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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.
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ADRs may be classified by e.g. cause and severity.
Types A and B were proposed in the 1970s,[2] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[3]
The American Food and Drug Administration defines a serious adverse event as one when the patient outcome is:[4]:
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, require care in usage.
A headache is severe, if it causes intense pain. There are scales like "visual analog scale" that help us assess the severity. A headache, on the other hand, can hardly ever be serious, unless it also satisfies the criteria for seriousness, listed above.
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[5]:
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[6], although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.
As research better explains the biochemistry of drug use, less ADRs are Type B and more are Type A. Common mechanisms are:
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.[7]
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[8][9] Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.
Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.[10].[11]
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[12]
Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.[12][11]
Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[11]
The risk of drug interactions is increased with polypharmacy.
These interactions are usually transient and mild until a new steady state is achieved.[13][14] These are mainly for drugs without much first-pass liver metabolism. The prinicple plasma proteins for drug binding are:[15]
Some drug interactions with warfarin are due to changes in protein binding.[15]
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.[16].
An example of synergism is two drugs that both prolong the QT interval.
A simple scale is available at http://annals.org/cgi/content/full/140/10/795.[1]
An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol.
A more complicated scale is the Naranjo algorithm.
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.
