Adverse drug reaction

adverse drug reaction

1. Adverse drug reaction Dr Shinde Viraj Ashok Junior Resident 1 Department of Pharmacology Guided by Dr V. M. Motghare Professor & Head D epartment of Pharmacology

2. overview

3. What are Adverse Drug Reactions ( ADRs )? A ny noxious change which is suspected to be due to a drug , occurs at doses normally used in man , requires treatment or decrease in dose or indicates caution for in future use of the same drug .

4. Adverse drug event – Any untoward medical occurrence that may present during treatment with medicine , but which may not have causal relationship with the treatment.

5. Statistics ADR to drugs are most common cause of iatrogenic disease. 3-5% hospitalisations due to adverse reactions results in 3,00,000 hospitalisations annually in US. Once hospitalised → 30% chance of ADR → R isk of each course is 5% 3% chance of life threatning reactions → Risk of each course is 0.4 %

6. Common causes of adr s Failing to take the correct dosages at the correct times. Overdosing. Allergies to chemical components of the medicine. Combining the medicine with alcohol. Taking other drugs or preparations that interact with the medicine. Taking a medicine that was prescribed for someone else.

7. Factors affecting Adverse Drug Reactions : Patient-related factors Age Sex Genetic influences Concurrent diseases ( renal ,liver , cardiac) Previous adverse drug reactions Compliance with dosing regimen Total number of medications Misc. (diet, smoking, environmental exposure)

8. Age Children are often at risk because their capacity to metabolize drugs is usually not fully developed Children younger than 18 may be at risk of developing Reye’s syndrome if given acetylsalicylic acid (aspirin) while infected with chickenpox or influenza.

9. Elderly 1. ADRs, including drug interactions, are a common cause of admission to hospitals in the elderly 2. Reasons for ADRs in the elderly: Concomitant use of several medications Decreased drug ADME activity due to age 3. These conditions are exacerbated by malnutrition and dehydration, common in the elderly

10. Pregnancy 1. Sulfonamides → Jaundice and brain damage in the fetus 2. Warfarin → Birth defects, and increased risk of bleeding problems in newborns and mothers 3. Lithium → Defects of the heart ( Ebstein’s Anomaly), lethargy, reduced muscle tone, and underactivity of the thyroid gland

11. Breast feeding → Many drugs can be passed from mother to infant via breast milk Amantadine (antiviral) Cyclophosphamide (antineoplastic) Cocaine (Schedule 2 FDA drug) Carisoprodol (skeletal muscle relaxant)

12. Drug-related factors Dose Duration Inherent toxicity of the agent Pharmacodynamic properties Pharmacokinetic properties Factors affecting Adverse Drug Reactions :

13. GENETIC BASIS Atypical pseodocholinesterase → Faulty hydrolysis: AR, normal action of succinylcholine hydrolysis takes 5 min ,here it takes 1-2 hours, results in prolonged respiratory failure. Hydroxylase polymorphism → Faulty oxidation, AR , Phenytoin toxicity ↑ in slow hydroxylators.

14. Genetic basis 3. Acetylator status → AR In fast acetylators → INH → Acetyl hydrazine → Hepatotoxicity In slow acetylators → INH → peripheral neuritis In slow acetylators → Dapsone → hemolysis. 4. G6PD deficiency → X linked recessive → Primaquine , sulfonamides, nitrofurantoin causes hemolytic anemia.

15. 5. Uroporphyrinogen Synthetase Enzyme deficiency → AD ,required for haem synthesis → Barbiturates , phenytoin , carbamazepine give rise to acute intermittent porphyria. Genetic basis

16. Type A - ( A ugmented ) Type B - ( B izarre ) Type C - ( C ontinuous ) Type D - ( D elayed ) Type E - ( E nding of Use ) Type F - ( F ailure of Efficacy) Types of ADR

17. Type A (Augmented) Predictable Type B ( Bizzare ) Unpredictable Expected- Und esirable Unexpected- Undesirable Based- Pharmacological properties of drug Based- Peculiarities of patient More common Less common Dose related Non dose related Mostly preventable and reversible More serious, requires drug withdrawl Includes- Side effects , Secondary effects , Toxic effects, Consequences of drug withdrawal Includes-Hypersensitivity/allergy , Idiosyncrasy ADR Classification

18. Types based on onset Onset of event: Acute - within 60 minutes Sub-acute - 1 to 24 hours Latent - > 2 days

19. Severity of ADR Minor Moderate Severe Lethal No treatment/ Antidote/ Prolongation of hospitalisation Requires treatment/ Change in treatment/ Prolongation by at least 1 day Requires intensive treatment , Life threatening, Permanent damage Directly/ Indirectly contributes to the death of the patient

20. FDA defines Serious ADR as which Results in death Life-threatening Require hospitalization Prolong hospitalization Cause disability Cause congenital anomalies Require intervention to prevent permanent injury

21. P harmacological properties of a drug Extension effects Predictable Dose - Related responses Prevention - Adjustment of dosage regimen Examples Benzodiazepines - S edation Furosemide - Water and electrolyte imbalance Heparin, warfarin - S pontaneous bleeding Insulin - H ypoglycemia Type A Reactions or Augmented

22. Adverse Effects P redictable , dose-dependent reactions unrelated to the goal of therapy O ften produced by the same drug-receptor interaction responsible for the therapeutic effect, differing only in the tissue/s or organ/s affected

23. Examples of Adverse Effects INH, Rifampicin, PZA – H epatotoxicity Streptomycin - O totoxicity , nephrotoxicity Captopril - Cough Simvastatin – Rhabdomyolysis Nitrates – Headache Propranolol – Bronchial asthma Tetracycline – Hypoplasia of the teeth

24. Type B Reactions or Bizarre A bnormal effects Unrelated from the drug’s known pharmacological actions

25. Characteristics of Bizarre Reactions N o formal dose-response curve (penicillin hypersensitivity – anaphylaxis ). R eaction disappears on discontinuation of the drug. R ecognizable as an immunological reaction. U ndetectable during conventional testing. L ittle or no relation to the usual pharmacological effects of the drug. D elay between exposure to the drug and the occurrence of the subsequent adverse reaction.

26. Example S of Bizarre Reactions Hypersensitivity reactions Stevens-Johnson’s Syndrome Hemolytic anemia

27. L ong term effects are usually related to the dose and duration of treatment Examples Ethambutol - Retinopathy NSAIDs - Nephrotoxicity Type C Reactions or Continuous

28. Carcinogenesis Teratogenesis Examples: Thalidomide Type D Reactions or Delayed

29. Type E Reactions or Ending of Use

30. Type F Reactions or Failure of Efficacy Counterfeit medicines Underdosing of medications Drug interactions

31. DRUG INTERACTION Warfarin which is highly protein bound is displaced by valproic acid leading to bleeding Aspirin inhibit platelet aggregation together with heparin an anticoagulant leads increased risk of bleeding.

32. 1. Side Effects - Undesirable effects at therapeutic doses e.g a)Atropine → Preanaesthetic medication → (undesirable ) dry mouth b) Codiene → S uppresses Cough (desirable ) → Constipation (undesirable) Making Use of side effects - Minoxidil → A ntihypertension → H ypertrichosis → Male pattern baldness Codeine → used in travellers diarrhoea Adverse drug effects may be categorised into

33. 2. Secondary Effects - Indirect consequence of primary action of drug Examples - a)Corticosteroids → ↓ Immunity → Latent T.B. activated b) Tetracyclines → ↓Bacterial flora → Super-infection. 3 . Toxic Effects - Exaggerated form of side effects due to overdosage /prolonged use Examples - a)High dose heparin → Bleeding b)Prolonged use of streptomycin →Ototoxicity, nephrotoxicity

34. 4. Allergy/Hypersensitivity- Immunologically mediated allergic responses occurs when sensitised individuals are re-exposed to same drug again Humoral -Type I,II,III Cell mediated-Type IV

35. Type I - Anaphylactic reactions due to IgE antibodies, min→2-3 hours Examples - urticaria ,angioedema , anaphylactic shock Type II - Cytolytic reactions due to antigen antibody complex , within 72 hours Examples - hemolytic anemia , SLE.

36. Type III – Retarded or A rthus reaction - Immune complex mediated reactions, 72 hours→1-2 weeks Examples - serum sickness (fever, arthralgia, lymphadenopathy), PAN , Steven Johnson syndrome , procainamide induced systemic lupus erythematous. Type IV - Delayed hypersensitivity reaction Examples - Contact dermatitis

37. 5. Idiosyncrasy - Genetically determined abnormal reactivity to a chemical. Here drug interacts with some unique features of individuals , not found in majority of subjects , produces uncharacteristic reaction . Examples - a) Barbiturates → excitement and mental confusion in some patients. b) Chloramphenicol → Aplastic anemia in some patients. c) Quinine/ quinidine → cramps, diarrhoea , purpura , asthma & vascular collapse.

38. 6. Drug Intolerance - - Characteristic toxic effects at therapeutic dose - Converse of tolerance - ↑ sensitivity to low doses Examples - Single dose triflupromazine → muscular dystonia

39. 7. Photosensitivity - Cutaneous reactions → sensitized skin → UV radiation. Two types: a) Phototoxicity b) Photoallergicity

40. Phototoxicity Photoallergy Drug/ metabolite accumulates in skin → absorbs light → photochemical and photobiological reaction → local tissue damage i.e.erythema,edema,blistering,hyperpigmentation Drug/metabolite → cell mediated immune response → UV light → papular or eczematous contact dermatitis like picture Short wavelengths (290-320nm) UV-B Longer wavelengths (320-400nm) UV-A More common e.g. Tetracyclines Less common e.g. Sulfonamides,Griseofulvin

41. 8 . Drug withdrawal reactions - Sudden interruption of drug → worsens clinical condition for which previously drug was used. Examples - a ) Corticosteroids in asthma → precipitates acute attacks , myalgia , depression b ) Beta Blockers → worsening of angina , precipitates myocardial infarction

42. 9 . Teratogenicity – Drug → pregnant mother → foetal abnormalities Examples- Thalidomide → Phocomelia . Diethylstilbesterol → Vaginal adenocarcinoma. Valproic acid → Neural tube defects. Antithyroid drugs → Foetal goiter , hypothyroidism. Phenytoin → Cleft lip , microcephaly.

43. Drugs can affect the foetus at 3 stages

44. Risk category of drugs during pregnancy Pregnancy Category Description A No risk : Adequate and well-controlled human studies - F ailed to demonstrate a risk to the foetus e.g. inj magnesium sulphate , thyroxine

45. Category Description B No evidence of risk in humans : Animal reproduction studies - F ailed to demonstrate a risk to the foetus & no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the foetus in any trimester . E.g. Penicillin V, amoxicillin , cefaclor , erythromycin paracetamol , lidocaine

46. Category Description C Risk cannot be ruled out: Animal reproduction studies have shown an adverse effect on the foetus and there are no adequate and well-controlled studies in pregnant women , But potential benefits may warrant use of the drug in pregnant women despite potential risks. E.g morphine , codeine , atropine , corticosteroids ,adrenaline , thiopentone , bupivacaine

47. category Description D Benefit may outweigh potential risk : Positive evidence of human foetal risk - on adverse reaction data from investigational or marketing experience or studies in humans , B ut potential benefits may warrant use of the drug in pregnant women despite potential risks . E.g. aspirin , phenytoin , carbamazepine, valproate, lorazepam , methotrexate

48. Category Description X Contraindicated in Pregnancy: Studies in animals or humans have demonstrated foetal abnormalities and/or There is positive evidence of human foetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits . E.g oestrogens , isotretinoin , ergometrine , thalidomide.

49. 10. Carcinogenecity and mutagenecity Carcinogenecity - Oxidation → reactive metabolites → structural gene damage e.g. Anticancer drugs , estrogens .

50. Mutagenicity Structural changes in DNA Oxidation of the drugs produces reactive metabolites Covalent interaction with DNA Inheritable Takes 10-40 years to develop Anti cancer drugs, radioisotopes Usually marketed for life threatening conditions

51. 11. Iatrogenic (Drug induced diseases) - Examples - a) NSAID'S → Peptic ulcers b) Hydralazine → DLE c) Phenothiazines → Parkinsonism d) INH → Hepatitis

52. 12. Drug Dependence - Use of drug produces a state in which person believes that continuous use is necessary for state of well being ( psychic dependence) or to avoid withdrawal symptoms ( physical dependence .) Psychological Physical Here person believes that state of wellbeing achieved only with action of drugs. Here repeated administration of drug required to maintain physiological equilibrium Discontinuation → withdrawl e.g. Opiods , Benzodiazepins e.g. Alcohol , Barbiturates , Benzodiazepins

53. Prevention of adr Avoid all inappropriate use of drugs. Use of appropriate dose , route & frequency of drug administration. Elicit & take into consideration previous history of drug reactions. Elicit h/o allergic diseases & exercise caution. Rule out possibility of drug interaction. Adopt correct drug administration technique. Carry out appropriate laboratory investigation. Be aware of interactions with certain foods, alcohol and even with household chemicals.

54. Management of ADR Discontinue the offending agent if - It can be safely stopped T he event is life-threatening or intolerable T here is a reasonable alternative C ontinuing the medication will further exacerbate the patient’s condition Continue the medication (modified as needed) if - I t is medically necessary T here is no reasonable alternative T he problem is mild and will resolve with time

55. Discontinue non-essential medications Administer appropriate treatment - e.g., atropine,protamine sulfate , digibind antibodies, flumazenil. Provide supportive or palliative care - e.g., hydration, glucocorticoids, warm / cold compresses, analgesics or antipruritics Consider rechallenge or desensitization

56. Principles of Descriptive toxicity testing in animals Effects of chemicals produced in laboratory animals when properly quantified apply to human beings. Exposure of experimental animals to toxic agents in high doses – necessary & valid method to discover possible hazards to human beings.

57. Management of poisoning Maintain vital & physiological functions from impairment Termination of exposure (decontamination) Prevention of absorption of ingested poison.(activated charcoal) Hastening elimination Urinary alkanlization Multidose activated charcoal Extracorporeal drug removal Antidote therapy

58. Pharmacovigilance Definition – Science and activities relating to the detection ,assessment , understanding and prevention of adverse effects or any other drug related problems . Activities involved in it Postmarketing surveillance Dissemination of ADR data Changes in labelling of medicines

59. Adr reporting form

60. Causality assessment Routine procedure in Pharmacovigilance Relationship of cause & effect Most outcomes : multiple interacting causes Aim : to define contribution due to drugs Problems : ADRs rarely specific Diagnostic tests usually absent Re challenge rarely ethically justified Various methods : None is precise, reliable

61. Causality Assessment Methods Algorithmic : (algorithm - specify how to solve problem) Series of questions Answers are weighted Overall score determines causality category e.g. Naranjo’s scale Probalistic : (based on probability) Set of explicitly defined causality categories e.g. WHO UMC method Uses of causality assessment Initial review of report Signal detection Scientific publications

62. The Naranjo ADR Probability Scale Questions Yes No Don’t Know 1) Are there previous conclusive reports on this reaction? +1 2) Did the ADR appear after the suspected drug was administered? +2 -1 3) Did the ADR improve when the drug was discontinued? +1 4) Did the ADR appear with re-challenge? +2 -1 5) Are there alternative causes for the ADR? -1 +2 6) Did the reaction appear when placebo was given? -1 +1 7) Was the drug detected in blood at toxic levels? +1 8) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? +1 10) Was the ADR confirmed by any objective evidence? +1

63. The Naranjo Probability Scale The score :- ≥ 9 = Definite 5-8 = Probable 1-4 = Possible 0 = Doubtful Naranjo CA et al. Clin Pharmacol Ther 1981;30:239-45.

64. Conclusion Every drug which has an effect has an adverse effect every time a drug is given risk is involved. What is there that is not a poison ? all things are poison & nothing is with out poison, solely dose determines that a thing is not a poison. For rational use of drug not only its clinical indications are important to be remembered equally important is remembering adverse effects. Early detection of adverse effects and its proper management can be life saving in many situations.

65. References Goodman and Gilman's -12 th The Pharmacological basis of therapeutics Essentials of pharmacotherapeutics 5 th edition – F.S.K. Barar Essentials of Medical Pharmacology 7 th - K. D. Tripathi

66. ADR REPORTING

67. Why report ADRs? To prevent drug-induced human suffering To avoid financial risks associated with unexpected risks

68. June 22, 1963 as amended on May 22, 1987 Republic Act 3720 “Food, Drugs and Devices and Cosmetics Act” Creation of Food and Drug Administration now Bureau of Food and Drugs April 20, 1994 BFAD Memorandum Circular No. 5 s. 1994 Submission of ADR reports by pharmaceutical establishments and parties concerned June 30, 1994 Department Order No. 345 - I s. 1994 Creation of National Adverse Drug Reaction Advisory Committee (NADRAC) GOVERNMENT POLICY ON ADR REPORTING

69. Reports from Participating Hospitals Reports from Private Practitioners Report from Drug Mfr. Traders/ Outlets Reports on Clinical Investiga- tions Reports from Regulatory Authorities Reports from Int’l ADR Centers BFAD ADR UNIT NADRAC WHO Collaborating Center Director - BFAD Secretary of Health - DOH ADR Monitoring System

70. REPORTING SCHEME NADRAC (Trend Analysis) CASE Reporter Fills Out a Form Hospital Therapeutic Committees ADRMP Office (Central Database) WHO WHO

71. THE PGH ADVERSE DRUG REACTION REPORTING SCHEME

72. How do we report ADRs? STEP 1 : Fill out the RED ALERT CARDS PGH FORM # P – 60170 PGH ADVERSE DRUG SURVEILLANCE ALERT CARD (Clip this on chart front cover) Name of patient:___________________________________ Ward & Bed No.:__________________________________ Name of suspect drug:______________________________ Manufacturer:_____________________________________ Lot/ Code No.:__________ (Retain empty vial or container) Describe the reaction:_______________________________ __________________________________________________________________________________________________ Reporter: _________________________________________ (Please Print) PLEASE NOTIFY: CENTRAL BLOCK PHARMACY Loc. 3163 / 3170

73. How do we report ADRs? STEP 2: Complete the ADR REPORT FORM The Resident - in - charge of the patient shall complete the necessary report of ADR circumstances.

74. How do we report ADRs? STEP 3: Submit the red alert card and the ADR report form to the Central Block Pharmacy for proper referral. STEP 4: The Pharmacy will then compile the reports for review of the ADR Subcommittee and submission to the Bureau of Food and Drugs (BFAD).

75. Pharmacist

76. The ADR Report Form should include the following: brand name of the suspect drug the manufacturer (if generic) the lot and batch number. It should be done in duplicate. ALL REPORTS ARE CONFIDENTIAL IMPORTANT!!!!

77. Common reports rash caused by Oxacillin red face, fever secondary to Vancomycin Uncommon reports hair loss due to anti thyroid agents neuroleptic malignant syndrome with risperidone Examples of Reported ADRs

78. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS 1. Critically review the total condition of the patient. Be particularly careful when you prescribe to children, elderly, seriously ill , pregnant patients and those with renal, cardiac or liver diseases.

79. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS 2. Use as few drugs as possible. Balance the seriousness of possible reactions against the beneficial effects of each drug that is being considered.

80. Know well the drugs that you use. Compare the efficacy and safety of each of the available competitive medications that appear to be worthy of consideration for the patient. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS

81. Do not change too readily from one drug you know to one you do not know. If you decide to use a new drug, know that drug. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS

82. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS Do not hesitate to use textbooks and other references providing information on drug reaction and interaction.

83. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS 6. Be especially careful when prescribing drugs known to exhibit a large variety of reactions/ interactions.

84. 7. Be aware of interactions with certain foods, alcohol and even with household chemicals. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS

85. 8. Regularly make an inventory of the drugs your patient is receiving. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS

86. 9. Review your patient regularly for all the drugs used and especially those bought without prescriptions. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS

87. TEN COMMANDMENTS to reduce ADVERSE DRUG REACTIONS 10. If your patient shows signs and symptoms not clearly explained by the course of illness, think of adverse drug reaction.

88. STATISTICS 5 % of adults are allergic to one or more medications 6 – 10% of ADRs result from a drug allergy 3% of hospital admissions are due to ADRs 28% of ADRs are preventable Drugs associated with ADRs: 29% analgesics, 10% sedatives, 9% antibiotics, and 7% antipsychotics. PGH: Antibiotics (35%), anti-TB meds (34%), anticonvulsants and ASA/NSAIDS (10% each)

89. ADRs: 4 th Leading Cause of Death Study: Drug reactions kill an estimated 100,000 a year April 14, 1998

90. What is an adverse drug experience ? An undesirable drug effect, whether harmless, resulting from medications administered in a dosage normally given. It becomes an adverse drug reaction when it is reported and subsequently evaluated to be secondary to the drug usage.

91. Key points to remember ADRs are undesirable are unintentional are suspected (not necessarily proven) may develop as a consequence of therapy (or other procedures)

92. Causes of ADR Pharmaceutical causes decreasing particle size or changing excipients Pharmacokinetic causes diazepam aminoglycosides Pharmacodynamic causes increased sensitivity of target organs in the body to drugs