ADR Identification and Management
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Adverse drug reactions
identification andmanagement
Robin Ferner
City Hospital Birmingham
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Identifying ADRs: What done it?2.
Diagnosis: gingival hypertrophy Infiltration
e.g. myelomonocytic leukaemia Drug causes
Phenytoin Calcium channel antagonists Calcineurin inhibitors (ciclosporin)
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Identifying ADRs: What done it? 3.
Diagnosis: marrow aplasia
Antiepileptics: carbamazepine, phenytoin
Anti-inflammatory drugs: penicillamine, sulfasalazine
Antimalarials: pyrimethamine, chloroquine
Antimicrobials: co-trimoxazole, chloramphenicol,
Antipsychotics: phenothiazines, clozapine,
Antithyroid drugs: carbimazole, propylthiouracil
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Alvir J et al. N Engl J Med 1993;329:162-167
Cumulative Incidence of Agranulocytosis among 11,555 Patients
Taking Clozapine
Alvir et al NEJM 1993; 329: 162 167
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Identifying ADRs: What done it?4.
Diagnosis: pulmonary fibrosis Cytotoxics
methotrexate, bleomycin, busulphan Amiodarone Ergot derivatives
methysergide, pergolide Antibacterials
nitrofurantoin
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Identifying ADRs: What done it?
5.
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Diagnosis: torsade de pointes
Antiarrhythmics : amiodarone, disopyramide, sotalol
Antiemetics : cisapride, domperidone, ondansetron
Antiinfectives : chloroquine, macrolides, some quinolones
Antipsychotics : chlorpromazine, thioridazine, pimozide
Addicts : levomethadyl, methadone
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Not all adverse reactions areto conventional medicine
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Dodds1938
Smith1949
Dieckmann1953
Identifying ADRs: takes patienceStilbestrol
Herbst1970
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Identifying ADRs: takes patienceStilbestrol and clear cell c/a vagina
Age at diagnosis (years ) A n n u a
l i n c i
d e n c e p e r 1
0 m
i l l i o n
Herbst AL. Am J Obstet G necol 1977 28:43-50.
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ADRs can be odd (2)
A deaf 88-year-old woman Rx pentoxifylline for tinnitus > auditory hallucinations Male voice singing in her right ear Favourite song "Amazing Grace", but
he often sang "Rock of Ages" and"Sweet By and By"!
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Diagnosis: 20 th 21 st century
Strategies1.Gestalt = pattern recognition2.Algorithmic3.Exhaustive4.Hypothetico-deductive
Sackett Clinical
Epidemiology 1991
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Diagnosis: 1. pattern recognition
The recognition of classicalpatterns of disease
Related to designated medicalevents (TEN, bone marrowaplasia)
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Diagnosis: 1. pattern recognition
Goya 1828Sur la feuille E . 23 du Louvre, la lgende efface etillisible s'intitulerait Cosa rara (Chose rare ),d'aprs le titre de la vente de 1877. L'enfant difforme ...
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Diagnosis: 1. pattern recognition
Nine children born of members of the group Thalidomide UKhave thalidomide-like deformities.
Dr Claus Newman: ...Their parents are not thalidomide,although for obvious reasons, they were mistaken forthalidomide people. It's all genetic...
Independent October 1, 2002
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Diagnosis: 1. pattern recognitionintra -ocular traumatic impact Berkson
Definitive anecdotes 1a: Extracellular deposition of drug or metabolite 1b: Intracellular deposition of drug or metabolite 2: Specific location or pattern of injury 3: Physicochemical dysfunction or tissue damage 4: Infection related
Aronson & Hauben BMJ 2006; 333:1267 9
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Definitive anecdotesDiagnosis: 1. pattern recognition
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Diagnosis: 2. by algorithm NaranjoClin Pharmacol Ther. 1981; 30 (2): 239 45.
Challenge Dechallenge Rechallenge
Timing
Alternative aetiology
at least sufficient exposureresolves after withdrawalrecurs after readministrationconsistent
considered
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Diagnosis: 2. by algorithmCausality term Assessment criteria WHO-UMC
Certain Event or laboratory test abnormality with plausible
time relation to exposure
Cannot be explained by diseases or other drugs
Response to withdrawal plausible (pharmacologically,pathologically)
Event definitive pharmacologically or
phenomenologically Rechallenge causes definite recurrence
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AlgorithmsKarch Naranjo Benichou Kramer Stricker
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Diagnosis: 2. by algorithm
Algorithmic
Consensual Expert Judgement
Probabilistic
Doubtful (74%)Possible (16%)Probable (10%)
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Diagnosis: 2. by algorithm
No evidence of validity, that is, consistent and reproducible approximation to the truth. Meyboom Drug Safety 1997; 16: 355-65
Final assessment produced by a givenalgorithm depends highly on the relative weightof each criterion, which is fixed more or lessarbitrarily by the author...
Theophile Drug Safety 2010; 33: 1045 54
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Diagnosis: 2. by algorithm
No evidence of validity, that is, consistent and reproducible approximation to the truth. Meyboom Drug Safety 1997; 16: 355-65
Final assessment produced by a givenalgorithm depends highly on the relative weightof each criterion, which is fixed more or lessarbitrarily by the author...
Theophile Drug Safety 2010; 33: 1045 54
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Diagnosis: 3. exhuastive
Generally impossible Anyway, without a prior hypothesis,
noise obscures signal
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Diagnosis: 4. hypothetico-deductive
Set out a hypothesis Seek information to confirm it
Doctors almost invariably fail to seekinformation to refute their hypotheses (cf.Karl Poppers view of scientific method)
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So: identification in anindividual
Explore the diagnostic space Consider the prior probabilities Adjust them according to DoTS
Treatment in an individual Consider specific therapy
Consider prevention