Drug-related side effects and adverse reactions: Difference between revisions
imported>Robert Badgett (Added WHO definitions of frequency) |
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==Classification== | ==Classification== | ||
ADRs may be classified by cause. | ADRs may be classified by cause and severity. | ||
===Cause=== | ===Cause=== | ||
*Type A: pharmacologically predictable | *Type A: pharmacologically predictable | ||
| Line 10: | Line 11: | ||
*Type E: end of dose reaction | *Type E: end of dose reaction | ||
*Type F: failure of therapy | *Type F: failure of therapy | ||
Types A and B were proposed in the 1970s,<ref>Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977:10.</ref> and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.<ref>Aronson JK. Drug therapy. In: Haslett C, Chilvers ER, Boon NA, Colledge NR, Hunter JAA, eds. Davidson's principles and practice of medicine 19th ed. Edinburgh: Elsevier Science, 2002:147-63. ISBN 0-44307-035-0.</ref> | |||
===Severity=== | |||
The American [[Food and Drug Administration]] defines severe effects as:<ref>{{cite web |url=http://www.fda.gov/medwatch/report/DESK/advevnt.htm |title=MedWatch - What Is A Serious Adverse Event? |accessdate=2007-09-18 |format= |work=}}</ref>: | |||
* Death | |||
* Life-Threatening | |||
* Hospitalization (initial or prolonged) | |||
* Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life. | |||
* Congenital Anomaly | |||
* - or - | |||
* Requires Intervention to Prevent Permanent Impairment or Damage | |||
==Describing ADRs== | ==Describing ADRs== | ||
Revision as of 01:52, 5 December 2007
Drug toxicity, also called adverse drug reaction (ADR) or adverse drug event (ADE), is defined as "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]
Classification
ADRs may be classified by cause and severity.
Cause
- Type A: pharmacologically predictable
- Type B: bizarre and unpredictable (idiosyncratic)
- Type C: arising from chronic use
- Type D: delayed reaction
- Type E: end of dose reaction
- Type F: failure of therapy
Types A and B were proposed in the 1970s,[3] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[4]
Severity
The American Food and Drug Administration defines severe effects as:[5]:
- Death
- Life-Threatening
- Hospitalization (initial or prolonged)
- Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
- Congenital Anomaly
- - or -
- Requires Intervention to Prevent Permanent Impairment or Damage
Describing ADRs
ADRs may be described by their frequency and severity
Frequency
The World Health Organization recommends standardization of descriptions of frequency.[6] Although the WHO document is not currenlty available online, their recommendations have been summarized by others.[7]
- 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:[8]:
- 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
Mechanisms
As research better explains the biochemistry of drug use, less ADRs are Type B and more are Type A. Common mechanisms are:
- Abnormal pharmacokinetics due to
- genetic factors
- comorbid disease states
- Synergistic effects between either
- a drug and a disease
- two drugs
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.[9]
Genetic factors
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[10][11] Pharmacogenomics is the study on the inherited basis of drug reactions.
Phase I reactions
Inheriting abnormal alleles of cytochrome P450can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.[12].[13]
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[14]
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.[14][13]
Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[13]
Interactions with other drugs
The risk of drug interactions is increased with polypharmacy.
Protein binding
These interactions are usually transient and mild until a new steady state is achieved.[15][16] These are mainly for drugs without much first-pass liver metabolism. The principle plasma proteins for drug binding are:[17]
- albumin
- α1-acid glycoprotein
- lipoproteins
Some drug interactions with warfarin are due to changes in protein binding.[17]
Cytochrome P450
Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.[18].
Synergistic effects
An example of synergism is two drugs that both prolong the cardiac QT interval.
Assessing causality
A simple scale is available at http://annals.org/cgi/content/full/140/10/795.[2]
- Note that an ADR should not be labeled as 'certain' unless the ADR abates with dechallenge and recurs with rechallenge are true.
A more complicated scale is the Naranjo algorithm.
Intolerance to multiple drugs
Amplification may contribute to multiple-drug intolerance (if the adverse effects that are reported are non-specific).[19] This is distinct from multiple drug hypersensitivity.[20]
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.
References
- ↑ National Library of Medicine. Drug toxicity. Retrieved on 2007-11-23.
- ↑ 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]
- ↑ Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977:10.
- ↑ 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.
- ↑ MedWatch - What Is A Serious Adverse Event?. Retrieved on 2007-09-18.
- ↑ Council for International Organizations of Medical Sciences. Guidelines for preparing core clinical safety information on drugs. Geneva: CIOMS, 1995.
- ↑ 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.
- ↑ MedWatch - What Is A Serious Adverse Event?. Retrieved on 2007-09-18.
- ↑ Clinical Drug Use. Retrieved on 2007-09-18.
- ↑ 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]
- ↑ 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.
- ↑ Drug-Interactions.com. Retrieved on 2007-09-18.
- ↑ 13.0 13.1 13.2 Weinshilboum R (2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
- ↑ 14.0 14.1 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.
- ↑ DeVane CL (2002). "Clinical significance of drug binding, protein binding, and binding displacement drug interactions". Psychopharmacology bulletin. 36 (3): 5–21. PMID 12473961. [e]
- ↑ Benet LZ, Hoener BA (2002). "Changes in plasma protein binding have little clinical relevance". Clin. Pharmacol. Ther. 71 (3): 115–21. DOI:10.1067/mcp.2002.121829. PMID 11907485. Research Blogging. OVID full text summary table at OVID
- ↑ 17.0 17.1 Sands CD, Chan ES, Welty TE (2002). "Revisiting the significance of warfarin protein-binding displacement interactions". The Annals of pharmacotherapy 36 (10): 1642–4. PMID 12369572. [e]
- ↑ Drug-Interactions.com. Retrieved on 2007-09-18.
- ↑ 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]
- ↑ 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]