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Adverse Drug Reactions

- Adverse Drug Reactions (ADR) are unwanted effects
caused by normal therapeutic doses, which may
present with various clinical signs and symptoms
- Drugs are great mimics of disease
- Adverse drug reactions are due to specific drug-drug
- Type A Reactions
o Constitutes approximately 80% of ADR
o Consequence of a drugs primary pharmacologic
effect or a low therapeutic index (extension of
drugs pharmacology)
o Dose-related
o Usually mild (but could also be serious and fatal)
o Usually due to inappropriate dosage
o Side effects are very mild type A reactions
o Accounts for most number of adverse reactions
o Responsible for 2-3% of consultations in general
- Type B Reactions
o Idiosyncratic
o Not predictable from the main pharmacologic
action of the drug
o Not dose-related
o Severe, with considerable mortality
- Type C Reactions
o Continuous reactions due to long-term drug use
- Type D Reactions
o Delayed reactions
- Type E Reactions
o End-of-use reactions
- Adverse drug reactions are frequent and severe in the
elderly, neonates, women, patients with hepatic or
renal impairment, and individuals with previous
history of adverse drug reactions

Identification of the Drug at Fault

1. Careful drug history
- Assesses causality of the effect to the drug
- Clinical event
- Time-course of development
- Did the effect disappear upon withdrawal and
reappear when given?
2. Provocation testing
- Taking in a small amount of the drug and seeing
whether a reaction occurs
- Skin testing
o Patch testing safe; useful for diagnosis of
contact sensitivity; does not reflect systemic
reactions; may cause allergy
o Prick and scratch testing not useful for
systemic reaction assessment; for topical
3. Serologic/Lymphocyte Testing
4. The best approach in patients undergoing multiple
drug therapy is to stop all potentially causal drugs and
reintroduce them one by one to identify which drug is
at fault.

Adverse Drug Reaction Monitoring or Surveillance

Phase I/II/III Trials
Phase I and II (early) trials assesses the tolerability and
dose-response relationship of new therapeutic agents,
but are insensitive to detecting adverse reactions
Phase III clinical trials establishes the incidence of
common adverse reactions and relate them to the
therapeutic benefit
Example: Thalidomide caused spontaneous
phocomelia, and an estimated 10,000 malformed
babies were born before it was pulled out of the

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Yellow Card Scheme and Post-Marketing (Phase IV)
Untoward effects that have nor been detected in
clinical trials become apparent when the drug is used
on a wider scale
Case reports remain the most sensitive means of
detecting rare, serious, and unusual adverse effects
3 stages:
o Data Collection
o Analysis
o Feedback
Relatively inexpensive, easy to manage, and facilitate
ongoing monitoring of all drugs, all consumers, and all
types of adverse reactions
The pharmaceutical company is responsible for
obtaining accurate reports on all patients treated with a
Example: Rofecoxib-induced cardiovascular
thrombolytic events including MI; photosensitivity and
onycholysis caused by benoxaprofen

Case-Control Studies
A large number of patients is monitored to detect a
rare Type B reactions
Identification of patients with a disorder postulated to
be caused by the drug, and to compare the frequency
of exposure to possible etiologic agents against a
control group
Example: stilboesterol with vaginal adenocarcinoma,
gatifloxacin with hypo/hyperglycemia, and salmeterol
or fenoterol use with increased fatality in asthmatics

Intensive Monitoring
Aberdeen-Dundee System
o Data from 70,000 hospital admissions are
abstracted and stored on a computer file before
Boston Collaborative Drug Surveillance Program
o All patients admitted to specifically designated
general wards
o Information on:
! Background information
! Medical history
! Drug exposure
! Side effects
! Outcome of treatment and changes in the
laboratory tests during hospital admission
o Follow up and investigate adverse reactions
suggested by less sophisticated detection systems
or by isolated case reports published in medical
o Example: the development of a rash in 7% of
those taking ampicillin was found in the BCDSP
(and clinical trials) by association of file data.
o There is possible chance associations arising from
multiple comparisons (Type I statistical error) "
need for critical review before accepting causal
The number of patients on intensive monitoring while
taking a drug will be too small making the detection of
new but uncommon adverse reactions too small for the
effect to be detectable

Monitoring from National Statistics
Data from death certificates, hospital discharge
diagnoses, or other similar records
Detects change in disease trends in relation to a
particular drug therapy
Large numbers of patients must suffer before any
change is detected
Data interpretation often difficult due to
incompleteness and provisional status of discharge

Analysis and conclusions are reported back to
prescribing doctors
Medical journals and media
If any acute/serious adverse drug reaction identified,
prescribing doctors are given notice via the MHRA or
the Commission on Human Medicines, or through the
pharmaceutical company marketing the drug.

Allergic Adverse Reactions

- Immune mechanisms are involved in a number of
adverse effects caused by drugs
- Allergy development " previous drug exposure or
some closely related substance
- Drugs are usually of low molecular weight (non-
antigenic) but they can combine with high molecular
weight entities " antigenic hapten conjugate
- Drug allergies are more common in older people,
women, and those with previous history of drug
- A single drug can be responsible for more than one
type of allergic response

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Type I Reactions
Due to the production of reaginic (IgE) antibodies to
an antigen
Antigen binds to surface-bound IgE on mas cells
leading to degranulation and release of histamine,
eicosanoids, and cytokines
Occurs in response to a foreign serum or penicillin
(could also occur with streptomycin)
There is massive local or systemic release of mast cells

Type II Reactions
Dues to antibodies of class IgG and IgM, which on
contact with antibodies on the surface of cells, bind
complement, causing cell lysis by complement fixation

Type III Immune Complex Arthus Reactions
Several clinical allergic states due to circulating
immune complexes
Example: serum sickness and immune complex
Mediated by immune complex-related mechanisms
that are not well understood
Immune complexes are deposited in organs causing
drug fever, urticarial, rash, lymphadenopathy, and

Type IV Delayed Hypersensitivity Reactions
Delayed reactions due to local or systemic
administration of drugs
Due to drug forming an antigenic conjugate with
dermal proteins and sensitized T cells reacting to the

Prevention of Allergic Drug Reactions

1. Detailed drug history
2. Drugs taken orally are less likely to cause severe
allergic reactions than those given by injection
3. Desensitization must only be used when there is a
need for continued drug use.
Involves giving a very small dose of the drug
and increasing it at regular intervals under
cover of a glucocorticosteroid and a B2-
adrenoceptor agonist
Antihistamine is administered in the presence
of a drug reaction
Must be done with a resuscitation and therapy
for anaphylactic shock close at hand
4. Prophylactic skin testing is not usually practicable;
negative test does not exclude the possibility of an
allergic reaction

Examples of Allergic and Other Adverse Drug

One of the most common manifestations of drug
Involves a number of immune and non-immune
mechanisms producing anything from mild
maculopapular rash to severe erythema multiforme
May be due to: B-lactams, sulphonamides,
antimicrobial agents, antiseizure medications, and

Lymph node enlargement
Due to a number of allergic factors

Blood Dyscarias
o Direct suppression of the megakaryocytes
o Occurs with: heparin, gold salts, cytotoxic agents,
quinidine, sulphonamides, and thiazides
Hemolytic anemia
o Caused by a number of drugs
o Immune mechanisms may be responsible
o Immune Mechanisms:
! Combination of the drug with the red cell
membrane, with the conjugate acting as an
antigen (occurs in penicillin-induced
hemolysis, or with chlorpromazine and
! Alteration of the red cell membrane by the
drug, making the red cell antigenic (occurs
with methyldopa, levodopa, mefenamic acid,
and beta-lactam antibiotics)
! Non-specific binding of plasma proteins to red
cells causing hemolysis (occurs with
Glucose-6-phosphate deficiency may predispose to
non-immune hemolysis
Aplastic Anemia
o Not common as an isolated entity
o May occur either in isolation or as a part of
general depression of bone marrow activity
o Occurs with chloramphenicol and cytotoxic drugs
o Caused by a variety of drugs including: cytotoxic drugs,
antithyroid drugs, suplhonamides and sulphonylureas,
antidepressants, antipsychotics, and anti-epileptic drugs
o No known link to allergy, and involves different

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Systemic Lupus Erythematosus (SLE)
Drugs like procainamide, isoniazid, hydralazine,
chlorpromazine, and anticonvulsants may produce
symptoms that resembles SLE
Development is closely associated to dose
The drugs act as haptens, combining with DNA and
forming antigens
Symptoms cease when drug is stopped

Acute vasculitis with purpura and renal involvement
could occur with penicillins, sulphonamide, and
Chronic vasculitis can occut with phenytoin

Renal Dysfunction
Nephrotic syndrome can be caused by several drugs
that causes immune-mediated glomerular injuries
Interstitial nephritis can be caused by non-steroidal
and anti-inflammatory drugs and penicillin (meticillin)
Direct tubular toxicity caused by Cisplatin,
aminoglycosides, amphotericin, radiocontrast media,
and vancomycin
Some drugs may cause electrolyte or acid-base
disturbances because of their direct or indirect effects
on the renal electrolyte excretion
Some drugs may cause unpredictable toxic effects on
acid-base balance
Obstructive uropathy can occur by uric acid crystals,
which formed as a consequence of chemotheraphy in
patients with hematological malignancies and those
who take in poorly soluble drugs

Other Reactions
Fever is a common manifestation of drug allergy
Liver damage as a side effect of drug intake may be
insidious (leading slowly to end-stage cirrhosis) or
acute and fulminant.
Chlorpromazine and erythromycin may lead to
increases in alkaline phosphatase and bilirubin
Gallstones may occur as a consequence of taking
fibrates and other lipid-lowering drugs or by
octreocide (somatostatin analog used to treat
enteropancreatic tumors)

The greatest enemy of knowledge is not ignorance; it
is the illusion of knowledge.
- Stephen Hawking