Adverse drug reaction

Traditional • Type A: augmented pharmacological effects, which are dose-dependent and predictable :Type A reactions, which constitute approximately 80% of adverse drug reactions, are usually a 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), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term side effects may be applied to minor type A reactions. • Type B: Type B reactions are not dose-dependent and are not predictable, and so may be called idiosyncratic. 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. Other types of adverse drug reactions are Type C, Type D, Type E, and Type F. Type C was categorized for chronic adverse drug reactions, Type D for delayed adverse drug reactions, Type E for withdrawal adverse drug reactions, and Type F for failure of therapy as an adverse drug reaction. Adverse drug reactions can also be categorized using time-relatedness, dose-relatedness, and susceptibility, which collectively are called the DoTS classification. • 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 abnormality • Requires intervention to prevent permanent impairment or damage Severity is a measure of the intensity of the adverse event in question. They are easily confused but can not be used interchangeably, requiring care in usage. Seriousness usually indicates patient outcome (such as negative outcomes including disability, long-term effects, and death). In adverse drug reactions, the seriousness of the reaction is important for reporting. ==Location==

Some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation. ==Mechanisms==

(drug-induced hepatitis) with granulomata. Other causes were excluded with extensive investigations. Liver biopsy. H&E stain. 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. The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria 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. Genetic factors Pharmacogenomics includes how genes can predict potential adverse drug reactions. However, pharmacogenomics is not limited to adverse events (of any type), but also looks at how genes may impact other responses to medications, such as low/no effect or expected/normal responses (especially based on drug metabolism). Phase I reactions Phase I reactions include metabolism by 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. 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. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: • albumin • α1-acid glycoprotein • lipoproteins Some drug interactions with warfarin are due to changes in protein binding. Additive drug effects Two or more drugs that contribute to the same mechanism in the body can have additive toxic or adverse effects. One example of this is multiple medications administered concurrently that prolong the QT interval, such as antiarrhythmics like sotalol and some macrolide antibiotics, such as systemic azithromycin. Another example of additive effects for adverse drug reactions is in serotonin toxicity (serotonin syndrome). If medications that cause increased serotonin levels are combined, they can cause serotonin toxicity (though therapeutic doses of one agent that increases serotonin levels can cause serotonin toxicity in certain cases and individuals). Additionally, Clarithromycin is a permeability glycoprotein (P-gp) efflux pump inhibitor, which when given with apixaban (a substrate for P-gp) will lead to increased absorption of apixaban, resulting in the same adverse effects as with CYP3A4 inhibition. == Management ==

Assessing causality Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). Monitoring bodies Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre. The European Union runs the European Medicines Agency (EMA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies. The FDA has a reporting system called the FDA Adverse Event Reporting System, where individuals can report adverse drug events. Both healthcare professionals and consumers can report to this program. In the UK, a monitoring system called the Yellow Card Scheme was established in 1964. The Yellow Card Scheme was set up to surveil medications and other health products. ==Epidemiology==

A study by the Agency for Healthcare Research and Quality (AHRQ) found that in 2011, sedatives and hypnotics were a leading source for adverse drug events seen in the hospital setting. Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were steroids, antibiotics, opiates/narcotics, and anticoagulants. Patients treated in urban teaching hospitals had higher rates of ADEs involving antibiotics and opiates/narcotics compared to those treated in urban nonteaching hospitals. Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals. Medication related harm (MRH) is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There was a wide range in incidence, from 0.4% to 51.2% of participants, and 35% to 59% of harm was preventable. Medication related harm incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17–51% of individuals). In the U.S., females had a higher rate of ADEs involving opiates and narcotics than males in 2011, while male patients had a higher rate of anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. In 2012, McKinsey & Company concluded that the cost of the 50-100 million preventable error-related adverse drug events would be between US$18–115 billion. An article published in The Journal of the American Medical Association (JAMA) in 2016 reported adverse drug event statistics from emergency departments around the United States in 2013-2014. From this article, an estimated prevalence of adverse drug events that were presented to the emergency department (ED) was 4 events out of every 1000 people. This article reported that 57.1% of these adverse drug events presented to the ED were in females. As well, out of all of the adverse drug events presented to the emergency department documented in this article, 17.6% were from anticoagulants, 16.1% were from antibiotics, and 13.3% from diabetic agents. ==See also==