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Adverse Drug Reactions Objectives To make health professionals and public more aware of adverse drug reactions. To explore the importance of monitoring and reporting ADRs. 2 Topics • Introduction & definitions of adverse drug reactions (ADR ) • Most common reasons of ADR • Prevention & Risk factors for ADR • General Classification of ADR • Examples of ADRs • Conclusion • Resources 3 Introduction The safety of medicines is an essential part of patient safety. √Definition ( WHO) of Adverse drug reaction (ADR) : Any noxious*, unintended, undesired effect of a drug . which occurs at doses used for prophylaxis, diagnosis, or therapy. pharmacovigilance : Preventing and detecting adverse effects from medicines يقظة, حذر,احتراس 4 Many drugs has been withdrawn • Fenfluramine anti-obesity medication • introduced in 1973 ; withdrawn in 1997 • Why ? reports of heart valve disease, and pulmonary hypertension, including a condition known as cardiac fibrosis. • cerivastatin. Treatment of hypelipdeimeia • Introduced in 1990s, withdrawn in 2001 • Why ? , 52 deaths were reported from rhabdomyolysis and its resultant renal failure • The story of thalidomide is will known 5 • Rofecoxib {Vioxx } • (NSAID) approved for tttt of osteoarthritis, acute pain conditions, and dysmenorrhoea. • Introduced in 1999, withdrawn in 2004 • Why ? because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. • More and more are left for you to explore ??? 6 Serious ADR ? The American FDA defines a serious adverse event as that which can cause one or more of the following : • • • • • • Death Life-Threatening event. Hospitalization Disability -. Congenital Anomaly Requires Intervention to Prevent Permanent Impairment or Damage 7 Some common causes of ADR√√ 1. Wrong diagnosis; 2. In appropriate dosage regimen:. 3. Poor assessment of the patients . 4. Non compliance 5. 6. 7. 8. Drug -drug interaction Drug food or herbal medicine interaction Self-medication counterfeit medicines : 9. expired medication 8 Risk factors for ADR • Drug-related factors – – – – Nature of the drug Degree of exposure (dose, duration, frequency) Route of administration Cross-sensitization • Host-related factors – Age : (elderly & neonates) – Sex : ( pregnancy ) – Genetic factors (HLA type, Acetylator status) – Concurrent medical illness (e.g. viral infection, bronchial asthma ) – Previous drug reaction – Multiple allergy syndrome 9 Host realted factors e.g Viral infections Ceratin veial infections make the patiants more predisposed for ADR examples are : • Acute EBV infections: make the patients predisposed for maculopapular exanthem with aminopenicillins • HIV infections: – Sulfonamides: MPE, SJS/TEN, DRESS – SJS/TEN to various drugs is 500 fold more frequent – Nevirapine and abacavir: frequent side effects 10 Host related factors • • • • • Renal impairment – failing excretion of drugs/active metabolites Liver disease – failing drug metabolism Some specific diseases – e.g Bronchial asthma Neonates – drug metabolizing systems are not fully developed History of allergies to some drugs – Health staff efforts to minimize ADR [1] Avoid inappropriate drugs in the context of clinical condition [2] Use right dose, route, frequency based on patient variables [3] Elicit medication history; consider untoward incidents [4] Elicit history of allergies [identify in patients with allergic diseases] [5] Rule out drug interactions [6] Adopt right technique: Eg slow iv injection of aminophylline [7] Carry out appropriate monitoring [Eg PT with warfarin; Li levels] 8) Monitor , occurred & report ADR 12 √√√Classification of Adverse effects of drugs Type A: Augmented pharmacologic effects ,Dose related , Type B: Bizarre effects, non-dose related, unpredictable Type C: Chronic effects : dose related & time-related Type D: Delayed effects , e.g., time –related Type E: End-of-use or withdrawal effects, Type F : Failure of therapy Type A effects (‘Augmented pharmacological actions’): Dose-related Related to a pharmacological effect Predictable. Very Common . Usually Low mortality Can be minimized by appropriate dosing Include toxicity & Side effects: 14 Type A effects (more details ’): A- Mediated by same receptors & same sites as for beneficial effects hypoglycemia caused by insulin (anti-diabetic) bleeding caused by warfarin (anti-coagulant) • hypnotic effect caused by H2 R antagonist : antihistaminics B-Mediated by same receptors but at different sites: e.g., prazosin controls hypertension via blocking α1 receptors in the peripheral blood vessels, but cause pupil constriction by action on α1 receptors in the radial muscle of iris C-Mediated by different types of receptors at different sites: e.g., propranolol relieves angina (β1 receptors in heart), but can cause bronchoconstriction ( β2 receptors in the bronchi) Type B: (‘Bizarre effects’): Uncommon , Not related to pharmacological action of the drug Unpredictable High mortality No simple dose-response relationship: Bizzare = strange Type B : more details • I. Allergic reactions: • Abnormal responses related to immune system • Type I: Immediate (anaphylactic reaction with penicillins) • Type II: Cytolytic reactions ( haemolysis with αmethyldopa) • Type III: Arthus reactions (serum sickness with streptokinase) • Type IV: Delayed allergic reaction (contact dermatitis with penicillins)* 17 Idiosyncratic adverse drug reactions Idiosyncratic reactions: May be related to genetic abnormality, e.g. oHemolysis by primaquine in G6PD deficiency oApnea caused by succinylcholine in patients with low plasma cholinestrase oIncreased peripheral neuritis in slow acetylators during isoniazid therapy 1I- oMore examples •Acute porphyria •Malignant hyperthermia •More examples 18 Type B 19 Type C: Chronic effect Dose-related and time-related Related to the cumulative dose Uncommon Typical example : Hypothalamic-pituitary-adrenal axis suppression by corticosteroids We may also include : • Some Drug induced diseases, (Iatrogenic diseases ) a) peptic ulcer caused by NSAIDs; b) c) d) e) Nephrotoxicity caused by ciclosporin , aminoglycosides Hepatoxicity caused by valproic acid Neurotoxicity caused by isoniazid Reproductive toxicity: decreased sperm count in male and an-ovulation in female caused by anti cancer drugs (alkylating agents) f) Drug Dependence & addiction ?? . chronic effects due to corticosteroids 21 Chronic effects due to immunosuppressant 22 Type D: Delayed effect Occurs or becomes apparent some time after the use of the drug ( even after several years ) • Uncommon ● • Typical example : , diethylstilbestrol increase incidence of vaginal carcinoma in offspring ● We may also consider the following as delayed drug effect : Carcinogenesis Teratogeneicity: Teratogeneicity: Valproate causes spina-bifida Phenytoin causes cleft palate & hare-lip 24 Type E: Ending of use or withdrawal effects • Occurs soon when a drug is stopped abruptly • Uncommon • Typical examples : – Opiate withdrawal syndrome – Myocardial ischaemia (-blocker withdrawal) – Acute adrenal insufficiency sudden stop of corticosteroid Failure of therapy • Unexpected failure of therapy • ● Dose-related particularly when used Often caused by drug interactions • Typical example : – failure of contraceptive pills due to concomitant use of strong enzyme inducer such as anticonvulsant drugs. • SDL : add more examples 26 Be also aware of ADR due to herbal medicine • OTC products & Herbal and traditional medicines also have safety problems allergic reactions, bronchospasm, dyspnoea, urticaria, angina due to Echinacea purpurea – Australian Adverse Drug Reaction Bulletin, v.18, No.1, 1999: 27 Reporting & monitoring ADR • Health professionals (physicians, pharmacists, nurses, dentists and others) are in the best position to report suspected ADRs as part of their daily patient care. • Health professionals should report ADRs even if they are doubtful about the precise relationship between the given medicine and reaction 28 Conclusion • ADR are common and can be dangerous • Many ADR can be predicated and avoided . • Special attention should be given to elderly, neonates , pregnant women those suffering from chronic disorders. • Self medication and OTC, polypharmacy , noncompliance increase the potential of incidence of ADR. • Risk factors include : drug related &patient related 29 More examples of ADR try to classify ?? • Abortion, miscarriage or uterine hemorrhage associated with misoprostol (Cytotec), • Addiction to many sedatives and analgesics such as diazepam, morphine, etc. • Birth defects associated with and Accutane. • Bleeding of the intestine associated with aspirin therapy • Deafness and kidney failure associated with gentamicin • Liver damage from paracetamol overdose • Melasma and thrombosis associated with use of estrogen-containing hormonal contraception such as the combined oral contraceptive pill 30 • Rhabdomyolysis associated with statins (anti-cholesterol drugs) • Seizures caused by withdrawal from benzodiazepine • Drowsiness or increase in appetite due to antihistamine use.. • Stroke or heart attack associated with sildenafil (Viagra) when used with nitroglycerine • Suicide, increased tendency associated to the use of fluoxetine and other SSRI antidepressants • Tardive dyskinesia associated with long-term use of metoclopramide and many antipsychotic 31 Where to find more information • http://www.smso.net/encyclolpedia : • • • • • • • Adverse_effects_of_drugs http://www.who.int Drug Safety Update – FDA: http://www.fda.gov/ EMEA: http://www.emea.europa.eu/ SIDC: http://www.sukl.sk http://www.liv.ac.uk/~druginfo/csm/adr%20presentation.htm : Clarifying Adverse Drug Events: A Clinician's Guide to Terminology, Documentation, and Reporting Jonathan R. Nebeker, MS, MD; Paul Barach, MD, MPH; and Matthew H. Samore, MD 18 May 2004 | Volume 140 Issue 10 | Pages 795-801