ADVERSE DRUG REACTIONS (ADRs)

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ADVERSE DRUG REACTIONS (ADRs) AND DRUG ALLERGY
Achara Srisodsai, Ph.D. Department of
Toxicology Faculty of Pharmaceutical
Sciences Khon Kaen University
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??????????????????????

1. ??????????????????????????????????????????????????
   ????
2. ?????????????????????????????????? ADRs
3. ???????????????????????????? ADRs ???????????
4. ???????????????????????????????????
5. ???????????????????????????????????
6. ??????????????????????????????????????

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OVERVIEW

• ADRs
• Definition
• Classification of ADRs
• Mechanisms
• Drug allergy
• Characteristics
• Mechanisms
• Clinical Manifestation

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THE FIRST APPEARANCE OF THALIDOMIDE
'Thalidomide Babies'
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(No Transcript)
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• First appeared in Germany on 1st October 1957.
• As a sedative with apparently remarkably few
  side effects.
• Prescribing to pregnant women to help combat
  morning sickness.
• The tests were conducted on rodents which
  metabolise the drug in a different way to humans.
  
• Later tests on rabbits and monkeys produced the
  same horrific side effects as in humans.

Thalidomide
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• Towards the end of the fifties, children began
  to be born with shocking disabilities.
• Probably the most renowned is Phocomelia, the
  name given to the flipper-like limbs which
  appeared on the children of women who took
  thalidomide.
• Babies effected by this tragedy were given the
  name 'Thalidomide Babies'.

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Why drugs can cause tragedy?
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Compound Success Rates By Stages
Discovery (2-10 Years)
Compound Success Rates by Stage
5,000-10,000 screened
Preclinical Testing Laboratory and animal testing
Phase I 20-80 healthy volunteers used to
determine safety and dosage
250 Enter preclinical testing
Phase II 100-300 patient volunteers to look for
efficacy and side effects
Phase III 1,000-5,000 patient volunteers used to
monitor adverse reactions to long-term use
5 Enter clinical testing
FDA Review/Approval
Years
Additional post-marketing testing
0 2 4 6 8 10
12 14 16
1 Approved by the FDA
Postmarketing survillence
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Limitations of premarketing clinical trials

• Short duration effects that develop with
  chronic use or
• those that have a long latency period are
  impossible to
• detect.
• Narrow population generally do not include
  special groups (e.g., children, elderly), to a
  large degree, and are not always representative
  of the population that may be exposed to the drug
  after approval.

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Summary of time lags after U.S. marketing before
adverse drug reactions were widely recognized
Adverse Reaction Drug Time Lag
(yr) Pulmonary embolism Oral contraceptives
3 Myocardial infarction Oral contraceptives
5 Deaths from asthma Sympathomimetic
aerosols 4 Jaundice Halothane 7 Colitis
Lincomycin 6 Colitis Clindamycin
5 Aplastic anemia Phenylbutazone 6
Venning, GR. Br. Med. J. 286365-368, 1983
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Limitations of premarketing clinical trials

• Narrow set of indications those for which
  efficacy is being studied and do not cover actual
  evolving use.
• Small size (generally include 3,000 to 4,000
  subjects) effects that occur rarely are very
  difficult to detect.

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Required sample size for detecting a rare
adverse drug reaction
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ADVERSE DRUG REACTIONS (ADRs)
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What is ADR?
WHO Any response to a drug which is noxious
and unintended, and which occurs at doses
normally used in man for prophylaxis, diagnosis,
or therapy of disease, or for the modification
of physiological functions.
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• Excluding.
• Therapeutic failures
• Intentional and accidental overdose
• Drug abuse
• Errors in drug administration

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Adverse Product Reaction (APR)
- ?????, ?????????, ????????????
Adverse Drug Events (ADEs)
- ????????? ??????????????????????????????????
Risk assessment of drug

• - ????????????????????????????????????????????????
  ???????????????????????
• ?????????????????????????????,
  ????????????????????????????????????????
• ????????????, ????????????????????????,
  ?????????????????????????

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Classification of Adverse Drug Reactions
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Classification of Adverse Drug Reactions
?????????????????????????? (Severity
classification)
1. ?????????? (Mild) ??????????????????
????????????????????????????????
?2.????????????? (Moderate) ?????????????????????
????????????????????????????????????????????????3
. ????????? (Severe) ????????????????????????????
???????????????????????????
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• Serious adverse events
• ????????? (fatal)
• ?????????? (life-threatening)
• ????? (disabling)
• ????????????????????????????????? (prolongs
  hospitalization)
• ??????????????????????????????????? (congenital
  anomaly)
• ????????????????????????????????????????????????
  ???
• (requires intervention)

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   ????????????????? (Causality classification)
   - ????????? (Definite) ?????????????????????????????????????????????? ??????????????????????? ????????????????????????????? ???????????????????????? (dechallenge) ???????????????????????????????????????? (rechallenge) ?????????????????????????????   - ???????? (Probable) ???????????????????????????????????????????????????????????????????????????????????
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• ???????? (Possible) ?????????????????????????????
  ?????????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ???????? ?????????????
• - ????????? (Doubtful/ Unlikely)
  ??????????????????????????????????????????????????
  ?????????????????????????

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

• Type A (augmented/predictable)
• - ????????????????????????????????????????????????
  ?????????
• ???? ????????????????????????????????????????????
• Type B (bizarre/unpredictable)
• - ????????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ??
• - ??????????????????? ????????????????????????????
  ???????????????
• ?????????

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3. Type C (chronic) - ???????????????????????????
?????????????????????????? ???????????????????????
????? ???? ??????????????? Benzodiazepines 4.
Type D (delayed) - ??????????????????????????????
?????????????? ???? ???????????? ????
????????????????????????????? 5. Type E
(end-of-treatment) - ????????????????????????????
(withdrawal) ?????????????
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• Type A (augmented/predictable) reactions
• Expected extensions of an individual drugs
  known
• pharmacologic properties and are responsible
  for the
• bulk of ADEs encountered.
• Even though their incidence and morbidity is
  high,
• they are rarely life-threatening, although they
  can
• produce significant disability.

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Causes of Type A reactions
1. Pharmaceutical causes - Drug quantity
- Drug release e.g. Osmosin (slow release
indomethacin) GI bleeding 2. Pharmacokinetic
causes - Drug absorption - Drug
elimination - Drug distribution - Drug
metabolism 3. Pharmacodynamic causes - Drug
receptors - Homeostatic mechanisms -
Disease
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Pharmacokinetic causes

• Drug absorption
• ??????????????????? ???? ??????????? digoxin
  ??????? atropine ?????????????????? digoxin
  ?????????????? (ADR?)
• Drug distribution
• Tetracycline ??????????????????????????????????
  ??????????????????????????????????????

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• Drug excretion
• ???????? aspirin ????????????????????????
  organic acid ???? urate ??????????????????
  ????????????????????????? hyperuricemia
• Drug metabolism
• Paracetamol ?????????????????? ?????????????
  unchanged form ???????????????????????
  ??????????????????????????????????? CYP2E1??????
  toxic metabolite ?????????????????????

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Paracetamol Metabolism
Sulphate conjugation
Glucuronide conjugation
50-60
25-35
CYP 2E1
N-acetylbenzoquinoimine (NAQI)
GSH
Covalently-bound paracetamol
Glutathione conjugation
2-4
Cell macromolecule
Hepatotoxicity
Mercapturic acid conjugates excreted in urine
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Factors predisposing to pharmacological adverse
drug reactions
Factor Example Toxicity Mechanism Pharma
ceutical Osmosin Gastrointestinal Release
of high (slow release bleeding
concentrations of indomethacin) active
drug locally in GI Pharmacokinetic
Digoxin Digoxin toxicity
Decreased elimination
(nausea, arrhythmias) if renal function
is impaired Pharmacodynamic Indomethacin
Left ventricular Water and sodium
failure retention Drug-drug TerfenadineTM
Prolonged QT Inhibition of interaction
Erythromycin interval and
metabolism of
torsades de
terfenadine by pointes
erythromycin Can affect absorption,
distribution, metabolism, or excretion.
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• Ways to minimize both pharmacokinetically- and
• pharmacodynamically-derived ADEs include
• Understanding the pharmacology of the drug
• being prescribed
• Monitoring drugs with a narrow therapeutic
• window
• Avoiding polypharmacy whenever possible

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• Type B (bizarre/unpredictable) reactions
• Type B reactions include idiosyncratic
  reactions,
• immunologic or allergic reactions
  (e.g.anaphylaxis),
• and carcinogenic/teratogenic events.
• While uncommon, are often among the most
• serious and potentially life-threatening of all
• ADEs, and are a major cause of important
• drug-induced disease.

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Mechanisms of Type B reaction

• Receptor abnormality malignant
• hyperthermia with general anesthetics

• Autosomal dominant genetic disorder of SM
• Mutation in the gene loci corresponding to
• skeletal muscle ryanodine receptor (RYR1),
• the calcium release channel of sarcoplasmic
• reticulum.
• Tachycardia, HT, severe muscle rigidity,
• hyperthermia

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• Abnormal biological system unmasked by
• drug primaquine induced haemolysis in
• patients deficient in glucose 6-phosphate
• dehydrogenase

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• Genetic heterogeneity among affected individuals
  with
• over 400 variants of the enzyme identified.
• - The severity of the problem can vary from
  hemolysis even in the
• absence of oxidative stress to hemolysis only on
  exposure
• to mild to marked oxidant stress.

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• Abnormalities in drug metabolism
• - Atypical pseudocholinesterase
• ??????????????? succinylcholine ???????? prolong
  apnea ????? cholinesterase ???????????????????????
  ?????????????????????????????????????????
  Atypical ChE ?? affinity ??? substrate ????????
  half life ???
• - Polymorphism drug oxidation
• ???? CYP2D6 polymorphism (debrisoquine/sparteine)
• CYP2C19 polymorphism (Mephenyltoin)

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???????????????? Type A ??? Type B ADRs
Type A Type B
1. Predictability 2. Dose-dependent 3.
Incident 4. Mortality 5. Treatment 6.
Pharmacological basis 7. Seriousness
Yes No
Yes No
Common Rare
No Yes
Adjust dose No
Yes No
No Yes
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• Summary points
• Adverse drug reactions are a common clinical
  problem
• They are diagnosed on clinical grounds from the
  temporal
• relation between the start and finish of drug
  treatment
• and the onset and offset of the reaction
• Pharmacological adverse reactions are generally
• dose-dependent, related to the pharmacokinetic
  properties
• of the drug, and resolve when the dose is
  reduced

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• Idiosyncratic adverse reactions are not related
  to the
• known pharmacology of the drug, do not show
  any
• simple dose-response relation, and resolve
  only when
• treatment is discontinued
• Vigilance by clinicians in detecting,
  diagnosing, and
• reporting adverse reactions is important for
  continued
• drug safety monitoring

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Drug allergy
??????????????????????????????????????????????????
?????????????????????????????????????????antibody?
?????? ???????????????????????????????????????????
????????????????????????
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?????????????????????????

1. ?????????????????????????? ???????????????????????
   ???????
2. ??????????????????
3. ???????????????????????????????????????
4. ?????????????????????????????????????
5. ????????????????????
6. ??????????????????????
7. ???????????? Ab ???? T-lymphocyte
8. ??????????????????????????????????????????????????
   ?????????

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???????????????????????????????????????
1. ???????????????????????????
???????????????????????????????????
???????????????????????????????????????? ?????????
?????antibody????????????????????????????? 2. ??
Reactive metabolite ?????????????????? ??????
metabolite ???????????????????????????????????? ??
???????????????????????????????? e.g.
penicillin 3. ????????????????????????????????????
????? ???? penicillenic acid, pennicilloic acid
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4. ???? polymerization ???????
?????????????????????????? polymerization
???????????????????????? ?????????????????? ????
ampicillin 5. ?? contaminants or additives
?????????????????? ??????????????????????????????
????? benzylpenicillin ??????????????? ???????????
????? ????? pennicilloylated protein 6.
???????????????????????????????????????? ????
penicillins, cephalosporins
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???????????????
Type I Anaphylactic/ Immediate type (e.g.,
Penicillin, insulin urticaria or
anaphylaxis) Type II Cytotoxic type (e.g.,
drug-induced haemolytic anaemia or
thrombocytopenia reduced platelets) Type III
Immune complex type (e.g., serum sickness-like
drug reactions) Type IV Cell-mediated or
delayed hypersensitivity (e.g., neomycin
contact dermatitis)
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Type I Anaphylactic/Immediate type

• ??????????????? ?????????
• ????????????????????????????? Ag
  ?????????????????? IgE ?????????????????? mast
  cells ??? basophils
• Systemic anaphylaxis, ?????, ??????????????,
  angioneurotic edema

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Type II Cytolytic Reactions

• ???????????????????????????????????????????????
• hemolytic anemia, thrombocytopenia,
  granulocytopenia

Phagocytes binding to the Fc portion of the IgG
and discharge their lysosomes causing cell lysis.
The Fab of IgG reacts with epitopes on the host
cell membrane. Phagocytes bind to the Fc portion.
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• Type III Immune Complex Reactions
• ?????????????????? IgG ????????????????????????
  immune complexes
• ??????????????? complement ?????????????????????
  ? ??????????????
• Glomerulonephritis

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IgG ??? IgM ?????????????? antigen
????????????????????????????? immune complex
??????????????????????????????????????????????????
?
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• ??????????????????? complement ???????????????????
  ???????????????????????????? antigen ????
  ??????????????? phargocyte ??????????????????????
  lysosomal enzyme ?????????????????????????????????
  ???????????????????????????
• ??????????????????????????????? arthus reaction
• ???????????????????????????????????????? serum
  sickness

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• Type IV Cell-Mediated Reactions
• ?????????????????????????????????????????? ????
  ?? macrophage ????? ??????????????????????????????
  ???? T cells
• Contact dermatitis, fixed-drug eruptions

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Urticaria
?????????? ???????????????????????
??????????????????????????????????????????????????
?????? ??????????????????? 24 ???????
????????????????? penicillin, sulfonamide
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Angioedma
- ?????????????????????? ????? -
??????????????????????????????????????? -
???????????????????????????????????, ??????, ????
????????? - ????????????????????????
?????????????- ????????????????? penicillin,
sulfonamide
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Erythema multiforme
- ????????????? ???????? ?????????????????????????
??????????????????????????????????????????????
iris ???? target ?????????????????????????-
????????????????? penicillin, sulfonamide,
barbiturate, NSAIDs, phenyltoin, allopurinol
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Fixed-drug eruptions
- ??????????????????????????? ???????????????????
? ???????????????????????? ??????????????????
????????????????????- ?????????????????
tetracyclin, sulfonamide
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Toxic Epidermal Necrolysis (TEN)
- ?????????????????????????????-
????????????????? penicillin, sulfonamide,
barbiturate, hydantoin, NSAIDs, phenyltoin,
allopurinol
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Steven Johnson Syndrome
- ???????????????????????????????? erythema
multiforme ??????????????????????????????
???????????????? ????????????? ????????? ?????????
??????????? ????????????? - ?????????????????
penicillin, sulfonamide, barbiturate, hydantoin,
NSAIDs, phenyltoin, allopurinol
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• ???????????????????
• ???????????? ?????????????????????????????
• www.who.int
• www.fda.gov/medwatch

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THE END