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An adverse drug reaction (ADR) is a harmful, unintended result caused by taking
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
. ADRs may occur following a single dose or prolonged administration of a
drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhala ...
or result from the combination of two or more drugs. The meaning of this term differs from the term " side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as '' pharmacovigilance''. An adverse drug event (ADE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not associated with the administration of the drug. An ADR is a special type of ADE in which a causative relationship can be shown. ADRs are only one type of medication-related harm, as harm can also be caused by omitting to take indicated medications.


Classification

ADRs may be classified by e.g. cause and severity.


Cause

*Type A: Augmented pharmacologic effects - dose dependent and predictable :Type A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drug's primary pharmacological effect (e.g. bleeding when using the anticoagulant
warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
) or a low
therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
of the drug (e.g. nausea from
digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is o ...
), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term 'side effects' is often applied to minor type A reactions. * Type B: Idiosyncratic Types A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.


Seriousness

The U.S
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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 abnormality * 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 can not be used interchangeably, requiring care in usage. A headache is severe if it causes intense pain. There are scales like "visual analog scale" that help clinicians assess the severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above.


Location

Adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...
s may be local, i.e. limited to a certain location, or systemic, where medication has caused adverse effects throughout the
systemic circulation The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, t ...
. For instance, some ocular antihypertensives cause systemic effects, Page 146 although they are administered locally as
eye drop Eye drops or eyedrops are liquid drops applied directly to the surface of the eye usually in small amounts such as a single drop or a few drops. Eye drops usually contain saline to match the salinity of the eye. Drops containing only saline ...
s, 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 ** genetic factors **
comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...
disease states *
Synergistic Synergy is an interaction or cooperation giving rise to a whole that is greater than the simple sum of its parts. The term ''synergy'' comes from the Attic Greek word συνεργία ' from ', , meaning "working together". History In Christia ...
effects between either ** a drug and a disease ** two drugs * Antagonism effects between either **a drug and a disease ** 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. The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia ( MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms.


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
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...
s of
cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
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 The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders (e.g., Crohn's disease, rheumatoid arthritis), and organ transplant recipients. Metabolism is catalyzed by S-meth ...
drugs mercaptopurine and azathioprine.


Interactions with other drugs

The risk of drug interactions is increased with polypharmacy.


=Protein binding

= These interactions are usually transient and mild until a new steady state is achieved.OVID full textsummary table at OVID
/ref> These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: #
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Album ...
# α1-acid glycoprotein # lipoproteins Some drug interactions with
warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
are due to changes in protein binding.


=Cytochrome P450

= Patients have abnormal metabolism by
cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
due to either inheriting abnormal
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...
s or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.


Synergistic effects

An example of synergism is two drugs that both prolong the
QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...
.


Assessing causality

Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply. An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR. Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies some ADRs may be missed as large numbers of test individuals are required to find that adverse drug reaction. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population.


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 The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are located primarily in Europe, Europe. The union has a total area of ...
runs the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...
(EMA). In the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
, the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) is responsible for monitoring post-marketing studies. In Canada, the Marketed Health Products Directorate of Health Canada is responsible for the surveillance of marketed health products. In
Australia Australia, officially the Commonwealth of Australia, is a sovereign country comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands. With an area of , Australia is the largest country by ...
, the Therapeutic Goods Administration (TGA) conducts postmarket monitoring of therapeutic products. In the UK the
Yellow Card Scheme The Yellow Card Scheme is the United Kingdom's system for collecting information on suspected adverse drug reactions (ADRs) to medicines. The scheme allows the safety of the medicines and vaccines that are on the market to be monitored. History ...
was established in 1963.


Epidemiology

A study by the Agency for Healthcare Research and Quality (AHRQ) found that in 2011, sedatives and hypnotics were a leading source for adverse drug events seen in the hospital setting. Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were steroids, antibiotics, opiates/narcotics, and anticoagulants. Patients treated in urban teaching hospitals had higher rates of ADEs involving antibiotics and opiates/narcotics compared to those treated in urban nonteaching hospitals. Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals. MRH is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There was a wide range in incidence, from 0.4% to 51.2% of participants, and 35% to 59% of harm was preventable. Medication related harm incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17–51% of individuals). In the U.S., females had a higher rate of ADEs involving opiates and narcotics than males in 2011, while male patients had a higher rate of anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. A study showed that 48% of patients had an adverse drug reaction to at least one drug, and pharmacist involvement helps to pick up adverse drug reactions. In 2012,
McKinsey & Company McKinsey & Company is a global management consulting firm founded in 1926 by University of Chicago professor James O. McKinsey, that offers professional services to corporations, governments, and other organizations. McKinsey is the oldest and ...
concluded that the cost of the 50-100 million preventable error-related adverse drug events would be between US$18–115 billion.


See also

* Alleged problems in the drug approval process *
Classification of Pharmaco-Therapeutic Referrals The ''Classification of Pharmaco-Therapeutic Referrals'' (''CPR'') is a taxonomy focused on defining and grouping together situations requiring a referral from pharmacists to physicians (and vice versa) regarding the pharmacotherapy used by the ...
* Drug therapy problems *
EudraVigilance EudraVigilance (European Union Drug Regulating Authorities Pharmacovigilance) is the European data processing network and management system for reporting and evaluation of suspected adverse reactions to medicines which have been authorised or bein ...
(
European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are located primarily in Europe, Europe. The union has a total area of ...
) * History of pharmacy *
Iatrogenesis Iatrogenesis is the causation of a disease, a harmful complication, or other ill effect by any medical activity, including diagnosis, intervention, error, or negligence. "Iatrogenic", ''Merriam-Webster.com'', Merriam-Webster, Inc., accessed 2 ...
* Lethal dose *
List of withdrawn drugs Drugs or medicines may be withdrawn from commercial markets because of risks to patients, but also because of commercial reasons (e.g. lack of demand and relatively high production costs). Where risks or harms is the reason for withdrawal, this w ...
* Paradoxical reaction * Polypharmacy *
Toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
*
Toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating e ...
* The Medical Letter on Drugs and Therapeutics *
Yellow Card Scheme The Yellow Card Scheme is the United Kingdom's system for collecting information on suspected adverse drug reactions (ADRs) to medicines. The scheme allows the safety of the medicines and vaccines that are on the market to be monitored. History ...
(UK)


References


Further reading


Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy


External links

{{DEFAULTSORT:Adverse Drug Reaction Pharmacy Clinical pharmacology Drug safety