Download Nonsteroidal Anti-inflammatory Drugs

2016 분당서울대병원 내과 연수강좌
개원가에서 흔히 접하는
약물알레르기
분당서울대병원
알레르기 내과
김세훈
약물유해반응의 분류
Type B (예측 불가능)
Type A (예측가능)
80%
고유약리작용과 관련
용량에 비례
모든 사람에서 가능
•
•
•
•
15~20%
고유약리작용과 무관
용량에 비례하지 않음
일부 취약인에서 발생
• Overdose, toxicity
• Side effects
• Secondary or indirect
effects
• Drug-drug interaction
•
•
•
•
Intolerance
Idiosyncratic reactions
Pseudoallergic reactions
Allergic (hypersensitivity)
reactions
•
•
•
•
약물알레르기/과민반응의 정의
• 약물알레르기
Drug allergy
• 약물과민반응
Drug hypersensitivity
– 면역학적 기전에 의해 나타나
는 약물유해반응
– 정상인들이 반응하지 않는
용량의 약물에 대한 반응
– 모든 면역반응(I, II, III, IV형)
– 비면역학적 기전까지 포함
(예: aspirin 과민성)
약물과민반응의 흔한 원인약물
 아스피린, NSAIDs 소염진통제
 항생제 : penicillin, cephalosporin, sulfonamide etc.
 항전간제: carbamazepine, phenytoin, phenobarbital etc.
 항결핵제
 조영제
 근육이완제 및 마취제
 마약성 진통제
 allopurinol
2014년 의약품 안전성 정보 보고 동향 분석
의약품 효능군별 보고비율(%)
보고건수
2013년
183,260 183,554
200000
12.9
12.5
150000
9.1
100000
7.6
7.9
7.2
6.3
5.4
6.2
92,375
50000
0
2014년
16.1
6239 14453
74,657
64,143
27,010
12,796
항악성종양제
해열.진통.소염제
X선조영제
주로 그람양성,
합성마약
음성균 작용
항생제
이상사례 증상별 보고빈도(%)
2013년
14.4
2014년
15.3
8.2
오심
9.2
가려움증
7.1
8.2
두드러기
8.3
8.1
구토
7
7.8
어지러움
(2015.04.01.) - 식품의약품안전처
Cause of anaphylaxis in Korea
Ye YM et al. Allergy Asthma Immunol Res, 2015
Causative drugs of
severe drug-induced anaphylaxis
Immunotherapy
and vaccines
3.9%
Others, 13.0%
Amoxicillin
+ Penicillin,
30.4%
Contrast media,
4.2%
NSAIDs,
14.1%
Muscle relaxants,
15.0%
Antibiotics
, 49.6%
Cephalosporin,
12.4%
Quinolone,, 4,6%
Other antibiotics,
2.2%
Severe drug-induced anaphylaxis: analysis of 333 cases recorded by the Allergy
Vigilance Network from 2002 to 2010. Renaudin J-M, et al. Allergy, 2013
Beta-lactam antibiotics
Allergy
Beta-lactam antibiotics
• Contain β-lactam ring
• Work by inhibiting cell wall
biosynthesis
• Most widely used group of
antibiotics
• Most frequent cause of drug
reactions mediated by immune
mechanisms
Allergy to penicillin
“claimed” vs. “real”
• Reaction by underlying illness
• Predictable other type of adverse reaction rather than allergic
• Allergenicity lost over time
• Lack of understanding drug allergy
• Alternate broad-spectrum antibiotics
– cost
– multidrug-resistant bacteria
Classification of hypersensitivity reactions
Immediate
Delayed (non-immediate)
Mechanism
IgE-mediated
T cell mediated
Onset
< 1hr (in special
condition <3hrs )
> 6hr (several hours~days)
Recovery
Few hours
Several days~ weeks
Clinical
feature
Urticaria
Angioedema
Anaphylaxis
Bronchospasm
Maculopapular eruption
Fixed drug eruption
HSS/DRESS*
SJS/TEN
AGEP
*HSS: hypersensitivity syndrome, DRESS: drug rash with eosinophilia and systemic
symptoms, SJS: Stevens Johnson syndrome, TEN: toxic epithermal necrolysis, AGEP:
acute generalized exanthematous pustulosis
IgE-mediated Immediate reactions
Carrier protein
Free drug
Drug hapten
Drug-specific IgE
Activation
Mast cell
Inflammatory
mediators and
cytokines
Inflammation
T cell-mediated delayed eruptions
Penicillin allergy
 Major determinant (95%)
Acylation of lysine residue
in serum or cell surface protein
 Minor determinant (5%)
Covalent linkage of penicillenic
acid to other macromolecule
 Act as haptens
Penicillin: cross-reactivity
 Cephalosporins
• 1st generation: <10%
• 3rd generation: 1~3%
• R1 side chain
 Carbapenems:
0.9% in Pc Allergic pt
 Monobactams: least
• Aztreonam
Cephalosporin: allergenicity
• Sensitization to structurally similar
R1 side chain groups (m/c)
• Sensitization to structurally similar
R2 side chain groups (infrequent)
• Sensitization to the core betalactam ring or its metabolites
(infrequent)
Cephalosporin: cross reactivity
• Side-chain specific
• With penicillin/amoxicillin
– 1st gen. cephalosporin
• Within cephalosporin
– Same side chain : ceftriaxone - cefotaxime
– Similar side chain : ceftriaxone - cefuroxime
• With carbapenem or monobactam
– unknown but probably quite low
– cf. ceftazidime – aztreonam : same side chain
Check list for history taking
in diagnosis
• Timing of onset (immediate vs. delayed)
• Signs and symptoms (type of reaction)
• Exact name of medication
• Treatment duration, dose, and route of medication
• Other possible cause or contributing factors of reaction;
other medication, underlying disease, etc.
• Treatment given and response
• Prior or subsequent history of exposure to the same or
structurally similar drugs
Values of Skin test
• Penicillin: (PPL+MDM+ampicillin+amoxicillin)
– specificity: 97~100%, sensitivity: approx. 70%
– negative predictive value (PPL+MDM): 99%
– positive predictive value : approximately 60%
• Cephalosporin: sensitivity 30~70%
– negative predictive value: 80%
– Values for prescreening test : not validated
Kranke B. et al. Immunol Allergy Clin N Am, 2009
Anne B et al. The Am J of Med. 2008
Other tests for diagnosis
• Specific IgE test : ImmunoCAP test
- Commercially available: Penicilloyl G, Penicilloyl V,
Ampicilloyl, Amoxilloyl, Cefaclor
- Low sensitivity, high specificity
• Provocation test (oral, injection)
- Often required for confirmation, when indicated
- Close observation by allergy specialist is needed
Penicillin 또는 Cephalosporin을 사용하고자 할때
Previous beta-lactam allergy history
(Immediate type)
Yes
Is the history confirmed?
Yes,
or test unavailable
Use antibiotics
No
(Prescreening skin test can
be done, but clinical utility is
not validated)
No, suspicious
Test available
Skin test +/- specific IgE test
Positive
Negative
1) Avoid, use alternatives
2) Skin test and graded
challenge, if low crossreactivity is expected
3) Consider desensitization
Positive
Provocation test, if possible
Negative
Use antibiotics
Penicillin 또는 Cephalosporin을 사용하고자 할때
Previous beta-lactam allergy history
(Delayed type)
Yes
Is the history confirmed?
Yes,
or test unavailable
Positive
Use antibiotics
No
(Prescreening skin test can
be done, but clinical utility is
not validated)
No, suspicious
Test available
Patch test or
Intradermal test delayed reading
Negative
1) Avoid, use alternatives
Positive
2) Graded challenge,
if low cross-reactivity is expected
Provocation test, if possible
Negative
Use antibiotics
Treatment when allergic reaction occurs
• Immediate reaction
- Urticaria, angioedema: antihistamine, systemic steroid
- Bronchospasm: short-acting β2 agonist, systemic steroid
- Anaphylaxis, severe angioedema: epinephrine
• Delayed reaction
- Simple drug eruptions: topical steroid
- Severe case, hypersensitivity syndrome : systemic steroid
- Severe cutaneous adverse reaction (SJS, TEN) : Immunoglobulin
NSAIDs Hypersensitivity
Chemical classification
Carboxylic acids
• Salicylic acids: Aspirin, diflunisal, salsalate, trisalicylate
• Acetic acids: Aceclofenac, diclofenac, etodolac,
indomethacin, ketorolac, nabumetone, sulindac, tolmetin
• Propionic acids: Dexketoprofen, dexibuprofen,
fenoprofen, flurbiprofen, ibuprofen, ketoprofen, loxoprofen,
Naproxen, oxaprozin
• Fenamic acids: Flufenamic acid, meclofenamic acid,
mefenamic acid, tolfenamic acid
Enolic acids
• Oxicams: Droxicam, isoxicam, lornoxicam, meloxicam,
piroxicam, tenoxicam
• Pyrazolones: Phenazone, phenylbutazone,
propyphenazone
Sulfonanilides
• Nimesulide
COX-2-selective inhibitors
• Celecoxib, etoricoxib, parecoxib, parvocoxib, rofecoxib
Para-aminophenol
• Acetaminophen (paracetamol)
Acetaminophen(Paracetamol)
Mechanism of Action of NSAIDs
Claudia J et al., Ann Allergy Asthma Immunol 2007;99:13-21
COX selectivity classification
Selectivity
Drugs
Strong COX-1 inhibitor
Piroxicam
Indomethacin
Sulindac
Ibuprofen (-profen)
Naproxen
Diclofenac (-fenac)
Ketorolac (-olac)
Aspirin
COX-1 ≒ COX-2
Weak COX inhibitor
(inhibition at high concentrations)
Acetaminophen
Salsalate
Preferential COX-2 inhibitor
(inhibition at high concentrations)
Nimesulide
Meloxicam
Selective COX-2 inhibitor
Celecoxib
Adverse drug ractions to NSAIDs
Kowalski et al. Allergy Asthma Immunol Res. 2015
NSAIDs/Aspirin Exacerbated
Respiratory Diseases
• Rhinosinusitis, asthma
•♀>♂
•10% of asthma
• Samter’s triad
– Aspirin hypersensitivity, nasal polyp, asthma
• Cox-1 inhibition
• Cross-reactive
• 30 minutes to 3 hours after NSAIDs intake
bronchial obstruction, dyspnea
and/or nasal congestion/rhinorrhea
NSAIDs/Aspirin & Urticaria/Angioedema
• NSAIDs/Aspirin Exacerbated Cutaneous Disease
– Exacerbate urticaria/angioedema in patients with chronic urticaria
– Cox-1 inhibition : Cross-reactive to multiple NSAIDs
• NSAIDs/Aspirin Induced Urticaria/Angioedema
– Induce urticaria/angioedema in patients without chronic urticaria
– Cox-1 inhibition : Cross-reactive to multiple NSAIDs
Non allergic NSAIDs hypersensitivity
Single NSAID Induced
Urticaria/Angioedema or Anaphylaxis






Allergic : IgE-mediated
Wheals / angioedema / anaphylaxis
Acute (usually immediate to several hours after exposure)
No underlying chronic diseases
Non cross-reactive or limited cross- reactive
More often in atopic, female, history of food or drug allergy
Single NSAID Induced
Delayed Reactions
 Allergic : T-cell mediated
 Various symptoms and organs involved
(e.g., maculopapular eruption fixed drug eruption, SJS/TEN, etc.)
 Delayed onset (usually more than 24 h after exposure)
 No underlying chronic diseases
 Non cross-reactive or limited cross- reactive
Diagnosis
 NSAIDs exacerbated respiratory disease,
NSAIDs exacerbated cutaneous disease,
NSAIDs induced urticaria/angioedema
- history taking: most important
- skin test: not useful
- oral provocation test(aspirin or culprit NSAIDs) is required for
confirmation
 Single NSAIDs induced urticaria/angioedema/anaphylaxis
Single NSAIDs induced delayed reaction
- history taking: most important
- skin test can be helpful (patch test for delayed reaction)
- oral provocation test with culprit drug when indicated
NSAIDs tolerance in patients with acute,
cross-reactive type of aspirin hypersensitivity
• Group A
• Group B
• Group C
NSAIDs cross-reacting
in majority of
hypersensitive patients
(60–100%)
NSAIDs cross-reacting
in minority of hypersensitive
patients (2–10%)
NSAIDs well tolerated
by all hypersensitive
patients
-Rhinitis/asthma type
-Rhinitis/asthma type
Ibuprofen
Indomethacin
Sulindac
Naproxen
Fenoprofen
Meclofenamate
Ketorolac
Etololac
Diclofenac
Ketoprofen
Flurbiprofen
Piroxicam
Nabumetone
Mefenamic acid
acetaminophen (doses below 1000 mg)
meloxicam
Nimesulide
-Urticaria/angioedema type
acetaminophen
meloxicam
nimesulide
selective COX-2 inhibitors
(celecoxib, rofecoxib)
selective cyclooxygenase inhibitors
(celecoxib, parvocoxib, parecoxib)
trisalicylate, salsalate
-Urticaria/angioedema
type
new selective COX-2 inhibitors
(etoricoxib, parecoxib)
환자 관리 및 예방
 원인약제 및 교차반응 가능약물의 회피
 일반적인 대체가능약물
- Weak COX-inhibitor: acetaminophen
- COX2-inhibitor: celecoxib
※ 드물게 교차반응 가능하므로 주의 필요 !!
 Single NSAIDs induced allergic reaction의 경우
- chemically unrelated NSAIDs
 반드시 사용이 필요한 경우: 탈감작 고려
Take Home Message
 투약 전 과거 약물알레르기 병력 확인: 가장 중요함
 약물알레르기 형태에 따른 접근 필요: 즉시형 vs. 지연형
 병력이 불분명할 경우 가능한 정확한 진단, 평가 필요
 예방: 원인약제 회피 및 대체가능약물 확인, 환자 교육