ADVERSE DRUG REACTIONS : ADVERSE DRUG REACTIONS Introduction : Definition: “an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug”
Trivial OR Serious Or fatal Introduction Slide 4: The World Health Organization defines it as:
An adverse drug reaction (ADR) is ‘a response to a medicine which is noxious, undesirable and unintended, and which occurs at doses normally used in human for diagnosis, prophylaxis and treatment ’. 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). EPIDEMIOLOGY : 5% adults in US are allergic to >1 drugs
30% of medical inpatients develop an ADR
3% of all hospital admissions are due to ADRs
Risk of an allergic reaction is approximately 1-3% for most drugs EPIDEMIOLOGY Impact of ADRs : Increased risk of death ; A study in the UK showed that the occurrence of ADRs in patients doubled the chances of death.
Prolongation of hospital stay; This is particularly significant now with the shortage of hospital beds. An American study showed that ADRs prolonged hospital stay by 1.9 days.
Increased costs In the US; the annual cost of drug-related morbidity and mortality is £76 billion. Impact of ADRs (…….) : Non-compliance ; In the elderly, only one-third would be compliant with their treatment. Lack of compliance might be due to ADRs and could lead to a resurgence of the disease for which the treatment was intended. Non-compliance might also lead to a life-threatening disease, for example, cerebral malaria in travelers who avoided taking mefloquine because of its tendency to cause depression.
Quality of life ; ADRs have a negative impact on patients' quality of life, such as when using alpha interferon in treating hepatitis C. (…….) Slide 8: Requires
Caution in future
immediately or after prolonged use
or after termination
Mild ADRs common, [incidence 10-25%]
Acceptability: linked to Therap. Use; Risk Benefit Ratio Slide 9: CLASSIFICATION
Rawlin and Thompson devised a classification scheme in 1991, which continues to be the most frequently used
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. Toxicity of overdose (e.g. hepatic failure with high dose Paracetamol),Side effects (e.g. sedation with antihistamines) ,Secondary effects (e.g. development of diarrhea with antibiotic therapy due to altered gastrointestinal bacterial flora),Drug interaction (e.g. Theophylline toxicity in the presence of erythromycin therapy) Slide 10: Type B:
Non-dose related; bizarre and unpredictable. Intolerance (e.g. tinnitus with use of Aspirin).Immune related such as hypersensitivity reactions (e.g. Anaphylaxis with penicillin administration ).Non-immune reactions such as porphyria, neuroleptic malignant syndrome, or malignant hyperthermia.
Idiosyncratic reaction(e.g. development of anemia with the use of anti-oxidant drugs in The presence of glucose-6 phosphate dehydrogenase deficiency).As the mechanisms of these specific reactions are better understood, these reactions may be re-classified as Type A. Slide 11: Type C:
Dose-related and time-related. This is related to duration and dosage of exposure. These reactions are associated with long-term drug therapy. An example is hypothalamic-pituitary-adrenal suppression from glucocorticoid therapy. Benzodiazepine dependence and Analgesic nephropathy. They are well known and can be anticipated. Slide 12: Type D:
These reactions refer to carcinogenic and teratogenic effects. These reactions are delayed in onset and are very rare since extensive mutagenicity and carcinogenicity studies are done before drug is licensed.
Withdrawal; end of dose reaction. An example is narcotic or beta-blocker withdrawal.
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, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.
About 80% of all adverse drug reactions are type A and for most prescription this type of reaction is described in handbooks such as the physician’s desk reference. Slide 13: Type “A” reactions Predictable, common and related to Pharmacological action of the drug
Usually dose dependent
Responds to dose reduction
Toxicity of overdose (e.g. hepatic failure with high dose Paracetamol)
Side effects (e.g. sedation with antihistamines)
Secondary effects (e.g. development of diarrhea with antibiotic therapy due to altered gastrointestinal bacterial flora)
Drug interaction (e.g. Theophylline toxicity in the presence of erythromycin therapy) Unpredictable, uncommon, usually not related to the pharmacological actions of the drug
Rarely dose dependent
Responds to drug withdrawal
Intolerance (e.g. tinnitus with use of Aspirin)
Hypersensitivity i.e. Immunological reaction (e.g. Anaphylaxis with penicillin administration.)
Pseudoallergic (Non-Immunological) reaction (e.g. radio contrast dye reaction).
Idiosyncratic reaction. (e.g. development of anemia with the use of anti-oxidant drugs in the presence of glucose-6 phosphate dehydrogenase deficiency). Type B reactions Manifestation : Drug-induced liver injury
QT interval prolongation
Thrombocytopenia Manifestation Describing ADR : ADRs may be described by their frequency and severity
The World Health Organization recommends standardization of descriptions of frequency. Although the WHO document is not currently available online, their recommendations have been summarized by others.
very common (>1/10 patients)
very rare (<1/100,000) Describing ADR Severity of ADR: : Minor: no need of therapy, antidote, or hospitalization
Moderate: requires drug change , specific treatment, hospitalization
Severe: Potentially life threatening; permanent damage, and prolonged hospitalization.
Lethal: Directly or indirectly leads to death Severity of ADR: Mechanisms : 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
comorbid disease states
Synergistic effects between either
a drug and a disease
two drugs Mechanisms Slide 18: 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.
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. 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. Slide 19: 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.
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. Slide 20: Impaired hepatic function
Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired hepatic function.
Impaired renal function
The National Kidney Disease Education Program provides guidance on dosing drugs in patients with reduced glomerular filtration rate. Food and Drug Administration provides guidance on the labeling of prescription medications to guide dosing for patients with impaired renal function. Although this categorization uses estimated creatinine clearance, using estimated glomerular filtration yields similar recommendations for dosing adjustments. Slide 21: Synergistic effects
An example of synergism is two drugs that both prolong the cardiac QT interval.
Other factors that my increase ADRs
The risk of drug interactions may be increased with polypharmacy.
Age (elder & young)
Gender (Female 1.5-1.7 fold greater risk of ADR than male) Age : Infants and very young children are at high risk of adverse drug reactions because their capacity to metabolize drugs is not fully developed. For example, newborns cannot metabolize and eliminate the antibiotic chloramphenicol.. Newborns who are given the drug may develop gray baby syndrome, a serious and often fatal reaction. If tetracycline , another antibiotic, is given to infants and young children during the period when their teeth are being formed (up to about age 8 yrs), it may permanently discolor tooth enamel. Children under age 18 are at risk of Reye's syndrome if they are given aspirin while they have influenza or chickenpox. Age Slide 23: Older people are at high risk of having an adverse drug reaction for several reasons ,They are likely to have many health problems and thus to be taking several prescription and over-the-counter drugs. Also, as in old age, the liver is less able to metabolize many drugs and the kidneys are less able to eliminate drugs from the body, increasing the risk of kidney damage by a drug and other adverse drug reactions. These age-related problems are often made worse by malnourishment and dehydration, which tend to become more common as people grow old.
Older people are also more sensitive to the effects of many drugs. For example, older people are more likely to experience light-headedness, loss of appetite, depression, confusion, and impaired coordination, putting them at risk of falling and fracturing a bone. Drugs that can cause these reactions include many antihistamines, sleep aids, antianxiety drugs, antihypertensives, and antidepressants Pregnancy and Breastfeeding : Many drugs—for example, antihypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers—pose a risk to the health and normal development of a fetus. To the extent possible, pregnant women should not take any drugs, especially during the first trimester. However, for some drugs, including ACE inhibitors and angiotensin II receptor blockers, risk is greatest during the last trimester of pregnancy. Use of any prescription drugs, over-the-counter drugs, and dietary supplements (including medicinal herbs) during pregnancy requires a doctor's supervision. Social drugs (alcohol and nicotine ) and illicit drugs (cocaine and Opioid such as heroin) also pose risks to the pregnancy and the fetus. Pregnancy and Breastfeeding (………) : Drugs and medicinal herbs may be transmitted through breast milk to a baby. Some drugs should not be taken by women who are breastfeeding, whereas others can be taken but require a doctor's supervision. Some drugs do not usually harm the breastfed baby. However, women who are breastfeeding should consult with a health care practitioner before they take any drugs. Social and illicit drugs may harm a breastfeeding baby. (………) Evaluation and Management of Drug Reaction : Evaluation and Management of Drug Reaction Evaluation and Management of Drug Reaction : Evaluation and Management of Drug Reaction Detecting ADRs : Clinical trials often do not include certain patient populations where the drug may be potentially used, including pregnant women or children, although recently the FDA has encouraged companies to study these patient populations by extending patent time. Premarketing trials frequently do not have sufficient power to reliably detect important ADRs, which may occur at rates of 1 in 10,000 or fewer drug exposures
FDA drug approval does not exclude the possibility of rare but serious ADRs Detecting ADRs Pharmacovigilance : WHO defines pharmacovigilance as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem”.
Pharmacovigilance is the process of:
monitoring the use of medicines to identify previously unrecognized adverse effects or
changes in the pattern of such effects
assessing the risks and benefits of medicines
providing information to optimize safe and effective use of medicines
monitoring the impact of any action taken. Pharmacovigilance The aims of pharmacovigilance : The principal aims of pharmacovigilance programmes are:
• to improve patient care and safety in relation to the use of medicines, and all medical and paramedical interventions;
• to improve public health and safety in relation to the use of medicines;
• to contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use;
• to promote understanding, education and clinical training in pharmacovigilance and its effective communication to health professionals and the public. The aims of pharmacovigilance Partners in pharmacovigilance : The management of the risks associated with the use of medicines demands close and effective collaboration between the key players in the field of pharmacovigilance.
Monitoring the safety of medicines: key partners
• Government • Industry
• Hospitals and academia
• Medical and pharmaceutical associations
• Poisons and medicines information centres
• Health professionals • Patients • Consumers • The media
• World Health Organization Partners in pharmacovigilance ADR detection methods : Premarketing clinical trials
Post approval spontaneous case reports
Aggregate population-based data sources
Computerized data collections
Post marketing studies
Case reports ADR detection methods Case reports : Case reports are simply reports of a single patient who was exposed to a medicine and experienced a particular adverse outcome. They are useful for raising hypotheses about the effects of medicines that can be tested with more rigorous study designs. They have been vital in alerting healthcare professionals to serious ADRs. In most cases, however, they are insufﬁcient to establish a causal association for the following reasons: they are prone to bias – a single case report linking a reaction to a drug could be just
coincidence or due to one of a large number of confounding inﬂuences Case reports (…….) : there is no comparison group not exposed to the drug to allow for a quantitative estimate of risk. (…….) Post-marketing epidemiological studies : Post-marketing epidemiological studies generally provide the best source of quantitative information on ADRs, given the limitations of clinical trials and case reports. They fall into two broad categories:
Cohort studies ;
They identify subsets of a deﬁned population and follow them over time,looking for differences in their outcome. Cohort studies are generally used to compare exposed patients to unexposed patients with subsequent events recorded and compared. Post-marketing epidemiological studies (…….) : For example, this technique has been used to investigate the potential link between the MMR vaccine and autism. The rate of autism in a vaccinated group was compared with the rate in
an unvaccinated group and a ﬁgure for the relative risk of autism calculated. (…….) Case-control studies : – They compare patients with a disease to controls without a disease, looking for differences in previous medicine exposures. A signiﬁcant excess of exposures to the suspect drug in the case group suggests that there may be an association with the drug.
Once the hypothesis had been raised that aspirin may be implicated with Reye’s syndrome,
the association was conﬁrmed by several rigorous case-control studies. Case-control studies ADR REPORTING : Different forms have been developed for reporting ADRs:
MEDWATCH by FDA
YELLOW CARD ADR REPORTING FDA Reporting Mechanisms: MEDWATCH : To improve the detection of previously unknown serious ADRs and knowledge about regulatory actions taken in response to reporting of these events, FDA introduced MEDWATCH in 1993.FDA encourages health professionals to monitor for and report serious adverse events and product problems to FDA. MedWatch is designed to educate health professionals about the critical importance of being aware of, monitoring for, and reporting adverse events and problems to FDA . FDA Reporting Mechanisms: MEDWATCH (…….) : It is designed to enhance the effectiveness of post marketing surveillance of medical products as they are used in clinical practice and to rapidly identify significant health hazards associated with these products. To increase awareness of drug and device-induced disease
To clarify what should (and should not) be reported to the agency
To facilitate reporting by operating a single system for health professionals to report ADRs and product problems
To provide regular feedback to the health care community about safety issues involving medical products. (…….) The yellow card system : The CSM yellow card scheme is regarded as one of the world’s best spontaneous reporting schemes for suspected ADRs, acting as an early warning system for the identiﬁcation of previously unrecognized reactions. It has helped to identify many safety issues including:
renal failure due to aristolochia in Chinese herbs
severe esophageal reactions with alendronate
serious cardiovascular reactions with cisapride.
About 20,000 yellow card reports are submitted each year by doctors, dentists, pharmacists,nurses and the pharmaceutical industry. About half that number represent serious The yellow card system (……) : ADRs, but it is generally accepted that there is under-reporting to CSM by a factor of 10.It follows from this that about 100,000 people in the UK suffer a serious ADR every year. The CSM has an expert working group on pediatric medicines. Its remit is to improve the availability of medicines for children within the regulatory framework and to advise on safety issues relating to speciﬁc medicines used in children. More information about registering an ADR can be located from
http://www.MHRA.gov.uk/aboutagency/regframework/csm/csmhome.htm (……) Strategies to Avoid ADR : An effective strategy to prevent the occurrence of ADR is always preferred. Some of the measures those may reduce the ADR are as follow;
Prescribe the drugs of known ADR only when there is no choice left
Obtain history of the patient
Educate the patient about the early symptoms of ADR
A person susceptible to certain reaction should be provided with cards Strategies to Avoid ADR Slide 44: Always discourage self medication
Always availability of safety measures in order to deal any kind of situation