76 Drug Allergies and ADRs

What is an adverse drug reaction (ADR)?

Any unintended pharmacologic effect of a drug at normal therapeutic doses

How are ADRs classified?

Type A or Type B

What is a type A Adverse drug reaction?

predictable and dose-dependent, related to the known properties of the drug

What characterizes Type B ADRs?

Unpredictable, not dose-dependent; they are unrelated to the pharmacological actions of the drug and instead are influenced by patient specific factors

What are the two subcategories of Type B adverse drug reactions?

Immediate (minutes after exposure) or delayed (days to months)

Define Urticaria

Hives, rash with red/pink raised patches with varying shapes and sizes

Define pruritus

itching, any rash or reaction that causes itching

Define erythema

redness on the skin from superficial capillaries, often due to inflammation with pruritus

What occurs when an erythemic rash is pressed down on?

red skin turns white due to blockage of blood flow

Define angioedema

swelling due to edema in the deeper dermal, cutaneous, and submucosal tissue

Define morbilliform

macular or maculopapular rash (sometimes both), within 1-10 mm lesions and healthy skin between the lesions

What is a drug allergy?

An adverse reaction involving a defined immune mechanism, usually antigen-antibody mediated and not hereditary (4 types)

What is a drug hypersensitivity reaction (DHR)?

A clinically allergy-like reaction that may be immune-mediated or nonimmune-mediated, do not always require contraindication to future administration

What is an idiosyncratic drug reaction?

An unusual, unpredictable reaction often associated with genetic differences

What is an example of an idiosyncratic reaction?

Hemolytic anemia after certain drugs in patients with G6PD deficiency

How are type I drug allergies mediated?

When do they occur?

List examples.

IgE-mediated; Immediate (within 15-30 mins),

urticaria, bronchospasm, angioedema, or anaphylaxis

How are type II drug allergies mediated?

When do they occur?

List examples.

antibody-mediated;

occurs 5–8 days after exposure,

hemolytic anemia and thrombocytopenia

How are type III drug allergies mediated?

When do they occur?

List examples.

Delayed immune-complex reactions,

usually ≥1 week after exposure,

serum sickness

what is serum sickness?

immune system reaction that happens when your body treats a foreign protein or certain medication as a threat

How are type IV drug allergies mediated?

When do they occur?

List examples.

Delayed T-cell-mediated reaction,

generally 48 hours to weeks after exposure,

SJS

What is drug intolerance?

A nonimmune adverse effect such as nausea, diarrhea, or stomach upset

What are papules and what are macules?

papules are raised spots and macules are flat spots

What is purpura?

Red/purple skin spots (lesions) due to bleeding underneath the skin. Purpura includes small (petechiae) and large (ecchymosis) spots

What is a hematoma?

Localized blood collection outside a blood vessel, often associated with trauma or anticoagulation

List examples of drugs that can cause hematoma

LMWH, other anticoagulants, and vitamin K (IM injection)

What is photosensitivity?

An exaggerated skin reaction to sunlight caused by a photosensitizing drug, sunlight reacts with the drug in the skin and causes tissue damage (looks like a severe sunburn)

How can photosensitivity present?

Sunburn-like erythema, blistering, or skin injury with sun exposure

What are the key drugs that can cause photosensitivity?

Amiodarone, FQs, loop and thiazide diuretics, MTX, oral and topical retinoids, st. johns wort, sulfa drugs, tacrolimus, tetracyclines, and voriconazole

Which anti-infectives/anti-fungals are associated with photosensitivity?

Tetracyclines, sulfonamides, fluoroquinolones, and voriconazole

What is thrombotic thrombocytopenic purpura (TTP)?

blood disorder where clots form throughout the body, consumes platelets and leads to bleeding under the skin and formation of purpura and petechiae on the skin

What are the consequences of TTP?

Thrombocytopenia, hemolytic anemia, and potential organ damage

List examples of medications that can cause TTP

Oral P2Y12 inhibitors (e.g., clopidogrel) and sulfinpyrazone

How can histamine release induced itching, swelling, and rashes be treated?

antihistamines

Which medications can be used to decrease swelling (non-severe)?

systemic steroids and sometimes NSAIDS

What can be used to revere bronchoconstriction if the patient is wheezing or cannot breathe?

epinephrine

What are nonimmune hypersensitivity reactions?

reactions that mimic drug allergies but are not immune mediated

How can opioids cause itching and flushing?

Direct histamine release from mast cells without IgE-mediated allergy

How can vancomycin cause an infusion-related reaction?

Rapid infusion can trigger histamine release, causing flushing, rash, or pruritus

What is the significance of HLA (human leukocyte antigen) alleles in drug hypersensitivity?

Specific genetic variants increase susceptibility to certain severe drug reactions

What is HLA-B*5701 associated with?

Abacavir hypersensitivity; screen before initiating abacavir

What are severe cutaneous adverse reactions (SCARs)?

Serious drug-induced skin reactions including SJS, TEN, and DRESS

What is SJS/TEN?

Severe mucocutaneous reactions involving epidermal detachment and skin loss equivalent to a 3rd degree burn

When do SJS and TEN typically occur? And what can they result in?

1-3 weeks after drug exposure; severe mucosal erosions, high body temperature, major fluid loss, and organ damage

What distinguishes SJS from TEN?

SJS: <10% body surface area detachment;

TEN: >30%; overlap: 10–30%

What findings suggest SJS/TEN?

Painful rash, mucosal erosions, blistering, skin detachment, fever, and systemic symptoms

How is SJS/TEN managed?

Immediately discontinue the causative drug; urgent hospitalization and supportive care

Why is medication rechallenge generally avoided after SJS/TEN?

Risk of recurrent, potentially fatal severe cutaneous reaction

Which medication class is contraindicated with TEN but may be used for SJS?

systemic steroids

Which antibiotics are most associated with severe skin reactions like SJS/TEN?

amoxicillin, ampicillin, bactrim, vancomycin

Which antiepileptics are associated with severe cutaneous reactions like SJS and TEN?

Carbamazepine, lamotrigine, phenytoin

Which drugs are most associated with severe cutaneous adverse reactions (SJS/TEN)?

allopurinol, amoxicillin, ampicillin, CBZ, ethosuximide, lamotrigine, nevirapine, phenytoin, bactrim, sulfasalazine, and vancomycin

What is DRESS?

Drug reaction with eosinophilia and systemic symptoms; a potentially life-threatening delayed drug reaction

What findings characterize DRESS?

Fever, rash, eosinophilia, lymphadenopathy, and internal organ involvement (Liver, kidneys, lungs, and other internal organs)

Can DRESS worsen after discontinuing the causative drug?

Yes; symptoms can persist or worsen after withdrawal

What is anaphylaxis and when does it occur?

Severe, life-threatening systemic allergic reaction involving multiple organ systems; usually within one hour of drug exposure

What are common symptoms of anaphylaxis?

Urticaria, angioedema, throat swelling, difficulty breathing, wheezing, hypotension, or gastrointestinal symptoms

Treatment of anaphylaxis can include…

EPI, benadryl, steroids, and IV fluids

What is first-line treatment for anaphylaxis?

Immediate IM epinephrine into the mid-outer thigh

What is the adult IM epinephrine dose for anaphylaxis?

0.3 mg of 1mg/mL pen

What is the pediatric IM epinephrine dose (same dose for pts weighing between 15-30 kg)?

0.15 mg of 1 mg/mL pen

Anaphylaxis emergency kits should contain which medication (drug, dose, and quantitiy)? And what is the criteria to administer it?

diphenhydramine (benadryl) 25 mg #2,

only take if there is no tongue or lip swelling

What is the epinephrine injector with voice instructions called?

Auvi-Q

Explain the steps of EpiPen admin

1. pull off blue safety release

2. hold in one hand with needle pointed down

3. jab orange end (needle end) into middle outer thigh at 90 degree angle

4. hold in place for 3 seconds

5. remove the needle and massage for 10 seconds

What should be done after using EpiPen?

Massage site for 10 seconds and obtain emergency medical care

How is Auvi-Q administered?

Remove outer case and red safety guard; place black end on outer thigh; press and hold 2 seconds

True or False: It is not normal to see liquid remaining in any epinephrine autoinjector after injection.

False

How does cephalosporin generation affect cross-reactivity with penicillins?

Later-generation cephalosporins generally have lower cross-reactivity than earlier generations

What is the role of side chains in beta-lactam cross-reactivity?

Similar side chains can increase cross-reactivity even between different beta-lactam subclasses

Which beta-lactam has minimal cross reactivity with penicillins and is generally okay to administer if there is a penicillin allergy?

Aztreonam

Which indication is an exception to nonsevere penicillin allergies?

AOM

Which medications are alternatives for AOM if there is a nonsevere penicillin allergy?

cefdinir, cefpodoxime, ceftriaxone, and cefuroxime

Which nonantibiotic medications contain sulfonamide groups and are therefore contraindicated or have warnings for sulfa allergies?

Thiazide and loop diuretics, sulfonylureas, acetazolamide, zonisamide, celecoxib, cidofovir, darunavir

What can desensitization accomplish for a biologic drug?

Temporarily permit treatment when a necessary drug previously caused hypersensitivity

What are common aspirin/NSAID hypersensitivity presentations?

Respiratory symptoms, urticaria, angioedema, and anaphylaxis

What reactions can radiocontrast media cause?

Immediate or delayed hypersensitivity-like reactions, ranging from mild rash to anaphylaxis

Which meds are contraindicated with peanut and soy allergies?

clevidipine and propofol

Which medication should NOT be used in egg allergy?

clevidipine, propofol, or the yellow fever vaccine

True or False: clevidipine and propofol should never be used in a person with egg or peanut allergies

True

Which flu vaccines are specifically made for patients with egg allergies?

Flublok and Flucelvax

What is an oral drug challenge?

Administration of a drug under supervision to evaluate tolerance

When should drug challenge generally be avoided?

History of severe reactions such as SJS, TEN, or DRESS

What is drug desensitization?

Temporary induction of drug tolerance through progressively increasing doses

How is desensitization generally performed?

Start with a very small dose and increase gradually under close monitoring

What drugs are examples of desensitization candidates?

Penicillin, aspirin, certain biologics, and some chemotherapeutic agents

What are the risks of desensitization?

Breakthrough hypersensitivity reactions, including anaphylaxis

What is the Naranjo Adverse Drug Reaction Probability Scale?

validated causality assessment scale to determine the likelihood that a drug caused the adverse reaction

What is FAERS (FDA MedWatch)?

FDA Adverse Event Reporting System, used to collect adverse event and medication error reports

Who may report adverse drug reactions to the FDA?

Healthcare professionals, patients, caregivers, and manufacturers

Is proof of drug causation required to submit an ADR report?

No; suspected reactions may be reported

Why is postmarketing ADR reporting important?

Rare reactions may not appear in clinical trials and can emerge after widespread use

Which phase of clinical trials includes post marketing surveillance for adverse reactions?

phase IV

What is an example of a safety change prompted by postmarketing reports?

Labeling updates, boxed warnings, restrictions, or product withdrawal

What is a boxed warning?

FDA's most prominent labeling warning that indicates risk of death or permanent disability

What is a contraindication?

indication that a drug cannot be used in the patient because the risks outweigh any possible benefit

What are warnings and precautions?

serious reactions that can result in death, hospitalization, medical intervention, disability, or teratogenicity but they may or may not change prescribing decisions

What are adverse reactions?

any undesirable or dangerous effects from a drug

What is a REMS?

Risk Evaluation and Mitigation Strategy required by the FDA to ensure benefits outweigh the risks of certain drugs

Who develops REMS programs and who approves them?

the manufacturer develops the REMS program and the FDA approves it

What is the purpose of REMS?

Ensure a medication's benefits outweigh its risks through additional safety measures

What is a Medication Guide?

FDA-approved patient handout describing important medication risks and safe use