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Somayyeh Nasiripour Pharm.D assistant professor at IUMS WHO definition: Any response to a drug which is Noxious and Unintended, and which occurs at doses used in men of prophylaxis, diagnosis or treatment. Adverse Event Diseases Genetics Diet Adverse Drug Reaction (event attributed to drug) Other factors All Spontaneous reports Other Drugs Compliance Events not attributed to drug Environment Preventable Medication Errors Not NotPreventable Preventable Inherent Drug InherentRisk Risk of Drug Adverse Drug Reactions Adverse Drug Events Potential Adverse Drug Events Trivial Medication Errors Adapted From: http://www.annals.org/cgi/content/full/142/1/77 4 The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. Vigilare = to watch alert watchfulness forbearance of sleep; wakefulness watchfulness in respect of danger; care; caution; circumspection the process of paying close and continuous attention 6 Adverse Drug Reactions are the 4th to 6th largest cause of mortality in the USA (Lazarou J. et al., 1998) 7 The percentage of hospital admissions due to drug related events in some countries is about or more than 10%. UK Study : 10.1 % (Bhalla et al, 2003) French study : 10.3 % prevalence of ADRs (Imbs et al, 1999) 8 Up to 40% patients in the community experience ADRs In the UK Non Steroidal Anti-Inflammatory Drug (NSAID) use alone accounts for1 65,000 emergency admissions/year 12,000 ulcer bleeding episodes/year 2,000 deaths/year 1Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291 In 1922, there was an enquiry into the JAUNDICE associated with the use of SALVARSAN, an organic arsenical used in the treatment of Syphillis. In 1961, it was reported in West Germany that there was an outbreak of PHOCOMELIA (hypoplastic and aplastic limb deformities) in the new born babies. It was shown subsequently that thalidomide, a non barbiturate hypnotic, was to blame. The crucial period of pregnancy during which thalidomide is TERATOGENIC is the first three months. History of drug safety after thalidomide disaster 1961 : Dr William McBride (Australia)( thalidomide 4000 cases) 1964 : UK started “yellow cards” system 1968 : start of WHO Programme for International Drug Monitoring Drug Year Adverse Reaction Sulfanilamide 1937 Liver damage due Solvent changed; to diethylene glycol FDA established Thalidomide 1961 Congenital Malformations Withdrawn Chloramphenicol 1966 Blood Dyscrasias Uses restricted Benoxaprofan 1982 Liver damage Withdrawn Aspirin 1986 Reye’s syndrome Uses restricted Flecainide 1989 Cardiac Arrhythmias Uses restricted Noscapine 1991 Gene toxicity Withdrawn Triazolam 1991 Psychiatric disorders Withdrawn Thursday, May 4, 2017 Outcome 12 drug year Adverse reaction Outcome Temafloxacin 1992 Various serious adverse effects Withdrawn Co-trimoxazole 1995 Serious allergic reactions Uses restricted Terfenadine 1997 Interactions (e.g. with grapefruit juice) Withdrawn from OTC sale Sotalol 1997 Cardiac arrhythmias Uses restricted Astemizole 1998 Interactions Withdrawn Cisapride 2000 Cardiac arrhythmias Withdrawn Cerivastatin 2001 Rhabdomylosis Withdrawn Thursday, May 4, 2017 ASHUTOSH MISHRA 13 Dose related adverse reactions have led to the concept of the THERAPEUTIC INDEX, or the TOXIC:THERAPEUTIC RATIO. This indicate the margin between the therapeutic dose and the toxic dose. The bigger the ratio, the better. Examples of drugs with a low TOXIC:THERPEUTIC RATIO: Anticoagulants (warfarin, heparin) Hypoglycemic drugs (insulin, sulfonylurea) Antiarrythmic drugs (lidocaine, amiodarone) ASHUTOSH Thursday, May 4, 2017 MISHRA 14 Most common adverse reactions are detected in premarketing clinical trials (reported in prescribing information) However, most clinical trials are of short duration, and patient numbers in trials are low compared to population Latent ADRs often missed 3000 patients at risk needed to detect with an incidence rate of 1/1000 with 95% certainty Most trials also exclude the very young and old, pregnant women, patients with multiple diseases, and any potentially interacting medications Additional ADRs are discovered once a drug enters the marketplace References: Ahmad S.R., J Gen Intern Med, 2003; 18:57-60 www.cc.nih.gov/researchers/training/ppt/calis_slides_2002-2003.ppt 15 Nonimmunologic Predictable Pharmacologic side effect Dry mouth from antihistamines Secondary pharmacologic side effect Drug toxicity Thrush while taking antibiotics Hepatotoxicity from methotrexate Drug-drug interactions Seizure from theophylline while taking erythromycin Drug overdose Seizure from excessive lidocaine (Xylocaine) Unpredictable Pseudoallergic Anaphylactoid reaction after radiocontrast media Idiosyncratic Hemolytic anemia in a patient with G6PD deficiency after primaquine therapy Tinnitus after a single, small dose of aspirin Intolerance G6PD = glucose-6-phosphate dehydrogenase. Adapted From: http://www.aafp.org/afp/20031101/1781.html 16 Type I reaction (IgE-mediated) Anaphylaxis from b-lactam antibiotic Type II reaction (cytotoxic) Hemolytic anemia from penicillin Type III reaction (immune complex) Serum sickness from anti-thymocyte globulin Type IV reaction (delayed, cell-mediated) Contact dermatitis from topical antihistamine Specific T-cell activation Morbilliform rash from sulfonamides Fas/Fas ligand-induced apoptosis Stevens-Johnson syndrome Toxic epidermal necrolysis Other Drug-induced, lupus-like syndrome Anticonvulsant hypersensitivity syndrome Adapted From: http://www.aafp.org/afp/20031101/1781.html 17 Adapted From: http://www.vh.org/adult/provider/pharmacyservices/PTNews/2003/may.html 18 Central Nervous System Hematologic Cardiovascular Renal/Genitourinary Sensory Dermatologic Neuropathy Auditory especially visible lesions or eruptions Gastrointestinal Metabolic 19 Used with permission from Carl Allen, DDS and eMedicine.com, Inc., 2005 20 Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005 21 The total cost of drug-related morbidity and mortality exceeds the cost of the medications themselves. Ref: Ernst Frank R, Grizzle Amy J. J Am Pharm Assoc. 2001; 41: 192-9 ثبت عوارض جدید: Unepected ADR تداخالت وابستگی Long term efficacy Risk factor کیفیت فراورده تشخیص سریع تر واکنش های ناخواسته Increase frequency رده بارداری و شیردهی “yellow cards” جمعیت بزرگی را در بر می گیرد مشاهده ای و هزینه ای ندارد عوارض ناخواسته ثبت میشود Only 2-4% of all ADRs are reported Only 10% of serious ADRs are reported Never assume that someone else will report! -1عدم اطالع از مكانیزم موجود براي ارسال گزارش -2عدم دسترسي به فرم مربوطه -3عدم اهميت عارضه از نظر گزارشگر -4نداشتن وقت در رابطه با فرم مربوطه -5اجتناب از درگيري در كارهاي اداري -6ترس از شكايات حقوقي ,كيفري توسط داروADR -7عدم اطمينان از بوجود آمدن NO The Yellow Card Scheme collects SUSPICIONS A reaction that: is fatal is life threatening is disabling results in hospitalisation prolongs hospitalisation Is teratogen Four critical pieces of information are needed: . Patient details 2 . Suspect drug 3 . Suspect reaction 4 . Reporter details 1 “All health-care professionals have a responsibility to inform colleagues about clinically important adverse drug reactions that they detect, even if a wellrecognised or causal link is uncertain.” Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255-59 If you suspect an ADR.. Patients who: are young, or old or female are taking multiple therapies 50% of patients on 5 drugs or more have more than one medical problem have a history of allergy or a previous reaction to drugs A symptom that appears soon after a new drug is started appears after a dosage increase disappears when the drug is stopped reappears when a drug is restarted Listen to the patient! Does the patient have a history of other drug-induced problems? ask the patient Does the patient take more than one drug ? could an interaction be causing the ADR? long term medication is unlikely to 30-50% are preventable Obvious interactions – many drugs interact with warfarin Use of contra-indicated drugs – use of a non-selective beta-blocker in an asthmatic bronchospasm Drug use in an inappropriate clinical indication or medically unnecessary – antibiotics for a viral infection antibiotics for viral infections Iranian ADR Monitoring Center مركز ثبت و بررسي عوارض ناخواسته داروها معاونت غذا و دارو وزارت بهداشت ،درمان و آموزش پزشكي تاریخ تدوین :فروردین 1384 Diclofenac Na ( VOLTAREN ) 176 cases of Foot drop and walking difficulty (1377-1381) 2 New cases (1385) 4 Cases of Para-plegia following IT injection 2 of them led to Death 1380-درود 5 cases of death 1382 آبان ماه Stevens Johnson Syndrome 5 years old child 1382 آذر ماه-تهران 2 cases of Cardiac Arrest 1382 بهمن ماه-تهران One case of Cardiac Arrest 1383 -تهران Anaphylactoid reactions 1383 دی ماه 250مورد پریتونیت شیمیایی اردیبهشت 1385 Many cases of Flushing and Red Neck Syndrome following rapid infusion of Vancomycin شناسايی و ارسال گزارش موارد افزايش فراوانی در عوارض و/يا عدم اثربخشی جهت بررسی فرآورده در موارد زير: -فنوباربيتال -وانکومايسين -فنی توئين واکسن MMR -هپارين هيدروکورتيزون کاسپين تامين و داروپخش اکسی توسين سيناوکس -سيکلوسپورين محلول پوويدون آيداين شيرخشک يارا نه ای کنتراسپتيوهای خوراکی -سفترياکسون تهران 1522 زنجان 15 لرستان 10 . Pharmacokinetic Pharmacodynamic Both Chemical Absorption(ciprofloxacin/antacids) Distribution(sulfa drugs/warfarin) Metabolism(erythromycin/terfenadine) Excretion(smx-tmp,NSAIDs/MTX) Anticholinergic,opioids,food (Cmax/AUC) Prokinetic agents C OCPs Divalent-trivalent cations PH t 1A2 2C9,2C19 2D6 3A4 TCA(tert.amines) Clozapine Theophylline Propranolol Tacrin Caffeine Halopridol Phenothiazines … 2C19: TCA(tert.amines) Citalopram Barbiturates Propranolol Omeprazol 2C9: bupropion Phenytoin Tolbutamide (S)-Warfarin NSAIDs TCA(second. amines) Fluoxetine Paroxetine Venlafaxine Nefazodone(mcpp met.) amphetamines Risperidone Codeine Hydrocodone Dextrometorphan Chlorpheniramine Propranolol metoprolol TCA(tert.amines) Fluoxetine Sertraline Venlafaxine Nefazodone Carbamazepine Quetiapine,pimozide Triazolobenzodiazepine Zolpidem Protease inhibitors Astemizole,Terfenadine Cisapride Macrolides Calcium channel blockers Sex hormones(estrogen) Corticosteroids Lovastatin Cyclosporine,Tacrolimus Sildenafil,tadalafil,vardenafil MTX/Sulfonamides,Trimethoprim,NSAIDs Probenecid Potassium/trimethoprim Li/Diuretics Inhibitor of 3A4 Digoxin ? TCA(tert.amines) Fluoxetine Sertraline Venlafaxine Nefazodone Carbamazepine Quetiapine,pimozide Buspirone Triazolobenzodiazepine Zolpidem Protease inhibitors Astemizole,Terfenadine Cisapride Macrolides Calcium channel blockers Sex hormones(estrogen) Corticosteroids Lovastatin Cyclosporine,Tacrolimus Sildenafil,tadalafil,vardenafil MAOI effect (reversible) MAO Cations(…90%) NSAIDS(fenbufen,naproxen…) Azlocillin/cipro Cyclosporine,cimetidine Seizure threshold(/foscarnet) Cipro,enoxacin,norfloxacin…inhibitor of 1A2 TCA(tert.amines) Clozapine Theophylline Propranolol Tacrin Caffeine Halopridol Phenothiazines … Warfarin(2C9 inhibition?) MTX Cyclosporine Azathiprione (leukopenia) Cimetidine transient reversible deafness. Ergot amputation Inhibition of 1A2, 3A4 TCA(tert.amines) Clozapine Theophylline Propranolol Tacrin Caffeine Halopridol Phenothiazines … TCA(tert.amines) Fluoxetine Sertraline Venlafaxine Nefazodone Carbamazepine Quetiapine,pimozide Buspirone Triazolobenzodiazepine Zolpidem Protease inhibitors Astemizole,Terfenadine Cisapride Macrolides Calcium channel blockers Sex hormones(estrogen) Corticosteroids Lovastatin Cyclosporine,Tacrolimu s Clarithromycin,fluconazol,itraconazol, protease inhibitor/rifampin Inducer of 1A2,2C ,3A4 Alcohol(disulfiram-like effect) 5FU warfarin Alcohol(disulfiram…) MAOI(weak) Amitriptyline(psychosis) PH Ket.,Food / Itra.,Food Rifampin(ket.,itra.),phenytoin, Carbamazepine Fluconazol inhibition of 2C9 Ket.,Itra. Inhibition of 3A4 Antihypertensives Warfarin…. effectiveness Digoxin …. level up to 75% Phenelzine,Haloperidol…. side effects Morphine….block analgesic effects Digoxin….Toxicity Warfarin…..effects Digoxin…. level up to 25% SSRIs…. Side effects Theophylline…. level up to 50% Inhibitor of 3A4 Thanks for your attention Hand book of Drug Informations (Apha), 2009