Adverse drug reaction

An adverse drug reaction (abbreviated ADR) is an expression that describes harm associated with the use of given medications at a normal dosage. 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. The study of ADRs is the concern of the field known as pharmacovigilance.

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

Cause

 * Type A: Augmented pharmacologic effects - dose dependent and predictable
 * Intolerance
 * Side Effects
 * Type B: Bizarre effects (or idiosyncratic) - dose independent and unpredictable
 * Type C: Chronic effects
 * Type D: Delayed effects
 * Type E: End-of-treatment effects
 * Type F: Failure of therapy
 * typeG: Genetic reactions

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 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 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. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migrane may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above.

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:
 * 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, 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
 * genetic factors
 * comorbid disease states
 * Synergistic effects between either
 * a drug and a disease
 * two drugs

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.

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. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: Some drug interactions with warfarin are due to changes in protein binding.
 * 1) albumin
 * 2) α1-acid glycoprotein
 * 3) 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.

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

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

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. 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 runs the European Medicines Agency (EMEA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies.