what are adverse drug reactions?

Key points

• Adverse drug reactions (ADRs) – unintended, harmful events attributed to the use of medicines – occur as a cause of and during a significant proportion of unscheduled hospital admissions.
• A careful medication history can assist a prescriber in understanding the patient's previous experiences with drug treatment, particularly in identifying previous ADRs that may preclude re-exposure to the drug.
• Preventing ADRs depends on avoiding treatment in cohorts of patients who are at increased susceptibility or providing treatment under a therapeutic plan that reduces the risk of an adverse effect (eg co-administration of other drugs, monitoring blood test results).
• Spontaneous reporting (using the Yellow Card Scheme in the UK) based on the suspicion of an ADR is an important part of pharmacovigilance but, overall, ADRs are vastly underreported across healthcare settings and sectors. If in doubt, it is best to submit a report.

An adverse drug reaction (ADR) is an injury caused by taking a medication. 

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.

In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.

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. An ADR is a special type of ADE in which a causative relationship can be shown.

Classification of adverse drug reactions

Traditionally, ADRs have been classified into two types:

1. Type A reactions – sometimes referred to as augmented reactions – which are ‘dose-dependent’ and predictable on the basis of the pharmacology of the drug-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)
2. Type B reactions – bizarre reactions – which are idiosyncratic and not predictable on the basis of the pharmacology.

Although still widely quoted, this basic classification does not work for all ADRs, such as with chronic adverse effects associated with cumulative drug exposure (eg osteoporosis with long-term corticosteroid treatment) or withdrawal reactions (eg rebound hypertension with centrally-acting antihypertensive cessation).

 An alternative and perhaps more comprehensive classification scheme is ‘DoTS’, which classifies reactions dependent on the Dose of the drug, the Time course of the reaction and relevant Susceptibility factors (such as genetic, pathological and other biological differences). As well as classifying reactions, DoTS has the advantage of being helpful to consider the diagnosis and prevention of ADRs in practice.

Severity

The U.S 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, 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.

Common mechanisms are:

• Abnormal pharmacokinetics due to
  • genetic factors
  • comorbid disease states -  comorbidity is the presence of one or more additional diseases or disorders co-occurring with (that is, concomitant or concurrent with) a primary disease or disorder; in the countable sense of the term, a comorbidity (plural comorbidities) is each additional disorder or disease. The additional disorder may be a behavioral or mental disorder.
• 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.

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:

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

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

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.

what is pharmacovigilance?

Pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.