Adverse effect (medicine)

In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as chemotherapy or surgery. An adverse effect may be termed a "side-effect" (when judged to be secondary to a main or therapeutic effect) and may result from an unsuitable or incorrect dosage or procedure (which could be due to medical error). Adverse effects are sometimes referred to as "iatrogenic" because they are generated by a physician/treatment. Some adverse effects only occur only when starting, increasing or discontinuing a treatment. Using a drug or other medical intervention which is contraindicated may increase the risk of adverse effects. Adverse effects may cause medical complications of a disease or procedure and negatively affect its prognosis. They may also lead to non-compliance with a treatment regimen.

The harmful outcome is usually indicated by some result such as morbidity, mortality, alteration in body weight, levels of enzymes, loss of function, or as a pathological change detected at the microscopic, macroscopic or physiological level. It may also be indicated by symptoms reported by a patient. Adverse effects may cause a reversible or irreversible change, including an increase or decrease in the susceptibility of the individual to other chemicals, foods, or procedures (e.g. drug interaction).

In clinical trials, a distinction is made between Adverse Events (AEs) and Serious Adverse Events (SAEs). Generally, any event which causes death, permanent damage, birth defects, or requires hospitalization is considered an SAE. ^[1] The results of these trials are often included in the labeling of the medication to provide information both for patients and the prescribing physicians.

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Reporting systems

In many countries, adverse effects are required by law to be reported, researched in clinical trials and included into the patient information accompanying medical devices and drugs for sale to the public.

UK

The Yellow Card Scheme is a UK initiative run by the Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) to gather information on adverse effects to medicines. This includes all licensed medicines from medicines issued on prescription to medicines bought over the counter from a supermarket. The Scheme also includes all herbal preparations and unlicensed medicines found in cosmetic treatments. ADRs can be reported by a number of healthcare professionals including doctors, pharmacists and nurses, as well as patients.

For further information see the Yellow Card Scheme website, or find copies of the Yellow Card in the appedices of a BNF.

To read reports from the UK Yellow Card Scheme you can download here.

USA

In the USA several reporting systems have been built, such as the Vaccine Adverse Event Reporting System (VAERS), the Manufacturer and User Facility Device Experience Database (MAUDE) and the Special Nutritionals Adverse Event Monitoring System. MedWatch is the main reporting center, operated by the Food and Drug Administration.

Australia

In Australia, adverse effect reporting is administered by the Adverse Drug Reactions Advisory Committee (ADRAC), a subcommittee of the Australian Drug Evaluation Committee (ADEC). Reporting is voluntary, and ADRAC requests health professionals to report all adverse reactions to its current drugs of interest, and serious adverse reactions to any drug. ADRAC publishes the Australian Adverse Drug Reactions Bulletin every 2 months.

Adverse effects of medical procedures

Surgery may have a number of undesirable or harmful after effects, such as infection, hemorrhage, inflammation, scarring, loss of function, changes in local blood flow, and so on. They can be reversible or irreversible, and a compromise must be found by the physician and the patient between the beneficial or life-saving consequences of surgery versus its adverse effects. For example, a limb may be lost to amputation in case of untreatable gangrene, but life is saved. Presently, one of the greatest advantages of minimally invasive surgery, such as laparoscopic surgery is the reduction of adverse effects.

Other non-surgical physical procedures such as high intensity radiotherapy may cause burns and alterations in the skin. In general, these therapies try to avoid damage to healthy tissues while maximizing the therapeutic effect.

Vaccination may have adverse effects, due to the nature of its biological preparation (sometimes using attenuated pathogens and toxins). Common adverse effects may be fever, malaise and local reactions in the vaccination site, such as eczema vaccinatum, a severe, sometimes fatal complication which may result in persons who have eczema or atopic dermatitis.

Diagnostic procedures may also have adverse effects, depending much on whether they are invasive, non-invasive or minimally invasive. For example, allergic reactions to x-ray contrasting material often occur, a colonoscopy may cause the perforation of the intestine wall, etc.

Adverse effects of drugs

Main article: adverse drug reaction

Adverse effects can occur as a collateral or side effect of many interventions, but they are particularly important in pharmacology, due to its wider, and sometimes uncontrollable, use by way of self-medication. Thus, responsible drug use becomes an important issue here.

Adverse effects, like intended effects of drugs, are a function of dosage or drug levels at the target organs, so they may be avoided or decreased by means of careful and precise pharmacokinetics (the change of drug levels in the organism in function of time after administration).

Adverse effects may also be caused by drug interaction, i.e., when physicians fail to check for all medicaments a patient is taking and prescribe new ones which interact agonistically or antagonistically (potentiate or decrease the intended therapeutic effect). Significant morbidity and mortality is caused around the world because of this. Drug-drug and food-drug interactions may occur, and even so-called "natural drugs" used in alternative medicine may have dangerous adverse effects. For example, extracts of St. John's wort (Hypericum perforatum), a phytotherapic used for treating mild depression are known to cause an increase in the cytochrome P450 enzymes responsible for the metabolism and elimination of many drugs, so that patients taking it are likely to experience a reduction in blood levels of drugs that they are taking for other purposes, such as cancer chemotherapeutic drugs, protease inhibitors for HIV and hormonal contraceptives.

The scientific field of activity associated with drug safety is increasingly government-regulated and is of major concern for the public as well as to drug manufacturers. The distinction between adverse and non-adverse effects is a major undertaking when a new drug is developed and tested before marketing it. This is done in toxicity studies to determine the non-adverse effect level (NOAEL). These studies are used to define the dosage to be used in human testing (phase I) as well as to calculate the maximum admissible daily intake. Imperfections in clinical trials, such as insufficient number of patients or short duration, sometimes lead to public health disasters such as those of fenfluramine (the so-called fen-phen episode), thalidomide and, more recently, of cerivastatin (Baycol®, Lipobay®) and rofecoxib (Vioxx®), where drastic adverse effects were observed, like teratogenesis, pulmonary hypertension, stroke, heart disease, neuropathy, etc., and a significant number of deaths, causing the forced or voluntary withdrawal of the drug from the market.

Most drugs have a large list of non-severe or mild adverse effects which do not rule out the interruption of usage. These effects have widely variable incidence, according to individual sensitivity. They comprise nausea, dizziness, diarrhea, malaise, vomit, headache, dermatitis, dry mouth, etc.

Controversies

Sometimes, putative medical adverse effects are regarded as controversial and generate heated discussions in society and lawsuits against drug manufacturers. One example is the recent controversy as to whether autism was linked to the MMR vaccine (or by thimerosal, a mercury-based preservative used in some vaccines). No link has been found in several large studies and no change in the rate of autism has occurred when thimerisal was removed from vaccines a decade ago in Canada and Europe.

Another instance is the potential adverse effects of silicone breast implants, which lead to hundreds of thousands of litigations against manufacturers of gel-based implants, due to allegations of damage to the immune system which have not yet been conclusively proven.

Due to the exceedingly high impact on public health of widely used medications, such as hormonal contraception and hormone replacement therapy, which may affect millions of users, even marginal probabilities of adverse effects of a severe nature, such as breast cancer, have led to public outcry and changes in medical therapy, although its benefits largely surpassed the statistical risks.

Limitations of adverse effects reporting

In principle, medical professionals are required to report all adverse effects related to a specific form of therapy. In practice, it is at the discretion of the professional to determine whether a medical event is at all related to the therapy. For example, a leg fracture in a skiing accident in a patient who years before took antibiotics for pneumonia is not likely to get reported.

As a result, routine adverse effects reporting may often not include long-term and subtle effects that may ultimately be attributed to a therapy.

Part of the difficulty is identifying the source of a complaint. A headache in a patient taking medication for influenza may be the underlying disease and may be an adverse effect. In patients with end-stage cancer, death is a very likely outcome and whether the drug is the cause or a bystander is often difficult to discern.

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

See also

• Biosafety
• Consultant pharmacist
• Contraindication
• Complication (medicine)
• Drug interaction
• Evidence-based medicine
• Food and Drug Administration
• Iatrogenesis
• List of withdrawn drugs
• Medical algorithm
• Medical error
• Medical prescription
• Nocebo
• Patient safety
• Perioperative mortality
• Pharmacovigilance
• Pharmacovigilance
• EudraVigilance
• Placebo (origins of technical term)
• Responsible drug use
• Toxicology

• Australian Adverse Drug Reactions Bulletin - published bimonthly by ADRAC
• Drugs of Concern DrugIntel.com site for tort lawyers with up-to-date information on drugs that cause severe adverse effects)
• Medication Errors a FDA site.
• Medical Product Safety Information. MedWatch, an useful page from Food and Drug Administration, listing safety alerts for drugs, biologics, devices and dietary supplements, recalls, market withdrawals, public health advisories, links to the VAERS and MAUDE databases, etc.)
• Medical Devices Safety National Library of Medicine (Medline Plus, useful lists of conventional drug and medical device articles and websites)
• When Medicine Hurts Instead of Helps - A special report by the Alliance for Aging Research on ADRs.