Adverse Drug Reaction

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Adverse Drug Reaction
?. ????? ?????????????? ???????????????????????
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Adverse Drug Reaction

• ???????????????????????????????????????
• Hippocratis, ??????????????????????????
• ?.?. 1785 ?????? ADR ??? Digitalis
• ?.?. 2000 ?????????????????? ADR

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??????? ??? WHO 1970
?????????????????????????????????????????????????
??????????????????????????????????????????????????
??????????????? ???????? ??????
??????????????????????????????????????????????????
????????????????????????
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Adverse Event (AE)
????????????????????????????????????????
???????????????????????????????????
????????????????? 3 ????? ???
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Side effect

• ??????????????????????????????????????????????????
  ?? ????????????????????????? ?????????????????
  ????????? ????????????????????????????????????

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Toxic reaction

• ??????????????????????????????????????????????????
  ?????????????????????????????????????
  ??????????????????????????????????????????????????
  ?????????????????????????

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Hypersensitivity

• ?????????????????????????????????????????????
• ????????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ????????????????????????

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Idiosyncrasy
??????????????????????????????????????
???????????????????????? ????????????????
???????????????????????????????
???????????????????????????????????????
??????????????????????????????????
????????????????????? enzymatic defect
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Drug interaction

• ?????????????????????????????????
• ??????????????????????????
• ??????????????????????????
• ??????? 2 ?????????????????

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Significant ADR by ASHP

• ??????????
• ?????????????????
• ?????????????????
• ??????????????????????????????
• ??????????????????????????

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Significant ADR by ASHP

• ??????????????????????????????
• ??????????????????? ???????????????????
• ????????????????????????
• ???????????????????????????? ???????

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Type of ADR

Pharmacological classification

• Rawlins ??? Thompson (1977)
• Grahame-Smith D.G.
• and Aronson J.K. (1992)

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Type of ADR
Causality classification
Severity classification
Seriousness Classification
Frequency Classification
Reaction time classification
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Grahame-Smith D.G. and Aronson J.K. 1992
??????????????????????????? Adaptive changes
Rebound phenomena Other effects
Type C (Chronic, continuous, long-term effects)
??????????????????????????????????????????????????
???????????????? ????????????????????????????????
Type D (Delayed effects)
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Causality classification
Definite ?????? Probable ???????? Possible
???????? Doubtful, Unlikely, Remote
????????/ ???????????
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Certain (definite, confirm, highly probable)
?????????
1. ???????????????????????????????????????????????
2. ??????????????????????????????
?????????????????????????????????????? 3.
??????????? (dechallange) ???????????????
?????????????????????????????????? 4.
???????????????????? (rechallange) ???????????
??????????
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Probable (Likely) ????????
1. ??????????????????????????????????????????? 2.
?????????????????????????????????
????????????????? ????????????????????? 3.
?????????????????????????? ??????????????????? 4.
?????????????????????????
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Possible ?????????
1. ???????????????????????????????????????????????
??? 2. ?????????????????????????????????
?????????????????????? 3. ????????????????????????
?????
Unlikely (doubtful) ???????????
1. ?????????????????????????????????????????? 2.
?????????????????????????????????
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Frequency Classification
Common ????????????????????????????
10 Occasional ?????????????????????????????
10 Rare ????????????????????????????? 1
?????????? 0.1 Very Rare ???????????????????????
?????? 0.1
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Severity classification

• ?????????????? (Mild/ minor)
• ????????????????? (Moderate)
• ????????????? (Severe)

Seriousness Classification

• Symptomatic only
• Serious

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Reaction time classification
Acute ??????? ????????????????????????????????????
0-60 ???? Sub-acute ??????? ?????????????????????
??????????????? 1-24 ??????? Latent
??????????????????????????????????????????????? 1
??? ??????????????
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Mechanism of Type A ADR
1. Pharmaceutical causes ??????????????????????
??? 1.1 ??????????? (drug quantity) 1.2
???????????????? (drug release)
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Mechanism of Type A ADR

• 2.Pharmacokinetic causes
• ??????????? ??????????? ??????????
• 3.Pharmacodynamic causes
• 3.1 Drug receptors
• 3.2 Homeostatic mechanism
• 3.3 Disease

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Mechanism of Type B ADR
1. Pharmaceutical causes ???????????? ??????
tetracycline ?????????? ????????? Fanconis
Syndrome 2. Pharmacokinetic causes 3.
Pharmacodynamic causes
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3. Pharmacodynamic causes

• 1. genetic causes
• - ?????????????? enzyme G6PD
• - Malignant hyperpyrexia
• 2. Immunological reasons for abnormal response
• - ??????????????????????????????????????
  ??????? hydralazine
• 3. Neoplastic and teratological reasons for
  abnormal response
• - oestrogen ???? androgen

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??????????????????????????????????

• ??????????????????
• ????????????
• ?????????????
• ???????????

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??????????????????

• ???????????????, peptide hormone ??? dextran
  ???????????????????????????
• ?????????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ?????????????????????

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???????????? penicillin ?????????????????????????
??????????????????????? ????????? penicillin
??????????????????????? ???? penicilloyl,
penicillinic acid ??? penicillamine
????????????????????????????????
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???????????????

• ????????????????????????? IgE
• ???????????????????? ???????????? IgE
  ??????? mast cell ???? basophil
• ????????eosinophil, chemotatic factor
  of anaphylaxis, leukotrienes ???? prostaglandin

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??????????????? penicillin

• penicilloyl ??????????????? accelerated allergic
  reaction
• penicilloates, penilloates, penicillamine ???
  penaldate ??????????????? immediate reaction

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????????? immune complex

• ?????????????????????????????????????????????????
  ??? immune complex
• ????????????????????? IgG ???? IgM ??????????
  IgE
• ????????????????????? serum sickness
  ??????????????????????????????????? 6
  ?????????????????
• ???????? ????????? ????? ??? ????????????????
  ????????

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????????? cytotoxic

• ???????????????????????????????????????????????
  ? ?????????? ???????????? ?? penicillin
  ??????????????????????????????????????? ????????
  hapten ????????????????????????? ???? lymphocyte
  ?????????????????????????????????

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cell-mediated immunity

• ???????????????????? allergic contact dermatitis
  ????? penicillin, sulfonamide ??? neomycin

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Predisposing factors
?????? ??????????????? ?????????????????????? ???
?????????????????? ???? ????????????????? ???
????????????? ADR ?????????????????????? ?????????
???? G6PD deficiency Metabolism ??? liver
disease Renal disease Polypharmacy and drug
interaction Multiple physicians

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????????????? ????????????????????????????????
1. Retrospective Surveillance Methods
2. Prospective or Concurrent Monitoring Systems
2.1 Spontaneous or voluntary reporting ADR 2.2
Intensive ADR Monitoring
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Spontaneous or voluntary reporting ADR
????? 1. ?????????????????????????????????
??????????????????? ADR ??????????????????????????
2. ????????????????????????????
???????????????????????????????????????????
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Spontaneous or voluntary reporting ADR

• 3. ???????????????????????????????????????????????
  ?????????? ADR ???????????? rare case ??????????
• 4. ??????????????????
• 5. ?????????????????????????????????????

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Spontaneous or voluntary reporting ADR

• ???????
• 1. ????????????????? ?????????????????????????????
  ????
• 2. ???????????????????????????????????????????
  ????????????????????????????????????????????????
• 3.???????????????????????????????? ADR ???

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Intensive ADR Monitoring
1. ??????? therapeutic Index (TI) ??? ????
theophylline, digoxin ??????? 2. ??????????? 3.
?????????????????????????????? 4.
????????????????????????????????? ????? ??? ??
???????
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????? 1. ????????????????????????
????????? ??? ????????????????????????????????????
?????? ? 2. ??????????????????????????????????????
??????????? 3. ???????????????????????????????
??????? 1. ????????????????????? 2.
?????????????????????????
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Identification of Adverse drug reaction

• ADR ????????????????
• ADR ?????????????????????????????????
• ????????????????? ADR ??????????????????
  ???????????????????????? ??????????????????
  ???????????????? ???????????? ????????????????????
  ??????????????????????? ???????????????????????

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Naranjos algorithm

• 1. Are there previous conclusive reports on this
  reaction?
• 2. Did the adverse event appear after the
  suspected drug was administered?
• 3. Did the adverse reaction improve when the
  drug was discontinued or a specific antagonist
  was administered?
• 4. Did the adverse reaction reappear when the
  drug was readministered?
• 5. Are there alternative causes (other than the
  drug) that could on their own have caused the
  reaction?

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• 6. Did the reaction reappear when a placebo was
  given?
• 7. Was the drug detected in the blood (or other
  fluids) in concentrations known to be toxic?
• 8. Was the reaction rnore severe when the dose
  was increased, or less severe when the dose was
  decreased?
• 9. Did the patient have a similar reaction to the
  same or similar drugs in any previous exposure?
• 10. Was the adverse event confirmed by any
  objective evidence?

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