Drug-related side effects and adverse reactions: Difference between revisions

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'''Drug toxicity''', also called '''adverse drug reaction''' (ADR) or '''adverse drug event''' (ADE), is defined as "manifestations of the adverse effects of [[drug]]s administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning..."<ref name="title">{{cite web |url=http://www.nlm.nih.gov/cgi/mesh/2007/MB_cgi?mode=&term=Drug+Toxicity |title=Drug toxicity|author=National Library of Medicine |accessdate=2007-11-23 |format= |work=}}</ref> 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">{{cite journal |author=Nebeker JR, Barach P, Samore MH |title=Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting |journal=Ann. Intern. Med. |volume=140 |issue=10 |pages=795-801 |year=2004 |pmid=15148066 |doi=}}</ref>
'''Drug-related side effects and adverse reactions''', also called '''drug-related side effects and adverse reactions''' (ADR), '''adverse drug event''' (ADE) or '''drug toxicity''', is defined as the "manifestations of the adverse effects of [[drug]]s administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning..."<ref name="title">{{cite web |url=http://www.nlm.nih.gov/cgi/mesh/2007/MB_cgi?mode=&term=Drug+Toxicity |title=Drug toxicity|author=National Library of Medicine |accessdate=2007-11-23 |format= |work=}}</ref> 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">{{cite journal |author=Nebeker JR, Barach P, Samore MH |title=Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting |journal=Ann. Intern. Med. |volume=140 |issue=10 |pages=795-801 |year=2004 |pmid=15148066 |doi=}}</ref>


The World Health Organization defines it as:
The World Health Organization defines it as:
<blockquote>An adverse drug reaction (ADR) is ‘a response to a medicine which is
<blockquote>An drug-related side effects and adverse reactions (ADR) is ‘a response to a medicine which is
noxious and unintended, and which occurs at doses normally used in
noxious and unintended, and which occurs at doses normally used in
man’.
man’.
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and that the phenomenon is noxious (an unexpected therapeutic
and that the phenomenon is noxious (an unexpected therapeutic
response, for example, may be a side effect but not an adverse reaction).<ref name=WHO-Adverse>{{citation
response, for example, may be a side effect but not an adverse reaction).<ref name=WHO-Adverse>{{citation
  | title = Safety of Medicines: A guide to detecting and reporting adverse drug reactions; Why health professionals need to take action
  | title = Safety of Medicines: A guide to detecting and reporting drug-related side effects and adverse reactionss; Why health professionals need to take action
  | id = WHO/EDM/QSM/2002.2
  | id = WHO/EDM/QSM/2002.2
  | author = World Health Organization
  | author = World Health Organization
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}}, p. 5</ref></blockquote>
}}, p. 5</ref></blockquote>


6% of hospital admissions<ref name="pmid15231615">{{cite journal |author=Pirmohamed M, James S, Meakin S, ''et al'' |title=Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients |journal=BMJ |volume=329 |issue=7456 |pages=15–9 |year=2004 |pmid=15231615 |doi=10.1136/bmj.329.7456.15}}</ref> and 2.5% of emergency department visits for injuries or poisonings<ref name="pmid17047216">{{cite journal |author=Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL |title=National surveillance of emergency department visits for outpatient adverse drug events |journal=JAMA |volume=296 |issue=15 |pages=1858–66 |year=2006 |pmid=17047216 |doi=10.1001/jama.296.15.1858}}</ref> may be due to adverse drug reactions. Adverse drug reactions also occur among ambulatory outpatients<ref name="pmid12700376">{{cite journal |author=Gandhi TK, Weingart SN, Borus J, ''et al'' |title=Adverse drug events in ambulatory care |journal=N. Engl. J. Med. |volume=348 |issue=16 |pages=1556–64 |year=2003 |pmid=12700376 |doi=10.1056/NEJMsa020703}}</ref> and among inpatients<ref name="pmid9002492">{{cite journal |author=Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP |title=Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality |journal=JAMA |volume=277 |issue=4 |pages=301–6 |year=1997 |pmid=9002492 |doi=}}</ref>.
6% of hospital admissions<ref name="pmid15231615">{{cite journal |author=Pirmohamed M, James S, Meakin S, ''et al'' |title=Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients |journal=BMJ |volume=329 |issue=7456 |pages=15–9 |year=2004 |pmid=15231615 |doi=10.1136/bmj.329.7456.15}}</ref> and 2.5% of emergency department visits for injuries or poisonings<ref name="pmid17047216">{{cite journal |author=Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL |title=National surveillance of emergency department visits for outpatient adverse drug events |journal=JAMA |volume=296 |issue=15 |pages=1858–66 |year=2006 |pmid=17047216 |doi=10.1001/jama.296.15.1858}}</ref> may be due to drug-related side effects and adverse reactionss. Adverse drug reactions also occur among ambulatory outpatients<ref name="pmid12700376">{{cite journal |author=Gandhi TK, Weingart SN, Borus J, ''et al'' |title=Adverse drug events in ambulatory care |journal=N. Engl. J. Med. |volume=348 |issue=16 |pages=1556–64 |year=2003 |pmid=12700376 |doi=10.1056/NEJMsa020703}}</ref> and among inpatients<ref name="pmid9002492">{{cite journal |author=Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP |title=Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality |journal=JAMA |volume=277 |issue=4 |pages=301–6 |year=1997 |pmid=9002492 |doi=}}</ref>. A minority of drug toxicity is recognized by health care providers.<ref name="pmid12622580">{{cite journal| author=Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC et al.| title=Incidence and preventability of adverse drug events among older persons in the ambulatory setting. | journal=JAMA | year= 2003 | volume= 289 | issue= 9 | pages= 1107-16 | pmid=12622580 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12622580  }} </ref>


==Classification==
==Classification==
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*Type F: Unexpected failure of therapy. This may be caused by [[drug interaction]]s. An example is failure of oral contraceptives due to induction of enzymes by a second drug.
*Type F: Unexpected failure of therapy. This may be caused by [[drug interaction]]s. 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,<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>
Types A and B were proposed in the 1970s,<ref>Rawlins MD, Thompson JW. Pathogenesis of drug-related side effects and adverse reactionss. In: Davies DM, ed. Textbook of drug-related side effects and adverse reactionss. 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>


===Manifestation===
===Manifestation===
====Immediate hypersensitivity====
Immediate hypersensitivity are over-reported and few patient reporting these have reactions on careful testing.<ref>{{Cite journal
| doi = 10.1016/j.jaip.2013.02.002
| issn = 2213-2198
| volume = 1
| issue = 3
| pages = 258-263
| last = Macy
| first = Eric
| coauthors = Eunis W. Ngor
| title = Safely Diagnosing Clinically Significant Penicillin Allergy Using Only Penicilloyl-Poly-Lysine, Penicillin, and Oral Amoxicillin
| journal = The Journal of Allergy and Clinical Immunology: In Practice
| accessdate = 2013-07-13
| date = 2013-05
| url = http://www.sciencedirect.com/science/article/pii/S2213219813001232
}}</ref><ref name="pmid15197017">{{cite journal| author=Messaad D, Sahla H, Benahmed S, Godard P, Bousquet J, Demoly P| title=Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction. | journal=Ann Intern Med | year= 2004 | volume= 140 | issue= 12 | pages= 1001-6 | pmid=15197017 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15197017  }} </ref>
====Drug-induced liver injury====
====Drug-induced liver injury====
{{main|Drug-induced liver injury}}
{{main|Drug-induced liver injury}}
====Drug reaction with eosinophilia and systemic symptoms====
Drug reaction with eosinophilia and systemic symptoms (DRESS) may be caused by medications including allopurinol, phenytoin, dapsone, carbamazepine, trimethoprim-sulfamethoxazole, penicillin, and [[non-steroidal anti-inflammatory agent]]s.<ref name="pmid20713773">{{cite journal| author=Chen YC, Chiu HC, Chu CY| title=Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases. | journal=Arch Dermatol | year= 2010 | volume= 146 | issue= 12 | pages= 1373-9 | pmid=20713773 | doi=10.1001/archdermatol.2010.198 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20713773  }} </ref>  About half of cases have eosinophilia.
====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 inhibitor]]s 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====
{{main|QT interval}}
====Hyperpigmentation====
Hyperpigmentation may occur due to drug toxicity.<ref name="pmid11705252">{{cite journal| author=Dereure O| title=Drug-induced skin pigmentation. Epidemiology, diagnosis and treatment. | journal=Am J Clin Dermatol | year= 2001 | volume= 2 | issue= 4 | pages= 253-62 | pmid=11705252 | doi= | pmc= | url= }} </ref><ref name="pmid4132858">{{cite journal| author=Levantine A, Almeyda J| title=Drug induced changes in pigmentation. | journal=Br J Dermatol | year= 1973 | volume= 89 | issue= 1 | pages= 105-12 | pmid=4132858 | doi= | pmc= | url= }} </ref>
====Thombocytopenia====
====Thombocytopenia====
{{main|Thombocytopenia}}
{{main|Thombocytopenia}}
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ADRs may be described by their frequency and severity
ADRs may be described by their frequency and severity
===Frequency===
===Frequency===
The [[World Health Organization]] recommends standardization of descriptions of frequency.<ref>Council for International Organizations of Medical Sciences. [http://www.who.int/bookorders/WHP/dartprt1.jsp?sesslan=1&codlan=1&codcol=84&codcch=21# ''Guidelines for preparing core clinical safety information on drugs'']. Geneva: CIOMS, 1995.</ref> Although the WHO document is not currenlty available online, their recommendations have been summarized by others.<ref name="pmid17660219">{{cite journal |author=Hoes JN, Jacobs JW, Boers M, ''et al'' |title=EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases |journal=Ann. Rheum. Dis. |volume=66 |issue=12 |pages=1560–7 |year=2007 |pmid=17660219 |doi=10.1136/ard.2007.072157}}</ref>
The [[World Health Organization]] recommends standardization of descriptions of frequency.<ref>Council for International Organizations of Medical Sciences. [http://www.who.int/bookorders/WHP/dartprt1.jsp?sesslan=1&codlan=1&codcol=84&codcch=21# ''Guidelines for preparing core clinical safety information on drugs'']. Geneva: CIOMS, 1995.</ref> Although the WHO document is not currently available online, their recommendations have been summarized by others.<ref name="pmid17660219">{{cite journal |author=Hoes JN, Jacobs JW, Boers M, ''et al'' |title=EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases |journal=Ann. Rheum. Dis. |volume=66 |issue=12 |pages=1560–7 |year=2007 |pmid=17660219 |doi=10.1136/ard.2007.072157}}</ref>
* very common (>1/10 patients)
* very common (>1/10 patients)
* common (>1/100)
* common (>1/100)
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* Requires Intervention to Prevent Permanent Impairment or Damage
* Requires Intervention to Prevent Permanent Impairment or Damage


==Mechanisms==
==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:
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  
* Abnormal pharmacokinetics due to  
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** a drug and a disease
** a drug and a disease
** two drugs
** two drugs
Risk factors are:<ref name="pmid20625022">{{cite journal| author=Onder G, Petrovic M, Tangiisuran B, Meinardi MC, Markito-Notenboom WP, Somers A et al.| title=Development and validation of a score to assess risk of drug-related side effects and adverse reactionss among in-hospital patients 65 years or older: the GerontoNet ADR risk score. | journal=Arch Intern Med | year= 2010 | volume= 170 | issue= 13 | pages= 1142-8 | pmid=20625022 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20625022 | doi=10.1001/archinternmed.2010.153 }} </ref>
* 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===
===Abnormal pharmacokinetics===
====Comorbid disease states====
====Comorbid disease states====
Various diseases, especially those that cause [[renal failure|renal]] or [[liver failure|hepatic]] insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.<ref>{{cite web |url=http://www.clinicaldruguse.com/ |title=Clinical Drug Use |accessdate=2007-09-18 |format= |work=}}</ref> However, heavy physician workload may reduce the ability of the physician to use these resources.<ref name="pmid18373140">{{cite journal |author=Sheen SS, Choi JE, Park RW, Kim EY, Lee YH, Kang UG |title=Overdose rate of drugs requiring renal dose adjustment: data analysis of 4 years prescriptions at a tertiary teaching hospital |journal=J Gen Intern Med |volume=23 |issue=4 |pages=423-8 |year=2008 |pmid=18373140 |doi=10.1007/s11606-007-0336-8 |url=http://dx.doi.org/10.1007/s11606-007-0336-8}}</ref>
Various diseases, especially those that cause [[renal failure|renal]] or [[liver failure|hepatic]] insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.<ref>{{cite web |url=http://www.clinicaldruguse.com/ |title=Clinical Drug Use |accessdate=2007-09-18 |format= |work=}}</ref> However, heavy physician workload may reduce the ability of the physician to use these resources.<ref name="pmid18373140">{{cite journal |author=Sheen SS, Choi JE, Park RW, Kim EY, Lee YH, Kang UG |title=Overdose rate of drugs requiring renal dose adjustment: data analysis of 4 years prescriptions at a tertiary teaching hospital |journal=J Gen Intern Med |volume=23 |issue=4 |pages=423-8 |year=2008 |pmid=18373140 |doi=10.1007/s11606-007-0336-8 |url=http://dx.doi.org/10.1007/s11606-007-0336-8}}</ref>
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====Genetic factors====
====Genetic factors====
{{main|Pharmacogenomics}}
{{main|Pharmacogenomics}}
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |pmid=11710893 |doi=}}</ref><ref name="pmid12571264">{{cite journal |author=Goldstein DB |title=Pharmacogenetics in the laboratory and the clinic |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=553–6 |year=2003 |pmid=12571264 |doi=10.1056/NEJMe020173}}</ref> 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.<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |pmid=11710893 |doi=}}</ref>
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing drug-related side effects and adverse reactionss: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |pmid=11710893 |doi=}}</ref><ref name="pmid12571264">{{cite journal |author=Goldstein DB |title=Pharmacogenetics in the laboratory and the clinic |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=553–6 |year=2003 |pmid=12571264 |doi=10.1056/NEJMe020173}}</ref> Pharmacogenomics is the study on the inherited basis of drug reactions. Among drugs frequently cited in drug-related side effects and adverse reactionss, 60% are metabolized by enzymes with genetic variations in metabolism. 7% to 22% of randomly selected have such variation.<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing drug-related side effects and adverse reactionss: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |pmid=11710893 |doi=}}</ref>


=====Phase I reactions=====
=====Phase I reactions=====
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Inheriting abnormal [[Thiopurine methyltransferase|thiopurine S-methyltransferase]] may affect the metabolism of the [[thiopurine]] drugs [[mercaptopurine]] and [[azathioprine]].<ref name="pmid12571261"/>
Inheriting abnormal [[Thiopurine methyltransferase|thiopurine S-methyltransferase]] may affect the metabolism of the [[thiopurine]] drugs [[mercaptopurine]] and [[azathioprine]].<ref name="pmid12571261"/>
====Impaired hepatic function====
[[Food and Drug Administration]] provides guidance on the labeling of prescription medications to guide dosing for patients with impaired hepatic function.<ref>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.</ref>
====Impaired renal function====
{| class="wikitable" align="right"
|+ [[Food and Drug Administration]] categories of renal function<ref name="fda-renalcategories>Food and Drug Administration, Guidance for Industry: [http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093606.htm 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.</ref>
! 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 [http://www.nkdep.nih.gov/ National Kidney Disease Education Program] provides guidance on dosing drugs in patients with reduced [[glomerular filtration rate]].<ref>The National Kidney Disease Education Program. (2009) [http://www.nkdep.nih.gov/professionals/ 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).</ref> [[Food and Drug Administration]] provides guidance on the labeling of prescription medications to guide dosing for patients with impaired renal function.<ref name="fda-renalcategories>Food and Drug Administration, Guidance for Industry: [http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093606.htm 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.</ref> Although this categorization uses estimated creatinine clearance, using estimated glomerular filtration yields similar recommendations for dosing adjustments.<ref name="pmid19446939">{{cite journal| author=Stevens LA, Nolin TD, Richardson MM, Feldman HI, Lewis JB, Rodby R et al.| title=Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. | journal=Am J Kidney Dis | year= 2009 | volume= 54 | issue= 1 | pages= 33-42 | pmid=19446939
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19446939 | doi=10.1053/j.ajkd.2009.03.008 | pmc=PMC2756662 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>


====Interactions with other drugs====
====Interactions with other drugs====
=====Protein binding=====
{{main|Drug interaction}}
These interactions are usually transient and mild until a new steady state is achieved.<ref name="pmid12473961">{{cite journal |author=DeVane CL |title=Clinical significance of drug binding, protein binding, and binding displacement drug interactions |journal=Psychopharmacology bulletin. |volume=36 |issue=3 |pages=5–21 |year=2002 |pmid=12473961 |doi=}}</ref><ref name="pmid11907485">{{cite journal |author=Benet LZ, Hoener BA |title=Changes in plasma protein binding have little clinical relevance |journal=Clin. Pharmacol. Ther. |volume=71 |issue=3 |pages=115–21 |year=2002 |pmid=11907485 |doi=10.1067/mcp.2002.121829}}[http://gateway.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=11907485.ui OVID full text] [http://gateway.ovid.com/ovidweb.cgi?T=JS&NEWS=N&PAGE=image&IMAGE=00003098-200203000-00001%7cTT2&D=ovft summary table at OVID]</ref> These are mainly for drugs without much first-pass liver metabolism. The principle plasma proteins for drug binding are:<ref name="pmid12369572">{{cite journal |author=Sands CD, Chan ES, Welty TE |title=Revisiting the significance of warfarin protein-binding displacement interactions |journal=The Annals of pharmacotherapy |volume=36 |issue=10 |pages=1642–4 |year=2002 |pmid=12369572 |doi=|url=http://www.theannals.com/cgi/reprint/36/10/1642}}</ref>
# [[albumin]]
# α1-acid glycoprotein
# lipoproteins
Some drug interactions with [[warfarin]] are due to changes in protein binding.<ref name="pmid12369572"/>
 
=====Cytochrome P450=====
Patients have abnormal metabolism by [[cytochrome P-450]] due to either inheriting abnormal [[allele]]s or due to drug interactions. Tables are available to check for drug interactions due to [[cytochrome P-450]] interactions.<ref>{{cite web |url=http://medicine.iupui.edu/flockhart/ |title=Drug-Interactions.com |accessdate=2007-09-18 |format= |work=}}</ref>.


===Synergistic effects===
===Synergistic effects===
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====Polypharmacy====
====Polypharmacy====
{{main|polypharmacy}}
{{main|polypharmacy}}
The risk of [[drug interaction]]s may be increased with [[polypharmacy]].
The risk of [[drug interaction]]s may be increased with [[polypharmacy]]. Using 11 or more chronic [[medication]]s is a risk factor for drug toxicity.<ref>{{Cite journal
| doi = 10.1136/bmj.d3514
| issn = 0959-8138
| volume = 342
| issue = jun21 1
| pages = d3514-d3514
| last = Guthrie
| first = B.
| coauthors = C. McCowan, P. Davey, C. R. Simpson, T. Dreischulte, K. Barnett
| title = High risk prescribing in primary care patients particularly  vulnerable to adverse drug events: cross sectional population database  analysis in Scottish general practice
| journal = BMJ
| accessdate = 2011-06-23
| date = 2011-06
| url = http://www.bmj.com/cgi/doi/10.1136/bmj.d3514
}}</ref>
 
====Fragmented health care====
====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.<ref name="pmid17608245">{{cite journal |author=Green JL, Hawley JN, Rask KJ |title=Is the number of prescribing physicians an independent risk factor for adverse drug events in an elderly outpatient population? |journal=Am J Geriatr Pharmacother |volume=5 |issue=1 |pages=31–9 |year=2007 |pmid=17608245 |doi=10.1016/j.amjopharm.2007.03.004 |issn=}}</ref>
When controlled for other factors such as the number of prescribing physicians, the number of medicatations may not be a risk factor for drug-related side effects and adverse reactionss.<ref name="pmid17608245">{{cite journal |author=Green JL, Hawley JN, Rask KJ |title=Is the number of prescribing physicians an independent risk factor for adverse drug events in an elderly outpatient population? |journal=Am J Geriatr Pharmacother |volume=5 |issue=1 |pages=31–9 |year=2007 |pmid=17608245 |doi=10.1016/j.amjopharm.2007.03.004 |issn=}}</ref>


==Assessing causality==
==Assessing causality==
A scale proposed by the [[World Health Organization]] (WHO) is below:<ref name="titleUMC">{{cite web |url=http://www.who-umc.org/DynPage.aspx?id=22682 |title=UMC Causality Assessment of Suspected Adverse Reactions|accessdate=2008-01-14 |author= |authorlink= |coauthors= |date= |format= |work= |publisher=World Health Organization |pages= |language= |archiveurl= |archivedate= |quote=}}</ref><ref name="pmid11072960">{{cite journal |author=Edwards IR, Aronson JK |title=Adverse drug reactions: definitions, diagnosis, and management |journal=Lancet |volume=356 |issue=9237 |pages=1255–9 |year=2000 |pmid=11072960 |doi=10.1016/S0140-6736(00)02799-9}}</ref><ref name="pmid15148066">{{cite journal |author=Nebeker JR, Barach P, Samore MH |title=Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting |journal=Ann. Intern. Med. |volume=140 |issue=10 |pages=795–801 |year=2004 |pmid=15148066 |doi=|url=http://annals.org/cgi/content/full/140/10/795}} ([http://annals.org/cgi/content/full/140/10/795/T2 See table 2])</ref>
A scale proposed by the [[World Health Organization]] (WHO) is below:<ref name="titleUMC">{{cite web |url=http://www.who-umc.org/DynPage.aspx?id=22682 |title=UMC Causality Assessment of Suspected Adverse Reactions|accessdate=2008-01-14 |author= |authorlink= |coauthors= |date= |format= |work= |publisher=World Health Organization |pages= |language= |archiveurl= |archivedate= |quote=}}</ref><ref name="pmid11072960">{{cite journal |author=Edwards IR, Aronson JK |title=Adverse drug reactions: definitions, diagnosis, and management |journal=Lancet |volume=356 |issue=9237 |pages=1255–9 |year=2000 |pmid=11072960 |doi=10.1016/S0140-6736(00)02799-9}}</ref><ref name="pmid15148066"/>


'''Certain'''
'''Certain'''
Line 140: Line 210:
[[Amplification (psychology)|Amplification]] may contribute to multiple-drug intolerance (if the adverse effects that are reported are non-specific).<ref name="pmid12622606">{{cite journal |author=Davies SJ, Jackson PR, Ramsay LE, Ghahramani P |title=Drug intolerance due to nonspecific adverse effects related to psychiatric morbidity in hypertensive patients |journal=Arch. Intern. Med. |volume=163 |issue=5 |pages=592-600 |year=2003 |pmid=12622606 |doi=}}</ref> This is distinct from multiple drug hypersensitivity.<ref name="pmid16433211">{{cite journal |author=Gex-Collet C, Helbling A, Pichler WJ |title=Multiple drug hypersensitivity--proof of multiple drug hypersensitivity by patch and lymphocyte transformation tests |journal=J Investig Allergol Clin Immunol |volume=15 |issue=4 |pages=293–6 |year=2005 |pmid=16433211 |doi=}}</ref>
[[Amplification (psychology)|Amplification]] may contribute to multiple-drug intolerance (if the adverse effects that are reported are non-specific).<ref name="pmid12622606">{{cite journal |author=Davies SJ, Jackson PR, Ramsay LE, Ghahramani P |title=Drug intolerance due to nonspecific adverse effects related to psychiatric morbidity in hypertensive patients |journal=Arch. Intern. Med. |volume=163 |issue=5 |pages=592-600 |year=2003 |pmid=12622606 |doi=}}</ref> This is distinct from multiple drug hypersensitivity.<ref name="pmid16433211">{{cite journal |author=Gex-Collet C, Helbling A, Pichler WJ |title=Multiple drug hypersensitivity--proof of multiple drug hypersensitivity by patch and lymphocyte transformation tests |journal=J Investig Allergol Clin Immunol |volume=15 |issue=4 |pages=293–6 |year=2005 |pmid=16433211 |doi=}}</ref>


==Monitoring bodies==
In the [[emergency department]], [[clinical prediction rule]]s are available to identify drug toxicity.<ref name="pmid22687179">{{cite journal| author=Hohl CM, Yu E, Hunte GS, Brubacher JR, Hosseini F, Argent CP et al.| title=Clinical decision rules to improve the detection of adverse drug events in emergency department patients. | journal=Acad Emerg Med | year= 2012 | volume= 19 | issue= 6 | pages= 640-9 | pmid=22687179 | doi=10.1111/j.1553-2712.2012.01379.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22687179  }} </ref>
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.<ref name="pmid11295958">{{cite journal |author=Cohen JS |title=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 |journal=Arch. Intern. Med. |volume=161 |issue=7 |pages=957–64 |year=2001 |pmid=11295958 |doi=}}</ref>
 
==Detection of toxicity in individual patients==
The question "In the past XX months, have you noticed any side effects, unwanted reactions, or other problems with medications you have taken?" may help detect toxic reactions.<ref>Steinman MA et al. [http://jama.ama-assn.org/cgi/content/full/304/14/1592 Managing Medications in Clinically Complex Elders: "There's Got to Be a Happy Medium"] JAMA. 2010;304(14):1592-1601 {{doi|10.1001/jama.2010.1482}}</ref>
 
==Detection of previously unrecognized toxicity in populations==
Unfortunately, more drug toxicity is not reported.<ref name="pmid16689555">{{cite journal| author=Hazell L, Shakir SA| title=Under-reporting of drug-related side effects and adverse reactionss : a systematic review. | journal=Drug Saf | year= 2006 | volume= 29 | issue= 5 | pages= 385-96 | pmid=16689555
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=16689555 }} </ref><ref name="pmid9131950">{{cite journal| author=Moride Y, Haramburu F, Requejo AA, Bégaud B| title=Under-reporting of drug-related side effects and adverse reactionss in general practice. | journal=Br J Clin Pharmacol | year= 1997 | volume= 43 | issue= 2 | pages= 177-81 | pmid=9131950
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=9131950 | pmc=PMC2042725 }} </ref><ref name="pmid3476980">{{cite journal| author=Scott HD, Rosenbaum SE, Waters WJ, Colt AM, Andrews LG, Juergens JP et al.| title=Rhode Island physicians' recognition and reporting of drug-related side effects and adverse reactionss. | journal=R I Med J | year= 1987 | volume= 70 | issue= 7 | pages= 311-6 | pmid=3476980
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=3476980 }} </ref> Reports of more than three cases of a rare disease associated with a drug suggests the drug may be causing the disease.<ref name="pmid7893579">{{cite journal| author=Begaud B, Moride Y, Tubert-Bitter P, Chaslerie A, Haramburu F| title=False-positives in spontaneous reporting: should we worry about them? | journal=Br J Clin Pharmacol | year= 1994 | volume= 38 | issue= 5 | pages= 401-4 | pmid=7893579
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=7893579 | pmc=PMC1364871 }} </ref> More complicated rules for signals are available.<ref name="pmid1958431">{{cite journal| author=Tubert P, Bégaud B, Haramburu F, Péré JC| title=Spontaneous reporting: how many cases are required to trigger a warning? | journal=Br J Clin Pharmacol | year= 1991 | volume= 32 | issue= 4 | pages= 407-8 | pmid=1958431
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=1958431 | pmc=PMC1368597 }} </ref>
 
===Scientific journals===
News of previously unrecognized drug toxicity may be first published in [[scientific journal]]s.  Published reports may be more helpful than spontaneous reports<ref name="pmid2257868">{{cite journal| author=Haramburu F, Bégaud B, Péré JC| title=Comparison of 500 spontaneous and 500 published reports of drug-related side effects and adverse reactionss. | journal=Eur J Clin Pharmacol | year= 1990 | volume= 39 | issue= 3 | pages= 287-8 | pmid=2257868
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=2257868 }} </ref> although drug toxicity is more likely to be spontaneously reported than published<ref name="pmid8804257">{{cite journal| author=Liu BA, Mittmann N, Knowles SR, Shear NH| title=Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports. | journal=CMAJ | year= 1996 | volume= 155 | issue= 5 | pages= 519-27 | pmid=8804257
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=8804257 | pmc=PMC1335030 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=8454983 Review in: J Fam Pract. 1993 Mar;36(3):341-3] </ref>. However, published reports may be lacking in quality.<ref name="pmid16421149">{{cite journal| author=Loke YK, Price D, Derry S, Aronson JK| title=Case reports of suspected drug-related side effects and adverse reactionss--systematic literature survey of follow-up. | journal=BMJ | year= 2006 | volume= 332 | issue= 7537 | pages= 335-9 | pmid=16421149 | doi=10.1136/bmj.38701.399942.63 | pmc=PMC1363912 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16421149  }} </ref>
 
Search strategies of [[MEDLINE]] are available.<ref name="pmid19404498">{{cite journal| author=Golder S, Loke Y| title=Search strategies to identify information on adverse effects: a systematic review. | journal=J Med Libr Assoc | year= 2009 | volume= 97 | issue= 2 | pages= 84-92 | pmid=19404498
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=19404498 | doi=10.3163/1536-5050.97.2.004 | pmc=PMC2670220 }} </ref>
 
===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 of America]], 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.<ref name="pmid11295958">{{cite journal |author=Cohen JS |title=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 |journal=Arch. Intern. Med. |volume=161 |issue=7 |pages=957–64 |year=2001 |pmid=11295958 |doi=}}</ref>


==Prevention==
==Prevention==
Criteria have been developed for predictable adverse drug reactions and thus provide a list of medications to avoid.<ref name="pmid9236554">{{cite journal |author=Beers MH |title=Explicit criteria for determining potentially inappropriate medication use by the elderly. An update |journal=Arch. Intern. Med. |volume=157 |issue=14 |pages=1531–6 |year=1997 |pmid=9236554 |doi= |issn=}}</ref><ref name="pmid14662625">{{cite journal |author=Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH |title=Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts |journal=Arch. Intern. Med. |volume=163 |issue=22 |pages=2716–24 |year=2003 |pmid=14662625 |doi=10.1001/archinte.163.22.2716 |issn=}}</ref>
===Computerized provider order entry===
The role of [[computerized provider order entry]] (CPOE) may prevent ADRs according to a [[systematic review]].<ref name="pmid18211517">{{cite journal| author=Shamliyan TA, Duval S, Du J, Kane RL| title=Just what the doctor ordered. Review of the evidence of the impact of computerized physician order entry system on medication errors. | journal=Health Serv Res | year= 2008 | volume= 43 | issue= 1 Pt 1 | pages= 32-53 | pmid=18211517 | doi=10.1111/j.1475-6773.2007.00751.x | pmc=PMC2323150 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18211517  }} </ref> However, individual studies have been inconsistent with both positive<ref name="pmid9794308">{{cite journal| author=Bates DW, Leape LL, Cullen DJ, Laird N, Petersen LA, Teich JM et al.| title=Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. | journal=JAMA | year= 1998 | volume= 280 | issue= 15 | pages= 1311-6 | pmid=9794308 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9794308  }} </ref><ref name="pmid17608868">{{cite journal |author=Raebel MA, Charles J, Dugan J, ''et al'' |title=Randomized trial to improve prescribing safety in ambulatory elderly patients |journal=J Am Geriatr Soc |volume=55 |issue=7 |pages=977–85 |year=2007 |pmid=17608868 |doi=10.1111/j.1532-5415.2007.01202.x}}</ref><ref name="pmid17460126">{{cite journal |author=Raebel MA, Carroll NM, Kelleher JA, Chester EA, Berga S, Magid DJ |title=Randomized trial to improve prescribing safety during pregnancy |journal=J Am Med Inform Assoc |volume=14 |issue=4 |pages=440–50 |year=2007 |pmid=17460126 |doi=10.1197/jamia.M2412}}</ref> and negative<ref name="pmid17460134">{{cite journal |author=Glassman PA, Belperio P, Lanto A, ''et al'' |title=The utility of adding retrospective medication profiling to computerized provider order entry in an ambulatory care population |journal=J Am Med Inform Assoc |volume=14 |issue=4 |pages=424–31 |year=2007 |pmid=17460134 |doi=10.1197/jamia.M2313}}</ref> effects on process measures. CPOE has difficulty in precision of alerting.<ref name="pmid16622171">{{cite journal |author=Judge J, Field TS, DeFlorio M, ''et al'' |title=Prescribers' responses to alerts during medication ordering in the long term care setting |journal=J Am Med Inform Assoc |volume=13 |issue=4 |pages=385–90 |year=2006 |pmid=16622171 |doi=10.1197/jamia.M1945 |issn=}}</ref>
 
Non-physicians may be able to successfully use CPOE.<ref name="pmid20185400">{{cite journal| author=Kazemi A, Fors UG, Tofighi S, Tessma M, Ellenius J| title=Physician order entry or nurse order entry? Comparison of two implementation strategies for a computerized order entry system aimed at reducing dosing medication errors. | journal=J Med Internet Res | year= 2010 | volume= 12 | issue= 1 | pages= e5 | pmid=20185400 | doi=10.2196/jmir.1284 | pmc=PMC2855204 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20185400  }} </ref>
 
Overriding of alerts may decrease patient safety.<ref name="pmid24166725">{{cite journal| author=Nanji KC, Slight SP, Seger DL, Cho I, Fiskio JM, Redden LM et al.| title=Overrides of medication-related clinical decision support alerts in outpatients. | journal=J Am Med Inform Assoc | year= 2014 | volume= 21 | issue= 3 | pages= 487-91 | pmid=24166725 | doi=10.1136/amiajnl-2013-001813 | pmc=PMC3994856 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24166725  }} </ref>
 
===Medication reconciliation===
Medication reconciliation may help.<ref name="pmid19398689">{{cite journal| author=Schnipper JL, Hamann C, Ndumele CD, Liang CL, Carty MG, Karson AS et al.| title=Effect of an electronic medication reconciliation application and process redesign on potential adverse drug events: a cluster-randomized trial. | journal=Arch Intern Med | year= 2009 | volume= 169 | issue= 8 | pages= 771-80 | pmid=19398689 | doi=10.1001/archinternmed.2009.51 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19398689  }} </ref>
 
===Lists of high risk medications===
The Beers list has been developed for predictable drug-related side effects and adverse reactionss and thus provide a list of medications to avoid.<ref name="pmid9236554">{{cite journal |author=Beers MH |title=Explicit criteria for determining potentially inappropriate medication use by the elderly. An update |journal=Arch. Intern. Med. |volume=157 |issue=14 |pages=1531–6 |year=1997 |pmid=9236554 |doi= |issn=}}</ref> After the original list of medications was not associated with clinical outcomes<ref name="pmid11802089">{{cite journal| author=Hanlon JT, Fillenbaum GG, Kuchibhatla M, Artz MB, Boult C, Gross CR et al.| title=Impact of inappropriate drug use on mortality and functional status in representative community dwelling elders. | journal=Med Care | year= 2002 | volume= 40 | issue= 2 | pages= 166-76 | pmid=11802089 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11802089  }} </ref>, the list is periodically revised with a [[Delphi method]].<ref name="pmid22376048">{{cite journal| author=American Geriatrics Society 2012 Beers Criteria Update Expert Panel| title=American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. | journal=J Am Geriatr Soc | year= 2012 | volume= 60 | issue= 4 | pages= 616-31 | pmid=22376048 | doi=10.1111/j.1532-5415.2012.03923.x | pmc=PMC3571677 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22376048  }} </ref><ref name="pmid14662625">{{cite journal |author=Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH |title=Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts |journal=Arch. Intern. Med. |volume=163 |issue=22 |pages=2716–24 |year=2003 |pmid=14662625 |doi=10.1001/archinte.163.22.2716 |issn=}}</ref> The [https://www.ncqa.org/HEDISQualityMeasurement/HEDISMeasures/HEDIS2013/HEDIS2013FinalNDCLists.aspx current list is online]. The Beers list has become a clinical measure of quality assurance.<ref>[http://www.qualitymeasures.ahrq.gov/content.aspx?id=47209 Use of high-risk medications in the elderly: percentage of Medicare members 66 years of age and older who received at least one high-risk medication.]</ref>


The role of [[computerized provider order entry]] (CPOE) has been inconsistent with both positive<ref name="pmid17608868">{{cite journal |author=Raebel MA, Charles J, Dugan J, ''et al'' |title=Randomized trial to improve prescribing safety in ambulatory elderly patients |journal=J Am Geriatr Soc |volume=55 |issue=7 |pages=977–85 |year=2007 |pmid=17608868 |doi=10.1111/j.1532-5415.2007.01202.x}}</ref><ref name="pmid17460126">{{cite journal |author=Raebel MA, Carroll NM, Kelleher JA, Chester EA, Berga S, Magid DJ |title=Randomized trial to improve prescribing safety during pregnancy |journal=J Am Med Inform Assoc |volume=14 |issue=4 |pages=440–50 |year=2007 |pmid=17460126 |doi=10.1197/jamia.M2412}}</ref> and negative<ref name="pmid17460134">{{cite journal |author=Glassman PA, Belperio P, Lanto A, ''et al'' |title=The utility of adding retrospective medication profiling to computerized provider order entry in an ambulatory care population |journal=J Am Med Inform Assoc |volume=14 |issue=4 |pages=424–31 |year=2007 |pmid=17460134 |doi=10.1197/jamia.M2313}}</ref> effects on process measures. CPOE has difficulty in precision of alerting.<ref name="pmid16622171">{{cite journal |author=Judge J, Field TS, DeFlorio M, ''et al'' |title=Prescribers' responses to alerts during medication ordering in the long term care setting |journal=J Am Med Inform Assoc |volume=13 |issue=4 |pages=385–90 |year=2006 |pmid=16622171 |doi=10.1197/jamia.M1945 |issn=}}</ref>
The STOPP and START Criteria criteria may be better.<ref name="pmid21670370">{{cite journal| author=Hamilton H, Gallagher P, Ryan C, Byrne S, O'Mahony D| title=Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalized patients. | journal=Arch Intern Med | year= 2011 | volume= 171 | issue= 11 | pages= 1013-9 | pmid=21670370 | doi=10.1001/archinternmed.2011.215 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21670370  }} </ref><ref name="pmid18829684">{{cite journal| author=Gallagher P, O'Mahony D| title=STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions): application to acutely ill elderly patients and comparison with Beers' criteria. | journal=Age Ageing | year= 2008 | volume= 37 | issue= 6 | pages= 673-9 | pmid=18829684 | doi=10.1093/ageing/afn197 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18829684  }} </ref>


===Genetic screening===
===Genetic screening===
{{Pharmacogenomics}}
{{main|Pharmacogenomics}}
[[Mass screening|Screening]] for [[HLA Antigens|HLA]]-B*5701 may reduce the incidence of [[hypersensitivity]] reactions to [[abacavir]] according to a [[randomized controlled trial]].<ref name="pmid18256392">{{cite journal |author=Mallal S, Phillips E, Carosi G, ''et al'' |title=HLA-B*5701 screening for hypersensitivity to abacavir |journal=N. Engl. J. Med. |volume=358 |issue=6 |pages=568–79 |year=2008 |month=February |pmid=18256392 |doi=10.1056/NEJMoa0706135 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18256392&promo=ONFLNS19 |issn=}}</ref>
[[Mass screening|Screening]] for [[HLA Antigens|HLA]]-B*5701 may reduce the incidence of [[hypersensitivity]] reactions to [[abacavir]] according to a [[randomized controlled trial]].<ref name="pmid18256392">{{cite journal |author=Mallal S, Phillips E, Carosi G, ''et al'' |title=HLA-B*5701 screening for hypersensitivity to abacavir |journal=N. Engl. J. Med. |volume=358 |issue=6 |pages=568–79 |year=2008 |month=February |pmid=18256392 |doi=10.1056/NEJMoa0706135 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18256392&promo=ONFLNS19 |issn=}}</ref>


==References==
==References==
<references/>
{{reflist|2}}
 
==External links==
* [http://www.who-umc.org/DynPage.aspx?id=13111&mn=1513 WHO - Uppsala Monitoring Centre: Practical Pharmacovigilance]
* [http://medicine.iupui.edu/flockhart/ Cytochrome P450 interaction tables]
* [http://www.clinicaldruguse.com/ Descriptions of drugs with abnormal pharmacokinetics]
* [http://w3.ouhsc.edu/platelets/ University of Oklahoma Health Sciences Center's Platelets on the Web]. This includes a database of reports of drug-induced thrombocytopenia.

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This editable Main Article is under development and subject to a disclaimer.

Drug-related side effects and adverse reactions, also called drug-related side effects and adverse reactions (ADR), adverse drug event (ADE) or drug toxicity, 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 drug-related side effects and adverse reactions (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 drug-related side effects and adverse reactionss. Adverse drug reactions also occur among ambulatory outpatients[6] and among inpatients[7]. A minority of drug toxicity is recognized by health care providers.[8]

Classification

Cause

The World Health Organization (WHO) classifies ADRs by cause:[9]

  • 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.[10]
  • 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,[11] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[12]

Manifestation

Immediate hypersensitivity

Immediate hypersensitivity are over-reported and few patient reporting these have reactions on careful testing.[13][14]

Drug-induced liver injury

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


Drug reaction with eosinophilia and systemic symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS) may be caused by medications including allopurinol, phenytoin, dapsone, carbamazepine, trimethoprim-sulfamethoxazole, penicillin, and non-steroidal anti-inflammatory agents.[15] About half of cases have eosinophilia.

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.


Hyperpigmentation

Hyperpigmentation may occur due to drug toxicity.[16][17]

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.[18] Although the WHO document is not currently available online, their recommendations have been summarized by others.[19]

  • 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:[20]:

  • 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:[21]

  • 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.[22] However, heavy physician workload may reduce the ability of the physician to use these resources.[23]

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.[24][25] Pharmacogenomics is the study on the inherited basis of drug reactions. Among drugs frequently cited in drug-related side effects and adverse reactionss, 60% are metabolized by enzymes with genetic variations in metabolism. 7% to 22% of randomly selected have such variation.[24]

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.[26].[27]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[28]

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.[28][27]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[27]

Impaired hepatic function

Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired hepatic function.[29]

Impaired renal function

Food and Drug Administration categories of renal function[30]
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.[31] Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired renal function.[30] Although this categorization uses estimated creatinine clearance, using estimated glomerular filtration yields similar recommendations for dosing adjustments.[32]

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. Using 11 or more chronic medications is a risk factor for drug toxicity.[33]

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 drug-related side effects and adverse reactionss.[34]

Assessing causality

A scale proposed by the World Health Organization (WHO) is below:[35][9][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).[36] This is distinct from multiple drug hypersensitivity.[37]

In the emergency department, clinical prediction rules are available to identify drug toxicity.[38]

Detection of toxicity in individual patients

The question "In the past XX months, have you noticed any side effects, unwanted reactions, or other problems with medications you have taken?" may help detect toxic reactions.[39]

Detection of previously unrecognized toxicity in populations

Unfortunately, more drug toxicity is not reported.[40][41][42] Reports of more than three cases of a rare disease associated with a drug suggests the drug may be causing the disease.[43] More complicated rules for signals are available.[44]

Scientific journals

News of previously unrecognized drug toxicity may be first published in scientific journals. Published reports may be more helpful than spontaneous reports[45] although drug toxicity is more likely to be spontaneously reported than published[46]. However, published reports may be lacking in quality.[47]

Search strategies of MEDLINE are available.[48]

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 of America, 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.[49]

Prevention

Computerized provider order entry

The role of computerized provider order entry (CPOE) may prevent ADRs according to a systematic review.[50] However, individual studies have been inconsistent with both positive[51][52][53] and negative[54] effects on process measures. CPOE has difficulty in precision of alerting.[55]

Non-physicians may be able to successfully use CPOE.[56]

Overriding of alerts may decrease patient safety.[57]

Medication reconciliation

Medication reconciliation may help.[58]

Lists of high risk medications

The Beers list has been developed for predictable drug-related side effects and adverse reactionss and thus provide a list of medications to avoid.[59] After the original list of medications was not associated with clinical outcomes[60], the list is periodically revised with a Delphi method.[61][62] The current list is online. The Beers list has become a clinical measure of quality assurance.[63]

The STOPP and START Criteria criteria may be better.[64][65]

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.[66]

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]
  3. ↑ World Health Organization (2002), Safety of Medicines: A guide to detecting and reporting drug-related side effects and adverse reactionss; 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. ↑ Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC et al. (2003). "Incidence and preventability of adverse drug events among older persons in the ambulatory setting.". JAMA 289 (9): 1107-16. PMID 12622580. [e]
  9. ↑ 9.0 9.1 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.
  10. ↑ 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]
  11. ↑ Rawlins MD, Thompson JW. Pathogenesis of drug-related side effects and adverse reactionss. In: Davies DM, ed. Textbook of drug-related side effects and adverse reactionss. Oxford: Oxford University Press, 1977:10.
  12. ↑ 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.
  13. ↑ Macy, Eric; Eunis W. Ngor (2013-05). "Safely Diagnosing Clinically Significant Penicillin Allergy Using Only Penicilloyl-Poly-Lysine, Penicillin, and Oral Amoxicillin". The Journal of Allergy and Clinical Immunology: In Practice 1 (3): 258-263. DOI:10.1016/j.jaip.2013.02.002. ISSN 2213-2198. Retrieved on 2013-07-13. Research Blogging.
  14. ↑ Messaad D, Sahla H, Benahmed S, Godard P, Bousquet J, Demoly P (2004). "Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.". Ann Intern Med 140 (12): 1001-6. PMID 15197017. [e]
  15. ↑ Chen YC, Chiu HC, Chu CY (2010). "Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases.". Arch Dermatol 146 (12): 1373-9. DOI:10.1001/archdermatol.2010.198. PMID 20713773. Research Blogging.
  16. ↑ Dereure O (2001). "Drug-induced skin pigmentation. Epidemiology, diagnosis and treatment.". Am J Clin Dermatol 2 (4): 253-62. PMID 11705252. [e]
  17. ↑ Levantine A, Almeyda J (1973). "Drug induced changes in pigmentation.". Br J Dermatol 89 (1): 105-12. PMID 4132858. [e]
  18. ↑ Council for International Organizations of Medical Sciences. Guidelines for preparing core clinical safety information on drugs. Geneva: CIOMS, 1995.
  19. ↑ 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.
  20. ↑ MedWatch - What Is A Serious Adverse Event?. Retrieved on 2007-09-18.
  21. ↑ 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 drug-related side effects and adverse reactionss 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.
  22. ↑ Clinical Drug Use. Retrieved on 2007-09-18.
  23. ↑ 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.
  24. ↑ 24.0 24.1 Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). "Potential role of pharmacogenomics in reducing drug-related side effects and adverse reactionss: a systematic review". JAMA 286 (18): 2270–9. PMID 11710893. [e]
  25. ↑ 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.
  26. ↑ Drug-Interactions.com. Retrieved on 2007-09-18.
  27. ↑ 27.0 27.1 27.2 Weinshilboum R (2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
  28. ↑ 28.0 28.1 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.
  29. ↑ 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.
  30. ↑ 30.0 30.1 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.
  31. ↑ 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).
  32. ↑ 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.
  33. ↑ Guthrie, B.; C. McCowan, P. Davey, C. R. Simpson, T. Dreischulte, K. Barnett (2011-06). "High risk prescribing in primary care patients particularly vulnerable to adverse drug events: cross sectional population database analysis in Scottish general practice". BMJ 342 (jun21 1): d3514-d3514. DOI:10.1136/bmj.d3514. ISSN 0959-8138. Retrieved on 2011-06-23. Research Blogging.
  34. ↑ 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.
  35. ↑ UMC Causality Assessment of Suspected Adverse Reactions. World Health Organization. Retrieved on 2008-01-14.
  36. ↑ 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]
  37. ↑ 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]
  38. ↑ Hohl CM, Yu E, Hunte GS, Brubacher JR, Hosseini F, Argent CP et al. (2012). "Clinical decision rules to improve the detection of adverse drug events in emergency department patients.". Acad Emerg Med 19 (6): 640-9. DOI:10.1111/j.1553-2712.2012.01379.x. PMID 22687179. Research Blogging.
  39. ↑ Steinman MA et al. Managing Medications in Clinically Complex Elders: "There's Got to Be a Happy Medium" JAMA. 2010;304(14):1592-1601 DOI:10.1001/jama.2010.1482
  40. ↑ Hazell L, Shakir SA (2006). "Under-reporting of drug-related side effects and adverse reactionss : a systematic review.". Drug Saf 29 (5): 385-96. PMID 16689555.
  41. ↑ Moride Y, Haramburu F, Requejo AA, Bégaud B (1997). "Under-reporting of drug-related side effects and adverse reactionss in general practice.". Br J Clin Pharmacol 43 (2): 177-81. PMID 9131950. PMC PMC2042725.
  42. ↑ Scott HD, Rosenbaum SE, Waters WJ, Colt AM, Andrews LG, Juergens JP et al. (1987). "Rhode Island physicians' recognition and reporting of drug-related side effects and adverse reactionss.". R I Med J 70 (7): 311-6. PMID 3476980.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ Haramburu F, Bégaud B, Péré JC (1990). "Comparison of 500 spontaneous and 500 published reports of drug-related side effects and adverse reactionss.". Eur J Clin Pharmacol 39 (3): 287-8. PMID 2257868.
  46. ↑ 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
  47. ↑ Loke YK, Price D, Derry S, Aronson JK (2006). "Case reports of suspected drug-related side effects and adverse reactionss--systematic literature survey of follow-up.". BMJ 332 (7537): 335-9. DOI:10.1136/bmj.38701.399942.63. PMID 16421149. PMC PMC1363912. Research Blogging.
  48. ↑ 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.
  49. ↑ 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]
  50. ↑ Shamliyan TA, Duval S, Du J, Kane RL (2008). "Just what the doctor ordered. Review of the evidence of the impact of computerized physician order entry system on medication errors.". Health Serv Res 43 (1 Pt 1): 32-53. DOI:10.1111/j.1475-6773.2007.00751.x. PMID 18211517. PMC PMC2323150. Research Blogging.
  51. ↑ Bates DW, Leape LL, Cullen DJ, Laird N, Petersen LA, Teich JM et al. (1998). "Effect of computerized physician order entry and a team intervention on prevention of serious medication errors.". JAMA 280 (15): 1311-6. PMID 9794308. [e]
  52. ↑ 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.
  53. ↑ 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.
  54. ↑ 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.
  55. ↑ 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.
  56. ↑ Kazemi A, Fors UG, Tofighi S, Tessma M, Ellenius J (2010). "Physician order entry or nurse order entry? Comparison of two implementation strategies for a computerized order entry system aimed at reducing dosing medication errors.". J Med Internet Res 12 (1): e5. DOI:10.2196/jmir.1284. PMID 20185400. PMC PMC2855204. Research Blogging.
  57. ↑ Nanji KC, Slight SP, Seger DL, Cho I, Fiskio JM, Redden LM et al. (2014). "Overrides of medication-related clinical decision support alerts in outpatients.". J Am Med Inform Assoc 21 (3): 487-91. DOI:10.1136/amiajnl-2013-001813. PMID 24166725. PMC PMC3994856. Research Blogging.
  58. ↑ Schnipper JL, Hamann C, Ndumele CD, Liang CL, Carty MG, Karson AS et al. (2009). "Effect of an electronic medication reconciliation application and process redesign on potential adverse drug events: a cluster-randomized trial.". Arch Intern Med 169 (8): 771-80. DOI:10.1001/archinternmed.2009.51. PMID 19398689. Research Blogging.
  59. ↑ 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]
  60. ↑ Hanlon JT, Fillenbaum GG, Kuchibhatla M, Artz MB, Boult C, Gross CR et al. (2002). "Impact of inappropriate drug use on mortality and functional status in representative community dwelling elders.". Med Care 40 (2): 166-76. PMID 11802089. [e]
  61. ↑ American Geriatrics Society 2012 Beers Criteria Update Expert Panel (2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults.". J Am Geriatr Soc 60 (4): 616-31. DOI:10.1111/j.1532-5415.2012.03923.x. PMID 22376048. PMC PMC3571677. Research Blogging.
  62. ↑ 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.
  63. ↑ Use of high-risk medications in the elderly: percentage of Medicare members 66 years of age and older who received at least one high-risk medication.
  64. ↑ Hamilton H, Gallagher P, Ryan C, Byrne S, O'Mahony D (2011). "Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalized patients.". Arch Intern Med 171 (11): 1013-9. DOI:10.1001/archinternmed.2011.215. PMID 21670370. Research Blogging.
  65. ↑ Gallagher P, O'Mahony D (2008). "STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions): application to acutely ill elderly patients and comparison with Beers' criteria.". Age Ageing 37 (6): 673-9. DOI:10.1093/ageing/afn197. PMID 18829684. Research Blogging.
  66. ↑ 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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