Adverse drug reaction

Adverse drug reaction

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Adverse drug reaction

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 e.g. cause and severity.

Cause

Type A: Augmented pharmacologic effects
Type B: Bizarre effects (or idiosyncratic)
Type C: Chronic effects
Type D: Delayed effects
Type E: End-of-treatment effects
Type F: Failure of therapy

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]

Seriousness and Severity

The American Food and Drug Administration defines a serious adverse event as one when the patient outcome is:^[4]:

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

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.

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^[5]:

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^[6], 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.^[7]

Genetic factors

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.

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.^[10].^[11]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine^[12]

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.^[12]^[11]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.^[11]

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.^[13]^[14] These are mainly for drugs without much first-pass liver metabolism. The prinicple plasma proteins for drug binding are:^[15]

albumin
?1-acid glycoprotein
lipoproteins

Some drug interactions with warfarin are due to changes in protein binding.^[15]

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.^[16].

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]

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.

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.