minutes as per response/relapse.

After controlling the emergency crisis successfully, a drug regimen specific for anti anaphylaxis action is used.

Second-line therapy –

v Corticosteroids – methylprednisolone, hydrocortisone, prednisolone

v Antihistaminic –  cimetidine, ranitidine, diphenhydramine

v Anti-asthmatic medications –albuterol, ipratropium bromide, magnesium sulfate

v Glucagon –  for patients on β blockers, to manage refractory hypotension

• Indications in which they are preferred?

Before the management therapy is initiated, a patient needs to be examined for proper diagnostic criteria. The investigation for clinical criteria is essential since the treatment protocol includes heavy doses of drugs, which may precipitate further complications.

Clinical criteria for anaphylaxis include –

1. Acute onset of illness lasting minutes to several hours, affecting the skin and/or mucosal tissue (pruritus hives/urticaria, flushing, edema). The onset shows associations with one or more than one of the conditions – i) Respiratory insufficiency – breathlessness, difficulty breathing, wheezing ii) Hypotension
2. Symptoms of organ dysfunction – loss of body control, pain, hypotonia

1. If a patient shows signs after exposure to an antigen (minutes-hours) as – skin, mucosal tissue reaction, respiratory compromise, fall in blood pressure with associated symptoms and GI symptoms of abdominal cramps, and vomiting.
2. Patients get exposed to a known allergen and develop hypotension rapidly.

The use of treatment is indicated as soon as these symptoms develop. The early symptoms for anaphylaxis include –

• cutaneous flushing
• chest tightness
• lightheadedness
• anxiety
• life-threatening laryngeal edema (symptom – hoarseness in voice)
• Side Effects

The side effects of these medications are as same as when used as an antiallergic drug. The side effect of epinephrine includes tachycardia, arrhythmias, and tremors.

• Contraindication

Since anaphylaxis is a life-threatening condition, the treatment protocol cannot be contraindicated as it may result in morbidity.

However, caution should be taken with the patients using adrenergic blockers since epinephrine administration may precipitate a severe hypertensive crisis, upon high adrenergic stimulation.