Unit: 5 ADVERSE DRUG REACTIONS (ADRs)

Definition:
Adverse Drug Reaction (ADR):
Any noxious(harmful, poisonous, or very unpleasant) change which is suspected to be
due to a drug, occurs at doses normally used in man, requires treatment or decrease in dose or
indicates caution in future use of the same drug.
World Health Organization (WHO) defined as Adverse Drug Reaction as: “Any
response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis,
diagnosis or therapy of disease or for the modification of physiological functions.” It excludes
ADRs due to overdose of medicine.
American Society of Health-System Pharmacists (ASHP) defines ADR as:
“Any unexpected, unintended, undesired, or excessive response to a drug that requires
discontinuing the drug (therapeutic or diagnostic), requires changing the drug therapy, requires
modifying the dose (except for minor dosage adjustments), necessitates admission to a hospital,
prolongs stay in a health care facility, necessitates supportive treatment, significantly
complicates diagnosis, negatively affects prognosis, or results in temporary or permanent harm,
disability, or death.”

Basically, it is defined as any undesired or unwanted effect of drug.

History about ADRs

1. In 1922: Jaundice associated with the use of Salvarsan, an organic arsenical used in the
treatment of Syphilis.
2. In 1937: In USA, 107 people died from taking an elixir of sulfanilamide that contained
the solvent diethylene glycol Establishment of the FDA, which was given the task of
enquiring into the safety of new drugs before allowing them to be marketed. .
3. In 1958: Thalidomide marketed in West Germany as a non barbiturate hypnotic & for
morning sickness during pregnancy based on animal toxicity report. In 1959-61
thalidomide disaster (4000-100000 case). In 1959 - 1961, it was reported in that there was
an outbreak of Phocomelia (hypo plastic and aplastic limb deformities) in the new born
babies.

Significant risk factors for ADRs / Factors affecting ADRs:

1. AGE: ADR can occur in any age group but the very young and the very old people are
particularly vulnerable to ADR because they have the ever changing body physiology.

2. GENDER: Females have 1.5 to 1.7 fold greater risk of developing ADR compared to
males due to changing hormonal level during menstruation, pregnancy and lactation.

3. POLYPHARMACY: The number of concurrent medicine prescribed particularly

without indication increases the risk and severity of ADR. More the medicine taken more
 the chances of developing ADRs due to drug interaction. Unfortunately the patient with
co-morbid condition has to receive more number of potent drugs for long period of time.
4. TYPE OF MEDICINE BEING ADMINISTERED: All the drugs are capable of
causing ADRs. However studies suggested that the drugs with narrow therapeutic index
like antibiotics, narcotic analgesic, anticonvulsants, anticoagulants, psychotherapeutic
drugs and cardiovascular drugs are potential group of developing ADRs in recipients.
Examples includes, aminoglycosides, some anticonvulsants, digoxin, heparin,
theophylline, and warfarin, phenytoin etc.
5. DOSE AND DURATION OF THERAPY: The greater the degree of drug exposure
with especially high dose and for long duration the greater the likelihood an ADR will
occur.
6. FORMULATION OF MEDICINE: ADRs can occur due to excipients in
pharmaceutical formulation. Example coloring agents, Sweeteners, preservatives or due
to contaminants.
7. ETHINICITY AND GENETICS: It is well known that there are inherited or genetic
differences to drug response. Response may vary from minimal effects to the desired
therapeutic response to an untoward result, manifested as an ADR. This is because of
differences in the genes encoding for the drug metabolizing enzymes, drug transporters,
or the drug targets. Example: primaquine, sulfonamides and nitrofurantoin are
contraindicated in the patients with absence of enzyme Glucose -6 phosphate
dehydrogenase because a severe reaction can occur, resulting in hemolytic anemia.

Classification of ADRs
1. Depending on Onset of event:
a. Acute (<60 minutes)
b. Sub-acute (1-24 hrs) and
c. Latent (>2 days)
2. Depending on Severity:
a. Minor ADRs
These are very simple reactions and here no therapy, antidote or
prolongation of hospitalization is required.
b. Moderate ADRs
This requires change in drug therapy, specific treatment or prolongs
hospital stay by atleast 1 day.
c. Severe ADRs
These are potentially life threatening reactions and cause permanent
damage or require intensive medical treatment.
d. Lethal ADRs
These types of reactions directly or indirectly contribute to death of the
patient.

3. Depending on the Type of reaction: According to Wills and Brown, basically the
ADRs are classified into two groups:-
a. Type A (Augmented)
b. Type B (Bizarre)
Further the ADRs are classified as
 c. Type C (Continuous use of medicine)
d. Type D (Delayed type )
e. Type E (End of the treatment)
f. Type F (Failure of therapy)
g. Type G (Genotoxicity)
h. Type H (Hypersensitivity)
i. Type U (Un classified)

1. Type-A reactions ( predictable or Augmented): these are based on the

pharmacological properties of the drug, which means that they are augmented, but
quantitatively normal response to the drug; include side effects, toxic effects and
consequences of drug withdrawal. They are more common, dose related and mostly
preventable and reversible. Eg. Bleeding due to use of anticoagulants .
2. Type-B reactions (unpredictable or Bizarre) : these are based on peculiarities of the
patient and not on drug’s known action; includes allergy and idiosyncrasy. They are less
common, often non-dose related, generally more serious and require withdrawal of the
drug. eg anaphylactic reactions due to use of penicillins.
3. Type-C reactions (continuous or long term) : type-C or continuing reactions, persists
for a relatively long time. An example is osteonecrosis of the jaw with bisphosphonates.
4. Type- D reaction: type-D or delayed reactions can occur after many years of treatment.
It is because of the accumulation drug and its metabolites in the body. E.g.
Chemotherapy. An example is leucopenia, which can occur up to six weeks after a dose
of lomustine(anticancer drug).
5. Type-E reactions: type-E reactions or end-of-use reactions are associated with the
withdrawal of a medicine, especially when drug is stopped abruptly. An example is
insomnia, anxiety and perceptual disturbances following the withdrawal of
benzodiazepines.
6. Type-F reactions or failure to therapy. eg antitubucular drug use.
Prevention of ADRs
Adverse drug effects can be minimized but not altogether eliminated by observing the
following practices:
• Avoid all inappropriate use of drugs.
• Use appropriate dose, route and frequency of drug administration based on patient’s
specific variables.
• Take into consideration previous history of drug reactions and history of allergic
diseases.
• Rule out possibility of drug interactions when more than one drug is prescribed.
• Perform TDM for the drugs with narrow therapeutic index drugs. Eg lithium, phenytoin,
etc
• Adopt correct drug administration technique (e.g. Intravenous injection of vancomycin
must be slow).
• Carry out appropriate laboratory monitoring (e.g. prothrombin time with warfarin, serum
drug level with lithium).

Management of ADRs
If it is non-immune ADR, then following steps should be followed for its management:
Step1: Drugs should be modified.
Step2: Alternative drug should be used.
Step3: Prophylactic regimen should be considered
 (if seen to be effective).
Step4: Patient/Physician education.

Some Examples of Drug induced diseases

Teratogens and Teratogenicity
Any substance that can induce or increase the incidence of a congenital malformation/
abnormalities when a pregnant women taken for any purpose is called teratogens.

The nature/ property/ character of a substance (Teratogens) which cause congenital

abnormalities in fetus when a pregnant women taken for any purpose is called teratogenicity.
The abnormalities may be hampering in fertilization & implantation (conception to 1 month),
hampering in organogenesis (1month to 2 month of gestation) and hampering in growth &
development (3 months to 9 months). So it is better to avoid to prescribe or take teratogenic
substances/ drugs either during or prior to conception except some safe drugs.

Some example of teratogenic drugs:

Photosensitivity
Photosensitivity is a skin problem that is triggered when expose to sunlight. It is an
immune system reaction where drugs or its metabolites accumulate in skin. When the skin is
exposed to sunlight there is photochemical reaction between UV light and accumulated drug on
skin that results some allergic reaction including redness of skin, itching, blistering, swelling etc.
The shorter UV light with wavelength 200-300nm cause phototoxicity and the longer UV light
with wavelength 300-400nm cause photoallergy. For example some drugs like Tetracycline,
doxycycline, nalidixic acid, voriconazole, amiodarone etc cause photosensitivity reaction. To
avoid this type of problem it is better not to expose to sunlight during therapy or use some
sunlight blocking creams.

Secondary Effects of drugs

It is the secondary effect of drug in place of primary action of drug. This type of ADR is due to
misuse and over use of some drugs.

For example when tetracycline is used for bacterial infection but due to over/misuse of this drug
cause reduction in bacterial microflora results superinfection.

Idiosyncrasy
It is the type of ADR that is caused due to genetically determined abnormal reactivity in
recipient when a drug id used. Here drug interacts with some unique features of individuals that
produce uncharacteristic reaction which is not found in majority of people. For example
Chloramphenicol cause aplastic anaemia in some patients, barbiturates cause mental confusion or
excitement in some patients.

Drug Dependence
It is property of some drugs that produces a state in which person believes that
continuous use is necessary for state of well being ( psychic dependence) or to avoid withdrawal
symptoms ( physical dependence.) i.e. these type of drugs form habit in recipients. Here repeated
administration of drug required to maintain physiological behavior. For example Opiods,
Benzodiazepines, Alcohol, Barbiturates produces dependence in recipients.

Drug Allergy/Hypersensitivity
It is an immunologically mediated allergic response occurs when sensitised individuals
are re-exposed to same drug again and again. Here drug acts as antigen and body system acts as
antibody. So there are antigen-antibody reaction results some allergic reaction such as rashes,
itching, blistering, swelling, anaphylactic shock etc. For example penicillin group of medicine
cause drug allergy in some individuals.
 Drugs Drug Induced Skin Diseases
Antibiotics(Penicllin) Urticaria
➢ Sulphonamides, barbiturates, lamotrigine and phenyl- Stevens–Johnson syndrom
butazone

Sulphonamides barbiturates, phenylbutazone and para- Toxic Erythema

aminosalicylate (PAS).
Penicillin, sulphonamides, neomycin, phenothiazines and Eczema
local anaesthetics
Paracetamol, trimethoprim-sulfa, Non-steroidal anti- Fixed Drug Eruption
inflammatory drugs (NSAIDs; including aspirin),
Some anticoagulants and antithyroid drugs Alopecia

Pharmacovigilance
Pharmacovigilance (PV or PhV), also known as drug safety, is the pharmacological science relating to
the collection, detection, assessment, monitoring, and prevention of adverse effects of the
medicine. Simply this is ADR monitoring tool.

The etymological roots for the word "pharmacovigilance" are: pharmakon (Greek for drug)
and vigilare (Latin for to keep watch)

According to WHO, Pharmacovigilance (PV) is defined as“the science and activities relating to the
detection, assessment, understanding and prevention of adverse effects or any other drug-related
problem.” WHO established its Programme for International Drug Monitoring in response to the
thalidomide disaster detected in 1961.

The aims of Pharmacovigilance are

• To promote rational and safe use of medicines

• To promote education and clinical training
• To contribute to the assessment of benefit, harm ,effectiveness and risk of medicines
• To improve public health and safety
• To enhance patient care and patient safety in relation to the use of medicines
• To support public health programmes by providing reliable, balanced information for the
effective assessment of the risk-benefit profile of medicines.

Pharmacovigilance In Nepal
Government of Nepal nominated Department of Drug Administration (DDA) in October
2004 as the focal point (National Pharmacovigilance centre) to liaison with WHO collaborating
centre for International Drug Monitoring, Sweden and started collecting adverse drug reactions.
Nepal became a WHO programme full member in July 2007.
At present, there are 13 regional pharmacovigilance centers in Nepal

1. Tribhuvan University Teaching Hospital, Maharajgunj

2. Civil Service Hospital, Minbhawan
3. Manipal Teaching Hospital, Pokhara
4. KIST Medical College, Imadol
5. Nepal Medical College Teaching Hospital, Jorpati
6. Patan Hospital, Lalitpur
7. B.P Koirala Institute of Health Science (BPKIHS), Dharan
8. Dhulikhel Hospital, Banepa
9. Shree Birendra Hospital, Chhauni
10. Norvic International Hospital, Thapathali
11. Nepal Cancer Hospital and Research Center, Harisiddhi
12. College of Medical Sciences - Teaching Hospital
13. Chitwan Medical College, Bharatpur Chitwan
Recently Kathmandu Medical College & Teaching Hospital, Kathmandu and Grande
International Hospital, Kathmandu have also established a pharmacovigilance centre.

Process of ADR monitoring

These regional pharmacovigilance centers operate under DDA (DDA being the National
centre for ADR monitoring). The regional centers reports ADRs to the National center (DDA)
via ‘Vigiflow’ (an online program) which are then forwarded to the Uppsala Monitoring Center
(UMC) Sweden (the international centre) by the National Centre through ‘Vigiflow’. Uppsala
Monitoring Center (UMC) Sweden is the main WHO headquarter for reporting ADRs occurring
throughout the world.

The role of pharmacist in monitoring the ADRs:

1. Analysis of each reported ADR

2. Identification of drugs and patients at high risk for being involved in ADRs
3. The development of policies and procedures for the ADR-monitoring and reporting
program
4. A description of the responsibilities and interactions of pharmacists, physicians, nurses,
risk managers, and other health professionals in the ADR program
5. Use of the ADR program for educational purposes
6. Development, maintenance, and evaluation of ADR records within the organization
7. The organizational dissemination and use of information obtained through the ADR
program
8. Reporting of serious ADRs to the FDA or the manufacturer (or both), and
9. Publication and presentation of important ADRs to the medical community.
 Some Examples of ADR Monitoring

Drug Adverse Reaction Outcome

Sulfanilamide Liver damage due to Solvent changed; FDA
diethylene glycol established
Thalidomide Congenital Withdrawn
Malformations
Chloramphenicol Blood Dyscrasias Uses restricted
Benoxaprofan Liver damage Withdrawn

Aspirin Reye’s syndrome Uses restricted

Flecainide Cardiac Arrhythmias Uses restricted

Noscapine Gene toxicity Withdrawn

Triazolam Psychiatric disorders Withdrawn

Co-trimoxazole Serious allergic Uses restricted

reactions