Drug-Induced Immune Response and Antiallergic Treatment Notes

Drug-Induced Immune Response and Antiallergic Treatment

Gell and Coombs Classification of Hypersensitivity Reactions

There are four distinct types of hypersensitivity reactions:

• Type I: Anaphylaxis - Immediate hypersensitivity, often life-threatening.
• Type II: Cytotoxic reactions - Antibody-mediated cellular destruction.
• Type III: Immune complex reactions - Formation and deposition of immune complexes.
• Type IV: Cell-mediated or delayed - T-cell mediated reactions.

Disorders Associated with Type I Hypersensitivity Reactions

Type I hypersensitivity reactions are linked to various disorders:

• Atopic diseases: Refers to a genetically determined state of hypersensitivity. Manifestations include:
  • Asthma
  • Hay fever
  • Allergic rhinitis
  • Allergic conjunctivitis
  • Atopic dermatitis
  • Allergic (extrinsic) asthma
• Systemic anaphylaxis: An acute, severe allergic reaction to an antigen (e.g., bee sting) to which the body has become hypersensitive. This is a medical emergency.

Symptoms of Allergic Drug Reactions

Allergic drug reactions can manifest with a range of symptoms, with varying frequencies:

• Skin reactions: $80\%$ of cases
• Anaphylaxis: $9\%$ to $15\%$ of cases
• Respiratory symptoms: $6\%$ to $9\%$ of cases
• Drug fever: $2\%$ to $6\%$ of cases

Factors Increasing the Risk of Allergic Reactions

Several factors can escalate the likelihood of experiencing allergic reactions:

• Chronic diseases: Conditions necessitating continuous and frequent drug treatment, especially with the same or cross-reactive drugs.
• Certain infections: Some infections predispose individuals to specific drug allergies.
  • For example, aminopenicillins are more likely to cause reactions in patients with Epstein-Barr Virus (EBV) infection.
  • Sulfonamides carry a higher risk in patients with AIDS.
• History of other drug allergy: A previous allergic reaction to any drug increases the risk of future reactions.
• Family history: A familial predisposition to allergic drug reactions can increase an individual's risk.

Penicillin Allergy

• The reported history of penicillin allergy ranges from $1\%$ to $10\%$ in the general population.
• Classes of Beta-Lactam Antibiotics: There are four main classes:
  1. Penicillins
  2. Cephalosporins
  3. Carbapenems
  4. Monobactams
• Allergic Symptoms: Commonly observed symptoms include:
  • Erythematous, maculopapular, and usually pruritic rash.
  • Urticaria (hives).
• Less Common Symptoms: These can be more severe:
  • Angioedema
  • Serum sickness
  • Arthralgias (joint pain)
  • Bronchospasm
  • Laryngeal edema
  • Anaphylaxis
• Cross-reactivity with Cephalosporins: Approximately $8\%$ of patients with a penicillin allergy may also react to cephalosporins due to cross-reactivity. In contrast, $2\%$ of the non-allergic group and $4\%$ of the general population may experience reactions to cephalosporins.

Sulfa Drug Allergy

• Co-trimoxazole (sulfamethoxazole-trimethoprim): This combination drug is widely used in the HIV population, primarily for prophylaxis against Pneumocystis carinii pneumonia.
• Prevalence of Hypersensitivity: The overall prevalence of sulfa hypersensitivity is approximately $3\%$ in the general population. However, in the HIV population, this rate is significantly higher, ranging from $17\%$ to $20\%$.
• Stevens-Johnson Syndrome: Patients taking sulfa drugs can develop severe non-urticarial drug eruptions like Stevens-Johnson Syndrome. The incidence is between $1/1000$ and $1/3000$ cases. If a patient develops this condition, the drug must be immediately discontinued, and re-challenge with the drug should be strictly avoided.

Diagnosis of Drug-Induced Immune Responses

Diagnosis involves a multi-faceted approach:

• History: A thorough patient history, including previous drug exposures and reactions, is crucial.
• Nonspecific Tests:
  • Eosinophil count: Elevated levels may suggest an allergic reaction.
  • IgE levels: Elevated immunoglobulin E levels can indicate allergic sensitization.
• Specific Tests:
  • Skin tests:
    • Puncture test: Small amounts of allergens are pricked into the skin.
    • Intradermal test: Allergens are injected just beneath the skin surface. A positive reaction (wheal and flare) indicates hypersensitivity.
  • Radioallergosorbent test (RAST): Measures specific IgE antibodies in the blood to particular allergens.
  • WBC histamine release: In vitro test measuring histamine release from basophils or mast cells upon allergen exposure.
  • Provocative challenge: A carefully controlled administration of the suspected drug to confirm allergy, performed only when benefits outweigh risks and under strict medical supervision.

Histamine: An Autacoid in Allergic Reactions

• Histamine was the first discovered autacoid (a local hormone).
• Histamine Receptors: There are four types of histamine receptors:
  • H1 receptor: Causes vasodilatation (widening of blood vessels) and edema formation; involved in allergic reactions.
  • H2 receptor: Primarily found on parietal cells of the stomach, where it stimulates gastric acid secretion.
  • H3 receptor: Predominantly found in the Central Nervous System (CNS), involved in neurotransmission.
  • H4 receptor: Largely expressed in hematopoietic cells (cells involved in blood formation), playing a role in immune responses.

Treatment of Allergic Reactions

Treatment strategies range from prevention to acute intervention and long-term management.

1. Prevention (Avoidance)

• The most preferred treatment is complete elimination of the allergen.
• Patients must be thoroughly informed about allergenic substances.
• They must actively avoid exposure to these substances.
• This may necessitate significant lifestyle changes, such as modifying diet, changing occupation or residence, withdrawing a causative drug, or removing a household pet.

2. Adrenaline (Epinephrine)

• Adrenaline is the drug of choice for reversing the manifestations of serious acute hypersensitivity reactions, especially anaphylaxis.
• Administration: Subcutaneous administration of adrenaline can alleviate symptoms and be lifesaving, particularly when the airway is compromised or in hypotensive shock (in which case, intravenous administration may be used).
• Mechanism: Adrenaline suppresses the release of histamine and leukotriene mediators from mast cells, thus counteracting the effects of the allergic reaction.

3. Glucocorticoid Drugs (Adrenal Steroids)

• Glucocorticoids are potent anti-inflammatory agents.
• Mechanism of Action: They inhibit phospholipase, an enzyme that converts membrane lipids into arachidonic acid. By blocking this early step, they prevent the formation of inflammatory mediators like leukotrienes, prostacyclins, thromboxanes, and prostaglandins via the lipoxygenase and cyclooxygenase pathways. (Note: aspirin and NSAIDs primarily inhibit cyclooxygenase).
  • $\text{Membrane lipids} \xrightarrow{\text{Phospholipase inhibited by Cortisol}} \text{Arachidonic acid} \begin{cases} \xrightarrow{\text{Lipoxygenase}} \text{Leukotrienes} \ \xrightarrow{\text{Cyclooxygenase inhibited by Aspirin, NSAIDS}} \text{Prostacyclins, Thromboxanes, Prostaglandins} \end{cases}$
• Examples: Dexamethasone, Prednisone, Cortisol.
• Comparative Steroid Potencies:

• Note: Beclomethasone ($8$ puffs $4$ times a day) is roughly equivalent to $14$ mg oral prednisone once a day.

4. Histamine H1 Receptor Blockers (Antihistamines)

• Mechanism: These drugs competitively block histamine from attaching to the H1 receptors on blood vessel walls, thereby preventing histamine's vasodilatory and edema-forming effects.
• Categories:
  • First-generation (sedating):
    • Ethanolamines: Carbinoxamine, Dimenhydrinate, Diphenhydramine (Benadryl).
    • Piperazine derivatives: Hydroxyzine, Cyclizine, Meclizine.
    • Alkylamines: Brompheniramine, Chlorpheniramine (often in OTC cold medications).
    • Phenothiazine derivative: Promethazine (Phenergan, also antiemetic).
    • Miscellaneous: Cyproheptadine (also antiserotonin activity).
    • Characteristics: Often cause slight to marked sedation and anticholinergic activity.
  • Second-generation (non-sedating):
    • Piperidine: Fexofenadine (Allegra).
    • Miscellaneous: Loratadine (Claritin), Cetirizine (Zyrtec).
    • Characteristics: Generally less sedating and have longer action compared to first-generation drugs.
• Clinical Use Examples and Dosing:

5. Mast Cell Membrane Stabilizers

• Mechanism: These drugs inhibit the release of inflammatory mediators (like histamine) from mast cells by stabilizing their cell membranes.
• Limitations: They cannot be used to treat acute allergic attacks because their action is not immediate.
• Clinical Use: They are used prophylactically (for prevention) of allergic rhinitis, conjunctivitis, and asthma attacks.
• Examples: Sodium cromoglycate, nedocromil, and ketotifen (ketotifen has a dual effect, also acting as an antihistamine).

6. Desensitization

• Purpose: This method aims to reduce or eliminate an organism's allergic reaction to a specific substance or stimulus.
• Process: Small, gradually increasing amounts of the allergen are administered until a normal exposure can be tolerated. This process is often complemented with a corticosteroid and a $\beta$-adrenergic agonist. An H1 antihistamine may be added if an adverse reaction occurs during the desensitization process.
• Successful Desensitizations (Examples):
  • Antibiotics: Penicillins, Sulfonamides, Aminoglycosides, Clindamycin, Cephalosporins, Vancomycin, Pentamidine, Anti-tubercular agents.
  • Other agents: Chemotherapeutics, Antivenoms, Heparin, Insulin, Deferoxamine, Measles vaccine, Tetanus toxoid, D-penicillamine, Corticotropin, Carbamazepine.

Summary of Treatment Approaches

Treatment involves a combination of prevention and active interventions:

• Prevention (avoidance of allergens)
• Treatment for Acute Reactions:
  • Adrenaline
  • Glucocorticoid Drugs (Adrenal Steroids)
  • Histamine H1 receptor blockers (antihistamines)
• Prophylactic/Long-term Treatment:
  • Mast Cell Membrane Stabilizers
  • Desensitization