Adverse Drug Reactions

Adverse Drug Reactions

1. Adverse Drug Reaction The negative and undesirable effects of drug therapy are known as adverse drug reaction. These reactions may be caused by the drug itself or one of its metabolites; from an interaction between two or more drugs or between a drug and food; or may be caused by an excipient in the product, such as dye or preservative. According to WHO, adverse drug reaction is defined as: “A response to a drug that is noxious and unintended, and that occurs at doses normally used in human for the prophylaxis, diagnosis or therapy of disease or for the modification of physiological function.”

2. Classification of ADRs Rawlins and Thompson classification :  In this classification, the ADRs are categorized into two classes ;  type A and type B reactions Type-A Reaction (95%) Type-A reactions are common and predictable with most identified prior to marketing. These are dose related and result directly from the pharmacological action of the drug, but can be due to drug-drug interactions, drug-food interactions, This represent approximately 70 to 80% of all ADRs

3. Examples of Type-A Reaction : Excessive effects of the pharmaclological action of a drug, Example: haemorrhage with anticoagulants. Unwanted pharmacological actions of a drug, Example: antimuscarinic effects of tricyclic antidepressants which can result in blurred vision, tachycardia, dry mouth and urinary retention. Withdrawal reactions, which may occurs with abrupt withdrawal of some drugs after prolonged use, Example: insomnia with hypnotics.

4. Type-B Reaction (5%) Type B reactions are unexpected effects which are unrelated to the known pharmacological action of the drug. This type of ADRs is uncommon, cannot be predicted, is not dose-related, and has no relation to the pharmacological action of the drug. In most cases, the mechanism involved in type-B reactions is unknown.

5. These reactions predominantly affect T he liver S kin , and H ematopoietic system. This class of ADRs includes drug allergies (hypersensitivity reactions) such as anaphylaxis from penicillin, Type-B ADRs may influence by genetic and environmental factors and are frequently not discovered until after a drug is marketed.

6. Wills and Brown classification:  To overcome the limitations of Rawlins and Thompson classification, adverse reactions are classified into nine categories based on their mechanism: 1.Type A (Augmented ) Dose related Pharmacologically predictable Improves if medication is withdrawn Common 2.Type B (Bugs) Non- dose related Pharmacologically predictable Involves reaction with microorganism Improves if medicine withdrawn 3.Type C (Chemical/Chronic) Dose related & time related They are not pharmacologically predictable, but may be seen based on the knowledge of physicochemical characteristics of the drug. Type C reactions are irritant reaction that is related to drug concentration. e g : contact dermatitis.

7. 4.Type D (Delivery/Delayed) Time related Type D reactions are independent of the chemical as well as pharmacological properties of the drug. Instead, they occur due to method of administration or nature of the drug formulation. It can be improved if medicine withdrawn or method of delivery changed. eg : infection at the site of injection 5.Type E (Exit/End of use) Withdrawal The reactions are pharmacologically predictable and begin only when the drug is withdrawn or the dose is reduced. The condition of the patient improves when the drug therapy is reintroduced. e g : withdrawal seizure when anticonvulsants like Phenytoin is withdrawn 6.Type F (Familial/Failure) Failure of therapy They only occur in genetically predisposed patient. It can be improved if medicine withdrawn. eg : hemolytic anemia with primaquin in G6PD deficient individuals.

8. 7.Type G ( Genotoxicity ) Irreversible genetic damage is caused by this Type G adverse reaction. eg : teratogenic agent like Thalidomide causes genetic damage to the developing fetus . 8.Type H (Hypersensitivity) They are also known as drug allergy and is often immune mediated response. 9.Type U (Unclassified) This includes those reactions in which the mechanism is unclear. eg : taste disturbances associated with Simvastatin .

9. Severity of ADR M inor : no need of therapy, antidote or hospitalization Moderate : requires drug change, specific treatment, hospitalization Severe : potentially life threatening, permanent damage, prolonged hospitalization Lethal : directly or indirectly leads to death

10. ADR Categories Side effects Secondary effects Toxic effects Intolerance Idiosyncrasy Drug allergy Photosensitivity Drug dependence Drug withdrawal reactions Teratogenicity Mutagenicity & carcinogenicity

11. Anaphylaxis Anaphylaxis is a severe life threatening allergic reaction. Common anaphylactic reactions are to foods, insect stings, medications, etc It occurs due to reaction of antigen with a specific class of antibody ( IgE ) bound to the surface of mast cells & basophils . When antigen reacts with antibody, the cell membrane permeability increases that leads to influx of calcium ions into cells. This causes degranulation of mast cells & basophils with the liberation of histamine & other mediators. This reaction may sometime lead to acute circulatory failure known as anaphylactic shock. Treatment: Adrenaline injection (Life saving drug)

12. Treatment of anaphylaxis Airway management; supplemental oxygen Apply tourniquet to obstruct blood flow from antigen source Intravenous fluids; glucocorticoids , antihistaminic drugs, bronchodilators Adrenaline injection i.m . or s.c .; adrenaline is physiological antagonist of histamine, quick reversal of hypotension, bronchospasm , laryngeal edema is seen

13. Organ specific adverse drug effects Hepatotoxicity Venous blood from stomach & intestine flows into the portal vein & then through liver before entering systemic circulation. The liver is the first organ to encounter ingested food & drugs. All of the major functions of liver are affected by the adverse drug reactions like hepatic transport & synthetic process. Major liver functions affected by adverse drug reactions are: Homeostasis Filtration of particulates Protein synthesis Bioactivation & detoxification Formation of bile & biliary secretion

14. Major adverse drug reaction of liver are: Fatty liver: ethanol, valproic acid Hepatocyte death: paracetamol , ethanol Bile duct damage: amoxicillin, methylene Sinusoidal disorders: steroids, cyclophosphamide Fibrosis & cirrhosis: ethanol, vitamin A

15. Nephrotoxicity Kidney plays important role in maintaining: Total body homeostasis Excretion of metabolic wastes Regulation of extracellular fluid volume Electrolyte composition Acid-base balance Synthesis & release of renin & erythropoietin Activation of vitamin D 3 Thus adverse drug reaction to kidney can disrupt all of these functions & effect body metabolism. Major adverse drug reaction of kidney are: Acute renal failure: NSAIDS, amphotericin B, cyclosporine Chronic kidney failure: aminoglycosides , cisplatin , lithium

16. Reasons for Adverse Reactions 1.Dispensing & Medication administration errors Over prescription by Physician as well as self medication by patients may lead to adverse drug reactions. 2.Failure to set therapeutic end point Physicians unable to set therapeutic end point for potent drugs or misuse of drugs like digitalis, corticosteroids, diuretics, etc may cause adverse drug reactions

17. 3.Bioavailability Differences Changes in formulation of drugs from different brands affects bioavailability & leads to adverse effects 4.Patient Factors Physiological & disease status of patients affects adverse drug reaction. Different age group like child, adult & elderly have difference in metabolism, excretion which affects drug response & adverse drug reactions.

18. 5.Multiple Drug Therapy Digoxin and beta-blockers may cause increased risk of bradycardia 6.Age and Sex Neonates have reduced drug clearance, resulting in increased risk of ADRs, Elderly taking a greater number of medicine so multiple drug therapy may influence the elder groups. Some ADRs appear to occur more frequently in females 7.Multiple disease states Patients with peptic ulcer disease being at increased risk of bleeding when prescribed NSAID, Those with asthma who may suffer bronchospasm with beta- adrenoceptor blocking drugs.

19. 8.Types of Drug Prescribed ADRs may be more likely to occur when the drug regimen includes medicines with a narrow therapeutic index such as, digoxin , anticoagulants and insulin 9.Dosage Drowsiness with antiepileptic drugs such as, phenytoin , Phenobarbital and carbamazepine 10.Route of Administration Rapid IV injection of digoxin for heart disease may cause nausea and arrhythmias

20. 11.Formulation ADRs can be due to excipients in pharmaceutical formulation, e.g., coloring agents, sweeteners and preservatives. Changes in formulation of digoxin resulting in changes in particle size which affected bioavailability lead to toxicity 12.Patient Compliance ADRs more frequently occur if the patient does not follow the prescribed regimen. Taking too much of a drug may lead to adverse effects)

21. Roll of the Nurses in ADRs Nurses can play an important role in identifying, documenting, monitoring, preventing, and reporting of ADRs in their routine practice . Identification and Documentation Should be looking out for potential ADRs during the course of their work with patients, whether in hospital or clinics. During review of prescription, alert for possible factors of ADRs. Similarly alertness during dispensing medicine. Patients are often more open about their experiences with medicines to nurses than to doctors.

22. It is therefore, important that nurses have direct contact with patient and are able to identify the possible ADRs. If possible ADRs are recorded , document the conformed suspected ADRs and can play a major role in preventing patients from ADRs . Monitoring and Reporting Nurses can actively improve the low reporting rates. They can report ADRs themselves as well as facilitated by encouraging physician & pharmacist to report.

23. Prevention/Management of Adverse drug reaction Since many ADRs are preventable, a major part of the nurse role in ADRs should be to reduce the occurrence of the problem through: Identifying potential side effects of drug therapy and advising a safe course of action. Avoiding unnecessary poly-pharmacy by encouraging and carrying out review of therapy and by compliances to patients. Choosing the least toxic drugs where possible .

24. Checking the history of allergy or previous reaction to a drug Checking the drug interaction and advising on what action to take Encouraging the patients to complete the course of medication Encouraging patients to report any new symptoms Advising on simplifying dose and drug regimens to encourage good compliance

25. Adverse Drug Reaction Reporting System Pharmacovigilance is the study of the safety of marketed drugs under the practical conditions of clinical use in large communities. As per WHO Pharmacovigilance ‘is the science and activities relating to the detection, assessment, understanding and prevention of adverse drug reactions or any other possible drug related problems’. The ultimate goal of this activity is to improve the safe and rational use of medicines, thereby improving patient care and public health.

26. Why PV is required ? The numbers of patients in clinical safety analysis remain far too small to detect uncommon or rare adverse drug reactions (ADRs), even if these are serious. Pharmacoepidemiology is the study of the use of, and effects of, drugs in large numbers of people. As the term implies, this form of enquiry uses the methods of epidemiology; it is concerned with all aspects of the benefit – risk ratio of drugs in populations. Pharmacolovigilance Centres are present in hospitals to report adverse drug reactions. They are centrally governed by Uppsala Monitoring Centre (UMC), Sweden. In UK, Yellow C ard Scheme is used to report adverse drug reactions by MHRA.