| Adverse drug reaction | |
|---|---|
| Classification and external resources | |
Adverse drug reaction leading to hepatitis (drug-induced hepatitis) with granulomata. Other causes were excluded with extensive investigations. Liver biopsy. H&E stain. |
|
| ICD-10 | T88.7, Y40-Y59 |
| ICD-9 | 995.2, E850-E858 |
| DiseasesDB | 295 |
| MeSH | D004362 |
An adverse drug reaction (abbreviated ADR) is an expression that describes harm associated with the use of given medications at a normal dosage. 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 expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial.[1] The study of ADRs is the concern of the field known as pharmacovigilance.
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ADRs may be classified by e.g. cause and severity.
Types A and B were proposed in the 1970s,[2] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[3]
The American Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following:[4]
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. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migrane may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above.
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:[5]
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,[6] 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, fewer ADRs are Type B and more are Type A. Common mechanisms are:
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.[7]
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[8][9] Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.
Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.[10][11]
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[12]
Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.[11][12]
Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[11]
The risk of drug interactions is increased with polypharmacy.
These interactions are usually transient and mild until a new steady state is achieved.[13][14] These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are:[15]
Some drug interactions with warfarin are due to changes in protein binding.[15]
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.[10]
An example of synergism is two drugs that both prolong the QT interval.
Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply.[16] 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). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR. A simple scale is available at http://annals.org/cgi/content/full/140/10/795.[1]
Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies some ADRs may be missed as large numbers of test individuals are required to find that adverse drug reaction. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population [1] [2] [3].
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.
| Condition | Substance |
|---|---|
| Abortion, miscarriage or uterine hemorrhage | misoprostol (Cytotec), a labor-inducing drug (this is a case where the adverse effect has been used legally and illegally for performing abortions) |
| Addiction | many sedatives and analgesics such as diazepam, morphine, etc. |
| Birth defects | Thalidomide and Accutane |
| Bleeding of the intestine | aspirin therapy |
| Cardiovascular disease | COX-2 inhibitors (i.e. Vioxx) |
| Deafness and kidney failure | gentamicin (an antibiotic) |
| Death, following sedation | propofol (Diprivan) |
| Depression or hepatic injury | interferon |
| Diabetes | atypical antipsychotic medications (neuroleptic psychiatric drugs) |
| Diarrhea | orlistat (Xenical) |
| Erectile dysfunction | many drugs, such as antidepressants |
| Fever | vaccination (in the past, imperfectly manufactured vaccines, such as BCG and poliomyelitis, have caused the very disease they intended to fight). |
| Glaucoma | corticosteroid-based eye drops |
| Hair loss and anemia | chemotherapy against cancer, leukemia, etc. |
| Headache | spinal anesthesia |
| Hypertension | ephedrine users, which prompted FDA to remove the status of dietary supplement of ephedra extracts |
| Insomnia | stimulants, Ritalin, Adderall, etc. |
| Lactic acidosis | stavudine (Zerit, for anti-HIV therapy) or metformin (for diabetes) |
| Liver failure | paracetamol |
| Melasma and thrombosis | estrogen-containing hormonal contraception such as the combined oral contraceptive pill |
| Irreversible Peripheral neuropathy | fluoroquinolone medications [17][18][19] |
| Rhabdomyolysis | statins (anti-cholesterol drugs) |
| Seizures | withdrawal from benzodiazepine |
| Drowsiness or increase in appetite | antihistamine use. Some antihistamines are used in sleep aids explicitly because they cause drowsiness. |
| Stroke or heart attack | sildenafil (Viagra) when used with nitroglycerine; COX-2 inhibitors |
| Suicide, increased tendency | fluoxetine and other SSRI antidepressants |
| Parkinsonism | MPTP a meperidine related drug considered highly neurotoxic |
| Tardive dyskinesia | long-term use of metoclopramide and many antipsychotic medications |
| Spontaneous Tendon rupture | fluoroquinolone drugs [20] even occurring as late as 6 months after treatment had been terminated.[21] |
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