Download Adverse drug reaction (ADR)

CLASSIFICATION, MECHANISMS, CLINICAL MANIFESTATIONS
INTRODUCTION TO ADVERSE
DRUG REACTIONS
What is PHARMACOVIGILANCE?
 Science and activities relating to the detection,
assessment, understanding & prevention of adverse
effects or any other possible drug-related problems.
 Etymology:
 pharmakon (Greek), “drug”
 vigilare (Latin), “to keep awake or alert, to keep watch”
What is Pharmacovigilance?
 “is the science of collecting, monitoring, researching,
assessing and evaluating information from healthcare
providers and patients on the adverse effects of
medications, biological products, herbal and traditional
medicines with a view to identifying new information
about hazards associated with medicines and preventing
harm to patients”
 Particularly concerned with adverse drug reactions; also
medication errors & drug interactions
Objectives
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To enumerate and give examples of the different
types of adverse drug reactions
To explain mechanisms of adverse drug reactions
To describe strategies to prevent or minimize
their occurrence
DEFINITIONS
 Adverse drug reaction (ADR): response to a drug
that is noxious & unintended, and which occurs at doses
normally used in man for the prophylaxis, diagnosis, or
the therapy of disease, or for the modification of
physiological function. (WHO)
 Adverse drug event (ADE): an untoward and
unexpected experience by a pt following the use of a
medicinal product but does not necessarily have a
causal relationship with the treatment.
ADE versus ADR
 ADE does not confer a definitive causality
relationship between the drug and the event but
just a mere suspicion.
 ADR on the other hand, defines a more certain or
probable relationship, the mechanisms of which
might be explained by some pharmacological
actions or in some cases, cannot yet be
conventionally explained
Difficulties with ADR’s
 ADR’s masquerade as other diseases
 Drug effects are the consequence of complex
interactions between the drugs, the patient and the
illness and external factors can also modify drug
response.
 ADR’s: drug-induced illness
Incidence of ADR’s (US data)
 30% of hospitalized patients will have one or more
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ADRs while in the hospital
3% with severe reactions
0.3% will die
5% of admissions to the medical service are caused
by ADRs developed on an out- patient basis
extremes of age
women (60%) > men (40%)
patients with past history of reactions to medications
IMPACT OF AE’s/ADR’s on PUBLIC HEALTH
 ADR’s are the 4th- to 6th largest cause of mortality in
the USA.
 16% of hospital admissions in the UK is due to
adverse drug reactions
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Economic consequences
 Some countries spend up to 15-20% of their hospital
budget dealing with drug complications
 Direct cost of managing drug-related morbidity and
mortality in the ambulatory setting : approx USD $
76.6 B per year (1995)
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Significance of ADR:
Vary in significance according to their nature
and circumstances:
 significant or insignificant
 apparent or hidden
 severe or mild
 acute or chronic
 immediate or delayed
Factors Affecting ADR’s (manifestation/severity)
•Patient-related factors
Age
Sex
Genetic influences
Concurrent diseases (renal, liver, cardiac)
Previous adverse drug reactions
Compliance with dosing regimen
Total number of medications
Misc. (diet, smoking, environmental exposure)
Factors Affecting Adverse Drug Reactions :
• Drug-related factors:
Dose
Duration
Inherent toxicity of the agent
Pharmacodynamic properties
Pharmacokinetic properties
Types of Adverse Drug Reactions :
• Type A ( Augmented )
• Type B ( Bizarre )
• Type C ( Continuous )
• Type D ( Delayed )
• Type E ( Ending of Use )
• Type F ( Failure of Treatment )
TYPE A ( AUGMENTED )
 An effect that is higher in intensity or magnitude
than the expected pharmacological effect.
 Can occur either as an extension effect or part of
the therapeutic effect or can occur as not part of the
intended therapeutic effect (as a side-effect).
 It has usually a dose-dependent mechanism.
TYPE A ( AUGMENTED )
 Augmented extension effect – an ADR resulting
from the intended or therapeutic effect of the drug.
- It is expected, and can be managed with dose
reduction or shifting to another class of drugs.
 Augmented side effect –an ADR that is not the
intended or therapeutic effect;
TYPE A ( AUGMENTED )
• Extension Effect:
• predictable, dose-related responses
arising from an extension of therapeutic
effect
E.g. Benzodiazepine - sedation
Insulin - hypoglycemia
Heparin - spontaneous bleeding
Beta-blocker - bradycardia
TYPE A ( AUGMENTED )
• Side Effect:
• predictable, dose-dependent reactions
unrelated to the goal of therapy
E.g. NSAID’s: Upper GI bleed
Beta-agonists (salbutamol): Tremors,
tachycardia
TYPE B (BIZARRE)
 Can be likened to a hypersensitivity or idiosyncratic
reactions.
 Often unpredictable.
 No conventional tests to demonstrate which pts
might experience this ADR in order to theoretically
prevent its occurrence.
 Not dose dependent to the medicine used
TYPE B (BIZARRE)
 Some can occur immediately such as penicillin
hypersensitivity & acute anaphylactic reactions.
 But some can occur at a much later time, even months
later, such as Steven-Johnson due to anti-zeizure
medications such as phenytoin, carbamazepine,
Phenobarbital, or sulfa-containing drug
 Not all cases can be explained by known
pharmacological actions of the suspected drug.
TYPE B (BIZARRE)
• No formal dose-response curve; very small doses of
the drug may elicit the reaction once allergy is
established
• Reaction disappears on discontinuation of the drug
• Illness is often recognizable as an immunological
reaction
• No relation to the usual pharmacological effects of
the drug
Stevens–Johnson syndrome (SJS)
 A life-threatening condition affecting the skin in
which cell death causes the epidermis to separate
from the dermis
 An unusual, severe reaction characterized by
blistering and sloughing of the mucous membranes;
the visceral organs may also be involved, and the
condition can be fatal.
Stevens Johnson syndrome
TYPE B (BIZARRE)
SYNDROMES of TYPE B ADR’s in CLINICAL
PRACTICE
• Connective tissue disease: drug-induced lupus
• Blood disorders: agranulocytosis
• Respiratory disorders
• Fever
• Rashes and skin lesions
IDIOSYNCRACY
• genetically determined abnormal response to a drug
• although dose-dependent, such reactions
are unpredictable in most instances
• cannot be attributed to drug allergy
E.g. Aspirin/sulphonamides
- hemolytic anemia due to erythrocyte G-6PD
deficiency
Drugs and Chemicals Likely to Induce
Hemolytic Anemia in G6PD Deficiency
Dapsone
Furazolidone
Glyburide
Methylene Blue
Nalidixic Acid
Naphthalene
Nitrofurantoin
Primaquine
Spiramycin
Sulfacetamide
Sulfamethoxazole
Sulfanilamide
Toluidine Blue
Trinitrotoluene
C-CONTINUOUS
 This ADR happens after a prolonged use of a drug
even at normal dosage.
 Related to DOSE & duration of treatment
 It affects organ systems.
 Long Term use of Steroids: Cushing’s syndrome
 INH for TB: hepatitis, neuropathy.
D-DELAYED
 Seen when a drug used at some earlier time has
some adverse effects observed much later on, such
as affecting the next generation.
 Diethylstilbestrol taken by women can cause vaginal
& other reproductive organ damage in female
offspring (vaginal CA).
 1960’s thalidomide used by pregnant women
invariably leads to the development of congenital
malformations (phocomelia).
D-DELAYED
• Carcinogenesis
• Teratogenecity
• Immunotoxicity
E-ENDING OF USE
(withdrawal syndromes)
• When a drug that was used on long term is suddenly
stopped, the pt suffers a form of withdrawal reaction.
• These drugs exhibit tolerance phenomenon or have
some dependency potential.
• Examples are: rebound hypertension following sudden
cessation of clonidine, adrenal insufficiency after
stopping prolonged steroid use, seizures from acutely
ceasing anticonvulsants, and uncomfortable withdrawal
syndromes from benzodiazepines and narcotics.
Hypothalamo-Pituitary Regulation of
Cortisol Secretion
Neural Stimuli
Neural Stimuli
Corticotropin
Releasing
Center
Hypothalamus
CRF
Anterior Pituitary
Plasma
Cortisol
Concentration
ACTH
ACTH
Plasma
Cortisol
Concentration
Adrenal Cortex
Type F- FAILURE OF TREATMENT
• Substandard drug
• No actual drug inside
• Toxic excipients
• Tolerance effects
• Antimicrobial resistance
Type F- FAILURE OF TREATMENT
• A new form of ADR recently recognized as a public health
threat.
• ADR monitoring systems can pick up unusual and
unexpected drug inefficacy and can detect possible fake, or
substandard quality medicines.
• Once detected, info can be useful to the drug regulators,
concerned industry & to the institutions that use these drugs.
• Patients’ lives & the public health is the ultimate beneficiary.
• Example: Oxytocin case
Classifying ADR’s accdg to
seriousness and severity
 ADR symptoms can be described as mild, moderate,
severe.
 These are descriptive terms of the intensity of a
particular sign or symptom.
 Serious, on the other hand defines the urgency and the
impending critical threat to the life of the patient or to
an organ-system.
Serious versus severe
 The term “severe” is often used to describe the
intensity (severity) of a specific event (as in mild,
moderate or severe myocardial infarction; the event
itself, however, may be of relatively minor medical
significance
 e.g. a severe headache may not be serious but a
mild stroke resulting in disability is serious
Explaining Risks to Patients
 When doctors explain drug risks to patients, he will
use lay terms.
So how common is common ?
 Common or Frequent is somewhere between 1 in
100 (1%) and 1 in 10 (10%).
 Uncommon or infrequent : between 1 in 1,000
(0.1%) and 1 in 100 (1%)
 Rare is between 1 in 10,000 (0.01%) and 1 in 1,000
(0.1%)
Interventions
 If and when a prescriber suspect an ADR, he is in a
critical position to intervene. The possible
interventions are as follows:
 Stop the drug or Stop all of the drugs (dechallenge)
 Change to another medication
 Maintain the use of the drug.
 Modify the dosages
 Use another medication to modify the ADR
Interventions
 Identify possible drug – drug interactions
 Advise the pt whether to stop or to continue the use of that
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medications depending on risk – benefit considerations.
Report the incident (the collection point for ADE is the
Bureau of Food and Drugs).
Do research.
Establish causality through a system of analysis and
assessment.
Re-instituting the stopped medications should not be done
just to re-affirm a suspicion of ADR as this might be
dangerous (re-challenge).
 The most important thing to remember is always
monitor the patient for the expectant good effects
of the medicines but also look for the possible or
potential negative effects.
Reporting
 While it is not mandatory for health professionals to
report observed ADR cases, in the interest of public
health, it is suggested that all doctors, nurses and
pharmacists report suspected and serious, lifethreatening ADRs.
 These can be the known and the unexpected, to the
Food and Drugs Administration of the Department
of Health using a standard form.
Reporting
 While the incidence may be rare in your
perspective, if there are similar cases that arose in
other areas and are similarly reported, a trend may
be established for further investigations or for
signaling.
 An early warning can save lives. .
Purpose of Safety Reports
 To learn from experience (of others)
 Reporting in itself does not improve safety.
 Collecting data contributes little to pt safety
advancement
 It is the response to reports that leads to change.
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Purpose of Safety Reports
 Within a health-care institution, reporting of a serious
event or serious “near-miss” should trigger an indepth investigation to identify underlying systems
failures and lead to efforts to redesign the systems to
prevent recurrence
 For national/international systems, to recognize
trends and patterns in occurrence of AE’s: generating
safety signals
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Simple Rules to Guide the Prescriber
 Use the lowest dose possible and titrate dose
accordingly (individualized management).
 Don’t be afraid to use a medicine when it is really
indicated just because of the known risk.
 Use as few medicines as possible, because the
incidence of ADRs increases with the number of
drugs
 Following the decision to use medicines, educate
your pt on what to expect and what to do in case of
some untoward events.
Simple Rules to Guide the Prescriber
 The prescriber should monitor both the expected
good and the unexpected bad effects.
 Even the over-the-counter medicines that do not
require a prescription may cause adverse reactions.
 Some doctors are afraid to modify the prescription
of their peers who are co-managing their patient.
 In the interest of patient safety, do not be afraid to
consult your peers if you think that the drugs they
prescribed are suspected to be cause of the ADRs.
Spontaneous Reporting
• identification of rare adverse effects
• monitor newly introduced drugs
• hypothesis generating and raising
signals or flags
• support the regulatory policies
• contribute to improvement in health
policies and practices
• reports are not admission of causality