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
  reporting ADRs.

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.
• vDefinition ( 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 ??????, ???, ????

5
Many drugs has been withdrawn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• introduced in 1973 withdrawn in 1997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• Introduced in 1990s, withdrawn in 2001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

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• Introduced in 1999, withdrawn in 2004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 ADRvv

1. Wrong diagnosis
2. In appropriate dosage regimen.
3. Poor assessment of the patients .
4. Non compliance
5. Drug -drug interaction
6. Drug food or herbal medicine interaction
7. Self-medication
8. counterfeit medicines
9. 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
vvvClassification 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 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 a1 receptors in the peripheral blood
  vessels, but cause pupil constriction by action
  on a1 receptors in the radial muscle of iris
• C-Mediated by different types of receptors at
  different sites
• e.g., propranolol relieves angina (ß1 receptors
  in heart), but can cause bronchoconstriction ( ß2
  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
  a-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, angina due 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 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

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/adr20presentat
  ion.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