The World Health Organization (WHO) defines an ADR as “a response to a drug that is noxious and unintended and occurs at doses normally used in man;” this definition was refined about a decade ago to include the concept of error, highlighting that preventative action may help avoid adverse effects. The American Society of Health-Systems Pharmacists (ASHP) guidelines on ADR are monitoring and reporting focuses on comprehensive ADR monitoring and reporting and suggests that methods for ranking ADRs be established.
The ASHP defines significant ADRs as any unexpected, unintended, undesired, or excessive response to a drug that:
1. Requires discontinuing the drug
2. Requires changing drug therapy
3. Requires modifying the drug dose
4. Requires admission to a hospital
5. Prolongs stay in a health care facility
6. Requires supportive treatment
7. Significantly complicates diagnosis
8. Negatively effects prognosis, or
9. Results in temporary or permanent harm, disability, or death
Why
adverse drug reactions?
Large proportions of negative reactions
to medicines are due to irrational use or human error and are therefore
preventable. The main ones are:
- Wrong diagnosis of the patient condition
- Prescription of the wrong drug or wrong dosage of the right drug
- Undetected medical, genetic or allergic condition in the patient which might cause a bad reaction to the drug
- Self-medication
- Lack of adherence to the prescribed course of the drug
- A large number of different drugs being taken by the patient (polypharmacy), which may interact.
However, it is important to remember
that even when the above situations are carefully avoided, all medicines have
side effects and some of those can be damaging. The effects of any medical
intervention cannot be predicted with absolute certainty. No drug is totally
devoid of risk. For all medicines there is a trade-off between the benefits and
the potential for harm.
Classification
ADRs may be classified by e.g. cause
and severity
Cause:
Ø Type A: Augmented pharmacologic
effects - dose dependent and predictable
v Intolerance
v Side Effects
Ø Type C: Chronic effects
Ø Type D: Delayed effects
Ø Type E: End-of-treatment effects
Ø Type F: Failure of therapy
Types A and B were proposed in the 1970 and the other types were proposed
subsequently when the first two proved insufficient to classify ADRs
Seriousness
and Severity:
The American Food
and Drug Administration defines a serious adverse event as one when the patient
outcome is one of the following:
- Death
- Life-threatening
- Hospitalization (initial or prolonged)
- Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
- Congenital anomaly
- Requires intervention to prevent permanent impairment or damage
Severity is a point on an arbitrary
scale of intensity of the adverse event in question. The terms
"severe" and "serious" when applied to adverse events are
technically very different. They are easily confused but cannot be used
interchangeably, require care in usage.
A headache is severe, if it causes
intense pain. There are scales like "visual analog scale" that helps
us assess the severity. On the other hand, a headache can hardly ever be serious,
unless it also satisfies the criteria for seriousness listed above.
PREDISPOSING FACTORS FOR ADVERSE DRUG REACTIONS (ADRs)
Multiple drug therapy
Incidence of ADRs from drug
interactions increase sharply with the number of drugs taken.
Age
The very young and very old are more
susceptible to having adverse reactions. This reflects age related differences
in body composition and in activity of metabolic pathways.
Gender
Women appear to be at greater at
risk of ADRs than men.
Current disease
Drug handling may be altered in
patients with impaired metabolism such as renal or liver impairment. Diseases
in which multiple drug treatment occurs are also associated with greater
likelihood of ADRs.
Pharmacokinetic Differences
There may be increased toxicity from
a drug because of genetic factors (e.g. difference in enzyme activity) or
environmental influences (e.g. high alcohol intake).
Ethnic Differences
Ethnic genetic or dietary
differences may increase the risk of ADRs. Examples include interaction of diet
with glucose 6-phosphate dehydrogenase deficiency; and iron overload resulting
from giving iron supplements to sickle cell patients when they do not need it.
Incomplete Medicines Reconciliation
Medicines reconciliation refers to
the checking of medicines patients are taking, either prescribed, over the
counter, folk medicines, or from other sources.
High risk settings where medicines reconciliation is a problem include
acute presentation to the Accident and Emergency Department and new interactions
within parts of the NHS which may currently hold separate clinic records e.g.
HIV services.
Location
Adverse effects
may be local, i.e. limited to a certain location, or systemic, where a
medication has caused adverse effects throughout the systemic
circulation.
For instance, some ocular antihypertensives cause systemic effects although they are administered
locally as eye drops,
since a fraction escapes to the systemic circulation.
Mechanisms
As research better explains the
biochemistry of drug use, fewer ADRs are Type B and more are Type A. Common
mechanisms are:
- Abnormal pharmacokinetics due to
- Synergistic effects between either
v a drug and a disease
v two drugs
Abnormal
pharmacokinetics
Comorbid
disease states
Various diseases, especially those
that cause renal
or hepatic
insufficiency, may alter drug metabolism. Resources are available that report
changes in a drug's metabolism due to disease states.
Genetic
factors
Abnormal drug metabolism may be due
to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug
reactions.
Phase
I reactions
Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check
for drug interactions due to P450 interactions.
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine.
Phase
II reactions
Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may
affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.
Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.
Protein
binding
These interactions are usually
transient and mild until a new steady state is achieved. These are mainly for
drugs without much first-pass liver metabolism. The principal plasma proteins
for drug binding are:
- albumin
- α1-acid glycoprotein
- lipoproteins
Cytochrome
P450
Patients have abnormal metabolism by
cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check
for drug interactions due to P450 interactions.
Interactions
with other drugs
Synergistic
effects
Limitations of adverse effects reporting
In principle, medical professionals are required to report all adverse effects related to a specific form of therapy. In practice, it is at the discretion of the professional to determine whether a medical event is at all related to the therapy. For example, a leg fracture in a skiing accident in a patient who years before took antibiotics for pneumonia is not likely to get reported.As a result, routine adverse effects reporting often may not include long-term and subtle effects that may ultimately be attributed to a therapy.
Part
of the difficulty is identifying the source of a complaint. A headache in a
patient taking medication for influenza may be caused
by the underlying disease or may be an adverse effect of the treatment. In
patients with end-stage cancer, death is a
very likely outcome and whether the drug is the cause or a bystander is often
difficult to discern.
Examples of adverse effects
associated with specific medications
|
Condition
|
Substance
|
|
aspirin therapy
|
|
|
Cardiovascular disease
|
COX-2
inhibitors (i.e. Vioxx)
|
|
many drugs, such as antidepressants
|
|
|
Vaccination (in the past, imperfectly manufactured vaccines, such as BCG and poliomyelitis, have caused the very disease they intended to fight).
|
|
Monitoring
bodies
Many countries have official bodies
that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala
Monitoring Centre, and the European Union runs the European
Medicines Agency (EMEA). In the United States, the Food
and Drug Administration (FDA) is
responsible for monitoring post-marketing studies.
PREVENTION:
ü
Be aware that you are at an
increased risk of ADR if you are taking two or more medications (and an
extremely increased risk if taking four or more).
ü
Make sure your doctor is aware of your
medication history and drugs you are currently taking -- including vitamins,
herbs and over-the-counter meds. If he or she doesn't ask (though they should),
bring it up and tell them yourself!
ü
If you are taking multiple drugs, ask your
doctors specifically: "Will this new medication interact with X, Y or
Z?" (the medications you're already taking)
ü
Be aware that certain drug categories are
especially risky in terms of interactions. These include:
a. Anticonvulsants
b. Antibiotics
c. Certain cardiac drugs such as digoxin, warfarin,
and amiodarone
ü
When picking up the
prescription, check again with the pharmacist by asking if this drug interacts
with any drug you are already taking, possible side effects, risks, etc.
ü
If you experience any unusual symptoms upon
taking the medication, call your doctor immediately and explain the problem.
THE ROLE OF PHARMACIST:
Medication therapy management (MTM) is a partnership of the pharmacist,
the patient or their caregiver, and other health professionals that
promotes the safe and effective use of medications and helps patients achieve
the targeted outcomes from medication therapy.
MTM was first proposed by Ronald Jordan, former APhA
president. MTM includes the analytical, consultative, educational and
monitoring services provided by pharmacists to help consumers get the best
results from medications through enhancing consumer understanding of medication
therapy, increasing consumer adherence to medications, controlling costs, and
preventing drug complications, conflicts, and interactions. This is the side of
pharmacy giving value to cognitive services and removing the pharmacist from a
solely distributive function. There are many topics/disease states that can be
improved by MTM, including, but not limited to Diabetes, Asthma,
and Elderly Care. A clinical pharmacist will typically provide medication therapy management services through review of a list of medications the patient provides. The things the pharmacist will be looking at include drug interactions, duplications of drugs from the same family, doses, routes of administration, and the formulation the patient is using. This review will also include evaluating medication habits to see where we may be able to optimize the benefit a patient receives.
Medication Therapy Management was coined by Congress in the Medicare Modernization Act of 2003 (MMA 2003). The MMA 2003 established the requirement that each Medicare Part D plan sponsor offer a Medication Therapy Management program to targeted beneficiaries beginning in 2006. At a minimum, targeted beneficiaries include those members with multiple chronic conditions, taking multiple Part D drugs, and likely to incur annual costs for covered Part D drugs that exceed a predetermined level. While plan sponsors are required to offer MTM to these targeted beneficiaries, other patients can also benefit from MTM and many plans have employed MTM programs as a proactive strategy to prevent medication-related complications and associated health care costs by extending the MTM benefit to their full population of members. It is important to also note that MTM may apply to populations outside of Medicare, including patients less than 65 years of age.
The provision of MTM services requires pharmacists to collaborate with both patients and prescribers to resolve medication-related complications. According to guidance set forth by the Centers for Medicare and Medicaid Services (CMS), each MTM-eligible patient should be covered for an annual Comprehensive Medication Review (CMR), inclusive of an interactive, person-to-person consultation. In addition to the annual Comprehensive Medication Review, quarterly targeted medication reviews are also required. Appropriate MTM services should also be provided on an ad hoc basis as medication-related complications are identified.
Improving Reporting in the Hospital
Setting
One of the most important methods to improve reporting is to change the
reporting culture of an institution. This requires a commitment from hospital
administration, management, and individual employees to value and support an
environment that recognizes and rewards AE and ADR reporting. From previous
successful campaigns for hand-washing and other quality measures a good first
step to changing the culture may involve an educational campaign that focuses
on the importance of ADR reporting and specifically addresses complacency,
insecurity, diffidence, indifference, and misunderstanding. All health care
professionals, including physicians, nurses, and pharmacists, should be
included and encouraged to report. Institution-wide presentations (eg, grand
rounds, continuing education courses, and inservices), media campaigns,
advertisements, and personal communications should all be considered.Goal-setting may be used to encourage ADR reporting within a health system. Depending on the institution, reporting goals can be broad or specific, identifying successful reporting by select departments, units, or personnel. Recognition of successful ADR reporting is an important feedback step and its extent and implementation should be determined by the institution.
According to a nationwide survey of hospitals, the most frequently used methods in support of a safety culture included taking a nonpunitive approach to ADEs (84.6%), using errors as an opportunity to learn (75.7%), communicating improvements resulting from reported events (67.6%), sharing reporting rates with staff (53.5%), and making ADEs nondiscoverable by plaintiffs in the course of litigation (48.3%). Other less frequently used methods included modifying performance appraisal instruments to reward reporting (19.1%) and providing incentives to staff for reporting (14.4%). Approximately 2% of hospitals surveyed had none of these measures in place.
Organizations such as the Agency for Healthcare Research and Quality and the Institute for Healthcare Improvement have developed systematic procedures for analyzing ADEs and ADE reporting that can be implemented by institutions. One such tool is Root Cause Analysis (RCA), which is a retrospective error analysis widely applied to the investigation of major industrial accidents.63 The application of RCA allows investigators to potentially uncover common root causes that link a seemingly disparate collection of AEs. RCA is a process-focused framework for identifying and addressing errors without attempting to assign individual blame. Another useful tool is the Failure Mode Effects Analysis (FMEA), which identifies where and how a process might fail and assesses the relative impact of different failures to focus attention on the parts most in need of change. Although FMEA was initially developed outside of health care, it is now being used by hundreds of hospitals.
A “trigger tool” analysis can be performed using an interactive automated program for detecting ADEs using a list of known signal words or “triggers” identified in patient medical records by customized software linked to hospital pharmacy records. This allows for a retrospective, focused assessment of ADEs, tracked over time within an institution, and may be modified to assess ADEs related to specific drugs, including high-risk drugs. The trigger tool analysis can also be performed by reviewing records manually without an automated program. Tracking ADEs over time allows for an assessment of whether implemented changes within an institution are resulting in improved medication safety. In addition, the results of a trigger tool analysis can be compared to an institution’s actual rate of AE reporting, which may provide insight into the degree of underreporting of AEs. Institutions may have dedicated medication safety officers (who could be physicians, pharmacists, or nursing administrators) in charge of developing process changes to improve medication safety and conducting and implementing the findings from RCAs, FMEAs, and trigger tool analyses. The medication safety officer also serves as the champion for an institution’s drug safety program, including medication error data management, trending, and benchmarking.
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