Adverse drug reaction

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Overview

An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted, negative consequences associated with the use of given medications. An ADR is a particular type of adverse effect. 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.^[1] The study of ADRs is the concern of the field known as pharmacovigilance.

Classification

ADRs may be classified by cause and severity.

Cause

• Type A: pharmacologically predictableddfd
• Type B: bizarre and unpredictable (or idiosyncratic)
• Type C: arising from chronic use
• Type D: delayed reaction
• Type E: end of dose reaction
• Type F: failure of therapy

Types A and B were proposed in the 11970s,^[1] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.^[1]

Severity

The American Food and Drug Administration defines severe adverse event (SAE) as:^[1]:

• 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
• - or -
• Requires Intervention to Prevent Permanent Impairment or Damage

Overall Drug Risk

While no official scale exists yet to communicate overall drug risk, the iGuard Drug Risk Rating System is a five color rating scale similar to the Homeland Security Advisory System^[1]:

• Red (High Risk)
• Orange (Elevated Risk)
• Yellow (Guarded Risk)
• Blue (General Risk)
• Green (Low Risk)

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^[1], 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, less ADRs are Type B and more are Type A. Common mechanisms are:

• Abnormal pharmacokinetics due to
  • genetic factors
  • comorbid disease states
• Synergistic 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.^[1]

Genetic factors

Main articles: Pharmacogenetics and Pharmacogenomics

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.^[1][1] Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.

Phase I reactions

Inheriting abnormal alleles of cytochrome P450can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.^[1].^[1]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine^[1]

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.^[1][1]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.^[1]

Interactions with other drugs

Main article: Drug interaction

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.^[1][1] These are mainly for drugs without much first-pass liver metabolism. The prinicple plasma proteins for drug binding are:^[1]

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

Some drug interactions with warfarin are due to changes in protein binding.^[1]

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.^[1].

Synergistic effects

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

Assessing causality

A simple scale is available at http://annals.org/cgi/content/full/140/10/795.^[1]

Note that an ADR should not be labeled as 'certain' unless the ADR abates with dechallenge and recurs with rechallenge are true.

A more complicated scale is the Naranjo algorithm.

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.

See also

• EudraVigilance (European Union)
• Paradoxical reaction
• Polypharmacy
• Toxicology
• The Medical Letter on Drugs and Therapeutics
• Yellow Card Scheme (UK)

References

v • d • e WikiDoc Research Resources for Adverse drug reaction
Articles on Adverse drug reaction	Most recent articles on Adverse drug reaction • Most cited articles on Adverse drug reaction • Review articles on Adverse drug reaction • Articles on Adverse drug reaction in N Eng J Med, Lancet, BMJ
Media (Slides, Video, Images, MP3) on Adverse drug reaction	Powerpoint slides on Adverse drug reaction • Images of Adverse drug reaction • Photos of Adverse drug reaction • Podcasts & MP3s on Adverse drug reaction • Videos on Adverse drug reaction
Evidence Based Medicine Regarding Adverse drug reaction	Cochrane Collaboration on Adverse drug reaction • Bandolier on Adverse drug reaction • TRIP on Adverse drug reaction
Cost Effectiveness of Adverse drug reaction	Cost Effectiveness of Adverse drug reaction
Clinical Trials Involving Adverse drug reaction	Ongoing Trials on Adverse drug reaction at Clinical Trials.gov • Trial results on Adverse drug reaction • Clinical Trials on Adverse drug reaction at Google
Guidelines / Policies / Government Resources (FDA/CDC) Regarding Adverse drug reaction	US National Guidelines Clearinghouse on Adverse drug reaction • NICE Guidance on Adverse drug reaction • NHS PRODIGY Guidance • FDA on Adverse drug reaction • CDC on Adverse drug reaction
Textbook Information on Adverse drug reaction	Books and Textbook Information on Adverse drug reaction
Pharmacology Resources on Adverse drug reaction	Dosing of Adverse drug reaction • Drug interactions with Adverse drug reaction • Side effects of Adverse drug reaction • Allergic reactions to Adverse drug reaction • Overdose information on Adverse drug reaction • Carcinogenicity information on Adverse drug reaction • Adverse drug reaction in pregnancy • Pharmacokinetics of Adverse drug reaction •
Genetics, Pharmacogenomics, and Proteinomics of Adverse drug reaction	Genetics of Adverse drug reaction • Pharmacogenomics of Adverse drug reaction • Proteomics of Adverse drug reaction
Newstories on Adverse drug reaction	Adverse drug reaction in the news • Be alerted to news on Adverse drug reaction • News trends on Adverse drug reaction
Commentary on Adverse drug reaction	Blogs on Adverse drug reaction
Patient Resources on Adverse drug reaction	Patient resources on Adverse drug reaction • Discussion groups on Adverse drug reaction • Patient Handouts on Adverse drug reaction • Directions to Hospitals Treating Adverse drug reaction • Risk calculators and risk factors for Adverse drug reaction
Healthcare Provider Resources on Adverse drug reaction	Symptoms of Adverse drug reaction • Causes & Risk Factors for Adverse drug reaction • Diagnostic studies for Adverse drug reaction • Treatment of Adverse drug reaction
Continuing Medical Education (CME) Programs on Adverse drug reaction	CME Programs on Adverse drug reaction
International Resources on Adverse drug reaction	Adverse drug reaction en Espanol • Adverse drug reaction en Francais
Business Resources on Adverse drug reaction	Adverse drug reaction in the Marketplace • Patents on Adverse drug reaction
Informatics Resources on Adverse drug reaction	List of terms related to Adverse drug reaction

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Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .