Adverse effect

"Side effect" redirects here. For other uses, see Side effect (disambiguation).

Adverse effect
Classification and external resources
ICD-10	T78.
ICD-9	995.89

In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as 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, such as drug interactions.

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. The results of these trials are often included in the labeling of the medication to provide information both for patients and the prescribing physicians.

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.

United Kingdom

The Yellow Card Scheme is a United Kingdom 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 supplements and unlicensed medicines found in cosmetic treatments. Adverse drug reactions (ADRs) can be reported by a number of health care professionals including physicians, 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.

United States

In the United States 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 healthcare 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 two months.The Government's Quality Use of Medicines program is tasked with acting on this reporting to reduce and minimize the number of preventable adverse effects each year.

New Zealand

Adverse reaction reporting is an important component of New Zealand's pharmacovigilance activities. The Centre for Adverse Reactions Monitoring (CARM) in Dunedin is New Zealand's national monitoring centre for adverse reactions. It collects and evaluates spontaneous reports of adverse reactions to medicines, vaccines, herbal products and dietary supplements from health professionals in New Zealand. Currently the CARM database holds over 80 000 reports and provides New Zealand-specific information on adverse reactions to these products, and serves to support clinical decision making when unusual symptoms are thought to be therapy related

Adverse effects of medical procedures

Surgery may have a number of undesirable or harmful 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 the patient's 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 radiation therapy 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. Very rarely, there is a serious adverse effect, 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 radiocontrast material often occur, and a colonoscopy may cause the perforation of the intestine wall.

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 therapeutic 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. This often occurs when patients fail to inform their physician and pharmacist of all the medications they are taking, including herbal and dietary supplements. The new medication may 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 so-called "natural drugs" used in alternative medicine can 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 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, vomiting, headache, dermatitis, dry mouth, etc. These can be considered a form of pseudo-allergic reaction, as not all users experience these effects; many users experience none at all.

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 thiomersal, 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 thimerosal 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. (1)

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 isotretinoin (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 Coronary artery 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 Bacillus Calmette-Guérin (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 anaesthesia
• Hypertension in ephedrine users, which prompted FDA to remove the status of dietary supplement of ephedra extracts
• Insomnia caused by stimulants, methylphenidate (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
• Priapism associaded with the use of sildenafil
• Rhabdomyolysis associated with statins (anti-cholesterol drugs)
• Seizures caused by withdrawal from benzodiazepines
• 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 nitroglycerin
• Suicide, increased tendency associated to the use of fluoxetine and other selective serotonin reuptake inhibitor (SSRI) antidepressants
• Tardive dyskinesia associated with long-term use of metoclopramide and many antipsychotic medications

See also

• Biosafety
• Classification of Pharmaco-Therapeutic Referrals
• Complication (medicine)
• Consultant pharmacist
• Contraindication
• Drug interaction
• EudraVigilance
• Evidence-based medicine
• Food and Drug Administration (United States)
• Iatrogenesis
• List of withdrawn drugs
• Medical algorithm
• Medical error
• Medical prescription
• Nocebo
• Patient safety
• Perioperative mortality
• Pharmacotoxicology
• Pharmacovigilance
• Placebo
• Polypharmacy
• Responsible drug use
• Toxicology

External links

• Patient Safety Network - includes a glossary and articles on adverse effects, drug reactions, medical error, iatrogenesis, among others.
• Australian Adverse Drug Reactions Bulletin - published bimonthly
• Medication Errors -- from the U.S. Food and Drug Administration.
• Medical Product Safety Information - MedWatch lists safety alerts for drugs, biologics, devices and dietary supplements, recalls, market withdrawals, public health advisories and links
• 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 - June 1998 report by the Alliance for Aging Research.

ca:Reacció adversa a medicament