An adverse drug reaction
) or adverse drug event
) 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. The study of ADRs is the concern of the field known as pharmacovigilance
ADRs may be classified by e.g. cause and severity.
- 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, 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::
- 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
- Red (High Risk)
- Orange (Elevated Risk)
- Yellow (Guarded Risk)
- Blue (General Risk)
- Green (Low Risk)
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.
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
Comorbid disease states
Various diseases, especially those that cause renal
insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.
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
, 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
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 prinicple plasma proteins for drug binding are:
- α1-acid glycoprotein
Some drug interactions with warfarin are due to changes in protein binding.
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..
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
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.
Examples of adverse effects associated with specific medications
- Abortion, miscarriage or uterine hemorrhage associated with misoprostol (Cytotec), a labor-inducing drug (this is a case where the adverse effect has been used legally and illegally for performing abortions)
- Addiction to many sedatives and analgesics such as diazepam, morphine, etc.
- Birth defects associated with Thalidomide and Accutane.
- Bleeding of the intestine associated with aspirin therapy
- Cardiovascular disease associated with COX-2 inhibitors (i.e. Vioxx)
- Deafness and kidney failure associated with gentamicin (an antibiotic)
- Death, following sedation in children using propofol (Diprivan)
- Dementia associated with heart bypass surgery
- Depression or hepatic injury caused by interferon
- Diabetes caused by atypical antipsychotic medications (neuroleptic psychiatric drugs)
- Diarrhea caused by the use of orlistat (Xenical)
- Erectile dysfunction associated with many drugs, such as antidepressants
- Fever associated with vaccination (in the past, imperfectly manufactured vaccines, such as BCG and poliomyelitis, have caused the very disease they intended to fight).
- Glaucoma associated with corticosteroid-based eye drops
- Hair loss and anemia may be caused by chemotherapy against cancer, leukemia, etc.
- Headache following spinal anesthesia
- Hypertension in ephedrine users, which prompted FDA to remove the status of dietary supplement of ephedra extracts
- Insomnia caused by stimulants, Ritalin, Adderall, etc.
- Lactic acidosis associated with the use of stavudine (Zerit, for anti-HIV therapy) or metformin (for diabetes)
- Liver damage from paracetamol
- Melasma and thrombosis associated with use of estrogen-containing hormonal contraception such as the combined oral contraceptive pill
- Rhabdomyolysis associated with statins (anti-cholesterol drugs)
- Seizures caused by withdrawal from benzodiazepine
- Drowsiness or increase in appetite due to antihistamine use. Some antihistamines are used in sleep aids explicitly because they cause drowsiness.
- Stroke or heart attack associated with sildenafil (Viagra) when used with nitroglycerine
- Suicide, increased tendency associated to the use of fluoxetine and other SSRI antidepressants
- Tardive dyskinesia associated with long-term use of metoclopramide and many antipsychotic medications