Adverse drug reaction

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Adverse drug reaction

A red skin rash due to a drug reaction

Classification and external resources

ICD-10 T88.7, Y40-Y59

ICD-9-CM 995.2, E850-E858

MeSH D004362

An adverse drug reaction (ADR) is an injury caused by taking a medication.[1] ADRs may occur following a single dose or
prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this expression
differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial.[2] The
study of ADRs is the concern of the field known aspharmacovigilance . An adverse drug event (ADE) refers to any injury
occurring at the time a drug is used, whether or not it is identified as a cause of the injury.[1] An ADR is a special type of
ADE in which a causative relationship can be shown.

Contents
[hide]

 1 Cause
 2 Seriousness and severity
 3 Location
 4 Mechanisms
o 4.1 Abnormal pharmacokinetics
 4.1.1 Comorbid disease states
 4.1.2 Genetic factors
 4.1.2.1 Phase I reactions
 4.1.2.2 Phase II reactions
 4.1.3 Interactions with other drugs
 4.1.3.1 Protein binding
 4.1.3.2 Cytochrome P450
o 4.2 Synergistic effects
 5 Assessing causality
 6 Monitoring bodies
 7 Epidemiology
  8 See also
 9 References
 10 External links

c,==Classification== ADRs may be classified by e.g. cause and severity.

Cause[edit]
 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) or a low therapeutic
index of the drug (e.g. nausea from digoxin), 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.[3]

 Type B: Idiosyncratic

Types A and B were proposed in the 1970s,[4] and the other types were proposed subsequently when the first two proved
insufficient to classify ADRs.[5]

Seriousness and severity[edit]

 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 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[edit]
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,[7] although they are administered locally as eye drops,
since a fraction escapes to the systemic circulation.

Mechanisms[edit]
Adverse drug reaction leading to hepatitis (drug-induced hepatitis) with granulomata. Other causes were excluded with
extensive investigations. Liver biopsy. H&E stain.

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

Abnormal pharmacokinetics[edit]

Comorbid disease states[edit]

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.[8]

Genetic factors[edit]

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[9][10]
Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.

Phase I reactions[edit]

Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug
interactions due to P450 interactions.[11][12]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as

Phase II reactions[edit]

Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism
of drugs such as isoniazid, hydralazine, and procainamide.[12][13]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine
and azathioprine.[12]

Interactions with other drugs[edit]

The risk of drug interactions is increased with polypharmacy.

These interactions are usually transient and mild until a new steady state is achieved.[14][15] These are mainly for drugs
without much first-pass liver metabolism. The principal plasma proteins for drug binding are:[16]

1. albumin
2. α1-acid glycoprotein
3. lipoproteins

Some drug interactions with warfarin are due to changes in protein binding.[16]

Cytochrome P450[edit]

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.[11]

Synergistic effects[edit]

An example of synergism is two drugs that both prolong the QT interval.

Assessing causality[edit]
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.[17] 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. A simple scale is available at
http://annals.org/cgi/content/full/140/10/795#T2.[2]

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.[18][19]

Monitoring bodies[edit]
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. In Canada, the Marketed
Health Products Directorate of Health Canada is responsible for the surveillance of marketed health products. In Australia,
the Therapeutic Goods Administration (TGA) conducts postmarket monitoring of therapeutic products.

Epidemiology[edit]
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.[20] 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 and 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, not-for-profit hospitals had higher rates of most ADE causes
compared to patients treated in public or private, for-profit hospitals.[21]

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 and narcotics, and anticoagulants) during hospitalization.[21]

See also[edit]
 Alleged problems in the drug approval process
 Classification of Pharmaco-Therapeutic Referrals
 Drug therapy problems
 EudraVigilance (European Union)
  History of pharmacy
 Iatrogenesis
 List of withdrawn drugs
 Paradoxical reaction
 Polypharmacy
 Toxicology
 The Medical Letter on Drugs and Therapeutics
 Yellow Card Scheme (UK)
 List of medication withdrawn from the market

References[edit]
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Registration of Pharmaceuticals for Human Use . 10 June 1996. p. 2. Retrieved 12 July 2014.
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documentation, and reporting".Ann. Intern. Med. 140 (10): 795–801. doi:10.7326/0003-4819-140-10-200405180-00017. PMID 15148066.
3. Jump up ^ Ritter, J M (2008).A Textbook of Clinical Pharmacology and Therapeutics . Great Britain. p. 62. ISBN 978-0-340-90046-8.
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Oxford: Oxford University Press, 1977:10.
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of medicine 19th ed. Edinburgh: Elsevier Science, 2002:147-
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7. Jump up ^ Rang, H. P. (2003).Pharmacology . Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 146
8. Jump up ^ "Clinical Drug Use". Archived from the original on 1 November 2007. Retrieved 2007-09-18.
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reactions: a systematic review".JAMA 286 (18): 2270–9. doi:10.1001/jama.286.18.2270. PMID 11710893.
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12. ^ Jump up to: a b c Weinshilboum R; Collins, Francis S.; Weinshilboum, Richard (2003). "Inheritance and drug response".N. Engl. J. Med. 348
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115–21. doi:10.1067/mcp.2002.121829. PMID 11907485.OVID full text summary table at OVID
16. ^ Jump up to: a b Sands CD, Chan ES, Welty TE (2002). "Revisiting the significance of warfarin protein-binding displacement interactions".
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