Adverse Drug Reactions

by
Dr. Ahmed Shaker Ali ( draft version )
 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
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 ‫قظة‬--‫ ي‬,‫ذر‬-‫س ح‬
, -‫حترا‬-‫ا‬
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 Many drugs has been withdrawn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• introduced in 1973 ; withdrawn in 1997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• Introduced in 1990s, withdrawn in 2001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
• 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• Introduced in 1999, withdrawn in 2004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 interaction
6. Drug food or herbal medicine interaction
7. Self-medication
8. 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

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 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

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 √√√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:

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 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
Bizzare = strange
 No simple dose-response
relationship:
 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
Idiosyncratic reactions:
1I-
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
oMore examples
•Acute porphyria
•Malignant hyperthermia
•More examples

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Type B

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 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 isoniazid
e) 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

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Chronic effects due to immunosuppressant

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 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:

Phenytoin causes
Valproate causes cleft palate & hare-lip
spina-bifida

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 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

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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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 Factors Affecting Drug
response and adverse drug
reaction
 Human Variability
• Differences in age, weight, genetics, and
gender are factors that influence the
differences in response to medication
among people.
 Age
• Infants and Neonates
– Drug distribution is different in a neonate and
infants ( high % of water ) , affect which
drugs ??

– Lower activity of Phase 1 metabolism.

Reduced renal function (GFR) They do not
eliminate drugs as efficiently as adults. What
you expect about half life
 Age
• Children
– Children metabolize certain drugs more
rapidly than adults.
– Metabolism rates increases between 1 year
and 12 years (depends on age and drug).
– After age 12 metabolism rates decline with
age to a normal adult level.
 Age
• The elderly
– Many Elderly use multiple drugs due to
chronic illness and multiple disease.
– In addition pathological change ( body
composition, renal function, possibly liver
function, predisposed for ADE for certain
drugs )
 Gender
• many studies have been completed and show that
men and women do show differences in absorption,
distribution, metabolism, and excretion (ADME).
• Gender based differences in drug response appear
to be related to hormonal fluctuations.
• Gender differences may also be due to differences
in body composition.
 Genetics
• The field of study, pharmacogenetics,
defines the hereditary basis of individual
differences in absorption, distribution,
metabolism, and excretion (ADME)
processes.
• The largest contributing factor to variability
is metabolism.
 Body Weight

• Weight is a factor in determining drug

dosage for infants, children, or obese
patients.
• Some drugs we will use equations to
estimate LBW ( lean body weight )
 Psychological Factors
• Psychological factors can influence
individual responses to drugs.
• When placebo drugs are given patients
receiving them can report therapeutic and
adverse effects.
• Another factor can be patient’s willingness
to follow prescribed dosage regimens.
 Drug – Drug Interactions
• Taking more than one drug at a time can
cause a drug-drug interaction.
• Drug – drug interactions can affect the
disposition (all processes of the ADME) of
any drug.
• Therapeutic effects and side effects can
be decreased or increased when more
than one drug is taken.
 Drug – Drug Interactions
• See examples of drug-drug interactions on page 256-257

• Common drug-drug interactions

– Additive effects – when two drugs effects
equal to the sum of the individual effects
– Synergism – two drugs produce greater
effect than the sum of the individual effects
– Potentiation – one drug increases the activity
of another drug
– Antidote – a drug given to block or reduce
toxic effects
 Drug – Drug Interactions
– Absorption – decreased intestinal absorption of oral
drugs occurs when drugs complex to produce
nonabsorbable compounds
– Displacement – a drug bound to a plasma protein is
removed when another drug of greater binding
potential binds to the same protein.
– Inhibition – one drug with the elimination of a second
drug may intensify the effects of the second drug
– Induction – a drug causes more metabolic enzymes
to be produced, increasing metabolic activity
– Urinary excretion – some drugs are altered by
raising urinary pH and decrease renal absorption
 Disease States
– The disposition (ADME process) and effect of some
drugs can be influenced by diseases other than the
one that the drug is intended for.
– Hepatic
– Cirrhosis and obstructive jaundice decrease hepatic
metabolism and will diminish drug elimination
– Viral hepatitis little change in disposition
– Circulatory
– Changes in blood flow can influence ADME and
therefore will have the potential to alter the effect of the
drug
 Disease States
– Renal
– Reduced renal function can effect the elimination of
many drugs and affect the plasma protein binding of
drugs
– Thyroid
– Changes in thyroid function can effect many aspects of
absorption excretion and metabolism
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

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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