Adverse drug reaction
From DrugPedia: A Wikipedia for Drug discovery
An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted, negative consequences associated with the use of given medications. An ADR is a particular type of adverse effect. 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.<ref name="pmid15148066">Nebeker JR, Barach P, Samore MH (2004). "Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting". Ann. Intern. Med. 140 (10): 795–801. PMID 15148066.</ref> The study of ADRs is the concern of the field known as pharmacovigilance.
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[edit] Classification
ADRs may be classified by e.g. cause and severity.
[edit] Cause
- Type A: Augmented pharmacologic effects
- Type B: Bizarre effects (or idiosyncratic)
- Type C: Chronic effects
- Type D: Delayed effects
- Type E: End-of-treatment effects
- Type F: Failure of therapy
Types A and B were proposed in the 1970s,<ref>Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977:10.</ref> and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.<ref>Aronson JK. Drug therapy. In: Haslett C, Chilvers ER, Boon NA, Colledge NR, Hunter JAA, eds. Davidson's principles and practice of medicine 19th ed. Edinburgh: Elsevier Science, 2002:147-63. ISBN 0-44307-035-0.</ref>
[edit] Seriousness and Severity
The American Food and Drug Administration defines a serious adverse event as one when the patient outcome is:<ref>Template:Cite web</ref>:
- 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 Anomaly
- - or -
- Requires Intervention to Prevent Permanent Impairment or Damage
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. A headache, on the other hand, can hardly ever be serious, unless it also satisfies the criteria for seriousness, listed above.
[edit] Overall Drug Risk
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<ref>Template:Cite news</ref>:
- Red (High Risk)
- Orange (Elevated Risk)
- Yellow (Guarded Risk)
- Blue (General Risk)
- Green (Low Risk)
[edit] Location
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<ref name=Rang146> Template:Cite book Page 146 </ref>, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.
[edit] Mechanisms
As research better explains the biochemistry of drug use, less ADRs are Type B and more are Type A. Common mechanisms are:
- Abnormal pharmacokinetics due to
- genetic factors
- comorbid disease states
- Synergistic effects between either
- a drug and a disease
- two drugs
[edit] Abnormal pharmacokinetics
[edit] 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.<ref>Template:Cite web</ref>
[edit] Genetic factors
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.<ref name="pmid11710893">Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). "Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review". JAMA 286 (18): 2270–9. doi:. PMID 11710893.</ref><ref name="pmid12571264">Goldstein DB (2003). "Pharmacogenetics in the laboratory and the clinic". N. Engl. J. Med. 348 (6): 553–6. doi:. PMID 12571264.</ref> Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.
[edit] Phase I reactions
Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.<ref>Template:Cite web</ref>.<ref name="pmid12571261">Weinshilboum R (2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. doi:. PMID 12571261.</ref>
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine<ref name="pmid12571262">Evans WE, McLeod HL (2003). "Pharmacogenomics--drug disposition, drug targets, and side effects". N. Engl. J. Med. 348 (6): 538–49. doi:. PMID 12571262.</ref>
[edit] 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.<ref name="pmid12571262"/><ref name="pmid12571261"/>
Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.<ref name="pmid12571261"/>
[edit] Interactions with other drugs
The risk of drug interactions is increased with polypharmacy.
[edit] Protein binding
These interactions are usually transient and mild until a new steady state is achieved.<ref name="pmid12473961">DeVane CL (2002). "Clinical significance of drug binding, protein binding, and binding displacement drug interactions". Psychopharmacology bulletin. 36 (3): 5–21. PMID 12473961.</ref><ref name="pmid11907485">Benet LZ, Hoener BA (2002). "Changes in plasma protein binding have little clinical relevance". Clin. Pharmacol. Ther. 71 (3): 115–21. doi:. PMID 11907485.OVID full text summary table at OVID</ref> These are mainly for drugs without much first-pass liver metabolism. The prinicple plasma proteins for drug binding are:<ref name="pmid12369572">Sands CD, Chan ES, Welty TE (2002). "Revisiting the significance of warfarin protein-binding displacement interactions". The Annals of pharmacotherapy 36 (10): 1642–4. doi:. PMID 12369572.</ref>
- albumin
- α1-acid glycoprotein
- lipoproteins
Some drug interactions with warfarin are due to changes in protein binding.<ref name="pmid12369572"/>
[edit] 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.<ref>Template:Cite web</ref>.
[edit] Synergistic effects
An example of synergism is two drugs that both prolong the QT interval.
[edit] Assessing causality
A simple scale is available at http://annals.org/cgi/content/full/140/10/795.<ref name="pmid15148066"/>
An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol.
A more complicated scale is the Naranjo algorithm.
[edit] Monitoring bodies
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.
[edit] See also
- EudraVigilance (European Union)
- Paradoxical reaction
- Polypharmacy
- Toxicology
- The Medical Letter on Drugs and Therapeutics
- Yellow Card Scheme (UK)
