Mechanisms and Classification of Adverse Drug Reactions - PowerPoint PPT Presentation

chas
mechanisms and classification of adverse drug reactions n.
Skip this Video
Loading SlideShow in 5 Seconds..
Mechanisms and Classification of Adverse Drug Reactions PowerPoint Presentation
Download Presentation
Mechanisms and Classification of Adverse Drug Reactions

play fullscreen
1 / 93
Download Presentation
Mechanisms and Classification of Adverse Drug Reactions
499 Views
Download Presentation

Mechanisms and Classification of Adverse Drug Reactions

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Mechanisms and Classification of Adverse Drug Reactions Professor Phil Routledge Department of Pharmacology, Therapeutics and Toxicology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University April 2012

  2. INCIDENCE OF ADVERSE DRUG REACTIONS IN HOSPITALISED PATIENTS • 39 prospective studies from US hospitals • Incidence of serious ADRs was 6.7% (CI 5.2-8.2) • Incidence of fatal ADRs 0.32% (CI 0.23-0.41) • Between 4th and 6th leading cause of death Lazarou J et al. JAMA 1998; 279: 1200-1205

  3. CAUSES OF DEATH IN THE USA 1994 1. Heart disease 2. Cancer 3. Stroke 4. Pulmonary disease 5.ADVERSE DRUG REACTIONS 6Road traffic accidents Lazarou J et al. JAMA 1998; 279: 1200-1205

  4. Deaths in England and Wales from medication errors and adverse effects of medicines (1990 to 2000) from “A Spoonful of sugar: medicines management in NHS hospitals” Audit Commission 2001

  5. ADR WORKSHOP • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX? • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED? • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs? • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic) • ARE THERE ANY POSSIBLE GENETIC FACTORS? • WHAT WOULD YOU DO FOR THE PATIENT?

  6. CARD 1 ( For advice on reporting reactions see IN CONFIDENCE__COMMITTEE ON SAFETY OF MEDICINES Adverse Reactions to Drugs section of BNF ) REPORT ON SUSPECTED ADVERSE REACTIONS Bloggs Josephine PATIENT'S DETAILS OTHER NAMES SURNAME 59 yrs This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. DATE OF BIRTH ( OR AGE ) 75 kg F WEIGHT ( kg ) SEX : M Hospital if relevant Consultant in charge/GP Principal Hospital number SUSPECTED DRUG ( Give brand name of drug and batch number if ROUTE DAILY DOSE known) Prosthetic Continuing DATE STOPPED DATE STARTED THERAPEUTIC INDICATION mitral valve SUSPECTED REACTIONS REPORTING DOCTOR Name Continuing Address DATE REACTION STARTED DATE REACTION ENDED OUTCOME ( e.g. fatal, recovered, continuing ) SEND TO CSM, FREEPOST, LONDON SW8 5BR Telephone Speciality OR if you are in one of the following NHS regions: Signature Date TO CSM Mersey, FREEPOST, Liverpool L3 3AB If you would like information about OR CSM West Midlands, FREEPOST, Birmingham B15 1BR other reports associated with the OR CSM Northern, FREEPOST 1085, Newcastle upon Tyne NE1 1BR suspected drug, tick here PTO OR CSM Wales, FREEPOST, Cardiff CF4 1ZZ DATE DRUG THERAPEUTIC OTHER DRUGS ROUTE DATE DRUG DAILY DOSE STARTED TAKEN IN THE LAST STOPPED INDICATION 3 MONTHS INCLUDING This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. SELF-MEDICATION Give brand name if known none Write if no other drug has been taken Heart Continuing Failure Additional information including medical history, investigations, known allergies, suspected drug interactions relevant to the reaction and LMP for drugs taken during pregnancy. Patient previously well-controlled on 5 mg warfarin • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX? • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED? • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs? • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic) • ARE THERE ANY POSSIBLE GENETIC FACTORS? • WHAT WOULD YOU DO FOR THE PATIENT? Chest pain ? AMI

  7. Routledge PA, Harris W, Mathew S and Monypenny IJ. Retromammary haemorrhage and warfarin therapy. Postgrad Med J. 74: 347-8 (1998)

  8. 70% of ADRs.Predictable and therefore often avoidable CLASSIFICATION OF ADRSType A versus Type B ADRs

  9. Philippus Aureolus Theophrastus Bombastus von Hohenheim 1538 All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.

  10. Adverse drug reactions as cause of admission to hospital • 18,820 patients admitted oversix months to a Liverpool Hospital and assessed for cause of admission • prevalence 6.5%, with ADR directly leading to the admissionin 80% of cases • Overall fatality was 0.15% • Most reactions were either definitelyor possibly avoidable(Type A ADRs) • Drugs most commonly implicated in causingthese admissions included low dose aspirin, diuretics, warfarin,and non-steroidal anti-inflammatory drugs other than aspirin,the most common reaction being gastrointestinal bleeding Pirmohamed M et al. BMJ 2004;329:15-19

  11. A more complicated classification

  12. EIDOS: a mechanistic classification DoTS: a clinical pharmacological classification Drug Dose-relatedness Drug Extrinsic Distribution Patient Adverse reaction Intrinsic Outcome Patient Adverse reaction Susceptibility factors Time-course Classifying adverse drug reactions: two complementary systems Ferner & Aronson. Drug Saf 2010;33:13-23 Aronson & Ferner. BMJ 2003;327:1222-5

  13. Mechanisms of Type A adverse drug reactions • Pharmaceutical • parent compound • excipients • Pharmacokinetic • metabolism • excretion • Pharmacodynamic What the body does to the drug What the drug does to the body Routledge PA. "Adverse Drug Reaction and Interactions: Mechanisms, Risk Factors, Detection, Management and Prevention" in Stephen's Detection of New Adverse Drug Reactions Talbot, John / Waller, Patrick (eds.) John Wiley and Sons (2004)

  14. RISK FACTORS FOR ANTICOAGULANT ASSOCIATED BLEEDING

  15. Audit of anticoagulant therapy and acute hospital admissions • St Mary’s Hospital London: over 3 months 1480 acute admissions, 112 (7.6%) on anticoagulant therapy • 74 had INRs in normal range • 29 over-anticoagulated, of which 17 (59%) admitted with bleeding symptoms • Reasons for over coagulation were: • Poor patient compliance (31%) • Influence of other medications (17%) • Congestive heart failure (28%) • Unknown (24%) • Overall 1.5% of all hospital admissions were due to warfarin complications and 16/21 patients with bleeding had INRs > 4.5 Hirri & Green, Clin Lab Haematol 2002; 1: 43-45

  16. CARD 2 CA 80kg 70 12345 Co-Amoxiclav (Augmentin) po 750 mg 1/04/95 9/04/95 Diverticulitis JAUNDICE 16/05/95 17/11/95   Metoclopramide po 10mg 1/04/95 1/04/95 Nausea Se. Bilirubin 94 umol/l, Alk Phos 324 iu/l, AST 228 iu/l, Gamma GT 276 iu/l. Ultrasound showed no abnormality. This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX? • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED? • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs? • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic) • ARE THERE ANY POSSIBLE GENETIC FACTORS? • WHAT WOULD YOU DO FOR THE PATIENT? Kombucha tea po 2 cups Nov 94 Cont. Arthritis This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. 24/11/95

  17. JAUNDICE AND CO-AMOXICLAV • Type B ADR, reporting rate 1 in 56,000 scripts in 1991 • Clavulanate likely causative agent • 50 % reports concern patients aged > 60y 70% of reactions occurred after stopping drug (up to 6 weeks’ delay) • Current Problems in Pharmacoviilance19:2 (1993) Smith PM, Wilton A, Routledge PA. European Journal of Gastroenterology & Hepatology 1991;3:95-96.

  18. DRUG INDUCED LIVER INJURY (DILI) DRUG ASSOCIATED LIVER INJURY (DALI?) • Amoxicillin-clavulanate • Ebrotidine • INH + RIP +PIZ • Ibuprofen • Flutamide • Ticlopidine • Diclofenac • Isoniazid • Medicinal herbs • Nimesulide • Amoxicillin-clavulanate (41) • Lofepramine (31) • Carbamazepine (19) • Diclofenac (19) • Azathioprine (18) • Ciprofloxacin (17) • Flucloxacillin (16) • Chlorpromazine (14) • Fusidic acid (13) • Amiodarone (12) Andrade RJ et al. Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period . Gastroenterology 2005; 129: 512-521 CVS Krishna, personal communication.

  19. 30% of ADRs.Less predictable and therefore often unavoidable CLASSIFICATION OF ADRSType A versus Type B ADRs

  20. Mechanisms of Type B adverse drug reactions • Allergic • Pseudoallergic • Pharmacogenetic susceptibility Routledge PA. "Adverse Drug Reaction and Interactions: Mechanisms, Risk Factors, Detection, Management and Prevention" in Stephen's Detection of New Adverse Drug Reactions Talbot, John / Waller, Patrick (eds.) John Wiley and Sons (2004)

  21. http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.htmlhttp://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html

  22. Human leucocyte antigen class II genotype in susceptibility & resistance to co-amoxiclav-induced liver injury • In 61 cases of co-amoxiclav-associated DILI, HLA-DRB1*15 was increased in patients (53%) versus both treated (33%: OR=2.29: 95% CI: 1.00-5.26) and population controls (30%: OR=2.59:95% CI: 1.44-4.68: p=0.002) • DRB1*07 reduced in patients (9.8%) compared to both treated (35%: OR=0.18: 95% CI: 0.06-0.52: p=0.0011, pc=0.0154) and population controls (29%: OR=0.266: 95% CI: 0.11-0.65: p=0.0019, pc=0.0266). • Results confirm the previously reported significant genetic risk for HLA-DRB1*15 and also provide evidence of a protective effect of the HLA-DRB1*07 family of alleles Donaldson PT et al. J Hepatol. 2010; 53:1049-53. Epub 2010 Aug 1

  23. CARD 3 This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. DY 75 45 • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX? • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED? • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs? • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic) • ARE THERE ANY POSSIBLE GENETIC FACTORS? • WHAT WOULD YOU DO FOR THE PATIENT? CLOZAPINE (Clozaril) ORAL 450mg 12/12/02 1/02/03 SCHIZOPHRENIA Sinus Tachycardia, Dyspnoea, fever, ST depression on ECG, eosinophilia 23/01/03 3/02/03 Lorazepam (Ativan) oral 4mg Nov 2000 continuing anxiety Patient consumes 24 units alcohol weekly This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. For Teaching Purposes only

  24. MYOCARDITIS AND CLOZAPINE • Reported from 4 countries with incidence between 5 and 100 cases per 100,000 patient-years. Fatality rate 3-30 cases per 100,000 patient-years • Type B reaction • Tachycardia (present in 25%) during first month may be premonitory sign • Nearly always within first 8 weeks of treatment • Rechallenge not warranted

  25. Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003. • 116 case reports of suspected myocarditis amongst clozapine-treated patients (c.1% treated patients). • Median age 30 years (SD 11.1 years) compared with 37 years from the Clozapine registry • Developed within median 16 days • Over nine-tenths prescribed clozapine 100-450 mg/day • 60 patients (52%) recovered • 12 patients (10%) died • Wide diversity of non-specific symptoms in afflicted patients • Case-control study would be suitable for investigation of baseline predictors. Haas SJ et al. Drug Saf. 2007;30(1):47-57.

  26. left ventricular myocardium shows vacuolization (arrow), disruption of myocardial fibers (arrowheads), and widespread foci of chronic inflammatory cells consisting of lymphocytes, eosinophils, and plasma cells (H&E, orig. ×200). Ansari A et al. Tex Heart Inst J. 2003; 30(1): 76–79

  27. Reversible Myocarditis in a Patient Receiving Clozapine Kirpekar VC, Deshpande SM & Joshi PP Indian Heart J 2001; 53: 779–781

  28. Drugs Known to Cause Toxic Myocarditis Ansari A et al. Tex Heart Inst J. 2003; 30(1): 76–79.

  29. Difficulties in identifying Iatrogenic Disease • The body has only a limited number of response to noxious stimuli so that iatrogenic disease may resemble disease caused by other mechanisms • There are rarely specific haematological, biochemical or histological tests to identify iatrogenic disease • Evidence may therefore be only circumstantial

  30. Criteria for identifying Adverse Drug Reactions • Timing of event relative to drug administration (and possible withdrawal) • Previous evidence in literature implicating drug • Absence of alternative explanations for event • Effects of rechallenge (when warranted)

  31. Cutaneous and Ocular Reactions to Practolol Felix RH wt al. Br Med J. 1974; 4: 321–324.

  32. PRACTOLOL • Company Safety database in 2100 subjects showed seven rashes (0.33%) and no eye complaints(Wiseman et al 1971) • However GP trial records indicated eye complaints in 20% and rash in 23% (including half of those with eye complaints)(Skegg and Doll 1977) • Record all adverse events in clinical trials, not just suspected adverse drug reactions(Skegg and Doll 1977) • Adverse event: “A particular untoward happening experienced by a patient, undesirable either generally or in the context of his/her disease”(Finney 1965)

  33. THE POPULARITY OF A MEDICINE This drug cures everyone. It’s the best thing since sliced bread! This drug got approved by NICE. What a nice drug This is a promising new drug. Let’s send a story to the Daily Mail This drug can kill! I wouldn’t give it to a dog!

  34. CARD 4 This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. AL 55 49 • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX? • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED? • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs? • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic) • ARE THERE ANY POSSIBLE GENETIC FACTORS? • WHAT WOULD YOU DO FOR THE PATIENT? PREMARIN ORAL 1.25mg Jan 2002 Feb 3rd 2003 Menopausal symptoms Transient weakness Left arm and leg (lasting 12 hours) Feb 2nd 2003 Feb 3rd 2003 Xiaoke Wan (Traditional Chinese Herbal Medicine) One tablet Oct. 2000 Continuing Oral This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. For Teaching Purposes only

  35. US WOMENS’ HEALTH INITIATIVE • Randomised controlled trial for 5 years in 16,000 asymptomatic post-menopausal women (mean 63, range 50-79 y) • CHD increased from 30 to 37 cases per 10,000 women • Stroke increased from 21-29 cases per 10,000 women • Breast cancer increased (30-38), colorectal cancer fell (16 to 10), hip fracture fell (15 to 10) cases per 10,000 women • Manson JE et al. New Engl J Med 2003; 349:523-534 (CHD findings)

  36. US WOMENS’ HEALTH INITIATIVE • A 24% overall increase in the risk of CHD (6 more heart attacks annually per 10,000 women using E+P • An 81% increased risk of CHD in the first year after starting E+P • Women who had higher baseline low-density lipoprotein (LDL) cholesterol levels at the beginning of the study were at particularly high risk of CHD with E+P use • New Engl J Med 2003; 349:523-534

  37. US WOMENS’ HEALTH INITIATIVE

  38. Aspirin and bleeding into the bowel Aspirin and bleeding into the brain Aspirin and Reye’s Syndrome DETECTION OF ADRs Sensitivity of methods Patients exposed to drug prior to marketing ( mean=2,500 ) Clinical trials ( pre-marketing ) Spontaneous post-marketing reporting schemes ( e.g. Yellow Card reports ) 1 in 1 in 100 1 in 1000 1 in 10,000 1 in 100,000 1million Incidence of ADR

  39. Baseline Risk and Risk Reduction • Relative risk reduction is often more impressive than absolute risk reduction • The lower the event rate in the control group, the larger the difference between relative risk reduction and absolute risk reduction Learning Tools for Evidence-Based Clinical Practice Risk Reduction:Absolute and Relative Risk Reduction. Alexandra Barratt, Peter C. Wyer, Rose Hatala, Thomas McGinn, Antonio L. Dans, Sheri Keitz, Virginia Moyer, Gordon Guyatt Robert Hayward (interactive version) for the Evidence-Based Medicine Teaching Tips Working Group

  40. Xiaoke/ Xiaoke-wan January 2004 In August 2003 the Agency seized a specific range of Xiaoke pills from a traditional Chinese outlet in Essex. The pills were labelled as containing glibenclamide, a prescription only medicine (POM) which can lead to a life threatening drop in blood sugar levels. Glibenclamide is an antihyperglycaemic drug which can be prescribed by qualified doctors to lower blood glucose levels in the management of diabetes. Improper use could result in coma and death. The Agency is looking into the possible illegal supply of the drug. The New Zealand Health Ministry has also identified the presence of glibenclamide in a traditional Chinese medicine called Xiaoke-wan.

  41. CARD 5 This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental XX 60kg 70 years • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX? • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED? • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs? • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic) • ARE THERE ANY POSSIBLE GENETIC FACTORS? • WHAT WOULD YOU DO FOR THE PATIENT? Infliximab (Remicade) Rheumatoid arthritis IV infusion 3mg/kg x 7 doses Sept 2001 April 2002 Weight loss, fever of unknown origin April 2002 Continuing Prednisolone 5mg May 1999 Continuing Rheumatoid arthritis Fever of 38.5, often at night, dry cough. Weight loss 4Kg. Tuberculin skin test negative in April 2000 This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. April 2002

  42. Increase COX2, PGE2, NO, Adhesion molecules, IL6, chemokines, collagenases and procoagulant activity ETANERCEPT INFLIXIMAB ADALIMUMAB ANAKINRA IL-1 TNF- Increases TNF-, osteoclast activation and angiogenic factors Increases IL-1 and cell death

  43. Tuberculosis Associated with Blocking Agents Against Tumor Necrosis Factor-Alpha (California, 2002 - 2003) Morbidity and Mortality Weekly Report (MMWR) 2004; 53: 683-686 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5330a4.htm

  44. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report • Interoggated BIOBADASER, launched in February 2000 by Spanish Society of Rheumatology • Estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001 • After official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case registered Gomez-Reino et al.Arthritis Rheum. 2003;48:2122-7.

  45. INFLIXIMAB AND TUBERCULOSIS • Patients should be evaluated for tuberculosis before treatment. • Active tuberculosis should be treated with standard treatment for at least 2 months before starting infliximab • Patients who have previously received adequate treatment for tuberculosis can start infliximab but should be monitored every 3 months for possible recurrence • In patients without active tuberculosis but who were previously not treated adequately, chemoprophylaxis should ideally be completed before starting infliximab • Patients should be advised to seek medical attention if symptoms suggestive of tuberculosis (e.g. persistent cough, weight loss, and fever) develop http://www.bnf.org/bnf/

  46. CARD 6 This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental T de P 80 y • HOW WOULD YOU EXPLAIN THE SYMPTOM/SIGN COMPLEX? • COULD THEY BE RELATED TO ANY OF THE MEDICINES LISTED? • IF SO, ARE THEY LIKELY TO BE TYPE A OR TYPE B ADRs? • IF SO, WHAT IS THE LIKELY MECHANISM (Pharmaceutical, pharmacokinetic or pharmacodynamic) • ARE THERE ANY POSSIBLE GENETIC FACTORS? • WHAT WOULD YOU DO FOR THE PATIENT? Thioridazine (Melleril) Oral 100 mg/day July 2001 Cont. Agitation Palpitations and syncope 13/12/2001 Amoxycillin (Amoxil) Oral 500 mg/day 7/12/01 15/12/01 URTI This yellow card is of a fictitious case and is for teaching purposes only. Any similarity it may have to any actual report is purely co-incidental. Rhythm strip from patient (attached)

  47. ANTIPSYCHOTICS AND SUDDEN DEATH TORSADES DE POINTES • Sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations • There are still only 10-15 such events in 10,000 person-years of observation

  48. TORSADES DE POINTES Torsades de Points Torsardes de Points Torsardes de Pointes Torsades des Pointes Torsades des Points Torsardes des Pontes Torsade de Pointes Torsades de Point Torsaad de Ponts Torsades des Point