Adverse Drug Reactions

ADR classes ADR reporting ADR.

Pharmacovigilance
 ‘the study of the safety of marketed drugs under the
practical conditions of clinical use in large communities’.

 is concerned with
 detection, assessment and prevention of adverse effects or
any other possible drug-related problems.

 with the ultimate goal of achieving rational and safe

clinical practice.
Definition of ADR
 The World Health Organization (WHO) defines

‘a response to a drug that is noxious and unintended

occurs at doses normally used in man for the

prophylaxis.
diagnosis
therapy of disease.
for modification of physiological function.

WHO, 1972. International drug monitoring: the role of national centres. Tech. Rep. Ser. 498, 1–25.
Factors affecting susceptibility
to ADRs
 Age………Elderly patients , Children .
 Gender…. Women.
 Co-morbidities.
 Concomitant medicines use
 Duration of therapy.
 Narrow therapeutic index drugs.
 Ethnicity…occurs more frequently in white individuals
compared to black individuals.
 Pharmacogenetic.
according to onset of
actions
according to severity of ADR’s Mild:
according to etiology
Acute:
with in 1 hr of administration of drug
Headache due to spinal anesthesia
Sub acute:
With in 24 hrs of the administration of the drug
Fever due to vaccination
Latent:
After 2 days of administration:
Rye syndrome in children
Bothersome but does not require changes in therapy.
Moderate:
Require hospitalization and changes in therapy
(misoprostol used for induction of labor causes uterine
hemorrhage)
Severe:
life threatening, permanent(Birth defect due to
thalidomide)
Excessive pharmacological effects
Secondary pharmacological effects
Idiosyncratic reactions
Genetically determined reactions
Drug interactions
Allergic drug reactions
 According to etiology
1- Appears due to overdose of drugs. E.G
Excessive May appear in normal and usual Antihypertensives
pharmacological therapeutic dose. Cardioactive agents
response. Patient with renal impairment, Hypoglycemics
extreme age, liver damage. Antidepressants

2- Drugs shows several antihistamine produce anti

Secondary pharmacological effect at usual allergy action as well as
pharmacological therapeutic dose drowsiness .
response.
3- Unpredictable, unusual and Drug induced cancer
Idiosyncratic unexpected reactions which cannot Lymphoid tumor with long
reactions. be readily explained. term immunotherapy as
cyclophosphamide
4- Genetic make up differences E.g Glucose 6 phosphate
Genetically dehydrogenase defficiency
determined developing hemolytic anemia
ADR’s. after the use of antimalarials
5- Digoxin with thiazide →
Drug hypokalemia
interactions.
6- Long term usage of
Toxicity followed drug corticosteroids therapy causes
withdrawal atrophy of adrenal glands and
sudden withdrawal leads to
acute adrenal crisis
7- Mild reactions to anaphylaxsis
Allergic reactions Disappear with the
discontinuation of drugs
Serum sickness, skin rashes,
brochial asthma, anaphylaxsis
E.g in case of withdrawal
of benzodiazipines,
tachycardia, delirium,
convulsions.
E.g penicillins causes
anaphylaxsis
 Immunological reactions
 The immune system is able to recognize drugs as foreign
substances, leading to allergic reactions.

 Immunological reactions are often distinct recognizable

responses.

 Rashes and angioedema to the life-threatening

bronchospasm and hypotension associated with anaphylaxis.
Rawlins and Thompson classification
 the ADRs are categorized into two classes
 type A and
 type B reactions.

Rawlins, M.D., 1981. Clinical pharmacology: adverse reactions to

drugs. Br. Med. J. 282, 974–976.
Type A reactions

 Reactions predictable from the drug’s known

pharmacology

 are usually dose dependent.

 hemorrhage with anticoagulants,

 hypoglycemia with sulphonylureas, etc.
Type B reactions

 Bizarre effects that cannot be predicted on the basis of

the drug’s pharmacology.
 These reactions are generally unrelated to dosage.
 Are comparatively rare,but they often cause serious
illness and death.
 Some examples are:
 anaphylaxis due to penicillin,
 and many immunological reactions
 Type A Type B
Associated with the a r
pharmacology of the
product
Predictable a r
Dose related a r
Common a r
Serious r a
Wills and brown classification of
ADR’s OR Extended Rawlin’s and
Thompson Classification
 1970 wills and brown classified ADR according to the
chemistry of drug.
m
DoTS system of classification
 The DoTS classification is based on
 Dose relatedness, Timing And patient Susceptibilit

Aronson, J.K., Ferner, R.E., 2003. Joining the DoTS: new approach to classifying
adverse drug reactions. Br. Med. J. 327, 1222–1225
ADR Detection

 Subjective report
 patient complaint
 Objective report:
 direct observation of event
 abnormal findings
 physical exam
 laboratory test
 diagnostic procedure
Spontaneous collect data about suspected ADRs, Yellow Card
Reporting not collected in a systematic manner scheme,Signal
reports submitted spontaneously by detection,Causality
people who make a connection assessment
between a drug and a suspected drug- Direct patient
induced event reporting

Causality whether a drug is responsible for a unstructured clinical

assessment suspected ADR is of great importance in assessment, also
both the regulatory environment and known as global
within the pharmaceutical industry. introspection.

Naranjo questionnaire and points Causality outcomes

alogrithms Highly probable
Probable
Possible
Doubtful
Direct patient Patients have been permitted to report
reporting directly to MHRA
 To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.
Yes No Do Not Know Score
1. Are there previous conclusive reports on +1 0 0 ____
this reaction?
2. Did the adve rse event appear after the +2 -1 0 ____
suspected drug wa s admi nist ered?
3. Did the adve rse reaction im prove when the +1 0 0 ____
drug wa s dis continued o r a specific
antagon ist was admi nis tered?
Naranjo ADR 4. Did the adve rse reactions appear when the
drug wa s readmi nis tered?
+2 -1 0 ____

Probability 5. Are there alt ernative cause s (other than the -1 +2 0 ____
Scale drug) that could on their own have caused
the reaction?
6. Did the reaction reappear when a placebo -1 +1 0 ____
was given ?
7. Was the drug de tected in the blood (or +1 0 0 ____
other fluids) in concen trations known to be
Naranjo CA. Clin toxic?
Pharmacol Ther 8. Was the reaction more severe when the +1 0 0 ____
dose was increased, or less severe when the
1981;30:239-45 dose was decreased?
9. Did the patient have a simil ar reaction to +1 0 0 ____
the same or simil ar drugs in any previous
expo sure ?
10. Was the adve rse even t confirmed by any +1 0 0 ____
objective evidence ?
Total Score ____

Total Score ADR Probability Classification

9 Highly Probable
5-8 Probable
1-4 Possible
0 Doub tful
Yellow Card
 established in 1964 following the thalidomide tragedy
 The Scheme is operated by the Medicines and Health
care Products Regulatory Authority (MHRA)
 all serious suspected ADRs are reported by health care
professionals concerning established medicines
 A suspicion is sufficient for a report to be submitted.
 For newer drugs and vaccines, all suspected ADRs even
if minor events, should be reported

on-line form (http:// www.yellowcard.gov.uk).

 Newer medicines under intensive surveillance are
identified with an inverted black triangle symbol in
product information and standard prescribing texts.
 Black triangle status is generally maintained for at
least 2 years, but the period varies
 All suspected ADRs occurring in children should be
reported
 When new ADRs are identified,
 restricting usage or withdrawing marketin authorisation
for the medicine.
 prescribers and suppliers be informed immediately
 Components of an ADR Report
− Product name and manufacturer
− Patient demographics
− Description of adverse event and outcome
− Date of onset
− Drug start and stop dates/times
− Dose, frequency, and method
− Relevant lab test results or other objective
evidence
− De-challenge and re-challenge information
− Confounding variables
REPORTING TO THE FDA….
MedWatch
 Three of the f ive major centers at the FDA are involved
wi th evaluat ing the safety and ef ficacy of drugs.
 Center for Drug Evaluat ion and Research (CDER)
 Adverse Events Repor ting System (AERS)
 Center for Biological Evaluation and Research (CBER)
 CFSAN Adverse Events Repor ting System (CAERS)
 Vaccine Adverse Event Repor ting System (VAERS)
MEDWATCH 3500A
Reporting
Form

https://www.accessdata.
fda.gov/scripts/medwatch
 Detection, Management of ADR
Roles of pharmacist
 When selecting a medicine, take account of all
relevant patient factors, which may predispose to an
ADR.
 another important role is the documentation of
identified ADRs.
 extracting a full ADR history from patient should be
considered at every opportunity.
 Identifying and assessing ADRs in clinical practice
 Preventing ADRs
 Monitoring therapy
 Explaining risks to patients
Identifying There are many triggers which can lead to the suspicion of an ADR.
and Simple questioning of patients could increase the chances of detecting
assessing potential ADRs.
Make judgement whether or not a particular event could be related to a
ADRs in
drug used .
clinical HCP’s should consider encouraging others to report ADRs.
practice Pharmacists should educate others to develop methods to detect ADRs
through prescription monitoring.
Preventing majority of ADRs are thought to be preventable
ADRs ADRs can be prevented by checking previous ADR history,
factors which predispose them to ADRs
improved sharing of information about patients between health care providers
Monitoring by direct measurement of serum concentration or by measurement of
therapy physiological markers
provide an evidence-based frequency of monitoring and acceptable values.
Warfarin remains one of the top 10 drugs involved in druginduced
admissions
Explaining studies have shown that patients want to receive information about
risks to side effects
patients to enable them to make an informed decision.
Patients increasingly access a wide range of information sources about
medicines and ADRs themselves;
Communicating the harms and benefits of medicines
is, therefore, an important role of health professionals.
 Remington
 DRUG-PRODUCT DEFECT AND
ADVERSEREACTION
 REPORTING PROGRAMS
 Monitoring Drug-Product Quality
 Ch 100