From Wikipedia, the free encyclopedia
An adverse drug reaction (abbreviated ADR) is an expression that describes harm associated with the use of given medications at a normal dose. 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. The study of ADRs is the concern of the field known as pharmacovigilance.
ADRs may be classified by e.g. cause and severity.
- Type A: Augmented pharmacologic effects - dose dependent and predictable
- Type B: Bizarre effects (or idiosyncratic) - dose independent and unpredictable
- Type C: Chronic effects
- Type D: Delayed effects
- Type E: End-of-treatment effects
- Type F: Failure of therapy
Types A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.
Seriousness and Severity
The American Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following:
- 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
- Requires Intervention to Prevent Permanent Impairment or Damage
Severity is a point on an arbitrary scale of intensity of the adverse event in question. The terms "severe" and "serious" when applied to adverse events are technically very different. They are easily confused but can not be used interchangeably, require care in usage.
A headache is severe, if it causes intense pain. There are scales like "visual analog scale" that help us assess the severity. On the other hand, a headache can hardly ever be serious, unless it also satisfies the criteria for seriousness listed above.
Overall Drug Risk
While no official scale exists yet to communicate overall drug risk, the iGuard Drug Risk Rating System is a five color rating scale similar to the Homeland Security Advisory System:
- Red (High Risk)
- Orange (Elevated Risk)
- Yellow (Guarded Risk)
- Blue (General Risk)
- Green (Low Risk)
Adverse effects may be local, i.e. limited to a certain location, or systemic, where a medication has caused adverse effects throughout the systemic circulation.
For instance, some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.
As research better explains the biochemistry of drug use, fewer ADRs are Type B and more are Type A. Common mechanisms are:
- Abnormal pharmacokinetics due to
- Synergistic effects between either
- a drug and a disease
- two drugs
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.
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.
Phase I reactions
Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine
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.
Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.
Interactions with other drugs
The risk of drug interactions is increased with polypharmacy.
These interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are:
- α1-acid glycoprotein
Some drug interactions with warfarin are due to changes in protein binding.
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..
An example of synergism is two drugs that both prolong the QT interval.
A simple scale is available at http://annals.org/cgi/content/full/140/10/795.
An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol.
A more complicated scale is the Naranjo algorithm.
Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre, and the European Union runs the European Medicines Agency (EMEA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies.
Examples of adverse effects associated with specific medications
- Abortion, miscarriage or uterine hemorrhage associated with misoprostol (Cytotec), a labor-inducing drug (this is a case where the adverse effect has been used legally and illegally for performing abortions)
- Addiction to many sedatives and analgesics such as diazepam, morphine, etc.
- Birth defects associated with Thalidomide and Accutane.
- Bleeding of the intestine associated with aspirin therapy
- Cardiovascular disease associated with COX-2 inhibitors (i.e. Vioxx)
- Deafness and kidney failure associated with gentamicin (an antibiotic)
- Death, following sedation in children using propofol (Diprivan)
- Dementia associated with heart bypass surgery
- Depression or hepatic injury caused by interferon
- Diabetes caused by atypical antipsychotic medications (neuroleptic psychiatric drugs)
- Diarrhea caused by the use of orlistat (Xenical)
- Erectile dysfunction associated with many drugs, such as antidepressants
- Fever associated with vaccination (in the past, imperfectly manufactured vaccines, such as BCG and poliomyelitis, have caused the very disease they intended to fight).
- Glaucoma associated with corticosteroid-based eye drops
- Hair loss and anemia may be caused by chemotherapy against cancer, leukemia, etc.
- Headache following spinal anesthesia
- Hypertension in ephedrine users, which prompted FDA to remove the status of dietary supplement of ephedra extracts
- Insomnia caused by stimulants, Ritalin, Adderall, etc.
- Lactic acidosis associated with the use of stavudine (Zerit, for anti-HIV therapy) or metformin (for diabetes)
- Liver damage from paracetamol
- Melasma and thrombosis associated with use of estrogen-containing hormonal contraception such as the combined oral contraceptive pill
- Irreversible Peripheral neuropathy associated with the use of fluoroquinolone medications 
- Rhabdomyolysis associated with statins (anti-cholesterol drugs)
- Seizures caused by withdrawal from benzodiazepine
- Drowsiness or increase in appetite due to antihistamine use. Some antihistamines are used in sleep aids explicitly because they cause drowsiness.
- Stroke or heart attack associated with sildenafil (Viagra) when used with nitroglycerine
- Suicide, increased tendency associated to the use of fluoxetine and other SSRI antidepressants
- Tardive dyskinesia associated with long-term use of metoclopramide and many antipsychotic medications
- Spontaneous Tendon rupture associated with fluoroquinolone drugs  even occurring as late as 6 months after treatment had been terminated.
- ^ Nebeker. Jonathan R. Clarifying Adverse Drug Events: A Clinician’s Guide to Terminology, Documentation, and Reporting. Ann Intern Med. 2004;140:795-801.
- ^ a b 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.
- ^ 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-
- ^ "MedWatch - What Is A Serious Adverse Event?". http://www.fda.gov/medwatch/report/DESK/advevnt.htm. Retrieved 2007-09-18.
- ^ "'Traffic-light' medicine risk website to launch". The Guardian. 2007-10-02. http://www.guardian.co.uk/business/2007/oct/02/7.
- ^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 146
- ^ "Clinical Drug Use". http://www.clinicaldruguse.com/. Retrieved 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. doi:10.1001/jama.286.18.2270. PMID 11710893.
- ^ Goldstein DB (2003). "Pharmacogenetics in the laboratory and the clinic". N. Engl. J. Med. 348 (6): 553–6. doi:10.1056/NEJMe020173. PMID 12571264.
- ^ a b "Drug-Interactions.com". http://medicine.iupui.edu/flockhart/. Retrieved 2007-09-18.
- ^ a b c Weinshilboum R (2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. doi:10.1056/NEJMra020021. PMID 12571261.
- ^ a b 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.
- ^ DeVane CL (2002). "Clinical significance of drug binding, protein binding, and binding displacement drug interactions". Psychopharmacology bulletin. 36 (3): 5–21. PMID 12473961.
- ^ Benet LZ, Hoener BA (2002). "Changes in plasma protein binding have little clinical relevance". Clin. Pharmacol. Ther. 71 (3): 115–21. doi:10.1067/mcp.2002.121829. PMID 11907485. OVID full text summary table at OVID
- ^ a b Sands CD, Chan ES, Welty TE (2002). "Revisiting the significance of warfarin protein-binding displacement interactions". The Annals of pharmacotherapy 36 (10): 1642–4. doi:10.1345/aph.1A208. PMID 12369572. http://www.theannals.com/cgi/reprint/36/10/1642.
- ^ Aoun M, Jacquy C, Debusscher L, et al. (July 1992). "Peripheral neuropathy associated with fluoroquinolones". Lancet 340 (8811): 127. doi:10.1016/0140-6736(92)90460-K. PMID 1352007. http://linkinghub.elsevier.com/retrieve/pii/0140-6736(92)90460-K.
- ^ Cohen JS (December 2001). "Peripheral neuropathy associated with fluoroquinolones". Ann Pharmacother 35 (12): 1540–7. doi:10.1345/aph.1Z429. PMID 11793615. http://www.theannals.com/cgi/pmidlookup?view=long&pmid=11793615.
- ^ Hedenmalm K, Spigset O (April 1996). "Peripheral sensory disturbances related to treatment with fluoroquinolones". J. Antimicrob. Chemother. 37 (4): 831–7. doi:10.1093/jac/37.4.831. PMID 8722551. http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8722551.
- ^ Jagose JT, McGregor DR, Nind GR, Bailey RR (December 1996). "Achilles tendon rupture due to ciprofloxacin". N. Z. Med. J. 109 (1035): 471–2. PMID 9006634.
- ^ Casparian JM, Luchi M, Moffat RE, Hinthorn D (May 2000). "Quinolones and tendon ruptures". South. Med. J. 93 (5): 488–91. PMID 10832946.