17.3 Adverse Drug Reactions & Hypersensitivity Recognition

Adverse Drug Reactions — Type A vs Type B

An adverse drug reaction (ADR) is any noxious, unintended response to a medicine used at normal doses. The Rawlins-Thompson classification divides ADRs into two broad families that the DHA exam tests directly.

A practical rule: Type A is the drug doing its job too well; Type B is the drug doing something unexpected. Exam stems that describe a reaction at a therapeutic dose with a known pharmacological mechanism point to Type A; stems describing rash, anaphylaxis, or cytopenias in a small number of patients point to Type B.

---

Gell and Coombs Hypersensitivity Classification

The Gell and Coombs system classifies immunological drug reactions into five types.

Type I — Immediate, IgE-Mediated

• Mechanism: drug-IgE cross-linking on mast cells releases histamine and mediators within minutes to hours.
• Manifestations: urticaria, angioedema, bronchospasm, anaphylaxis.
• Classic drugs: penicillin, cephalosporins, iodinated contrast, latex, some muscle relaxants.
• Skin test: prick testing may detect specific IgE.

Type II — Cytotoxic

• Mechanism: IgG or IgM binds drug on a cell surface; complement lyses the cell.
• Manifestations: haemolytic anaemia (e.g. methyldopa, penicillin high-dose), thrombocytopenia (heparin-induced thrombocytopenia, quinine), neutropenia.
• Timing: hours to days.

Type III — Immune-Complex

• Mechanism: drug-antibody complexes deposit in tissues and activate complement.
• Manifestations: serum sickness — fever, arthralgia, urticarial rash, lymphadenopathy; drug-induced vasculitis; interstitial nephritis.
• Classic drugs: penicillin, sulfonamides, antithymocyte globulin.
• Timing: 1–3 weeks after exposure.

Type IV — Delayed, T-Cell Mediated

• Mechanism: sensitised T-cells react to drug antigen presented in skin or tissue.
• Manifestations: contact dermatitis (topical antibiotics, nickel), maculopapular drug rash, and the severe cutaneous adverse reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
• Timing: 2–14 days.
• Classic drugs for SJS/TEN: sulfonamides, allopurinol, anticonvulsants (carbamazepine, lamotrigine, phenytoin), nevirapine, NSAIDs (oxicam class).

Type V — Receptor-Mediated (Anti-Receptor Antibody)

• Mechanism: autoantibodies bind and stimulate or block a cell-surface receptor.
• Examples: Graves disease (anti-TSH receptor stimulating antibody); myasthenia gravis (anti-AChR blocking antibody). Drug-induced versions are rare but the classification is tested.

---

Penicillin–Cephalosporin Cross-Reactivity

A frequently tested calculation: the overall cross-reactivity between penicillin and cephalosporins is approximately 1–2%, and is driven mainly by shared side-chain similarity rather than the beta-lactam ring itself. Cross-reactivity is higher with first-generation cephalosporins (e.g. cephalexin, cefazolin) and much lower with third- and fourth-generation agents (e.g. ceftriaxone, cefepime). A patient with a confirmed IgE-mediated penicillin allergy should not receive a first-generation cephalosporin without allergy assessment; later-generation cephalosporins are often tolerated.

---

Severe Cutaneous Adverse Reactions (SCARs)

Three SCARs are exam-critical:

Red Flags That Demand Immediate Action

• Mucosal involvement: oral blisters, painful swallowing, conjunctivitis, genital ulceration.
• Skin blistering or peeling: positive Nikolsky sign (epidermis shears with lateral pressure).
• Eosinophilia with organ involvement (liver, kidney, lung): think DRESS.
• Rapid progression, fever, facial oedema.

The pharmacist's response to any suspected SCAR is: stop the suspected drug immediately, document, and refer the patient for urgent medical assessment — never re-challenge, never taper. Common culprit drugs (sulfonamides, allopurinol, carbamazepine, lamotrigine, phenytoin, nevirapine) should be flagged on the patient's profile for life.

---

Anaphylaxis

Anaphylaxis is a severe, life-threatening Type I hypersensitivity reaction with rapid onset. Diagnostic criteria include skin/mucosal change PLUS respiratory compromise OR hypotension OR gastrointestinal symptoms after a known allergen.

First-Line Treatment

• Adrenaline (epinephrine) IM 0.5 mg (0.5 mL of 1:1000) in the anterolateral thigh for adults. Repeat every 5 minutes if no response.
• NOT IV adrenaline in the first instance; IV adrenaline is reserved for refractory anaphylaxis in a monitored setting.
• Airway, oxygen, IV fluid resuscitation; lay the patient flat with legs raised (not sitting up).
• Adjuncts: antihistamine (e.g. chlorphenamine), corticosteroid (e.g. hydrocortisone 200 mg IV) — these are second-line and do not replace adrenaline.
• After stabilisation: observe for biphasic reaction for at least 6–12 hours; consider an adrenaline auto-injector for discharge and an allergy referral.

A common exam trap asks which drug is first-line for anaphylaxis — the answer is always IM adrenaline. Antihistamines and steroids are adjuncts; they will not abort anaphylaxis. A second trap offers IV adrenaline as the first-line option — this is wrong for initial treatment; IV adrenaline is reserved for refractory anaphylaxis in a monitored setting because dosing errors and arrhythmias are common. A third trap asks where to inject — the anterolateral thigh (vastus lateralis) gives the fastest rise in plasma concentration; subcutaneous injection is slower and not recommended in acute anaphylaxis.