Adverse drug reaction

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]


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.[1] The study of ADRs is the concern of the field known as pharmacovigilance.

Informing a patient that ARDs may be a sign that a drug is working may increase acceptance of a medication[2].


ADRs may be classified by cause and severity.


  • Type A: pharmacologically predictableddfd
  • Type B: bizarre and unpredictable (or idiosyncratic)
  • Type C: arising from chronic use
  • Type D: delayed reaction
  • Type E: end of dose reaction
  • Type F: failure of therapy

Types A and B were proposed in the 11970s,[3] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[4]


The American Food and Drug Administration defines severe adverse event (SAE) as:[5]:

  • 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

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[6]:

  • Red (High Risk)
  • Orange (Elevated Risk)
  • Yellow (Guarded Risk)
  • Blue (General Risk)
  • Green (Low Risk)


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[7], 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, 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

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.[8]

Genetic factors

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[9][10] Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.

Phase I reactions

Inheriting abnormal alleles of cytochrome P450can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.[11].[12]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[13]

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.[13][12]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[12]

Interactions with other drugs

The risk of drug interactions is increased with polypharmacy.

Protein binding

These interactions are usually transient and mild until a new steady state is achieved.[14][15] These are mainly for drugs without much first-pass liver metabolism. The prinicple plasma proteins for drug binding are:[16]

  1. albumin
  2. α1-acid glycoprotein
  3. lipoproteins

Some drug interactions with warfarin are due to changes in protein binding.[16]

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.[17].

Synergistic effects

An example of synergism is two drugs that both prolong the QT interval.

Assessing causality

A simple scale is available at[1]

Note that an ADR should not be labeled as 'certain' unless the ADR abates with dechallenge and recurs with rechallenge are true.

A more complicated scale is the Naranjo algorithm.

Publications reporting adverse drug reactions

Reporting standards

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommends standard items to be included in publications[18][19].

Systematic reviews do not well search for or report adverse drug reactions[20][21]. This difficulty may in part be due to problematic reporting of adverse drug reactions in trials[22][22] incuding outcome reporting bias[23].

Searching for publications

Various search strategies have been developed to locate publications that report adverse drug reactions[24].

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.


Physical Examination



See also


  1. 1.0 1.1 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.
  2. Leibowitz KA, Howe LC, Crum AJ (2021). "Changing mindsets about side effects". BMJ Open. 11 (2): e040134. doi:10.1136/bmjopen-2020-040134. PMC 7849892 Check |pmc= value (help). PMID 33526496 Check |pmid= value (help).
  3. Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977:10.
  4. 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.
  5. "MedWatch - What Is A Serious Adverse Event?". Retrieved 2007-09-18.
  6. "'Traffic-light' medicine risk website to launch". The Guardian. 2007-10-02. Check date values in: |date= (help)
  7. Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 146
  8. "Clinical Drug Use". Retrieved 2007-09-18.
  9. 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. PMID 11710893.
  10. Goldstein DB (2003). "Pharmacogenetics in the laboratory and the clinic". N. Engl. J. Med. 348 (6): 553–6. doi:10.1056/NEJMe020173. PMID 12571264.
  11. "". Retrieved 2007-09-18.
  12. 12.0 12.1 12.2 Weinshilboum R (2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. doi:10.1056/NEJMra020021. PMID 12571261.
  13. 13.0 13.1 Evans WE, McLeod HL (2003). "Pharmacogenomics--drug disposition, drug targets, and side effects". N. Engl. J. Med. 348 (6): 538–49. doi:10.1056/NEJMra020526. PMID 12571262.
  14. DeVane CL (2002). "Clinical significance of drug binding, protein binding, and binding displacement drug interactions". Psychopharmacology bulletin. 36 (3): 5–21. PMID 12473961.
  15. Benet LZ, Hoener BA (2002). "Changes in plasma protein binding have little clinical relevance". Clin. Pharmacol. Ther. 71 (3): 115–21. doi:10.1067/mcp.2002.121829. PMID 11907485.OVID full text summary table at OVID
  16. 16.0 16.1 Sands CD, Chan ES, Welty TE (2002). "Revisiting the significance of warfarin protein-binding displacement interactions". The Annals of pharmacotherapy. 36 (10): 1642–4. PMID 12369572.
  17. "". Retrieved 2007-09-18.
  18. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG; et al. (2016). "PRISMA harms checklist: improving harms reporting in systematic reviews". BMJ. 352: i157. doi:10.1136/bmj.i157. PMID 26830668.
  19. PRISMA for reviews including harms outcomes. Available at
  20. Golder S, Loke Y, McIntosh HM (2008). "Poor reporting and inadequate searches were apparent in systematic reviews of adverse effects". J Clin Epidemiol. 61 (5): 440–8. doi:10.1016/j.jclinepi.2007.06.005. PMID 18394536.
  21. Zorzela L, Golder S, Liu Y, Pilkington K, Hartling L, Joffe A; et al. (2014). "Quality of reporting in systematic reviews of adverse events: systematic review". BMJ. 348: f7668. doi:10.1136/bmj.f7668. PMC 3898583. PMID 24401468.
  22. 22.0 22.1 Barhli A, Joulia ML, Tournigand C, Kempf E (2021). "Adverse events reporting in phase 3 oncology clinical trials of checkpoint inhibitors: A systematic review". Crit Rev Oncol Hematol. 157: 103162. doi:10.1016/j.critrevonc.2020.103162. PMID 33260049 Check |pmid= value (help).
  23. Saini P, Loke YK, Gamble C, Altman DG, Williamson PR, Kirkham JJ (2014). "Selective reporting bias of harm outcomes within studies: findings from a cohort of systematic reviews". BMJ. 349: g6501. doi:10.1136/bmj.g6501. PMC 4240443. PMID 25416499.
  24. Golder S, Farrah K, Mierzwinski-Urban M, Wright K, Loke YK (2019). "The development of search filters for adverse effects of medical devices in medline and embase". Health Info Libr J. 36 (3): 244–263. doi:10.1111/hir.12260. PMC 6853259 Check |pmc= value (help). PMID 31187590.
  25. 25.0 25.1 25.2 25.3 25.4 25.5 25.6 "Dermatology Atlas".

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