Adverse Drug Reactions

1. Adverse Drug Reactions

2. Objectives • To make health professionals and public more aware of adverse drug reactions. • To explore the importance of monitoring and reportingADRs.

3. 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

4. . 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 احتراس, حذر, يقظة

5. Many drugs has been withdrawn • Fenfluramineanti-obesity medication • introduced in 1973 ; withdrawn in 1997 • Why ?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 Treatment of hypelipdeimeia • Introduced in 1990s, withdrawn in 2001 • Why ?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

6. 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 • Introduced in 1999, withdrawn in 2004 • Why ?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 ???

7. 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

8. Some common causes of ADR√√ • Wrong diagnosis; • In appropriate dosage regimen:. • Poor assessment of the patients . • Non compliance • Drug -drug interaction • Drug food or herbal medicine interaction • Self-medication • counterfeit medicines : • expired medication

9. 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

10. 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

11. 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 –

12. 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

13. √√√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

14. 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:

15. Type A effects(more details ’): A- Mediated by same receptors & same sitesas 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)

16. Type B: (‘Bizarre effects’): • Uncommon , • Not related to pharmacological action of the drug • Unpredictable • High mortality • No simple dose-response relationship: Bizzare = strange

17. 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 α-methyldopa) • Type III: Arthus reactions (serum sickness with streptokinase) • Type IV: Delayed allergic reaction (contact dermatitis with penicillins)*

18. Idiosyncratic adverse drug reactions • 1I- Idiosyncratic reactions: • May be related to genetic abnormality, e.g. • Hemolysis by primaquine in G6PD deficiency • Apnea caused by succinylcholine in patients with low plasma cholinestrase • Increased peripheral neuritis in slow acetylators during isoniazid therapy • More examples • Acute porphyria • Malignant hyperthermia • More examples

19. Type B

20. 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 ) • peptic ulcer caused by NSAIDs; • 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) • Drug Dependence & addiction ?? .

21. chronic effects due to corticosteroids

22. Chronic effects due to immunosuppressant

23. 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:

24. Teratogeneicity: • Phenytoin causes cleft palate & hare-lip • Valproate causes spina-bifida

25. 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

26. 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

27. Be also aware of ADR due to herbal medicine • OTC products & Herbal and traditional medicines also have safety problems allergic reactions, bronchospasm, dyspnoea, urticaria, anginadue to Echinacea purpurea – Australian Adverse Drug Reaction Bulletin, v.18, No.1, 1999:

28. 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

29. 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

30. More examples of ADR try to classify ?? • Abortion, miscarriage or uterinehemorrhage 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

31. 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

32. 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