Pharmacology

Adverse drug reactions: causes,

types, pathways and mechanisms
Agnes Kanneh looks at what can happen when an
intervention related to received medication in children
and young people goes wrong
Summary
An adverse drug reaction is defined as an
appreciably harmful or unpleasant reaction resulting
from an intervention related to having received
medication. This article describes adverse drug
reactions in children and young people, their causes,
types, pathways and mechanisms. Part two, to be
published in June, will address the rights of those
who are offered and receive prescribed drugs.
Keywords
Drugs: adverse reactions, risks and benefits,
prescribing, toxicity, immune reaction
THE MANAGEMENT of medicines prescribed to
children and young people brings many challenges
and rewards; the spectrum of clinical outcomes
ranges from successful, uneventful therapy to poor
response, and the child or young persons experience
of adverse drug reactions (ADRs). Iatrogenic, or
treatment-induced illness, cannot always be predicted
or prevented, and possible therapeutic benefits and
risks should be considered in paediatric as in adult
drug therapy. Aronson and Ferner (2005) define
an ADR as an appreciably harmful or unpleasant
reaction, resulting from an intervention related to the
use of a medicinal product.
Almost 10 per cent of inpatient children and
young people experience ADRs (Sammons and
Choonara 2007), so there is now a recognition of
the need to optimise drug therapy for children and
young people (Rieder 2009, European Medicines
Agency 2009), to promote timely access to
appropriate medicines and to translate relevant
knowledge into practice (Gazarian 2009). Childrens
nurses roles, responsibilities and accountability
NURSING CHILDREN AND YOUNG PEOPLE

in this area continue to change, from in the past

only administering already prescribed drugs to now
prescribing drugs, leading and educating on their use
(Allen 2009, Bojakowski and Filer 2009). People of
any age who become ill may require medication and,
as risk-free drug treatment cannot be guaranteed,
Ritter (2009) proposed that the balance between
benefit and harm is key rather than an unachievable
ideal of absolute safety.

Drug interactions and adverse effects

Drug interactions can be pharmacokinetic in the
bodys drug-handling process or pharmacodynamic
in the actions, effects and adverse effects of what is
administered. One drug can inhibit the elimination or
potentiate the action of another, interactions which
can be used to advantage but can also increase the
risk of ADRs. Food or drink consumed, or other
substances present in the body, may also affect the
action of a particular medicine. These phenomena are
summarised in Box 1 (page 24).
Such interactions can be synergistic, antagonistic
or cumulative. Printed information on specific
product characteristic alerts practitioners to, and
aims to protect the recipient from, ADRs by listing
contraindications and instructions and specific drug
information to safeguard each pharmacotherapeutic
intervention (Martinbiancho et al 2007). The practical
implications are listed.
Manufacturers instructions and information from
pharmacists These should be heeded to ensure
safety, efficacy and quality of medicinal products
and drugs in relation to safe storage, preparation
and administration. Haphazard procedures can
destabilise the physical structure and chemical
integrity of drug molecules, thereby increasing the
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Pharmacology
Figure 1 Drug pathways through the body on administration, influenced by
the route used
Stomach
Small intestines
First-pass metabolism
Oral drugs or
medicines

Liver

Rectal
Subcutaneous
Intrapulmonary
Intramuscular
Bound to plasma proteins

Intravenous

Systemic circulation
Free/active/unbound

Free/unbound
Drug at target sites

Liver
Biotransformation

Intended
action

Oxidation
Reduction
Hydrolysis
Conjugation

Excretion by kidneys

Box 1 Factors affecting the action of medicines

Handling processes during storage or
administration.
Physical and chemical characteristics
of the substances concerned and their
pharmacodynamic effects.
Competition with other drugs or substances
present in the body.
The individual characteristics (genetic factors, age,
sex, history) and health status, including atopic
tendencies of the person receiving the drug.
tablets or opening capsules that should be
administered whole (Conroy 2003, Napoleone
2010).
Polypharmacy This raises the risk of ADRs because
drugs may compete with each for receptor sites
or reduce, increase or alter each others effects
(Paediatric Formulary Committee 2010). Multiple
drug therapies are no longer common practice
in the care of children and young people, as in
the treatment of childhood epilepsy for example
(Wheless et al 2007).
Individual characteristics Individuals are unique
and variations in their responses in terms of
efficacy, toxicity and ADRs to medication are
related to their genetic inheritance, age, sex and the
environment in which they live (Yong et al 2006,
Zopf et al 2008, Becker and Leeder 2010). For these
reasons, a thorough medical history and clinical
assessment before initiating drug therapy are crucial
in medicines management. Otherwise important
details, such as past serious ADRs and allergies, can
be missed.

Drug pathways
Urine
* Clearance occurs via the
kidneys for most drugs
risk of abnormal reactions leading to ADRs. Errors
may include the following:
Using the wrong diluents/admixtures for
intravenously (IV) administered drugs.
Not protecting IV infusion fluids from light, heat
or cold as indicated.
Not checking the expiry dates of drugs or
IV fluids to ensure their validity.
Not checking infusion solutions for particulates
before commencing the IV therapy.
Crushing enteric-coated or sustained-release
24 May 2011 | Volume 23 | Number 4

Depending on their route of administration, drugs

take specific pathways to access their site of
action and to be removed from the body (Figure 1).
Readers are referred to Kanneh (2002), Conroy
(2003), Costello (2007) for details of paediatric
pharmacokinetics and pharmacodynamics. When
received orally, drugs react and relate to the
processes of digestion and absorption as well as
distribution, metabolism and elimination. The oral
route is the most common for children, as for adults,
and will be dealt with in this article.
Administration and absorption Any
physiological or pathological state that affects
the gastrointestinal tract, any oral intake that
alters gastric pH, residual food or drink and any
condition causing decreased or increased transit
NURSING CHILDREN AND YOUNG PEOPLE

time can cause ADRs in per oral medication.

The bioavailability of drugs received by different
routes varies, so that different dosages apply
to different routes, such as the oral versus
intravenous route. Failure to observe the stipulated
three to five minutes for bolus intravenous
drug administration (UCL Hospitals Pharmacy
Department 2010), for example, can cause toxicity
or speed shock, where a large concentration of the
drug accesses organ systems in a short period.
Distribution For the medication to reach its site
of action and be eliminated from the body after its
intended action, appropriate distribution around
the body is essential. Hence, effective hydration
and a functional circulatory system are important.
Caution should therefore be exercised in repeated
drug administration to anyone with circulatory
compromise, because toxic ADRs can occur when
normal circulation is subsequently restored. The
nutritional state of the person also matters because
reduced plasma proteins can mean reduced binding
sites for drugs. Diseases that cause plasma protein
loss similarly alter drug-binding capacity. This
raises the amount of unbound, active drug thereby
increasing the risk of toxic ADRs.
Metabolism Cellular components are the target sites
of action for many manufactured drugs which, if
fat-soluble, have easy access through the lipid bilayer
of cell membranes. Fat-soluble drugs then need to
be metabolised into a water-soluble form to prevent
repeated diffusion back into the bloodstream. The
metabolism of 70 to 80 per cent of prescribed drugs
is carried out in the liver by a group of enzymes
called cytochrome P450s (CYP450) (Bennett and
Brown 2008). Genetic influences altering these
enzymes, or inhibition of an enzyme by another
drug, can disturb metabolism and cause ADRs
(Fattahi et al 2005, Clemerson and Payne 2008). In
the presence of liver immaturity or disease where the
organs metabolising capacity is reduced, or in severe
renal impairment where there is low renal excretory
capacity, risk for ADRs is increased (Campoy and
Elwell 2005).
Elimination Once metabolised into the water-soluble
form, most drugs are excreted from the body via the
kidneys in urine. Thus, caution is required in infancy,
while kidney function is immature, and in any case
of renal impairment. Specific guidelines (British
National Formulary for Children 2010) highlight the
crucial role of clinical assessment and monitoring
of circulatory, hepatic and renal capacity in safe,
effective drug therapy.
NURSING CHILDREN AND YOUNG PEOPLE

Caution should be exercised in repeated

drug administration to anyone with
circulatory compromise
Classification of adverse drug reactions
Drug interactions are conventionally described in
terms of types and mechanisms (Middleton 2006).
Knowledge, understanding and awareness of these
enable the practitioner to monitor drug therapy and
detect ADRs.
Types of adverse drug reactions Type A ADRs
are an extension or augmentation of the normal
pharmacological actions and effects of a substance.
They are usually identified in the drug development
phase and are therefore known at the time of
marketing authorisation. They are predictable and
dose related and made evident in the labelling and
other information (Pirmohamed and Park 2003).
Type B ADRs These are relatively uncommon, cannot
be predicted from the known pharmacology of the
drug and are not dose related. Immunological or
idiosyncratic ADRs fall into this category. They are
detected in the pharmacovigilance phase of the
drugs shelf-life by spontaneous reporting via the
yellow card scheme, for example.
Type C ADRs These relate to the cumulative toxic
effects of a drug used over time. The adverse effects
increase gradually.
Type D ADRs These are rare and only become
evident some time after the treatment has been
completed.
Type E ADRs These relate to the effects of abrupt
withdrawal of a drug that is being received long term.

Mechanisms of adverse drug reactions

Direct cytoxicity The toxic effects of a compound
or its metabolites can manifest in various organ
systems, inducing noxious chemical reactions,
physiological dysfunction, DNA damage or injury
to cellular structures and tissues (Holt and Ju 2006,
Zaccara et al 2007, Tarantino et al 2009, Elbe and
Savage 2010).
Hypersensitivity The individuals immune system
shows an exaggerated response to a drug or its
metabolites. Hypersensitivity reactions include
allergies, but previous exposure to the drug is not
a prerequisite in hypersensitivity (Schnyder and
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Pharmacology
Pichler 2009). Anaphylaxis, a severe systemic form of
immunoglobulin E-mediated type 1 hypersensitivity,
is an example of a severe immune-mediated ADR
that can occur in penicillin therapy in susceptible
individuals.
The results of direct cytotoxicity or an excessive
immune reaction, or both, manifest most commonly
in the skin, liver, lungs, bone marrow and kidneys
(Holt and Ju 2006, Roujeau 2006, Zaccara et al
2007). A macular, papular or vesicular rash may
follow administration of the drug; monitoring
of liver and kidney function may show varying
degrees of damage, particularly in polypharmacy
or recreational drug misuse; pneumonitis or
interstitial fibrosis of the lungs can occur in some
drug regimens; and bone marrow dysfunction may
be found in others.
Effective integration of theory and practice and
the application of the content of this article can help
to safeguard the child and young person requiring
drug therapy, as well as the professional standing of
the practitioner.

Conclusion
No drug is completely safe so the possibility of ADRs
must always be borne in mind during drug therapy.
Drug interactions and ADRs can be pharmacokinetic
and pharmacodynamic in nature. They exist in various
types and mechanisms that depend on the individual,
their health status and environmental factors. ADR
classification can vary from immune-mediated
to that experienced on the sudden withdrawal of
medication in chronic disorders, such as epilepsy.
Knowledge, understanding, integration and the
application to practice can help promote positive
pharmacotherapeutic outcomes, especially in current
times when the practitioner is expected to engage in
informed, up-to-date, evidence-based practice.
This article has been subject
to open peer review and
checked using antiplagiarism
software

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Agnes Kanneh is visiting lecturer

in applied biological sciences,
School of Community and Health
Sciences, City University, London

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