Adverse Drug Reactions

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Objectives

To make health professionals and public more aware of adverse drug reactions.

To explore the importance of monitoring and reporting ADRs.

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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

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.

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 , حذر, احتراس يقظة

Introduction

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Many drugs has been withdrawn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• introduced in 1973 ; withdrawn in 1997• Why ?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• Introduced in 1990s, withdrawn in 2001• Why ?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

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• 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• Introduced in 1999, withdrawn in 2004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 ???

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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

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Some common causes of ADR√√

1. Wrong diagnosis; 2. In appropriate dosage regimen:. 3. Poor assessment of the patients . 4. Non compliance

5. Drug -drug interaction6. Drug food or herbal medicine interaction7. Self-medication8. counterfeit medicines : 9. expired medication

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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

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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

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 –

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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

√√√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

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Dose-related Related to a pharmacological effect Predictable. Very Common . Usually Low mortalityCan be minimized by appropriate dosing Include toxicity & Side effects:

Type A effects (‘Augmented pharmacological actions’):

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

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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)*

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Idiosyncratic adverse drug reactions

1I- Idiosyncratic reactions: May be related to genetic abnormality, e.g.

oHemolysis by primaquine in G6PD deficiencyoApnea caused by succinylcholine in patients with low plasma cholinestraseoIncreased peripheral neuritis in slow acetylators during isoniazid therapy

oMore examples •Acute porphyria•Malignant hyperthermia•More examples

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Type B

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) Nephrotoxicity caused by ciclosporin , aminoglycosides c) Hepatoxicity caused by valproic acid d) Neurotoxicity caused by isoniazide) Reproductive toxicity: decreased sperm count in male and an-ovulation in

female caused by anti cancer drugs (alkylating agents)f) Drug Dependence & addiction ?? .

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chronic effects due to corticosteroids

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Chronic effects due to immunosuppressant

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 :CarcinogenesisTeratogeneicity:

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Teratogeneicity:

Valproate causes spina-bifida

Phenytoin causes cleft palate & hare-lip

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

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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

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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:

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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

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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

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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

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• 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

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