Drug-related side effects and adverse reactions

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Drug toxicity, also called adverse drug reaction (ADR) or adverse drug event (ADE), is defined as the "manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning..."[1] 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.[2]

The World Health Organization defines it as:

An adverse drug reaction (ADR) is ‘a response to a medicine which is

noxious and unintended, and which occurs at doses normally used in man’. In this description it is of importance that it concerns the response of a patient, in which individual factors may play an important role, and that the phenomenon is noxious (an unexpected therapeutic

response, for example, may be a side effect but not an adverse reaction).[3]

6% of hospital admissions[4] and 2.5% of emergency department visits for injuries or poisonings[5] may be due to adverse drug reactions. Adverse drug reactions also occur among ambulatory outpatients[6] and among inpatients[7].

Classification

Cause

The World Health Organization (WHO) classifies ADRs by cause:[8]

  • Type A: Dose-related; pharmacologically predictable. In a study of older adults, this type was the most common with the most common offending drugs being warfarin, insulin, and digoxin.[9]
  • Type B: Non-dose related; bizarre and unpredictable.
  • Type C: Dose-related and time-related. This is related to duration and dosage of exposure. An example is hypothalamic-pituitary-adrenal suppression from glucocorticoid therapy.
  • Type D: Time-related; delayed reaction. An example is tardive dyskinesia.
  • Type E: Withdrawal; end of dose reaction. An example is narcotic or beta-blocker withdrawal.
  • Type F: Unexpected failure of therapy. This may be caused by drug interactions. An example is failure of oral contraceptives due to induction of enzymes by a second drug.

Types A and B were proposed in the 1970s,[10] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[11]

Manifestation

Drug-induced liver injury

For more information, see: Drug-induced liver injury.


Drug-drug interactions

Some interactions are due to the system of cytochrome P-450 enzymes used to clear drugs from the body. These interactions can be complex, involving either increasing or decreasing the activity of a given cytochrome pathway, or preferentially (i.e., competitive inhibition) using the pathway rather than other drugs. As one example, theophylline and ciprofloxacin up-regulate the cytochrome pathway that also clears estrogen and phenytoin. As a result, oral contraceptives and anticonvulsants may fail because the pathway clears them too quickly and an adequate blood level cannot be maintained.

Drug-disease interactions

Drug-food interactions

Monoamine oxidase inhibitors can cause fatal hypertension in patients who have also consumed food containing high concentrations of tyramine. The suspect foods form an odd assortment, such as Chianti wine, some smoked fish and aged cheese.

QT interval prolongation

For more information, see: QT interval.


Thombocytopenia

For more information, see: Thombocytopenia.


Describing ADRs

ADRs may be described by their frequency and severity

Frequency

The World Health Organization recommends standardization of descriptions of frequency.[12] Although the WHO document is not currenlty available online, their recommendations have been summarized by others.[13]

  • very common (>1/10 patients)
  • common (>1/100)
  • uncommon (>1/1000)
  • rare (>1/10,000)
  • very rare (<1/100,000)

Severity

The American Food and Drug Administration defines severe effects as:[14]:

  • 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

Etiology / cause

As research better explains the biochemistry of drug use, less ADRs are Type B ('idiosyncratic') and more are Type A (pharmacologically predictable). Common mechanisms are:

  • Abnormal pharmacokinetics due to
    • genetic factors
    • comorbid disease states
  • Synergistic effects between either
    • a drug and a disease
    • two drugs

Risk factors are:[15]

  • The number of drugs
  • History of prior drug toxicity
  • Presence of heart failure
  • Presence of liver disease
  • Presence of renal failure
  • Presence of 4 or more medical conditions

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.[16] However, heavy physician workload may reduce the ability of the physician to use these resources.[17]

Genetic factors

For more information, see: Pharmacogenomics.

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[18][19] Pharmacogenomics is the study on the inherited basis of drug reactions. Among drugs frequently cited in adverse drug reactions, 60% are metabolized by enzymes with genetic variations in metabolism. 7% to 22% of randomly selected have such variation.[18]

Phase I reactions

Inheriting abnormal alleles of cytochrome P-450 can alter drug metabolism. Tables are available to check for drug interactions due to cytochrome P-450 interactions.[20].[21]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[22]

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.[22][21]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[21]

Impaired hepatic function

Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired hepatic function.[23]

Impaired renal function

Food and Drug Administration categories of renal function[24]
Group Description Estimated creatinine clearance (ml/min)
1 Normal renal function > 80 mL/min
2 Mild renal function > 50-80 mL/min
3 Moderate renal function > 30-50 mL/min
4 Severe renal function <30 mL/min
5 ESRD Requiring dialysis

The National Kidney Disease Education Program provides guidance on dosing drugs in patients with reduced glomerular filtration rate.[25] Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired renal function.[24] Although this categorization uses estimated creatinine clearance, using estimated glomerular filtration yields similar recommendations for dosing adjustments.[26]

Interactions with other drugs

For more information, see: Drug interaction.


Synergistic effects

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

Other factors that my increase ADRs

Polypharmacy

For more information, see: polypharmacy.

The risk of drug interactions may be increased with polypharmacy.

Fragmented health care

When controlled for other factors such as the number of prescribing physicians, the number of medicatations may not be a risk factor for adverse drug reactions.[27]

Assessing causality

A scale proposed by the World Health Organization (WHO) is below:[28][8][2]

Certain

  • "A clinical event, including a laboratory test abnormality, that occurs in a plausible time relation to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals"
  • "The response to withdrawal of the drug (dechallenge) should be clinically plausible"
  • "The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary"

Probable/likely

  • "A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge)"
  • "Rechallenge information is not required to fulfil this definition"

Possible

  • "A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals"
  • "Information on drug withdrawal may be lacking or unclear"

Unlikely

  • "A clinical event, including a laboratory test abnormality, with a temporal relation to administration of the drug, which makes a causal relation improbable, and in which other drugs, chemicals, or underlying disease provide plausible explanations"

Conditional/unclassified

  • "A clinical event, including a laboratory test abnormality, reported as an adverse reaction, about which more data are essential for a proper assessment or the additional data are being examined"

Unassessable/unclassifiable

  • "A report suggesting an adverse reaction that cannot be judged, because information is insufficient or contradictory and cannot be supplemented or verified"

An alternative scale is the Naranjo algorithm.

Intolerance to multiple drugs

Amplification may contribute to multiple-drug intolerance (if the adverse effects that are reported are non-specific).[29] This is distinct from multiple drug hypersensitivity.[30]

Monitoring

Unfortunately, more drug toxicity is not reported.[31][32][33] Reports of more than three cases of a rare disease associated with a drug suggests the drug may be causing the disease.[34] More complicated rules for signals are available.[35]

Scientific journals

News of previously unrecognized drug toxicity may be first published in scientific journals. Published reports may be more helpful than spontaneous reports[36] although drug toxicity is more likely to be spontaneously reported than published[37].

Search strategies of MEDLINE are available.[38]

Monitoring bodies

Many countries have official bodies that monitor drug safety and reactions. On an international level, the World Health Organization (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. However, the book, Physicians' Desk Reference, which is a collection of FDA approved drug labels, may contribute to adverse drug effects by systematically underreporting the lowest effect dose of drugs.[39]

Prevention

Criteria have been developed for predictable adverse drug reactions and thus provide a list of medications to avoid.[40][41]

The role of computerized provider order entry (CPOE) has been inconsistent with both positive[42][43] and negative[44] effects on process measures. CPOE has difficulty in precision of alerting.[45]

Genetic screening

For more information, see: Pharmacogenomics.

Screening for HLA-B*5701 may reduce the incidence of hypersensitivity reactions to abacavir according to a randomized controlled trial.[46]

References

  1. ↑ National Library of Medicine. Drug toxicity. Retrieved on 2007-11-23.
  2. ↑ 2.0 2.1 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. [e] Cite error: Invalid <ref> tag; name "pmid15148066" defined multiple times with different content
  3. ↑ World Health Organization (2002), Safety of Medicines: A guide to detecting and reporting adverse drug reactions; Why health professionals need to take action, WHO/EDM/QSM/2002.2, p. 5
  4. ↑ Pirmohamed M, James S, Meakin S, et al (2004). "Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients". BMJ 329 (7456): 15–9. DOI:10.1136/bmj.329.7456.15. PMID 15231615. Research Blogging.
  5. ↑ Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL (2006). "National surveillance of emergency department visits for outpatient adverse drug events". JAMA 296 (15): 1858–66. DOI:10.1001/jama.296.15.1858. PMID 17047216. Research Blogging.
  6. ↑ Gandhi TK, Weingart SN, Borus J, et al (2003). "Adverse drug events in ambulatory care". N. Engl. J. Med. 348 (16): 1556–64. DOI:10.1056/NEJMsa020703. PMID 12700376. Research Blogging.
  7. ↑ Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP (1997). "Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality". JAMA 277 (4): 301–6. PMID 9002492. [e]
  8. ↑ 8.0 8.1 Edwards IR, Aronson JK (2000). "Adverse drug reactions: definitions, diagnosis, and management". Lancet 356 (9237): 1255–9. DOI:10.1016/S0140-6736(00)02799-9. PMID 11072960. Research Blogging.
  9. ↑ Budnitz DS, Shehab N, Kegler SR, Richards CL (2007). "Medication use leading to emergency department visits for adverse drug events in older adults". Ann. Intern. Med. 147 (11): 755–65. PMID 18056659. [e]
  10. ↑ Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977:10.
  11. ↑ 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.
  12. ↑ Council for International Organizations of Medical Sciences. Guidelines for preparing core clinical safety information on drugs. Geneva: CIOMS, 1995.
  13. ↑ Hoes JN, Jacobs JW, Boers M, et al (2007). "EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases". Ann. Rheum. Dis. 66 (12): 1560–7. DOI:10.1136/ard.2007.072157. PMID 17660219. Research Blogging.
  14. ↑ MedWatch - What Is A Serious Adverse Event?. Retrieved on 2007-09-18.
  15. ↑ Onder G, Petrovic M, Tangiisuran B, Meinardi MC, Markito-Notenboom WP, Somers A et al. (2010). "Development and validation of a score to assess risk of adverse drug reactions among in-hospital patients 65 years or older: the GerontoNet ADR risk score.". Arch Intern Med 170 (13): 1142-8. DOI:10.1001/archinternmed.2010.153. PMID 20625022. Research Blogging.
  16. ↑ Clinical Drug Use. Retrieved on 2007-09-18.
  17. ↑ Sheen SS, Choi JE, Park RW, Kim EY, Lee YH, Kang UG (2008). "Overdose rate of drugs requiring renal dose adjustment: data analysis of 4 years prescriptions at a tertiary teaching hospital". J Gen Intern Med 23 (4): 423-8. DOI:10.1007/s11606-007-0336-8. PMID 18373140. Research Blogging.
  18. ↑ 18.0 18.1 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. [e]
  19. ↑ Goldstein DB (2003). "Pharmacogenetics in the laboratory and the clinic". N. Engl. J. Med. 348 (6): 553–6. DOI:10.1056/NEJMe020173. PMID 12571264. Research Blogging.
  20. ↑ Drug-Interactions.com. Retrieved on 2007-09-18.
  21. ↑ 21.0 21.1 21.2 Weinshilboum R (2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
  22. ↑ 22.0 22.1 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. Research Blogging.
  23. ↑ Food and Drug Administration, Guidance for Industry: [http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093606.htm Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling], US Department of Health and Human Services, Rockville, MD (1998) May.
  24. ↑ 24.0 24.1 Food and Drug Administration, Guidance for Industry: Pharmacokinetics in Patients With Impaired Renal Function—Study Design, Data Analysis, and Impact on Dosing and Labeling, US Department of Health and Human Services, Rockville, MD (1998) May.
  25. ↑ The National Kidney Disease Education Program. (2009) Chronic Kidney Disease and Drug Dosing: Information for Providers National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), U.S. Department of Health & Human Services (DHHS).
  26. ↑ Stevens LA, Nolin TD, Richardson MM, Feldman HI, Lewis JB, Rodby R et al. (2009). "Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations.". Am J Kidney Dis 54 (1): 33-42. DOI:10.1053/j.ajkd.2009.03.008. PMID 19446939. PMC PMC2756662. Research Blogging.
  27. ↑ Green JL, Hawley JN, Rask KJ (2007). "Is the number of prescribing physicians an independent risk factor for adverse drug events in an elderly outpatient population?". Am J Geriatr Pharmacother 5 (1): 31–9. DOI:10.1016/j.amjopharm.2007.03.004. PMID 17608245. Research Blogging.
  28. ↑ UMC Causality Assessment of Suspected Adverse Reactions. World Health Organization. Retrieved on 2008-01-14.
  29. ↑ Davies SJ, Jackson PR, Ramsay LE, Ghahramani P (2003). "Drug intolerance due to nonspecific adverse effects related to psychiatric morbidity in hypertensive patients". Arch. Intern. Med. 163 (5): 592-600. PMID 12622606. [e]
  30. ↑ Gex-Collet C, Helbling A, Pichler WJ (2005). "Multiple drug hypersensitivity--proof of multiple drug hypersensitivity by patch and lymphocyte transformation tests". J Investig Allergol Clin Immunol 15 (4): 293–6. PMID 16433211. [e]
  31. ↑ Hazell L, Shakir SA (2006). "Under-reporting of adverse drug reactions : a systematic review.". Drug Saf 29 (5): 385-96. PMID 16689555.
  32. ↑ Moride Y, Haramburu F, Requejo AA, Bégaud B (1997). "Under-reporting of adverse drug reactions in general practice.". Br J Clin Pharmacol 43 (2): 177-81. PMID 9131950. PMC PMC2042725.
  33. ↑ Scott HD, Rosenbaum SE, Waters WJ, Colt AM, Andrews LG, Juergens JP et al. (1987). "Rhode Island physicians' recognition and reporting of adverse drug reactions.". R I Med J 70 (7): 311-6. PMID 3476980.
  34. ↑ Begaud B, Moride Y, Tubert-Bitter P, Chaslerie A, Haramburu F (1994). "False-positives in spontaneous reporting: should we worry about them?". Br J Clin Pharmacol 38 (5): 401-4. PMID 7893579. PMC PMC1364871.
  35. ↑ Tubert P, Bégaud B, Haramburu F, Péré JC (1991). "Spontaneous reporting: how many cases are required to trigger a warning?". Br J Clin Pharmacol 32 (4): 407-8. PMID 1958431. PMC PMC1368597.
  36. ↑ Haramburu F, Bégaud B, Péré JC (1990). "Comparison of 500 spontaneous and 500 published reports of adverse drug reactions.". Eur J Clin Pharmacol 39 (3): 287-8. PMID 2257868.
  37. ↑ Liu BA, Mittmann N, Knowles SR, Shear NH (1996). "Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports.". CMAJ 155 (5): 519-27. PMID 8804257. PMC PMC1335030. Review in: J Fam Pract. 1993 Mar;36(3):341-3
  38. ↑ Golder S, Loke Y (2009). "Search strategies to identify information on adverse effects: a systematic review.". J Med Libr Assoc 97 (2): 84-92. DOI:10.3163/1536-5050.97.2.004. PMID 19404498. PMC PMC2670220. Research Blogging.
  39. ↑ Cohen JS (2001). "Dose discrepancies between the Physicians' Desk Reference and the medical literature, and their possible role in the high incidence of dose-related adverse drug events". Arch. Intern. Med. 161 (7): 957–64. PMID 11295958. [e]
  40. ↑ Beers MH (1997). "Explicit criteria for determining potentially inappropriate medication use by the elderly. An update". Arch. Intern. Med. 157 (14): 1531–6. PMID 9236554. [e]
  41. ↑ Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH (2003). "Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts". Arch. Intern. Med. 163 (22): 2716–24. DOI:10.1001/archinte.163.22.2716. PMID 14662625. Research Blogging.
  42. ↑ Raebel MA, Charles J, Dugan J, et al (2007). "Randomized trial to improve prescribing safety in ambulatory elderly patients". J Am Geriatr Soc 55 (7): 977–85. DOI:10.1111/j.1532-5415.2007.01202.x. PMID 17608868. Research Blogging.
  43. ↑ Raebel MA, Carroll NM, Kelleher JA, Chester EA, Berga S, Magid DJ (2007). "Randomized trial to improve prescribing safety during pregnancy". J Am Med Inform Assoc 14 (4): 440–50. DOI:10.1197/jamia.M2412. PMID 17460126. Research Blogging.
  44. ↑ Glassman PA, Belperio P, Lanto A, et al (2007). "The utility of adding retrospective medication profiling to computerized provider order entry in an ambulatory care population". J Am Med Inform Assoc 14 (4): 424–31. DOI:10.1197/jamia.M2313. PMID 17460134. Research Blogging.
  45. ↑ Judge J, Field TS, DeFlorio M, et al (2006). "Prescribers' responses to alerts during medication ordering in the long term care setting". J Am Med Inform Assoc 13 (4): 385–90. DOI:10.1197/jamia.M1945. PMID 16622171. Research Blogging.
  46. ↑ Mallal S, Phillips E, Carosi G, et al (February 2008). "HLA-B*5701 screening for hypersensitivity to abacavir". N. Engl. J. Med. 358 (6): 568–79. DOI:10.1056/NEJMoa0706135. PMID 18256392. Research Blogging.

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