McDanel Exam 3

Type A Reactions

Predictable (80% of all ADR’s)

Related to known pharmacological action of the drug

(Overdose, Side effects, secondary effects, drug interactions)

Type B Reactions

Unpredictable (20% of all ADR’s)

Unrelated to the pharmacologic action of the drug

(Drug intolerance, Nonallergic reactions with immune manifestations, hypersensitivity reactions)

Hypersensitivity reactions make up…

10-25% of ADR’s

What are the most common agents implicated in drug allergy

Penicillin and Sulfonamide antibiotics

Pathophysiology of Drug Reactions

Immunologic response to a pharmaceutical agent and/or excipient

Classically defined as an IgE-mediated reaction

Release of vasoactive mediators from tissue mast cells and peripheral basophils

Type I Reaction

(Anaphylactic or IgE-Mediated)

Allergen binds to IgE on basophils or mast cells, resulting in release of inflammatory mediators

30-120 mins

Type II Reaction

(Cytotoxic)

Antigen-specific antibody to IgG or IgM initiates cell destruction

>72 hrs to weeks

Type III Reaction

(Immune Complex)

Antigen-antibody complexes form, deposit on blood vessel walls → activate complement system

>72 hrs to weeks

Type IV Reaction

(Cell-mediated or Delayed)

Antigens caused activation of T lymphocytes → release of cytokines and recruit effector cells

>72 hrs

When is a drug allergy suspected?

Symptoms are compatible with immune drug reaction

Temporal relationship between drug administration and adverse event

The class/structure of the drug is associated with immune reactions

The patient previously received the drug

Symptoms improved with withdrawal

No other clear explanation for the reaction

Assessment of Drug Allergies

Clinical History: A thorough history is important, careful history and reviewing all available medical records is critical, NO GENETIC PREDISPOSITION

Diagnosis: Clinical history, records, and physical exam, Skin testing and drug challenge, Biopsy

Clinical Evaluation of Drug Allergies

What caused the reaction?

Why were you taking it?

What was the reaction?

How long ago?

Time from symptom to onset?

Length of reaction?

How did you treat the reaction?

Were you taking other meds at the time?

Have you taken same or similar meds since?

Most common to least common drug induced dermatologic reactions

Exanthems → Urticaria, Angiodema, Anaphylaxis → Fixed Drug Eruptions → Others

Exanthems Background

Most common ~ 90% of all drug reactions

AKA morbilliform drug eruption, maculopapular rash

Exanthems Characteristics

Erythema, burning

Macules = small, flat, and distinct

Papules = small and raised

Pruritis, Mild fever

Trunk; may extend to extremities, sparing the face

Exanthems Allergy

Type IV

Onset: 5-10 days (if previous exposure: 2-3 days)

Resolution: 2-14 days

Exanthems treatment

Stop causative drug

relief of symptoms

antihistamines: pruritis

High potency topical steroids may be used 1-2x/day for 1 week

Prevention: Avoidance, pre-medication

Picture of Exanthems

Common offending drugs for Exanthems

Anticonvulsants: Barbiturates, carbamazepine, phenytoin

Antihypertensives: Captopril, furosemide, thiazide diuretics

Antibiotics: Amphotericin, cephalosporins, erythromycin, gentamicin, nitrofurantoin, penicillins, rifampin, sulfonamides, tetracyclines

Other: Abacavir, allopurinol, golds salts, phenothiazines

Contributing Factors to exanthems

Epstein-Barr Virus

Cytomegalovirus

Herpes

HIV

Cystic Fibrosis

Autoimmune disorders

Multiple Medications

Urticaria Background

2nd most common

1st OR after many uneventful exposures

15% to 20% experience urticaria during their lifetime

>20% of all dermatologic reactions to drugs

Urticaria Characteristics

Hives= raised, red, wheals

Pale in the center with surrounding erythema

Intense pruritis

1mm to several cm

Enlarge/combine and migrate

Anywhere on the body

Urticaria Allergy

Type I

Onset: 30-120min, Accelerated: 1-6 hours, Delayed: days

if previous exposure: minutes and likely to progress to anaphylaxis

Resolution: few hours to <24 hours

Urticaria Treatment

Stop causative drug

Relief of symptoms

2nd generation antihistamines help pruritis

Emergent treatment if angiodema, systemic symptoms, or anaphylaxis

Prevention: Avoidance, Evaluation is >5-10 years, Induction of tolerance

Urticaria picture

Angiodema Background

Often accompanies urticaria in 50% of cases

May happen alone

Disfiguring if involves face and lips

May be life threatening if airway obstruction occurs

Angiodema Characteristics

intense asymmetric swelling and mucosal membranes

Not pruritic; painful

Most often involves tongue, lips, and eyelids

May have systemic symptoms or GI involvement

Angiodema Allergy

Type I

Onset: Immediate=30-120mins, Accelerated=30min to 48 hrs

If previous exposure: minutes and likely to progress to anaphylaxis

Resolution: Slow, up to 72 hours

Angiodema Treatment

Stop causative drug

Emergent treatment: Epinephrine, antihistamines, corticosteroids

Prevention: Avoidance, induction of tolerance

Angiodema pictures

Urticaria/Angiodema common offending drugs

~10% per year loss of IgE, thus 80% loss of sensitivity at 8-10 years

Anitbiotics, Anticonvulsants, local anesthetics, radiographic contrast media, ACE-inhibitors, amphetamines, Iron, NSAID’s, Opiate analgesics

Anaphylaxis

Drugs are 2nd or 3rd most common cause of anaphylaxis

Most severe and potentially life-threatening form of immediate type I hypersensitivity

Symptoms: CV, cutaneous, GI, neurologic, respiratory

Should be treated with epinephrine, IV fluids, oxygen

Epinephrine Mechanism of Action

stimulates alpha, beta1 and 2 adrenergic receptors resulting in:

Relaxation of smooth muscle of the bronchial tree

Cardiac stimulation

Dilation of skeletal muscle vasculature

Epinephrine Onset of Action

IM or SQ: Rapid

IV: <5 minutes

Proper administration technique for autoinjectors

IM or SQ injection

Administer at a 90 degree angle into the outer thigh

Autoinjector Administration Pearls

Should always be carrier

Always call 911 after use

Store at room temp

Do not inject into any other part of the body

Can and should give injection through clothing

Massage area for ~ 10 seconds

Intranasal Epinephrine

for adult and pediatric patients aged 4 years and older

Second dose in the same nostril after 5 minutes

Neffy administration pearls

Inhaling is not required

Patient can be in any position

Works through stuffy nose

Avoid sniffing during and after administration

>2 doses should be given under medical supervision

Not for patients with anatomical nasal conditions

May increase systemic absorption of nasal products for 2 weeks

Epinephrine side effects

Palpitations

Dizziness

Sweating

Nausea or vomiting

Headache

Respiratory difficulties

Anxiety

Pallor

Death due to anaphylaxis is often due to…

a delay in giving epinephrine

Angiodema: ACEI-Induced Background

Leading cause of drug-induced angiodema in US

No specific drug/dose

~30% of ETC visits for angiodema

Mortality: Death rate 0.34 per million persons/yr, >50% deaths are in black patients

Angiodema: ACEI-Induced Characteristics

Angiodema of lips, tongue or face

No urticaria

May have GI involvement

Airway involvement is not common, but may occur

Angiodema: ACEI-Induced Allergy

Bradykinin

Onset: 10x higher risk in first 1-4 weeks

Develops over min to hrs, peaks, then resolves

Resolution: 2-5 days

Angiodema: ACEI-Induced Treatment

Stop causative drug

Monitor for resolution

protect airway

Non-FDA-approved meds

Prevention: recurrence may happen in 50% of pts even after stopping, contraindicated all ACEI, aliskiren, & ARBs

ACE-Inhibitors

35% of all antihypertensive prescriptions in US

>40 million patients globally are taking an ACE-I

Routinely used in: hypertension, myocardial infarction, heart failure, diabetes, chronic kidney disease

ACEI-Induced angiodema Risk Factors

Smoking, seasonal, >65 years, black, history of angiodema to NSAID’s, aspirin or NSAID use, History of previous angiodema

ACEI-Induced Angiodema Management

Observe in ED/hospital many don’t need treatment

Non-allergic reaction → antihistamines, corticosteroids, or epinephrine NOT effective but often used

Drugs targeted at bradykinin production or the bradykinin receptor have been evaluated

Fixed Drug Eruption Background

Distinctive FIXED round or oval macule evolving to edematous plaques

Defining Features: post-inflammatory hyperpigmentation and recurrence of lesions at exactly the same sites with drug re-exposure

Fixed Drug Eruption Characteristics

Solitary pruritic/burning erythematous macule (Evolves to edematous plaques, Vesicles/bullae may develop

Can occur anywhere: Lips, tongue, face, hands, feet, penis, or perianal areas, no systemic symptoms

Fixed Drug Eruption Allergy

Type IV

Onset: 30min to 8 hrs up to 2 weeks (may be confirmed by oral re-challenge within hours

Resolution: 7-14 days after drug discontinuation

Fixed Drug Eruption Treatment

Stop causative drug

Mid-high potency topical corticosteroids

Systemic antihistamines

Supportive care if needed for symptomatic relief

Diagnosis: History, biopsy, challenge, or patch test

Fixed Drug Eruption Picture

Fixed Drug Eruptions (Common Offending Drugs)

Antibiotics (Dapsone, Penicillins, Quinolones, Bactrim, Tetracyclines)

Other: APAP, anticonvulsants, Antimalarials, barbiturates, NSAID’s

Types of Severe Cutaneous Adverse Reaction (SCAR)

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

(Drug reaction with eosinophilia and systemic symptoms)

(Acute Generalized Exanthematous Pustulosis)

Prodrome for SJS and TEN

Fever/influenza-like illness 1-3 days prior to skin lesions

SJS and TEN differentiation

SJS = <10% BSA

SJS/TEN overlap = 10-30% BSA

TEN = >30% BSA

SJS and TEN Background

all ages, all races and both sexes (female>male)

0.4 to 1.2 cases/million persons annually worldwide

Drug-induced 80-95% of the time

Mortality ~30%

SJS and TEN Characteristics

Widely distributed dusky red burning/painful macules → edematous → flaccid blisters → epidermal necrosis, detachment, sloughing

Initially on trunk/face, spread to neck, extremities in 3-4 days

90% have mucosal involvement

SJS and TEN Allergy

Type IV

Causative drugs act as haptens providing antigenic stimulus

Cytotoxic T-cell mediated against keratinocytes, epidermal necrosis

Onset: 4-28 days, Rare: >8 weeks

Resolution: Weeks to months

SJS and TEN Treatment

Prompt withdrawal

supportive care

treat like a burn in the ICU

Absolute avoidance of the culprit drug

pain meds, antihistamines, topical steroids

IV immunoglobulin - first line

SJS and TEN Pictures

SJS/TEN Risk Factors

HIV

Active malignancy

Systemic lupus erythematosus

Radiotherapy

High doses of meds

Autoimmune diseases

Concomitant viral infections

GENETICS

SJS/TEN Genetics

Certain HLA genotypes associated with TEN

Genotypic testing may be considered in higher risk populations

HLA-B*15:02 allele is present in 7-10% of Asian or South Asian ancestry (must be screened before starting carbamazepine, etc.)

SJS/TEN Common Offending Drugs

Allopurinol, carbamazepine, fosphenytoin, lamotrigine, meloxicam, nevirapine, phenobarbital, phenytoin, piroxicam, sulfadiazine, sulfadoxine, sulfamethoxazole, sulfasalazine

Skin Testing

Useful to rule out Type I hypersensitivity, performed in steps

Some protocols for delayed intradermal testing for TypeI V reactions

Step 1: Skin prick test, measured at 15 mins (Histamine control, saline control, and active drug)(positive is wheal >3mm and flare >5mm of neg control)

Step 2: (if negative): intradermal test in duplicates, measured at 20 min

Step 3: (If negative) Drug Challenge followed by observation

Direct Drug Challenge

Type I and IV

More commonly done than skin testing

1 or 2 step drug challenge is indicated if after evaluation they are deemed unlikely to be allergic

Induction of Tolerance

Desensitization

Promote temporary drug tolerance in a patient with a true Type I IgE-mediated allergy

Start at super small dose and give at increasing concentrations

Often completed in 4 to 12 hours

usually done in ICU

Will only tolerate that course of therapy

Procedure will need to be repeated for future courses of therapy

Patch Testing

Type IV

Useful if a drug was applied topically in the instance of contact dermatitis

used in specific dermatologic reactions such as exanthematous, fixed drug eruptions, DRESS

Not useful for SJS/TEN or urticarial reactions

Important documentation for an accurate allergy list

Update with comments to qualify allergy

Accurate reaction symptoms listed

Time since reaction and severity

Remove medications that are not valid

Allergy vs intolerance