Adverse effect

Last updated
Adverse effect
Specialty Pharmacology

An adverse effect is an undesired harmful 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. If it results from an unsuitable or incorrect dosage or procedure, this is called a medical error and not a complication. Adverse effects are sometimes referred to as "iatrogenic" because they are generated by a physician/treatment. Some adverse effects occur only when starting, increasing or discontinuing a treatment. Adverse effects can also be caused by placebo treatments (in which case the adverse effects are referred to as nocebo effects. [1] [2] Using a drug or other medical intervention which is contraindicated may increase the risk of adverse effects. Adverse effects may cause complications of a disease or procedure and negatively affect its prognosis. They may also lead to non-compliance with a treatment regimen. Adverse effects of medical treatment resulted in 142,000 deaths in 2013 up from 94,000 deaths in 1990 globally. [3]

Contents

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.

Classification

In terms of drugs, adverse events may be defined as: “Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.” [4]

In clinical trials, a distinction is made between an adverse event and a serious adverse event. Generally, any event which causes death, permanent damage, birth defects, or requires hospitalization is considered a serious adverse event. [5] The results of trials are often included in the labelling of the medication to provide information both for patients and the prescribing physicians.

The term "life-threatening" in the context of a serious adverse event refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. [4]

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. Investigators in human clinical trials are obligated to report these events in clinical study reports. [6] Research suggests that these events are often inadequately reported in publicly available reports. [7] Because of the lack of these data and uncertainty about methods for synthesising them, individuals conducting systematic reviews and meta-analyses of therapeutic interventions often unknowingly overemphasise health benefit. [8] To balance the overemphasis on benefit, scholars have called for more complete reporting of harm from clinical trials. [9]

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.

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

Canada

In Canada, adverse reaction reporting is an important component of the surveillance of marketed health products conducted by the Health Products and Food Branch (HPFB) of Health Canada. Within HPFB, the Marketed Health Products Directorate leads the coordination and implementation of consistent monitoring practices with regards to assessment of signals and safety trends, and risk communications concerning regulated marketed health products.

MHPD also works closely with international organizations to facilitate the sharing of information. Adverse reaction reporting is mandatory for the industry and voluntary for consumers and health professionals.

Limitations

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

Part of the difficulty is identifying the source of a complaint. A headache in a patient taking medication for influenza may be caused by the underlying disease or may be an adverse effect of the treatment. 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. [ citation needed ]

By situation

Medical procedures

Surgery may have a number of undesirable or harmful effects, such as infection, hemorrhage, inflammation, scarring, loss of function, or changes in local blood flow. 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 nonsurgical 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, minimally invasive or noninvasive. For example, allergic reactions to radiocontrast materials often occur, and a colonoscopy may cause the perforation of the intestinal wall.

Medications

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), causing significant morbidity and mortality around the world. 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 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 nonadverse 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 nonadverse 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, such as teratogenesis, pulmonary hypertension, stroke, heart disease, neuropathy, 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 nonsevere or mild adverse effects which do not rule out continued usage. These effects, which have a widely variable incidence according to individual sensitivity, include 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.

The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia [10] (MATCH-D) warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. [11]

Drugs contain side effects which is the reason why commercials or advertisements put many disclaimers about the unwanted symptoms after taking the drug(s).

Examples with specific medications

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 despite removal of thimerosal from vaccines a decade ago the rate of autism has not decreased as would be expected if it had been the causative agent. [40] [41]

Another instance is the potential adverse effects of silicone breast implants, which led 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. [42]

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.

See also

Related Research Articles

Ciprofloxacin chemical compound

Ciprofloxacin is an antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain type of infectious diarrhea, respiratory tract infections, skin infections, typhoid fever, and urinary tract infections, among others. For some infections it is used in addition to other antibiotics. It can be taken by mouth, as eye drops, as ear drops, or intravenously.

Carbamazepine Anticonvulsant medication

Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used in schizophrenia along with other medications and as a second-line agent in bipolar disorder. Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures. It is not effective for absence or myoclonic seizures.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of a drug class that reduces pain, decreases fever, prevents blood clots, and in higher doses, decreases inflammation. Side effects depend on the specific drug but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

Proton-pump inhibitor drug for reducing stomach acid

Proton-pump inhibitors (PPIs) are members of a class of medications whose main action is a profound and prolonged reduction of stomach acid production. Within the class of medications, there is no clear evidence that one agent works better than another.

Methylphenidate Medication of the stimulant class

Methylphenidate (MP), sold under the trade name Ritalin among others, is a stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is a first line medication for ADHD. It may be taken by mouth or applied to the skin, and different formulations have varying durations of effect.

Allopurinol chemical compound

Allopurinol, sold under the brand name Zyloprim among others, is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth or injected into a vein.

Metronidazole Antibiotic and antiprotozoal medication

Metronidazole, marketed under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is effective for dracunculiasis, giardiasis, trichomoniasis, and amebiasis. It is an option for a first episode of mild-to-moderate Clostridium difficile colitis if vancomycin or fidaxomicin is unavailable. Metronidazole is available by mouth, as a cream, and by injection into a vein.

Dexamethasone Type of corticosteroid medication

Dexamethasone is a type of corticosteroid medication. It is used in the treatment of many conditions, including rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, and along with antibiotics in tuberculosis. In adrenocortical insufficiency, it should be used together with a medication that has greater mineralocorticoid effects such as fludrocortisone. In preterm labor, it may be used to improve outcomes in the baby. It may be given by mouth, as an injection into a muscle, or as an injection into a vein. The effects of dexamethasone are frequently seen within a day and last for about three days.

Filgrastim Medication used to treat low blood neutrophils

Filgrastim, sold under the brand name Neupogen among others, is a medication used to treat low neutrophil count. Low neutrophil counts may occur with HIV/AIDS, following chemotherapy or radiation poisoning, or be of an unknown cause. It may also be used to increase white blood cells for gathering during leukapheresis. It is given either by injection into a vein or under the skin.

Pethidine chemical compound

Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, Germany. Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines, the prodines, bemidones and others more distant, including diphenoxylate and analogues.

Dapsone Medication

Dapsone, also known as diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment and prevention of pneumocystis pneumonia and for the prevention of toxoplasmosis in those who have poor immune function. Additionally, it has been used for acne, dermatitis herpetiformis, and various other skin conditions. Dapsone is available both topically and by mouth.

Abacavir Chemical compound

Abacavir, sold under the brand name Ziagen, is a medication used to prevent and treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.

Ezetimibe Medication used to treat high cholesterol

Ezetimibe is a medication used to treat high blood cholesterol and certain other lipid abnormalities. Generally it is used together with dietary changes and a statin. Alone, it is less preferred than a statin. It is taken by mouth. It is also available in the fixed combinations ezetimibe/simvastatin, ezetimibe/atorvastatin, and ezetimibe/rosuvastatin.

Polypharmacy is the concurrent use of multiple medications by a patient. Polypharmacy is most common in the elderly, affecting about 40% of older adults living in their own homes. About 21% of adults with intellectual disability are also exposed to polypharmacy. Polypharmacy is not necessarily ill-advised, but in many instances can lead to negative outcomes or poor treatment effectiveness, often being more harmful than helpful or presenting too much risk for too little benefit. Therefore, health professionals consider it a situation that requires monitoring and review to validate whether all of the medications are still necessary. Concerns about polypharmacy include increased adverse drug reactions, drug interactions, prescribing cascade, and higher costs. Polypharmacy is often associated with a decreased quality of life, including decreased mobility and cognition.

Pharmacovigilance, also known as drug safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products. The etymological roots for the word "pharmacovigilance" are: pharmakon and vigilare. As such, pharmacovigilance heavily focuses on adverse drug reactions, or ADRs, which are defined as any response to a drug which is noxious and unintended, including lack of efficacy. Medication errors such as overdose, and misuse and abuse of a drug as well as drug exposure during pregnancy and breastfeeding, are also of interest, even without an adverse event, because they may result in an adverse drug reaction.

Adverse drug reaction unintended effect of drugs, which may occur following a single dose or prolonged administration of a drug or result from the combination of different drugs

An adverse drug reaction (ADR) is an injury caused by taking 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 term differs from the term "side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as pharmacovigilance. 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. ADRs are only one type of medication-related harm, as harm can also be caused by omitting to take indicated medications.

Levothyroxine chemical compound

Levothyroxine, also known as L-thyroxine, is a manufactured form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency, including the severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken by mouth or given by injection into a vein. Maximum effect from a specific dose can take up to six weeks to occur.

Lenalidomide chemical compound

Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma (MM) and myelodysplastic syndromes (MDS). For MM it is used after at least one other treatment and generally together with dexamethasone. It is taken by mouth.

Iatrogenesis causation of a disease, a harmful complication, or other ill effect by any medical activity, including diagnosis, intervention, error, or negligence

Iatrogenesis is the causation of a disease, a harmful complication, or other ill effect by any medical activity, including diagnosis, intervention, error, or negligence. First used in this sense in 1924, the term was introduced to sociology in 1976 by Ivan Illich, alleging that industrialized societies impair quality of life by overmedicalizing life. Iatrogenesis may thus include mental suffering via medical beliefs or a practitioner's statements. Some iatrogenic events are obvious, like amputation of the wrong limb, whereas others, like drug interactions, can evade recognition. In a 2013 estimate, about 20 million negative effects from treatment had occurred globally. In 2013, an estimated 142,000 persons died from adverse effects of medical treatment, up from an estimated 94,000 in 1990.

COVID-19 drug development Preventative and therapeutic medications for COVID-19 infection

COVID‑19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID‑19). Internationally by August 2020, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing over 500 potential therapies for COVID‑19 disease in various stages of preclinical or clinical research.

References

  1. Howick, Jeremy; Webster, Rebecca; Kirby, Nigel; Hood, Kerry (2018-12-11). "Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials". Trials. 19 (1): 674. doi:10.1186/s13063-018-3042-4. ISSN   1745-6215. PMC   6288933 . PMID   30526685.
  2. Howick, Jeremy (2020). "Unethical informed consent caused by overlooking poorly measured nocebo effects". Journal of Medical Ethics: medethics-2019-105903. doi:10.1136/medethics-2019-105903. PMID   32063581.
  3. GBD 2013 Mortality Causes of Death Collaborators (January 2015). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC   4340604 . PMID   25530442.
  4. 1 2 Expert Working Group (Efficacy) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). (August 25, 2007). "Guideline for Industry – Clinical safety data management: definitions and standards for expedited reporting" (PDF). FDA Center for Drug Evaluation and Research. Archived (PDF) from the original on May 11, 2009.
  5. Office of the Commissioner. "Reporting Serious Problems to FDA - What is a Serious Adverse Event?". www.fda.gov. Archived from the original on 25 January 2018. Retrieved 15 March 2018.
  6. Expert working group (efficacy) of the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use (August 25, 2007). "Guideline for Industry Structure and Content of Clinical Study Reports" (PDF). FDA Center for Drug Evaluation and Research. Archived (PDF) from the original on May 25, 2009.
  7. Ioannidis JP, Lau J (2001). "Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas". JAMA. 285 (4): 437–43. doi: 10.1001/jama.285.4.437 . PMID   11242428.
  8. Chou R, Helfand M (June 2005). "Challenges in systematic reviews that assess treatment harms". Annals of Internal Medicine. 142 (12 Pt 2): 1090–9. doi: 10.7326/0003-4819-142-12_part_2-200506211-00009 . PMID   15968034.
  9. Ioannidis JP, Evans SJ, Gøtzsche PC, O'Neill RT, Altman DG, Schulz K, Moher D (November 2004). "Better reporting of harms in randomized trials: an extension of the CONSORT statement". Annals of Internal Medicine. 141 (10): 781–8. doi:10.7326/0003-4819-141-10-200411160-00009. PMID   15545678. S2CID   17032571.
  10. "MATCH-D Medication Appropriateness Tool for Comorbid Health conditions during Dementia". www.match-d.com.au. Retrieved 2019-06-01.
  11. Page AT, Potter K, Clifford R, McLachlan AJ, Etherton-Beer C (October 2016). "Medication appropriateness tool for co-morbid health conditions in dementia: consensus recommendations from a multidisciplinary expert panel". Internal Medicine Journal. 46 (10): 1189–1197. doi:10.1111/imj.13215. PMC   5129475 . PMID   27527376.
  12. "Mifepristone and Misoprostol for Abortion". WebMD. Archived from the original on March 30, 2013. Retrieved March 20, 2013.
  13. "Morphine Addiction Withdrawal Symptoms and Treatment". rehabinfo. Archived from the original on March 18, 2013. Retrieved March 20, 2013.
  14. "Even Low Dose of Aspirin Can Cause Intestinal Bleeding". WebMD News. November 9, 2000. Archived from the original on April 20, 2013. Retrieved March 20, 2013.
  15. "Coronary Heart Disease". Weitz & Luxenberg P.C. Archived from the original on May 30, 2013. Retrieved March 20, 2013.
  16. "Kidney Damage". Gentamicin Information Center. Archived from the original on 2013-05-04. Retrieved 2013-04-28.
  17. Bray RJ (1998). "Propofol infusion syndrome in children". Paediatric Anaesthesia. 8 (6): 491–9. doi:10.1046/j.1460-9592.1998.00282.x. PMID   9836214.
  18. Kraus MR, Schäfer A, Schöttker K, Keicher C, Weissbrich B, Hofbauer I, Scheurlen M (April 2008). "Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study". Gut. 57 (4): 531–6. doi:10.1136/gut.2007.131607. PMID   18079286. S2CID   33773564.
  19. "Diabetes and Antipsychotic Drugs". Medsafe. Archived from the original on April 11, 2013. Retrieved March 20, 2013.
  20. "Xenical and Diarrhea: a study of 591 users". eHealthMe. Archived from the original on September 20, 2011. Retrieved March 20, 2013.
  21. "Can anti-depressants cause sexual dysfunction?". WebMD. May 15, 2011. Archived from the original on March 21, 2013. Retrieved March 20, 2013.
  22. Tapiainen T, Heininger U (June 2005). "Fever following immunization". Expert Review of Vaccines. 4 (3): 419–27. doi:10.1586/14760584.4.3.419. PMID   16026253. S2CID   20270210.
  23. "Possible Side-effects from Vaccines". Centers for Disease Control and Prevention (CDC). 2018-07-12. Archived from the original on March 17, 2017. Retrieved March 20, 2013.
  24. Tripathi RC, Parapuram SK, Tripathi BJ, Zhong Y, Chalam KV (December 1999). "Corticosteroids and glaucoma risk". Drugs & Aging. 15 (6): 439–50. doi:10.2165/00002512-199915060-00004. PMID   10641955. S2CID   22380777.
  25. "Chemotherapy and hair loss: What to expect during treatment". Mayo Clinic. March 6, 2012. Archived from the original on February 5, 2013. Retrieved March 20, 2013.
  26. "Headache After an Epidural or Spinal Anaesthetic". Archived from the original on June 8, 2015. Retrieved March 20, 2013.
  27. "Ephedra (Ephedra sinica) / ma huang". Mayo Clinic. September 1, 2012. Archived from the original on May 12, 2013. Retrieved May 20, 2013.
  28. Bergeson, B. (May 6, 2010). "What Are the Side Effects of Adults Taking Ritalin?". Livestrong. Archived from the original on February 18, 2013. Retrieved March 20, 2013.
  29. Mokrzycki MH, Harris C, May H, Laut J, Palmisano J (January 2000). "Lactic acidosis associated with stavudine administration: a report of five cases". Clinical Infectious Diseases. 30 (1): 198–200. doi: 10.1086/313594 . PMID   10619755.
  30. "Metformin and Fatal Lactic Acidosis". Archived from the original on April 5, 2013. Retrieved March 20, 2013.
  31. Patten SB, Neutel CI (February 2000). "Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis and management". Drug Safety. 22 (2): 111–22. doi:10.2165/00002018-200022020-00004. PMID   10672894. S2CID   25933949.
  32. Willacy H (January 4, 2013). "Paracetamol Poisoning". Patient.info. Archived from the original on June 26, 2015. Retrieved March 20, 2013.
  33. "What is Melasma?". wiseGEEK. Archived from the original on March 27, 2013. Retrieved March 20, 2013.
  34. Reid R (December 2010). "SOGC clinical practice guideline. No. 252, December 2010. Oral contraceptives and the risk of venous thromboembolism: an update". Journal of Obstetrics and Gynaecology Canada. 32 (12): 1192–1197. doi:10.1016/S1701-2163(16)34746-6. PMID   21176332.
  35. Wills BK, Albinson C, Wahl M, Clifton J (2007). "Sildenafil citrate ingestion and prolonged priapism and tachycardia in a pediatric patient". Clinical Toxicology. 45 (7): 798–800. doi:10.1080/15563650701664483. PMID   17952749. S2CID   6629753.
  36. Behrenbeck T (December 14, 2012). "How do you know if you have rhabdomyolysis from statin use?". Mayo Clinic. Archived from the original on June 1, 2013. Retrieved March 20, 2013.
  37. Fialip J, Aumaitre O, Eschalier A, Maradeix B, Dordain G, Lavarenne J (December 1987). "Benzodiazepine withdrawal seizures: analysis of 48 case reports". Clinical Neuropharmacology. 10 (6): 538–44. doi:10.1097/00002826-198712000-00005. PMID   3427560.
  38. Kenny T (April 20, 2011). "Antihistamines". Patient.info. Retrieved March 20, 2013.
  39. "Metoclopramide & Tardive Dyskinesia". Tardive Dyskinesia Center. Archived from the original on March 23, 2013. Retrieved March 20, 2013.
  40. "Thimerosal in Vaccines". U.S. Food and Drug Administration (FDA). Archived from the original on January 6, 2013. Retrieved March 16, 2013.
  41. Jaslow, R. (March 29, 2012). "CDC sees autism rate rise 25%". CBS News. Archived from the original on March 20, 2013. Retrieved March 16, 2013.
  42. "Silicone Breast Implants in Relation to Connective Tissue Diseases and Immunologic Dysfunction". Archived from the original on 2013-03-03. Retrieved March 16, 2013.
Classification
D