Adverse

Drug Reaction

Dr Elsa Haniffah Mejia Mohamed

Dr Nur Lisa Zaharan
Pharmacology Department
“Cured yesterday of my disease. I died last night of my
physician”
 What will be covered:

Definition of ADR

Risk factors for ADR

Classification of ADR

Strategies to minimise ADR

Is natural safer?
Adverse Drug
Reactions: Definition

An appreciably harmful or
unpleasant reaction resulting
from an intervention related to
the use of a medicinal product;
adverse effects usually predict
hazard from future administration
and warrant prevention, or
specific treatment, or alteration
of the dosage regimen, or
withdrawal of the product
 The Reports and Findings………..
A meta-analysis of 39 studies found an in-hospital incidence of ADRs of
6.7%, and an incidence of fatal ADRs of 0.3%
This makes fatal ADRs amongst the top six leading causes of death

Almost one in ten children in hospital will experience an ADR, 12% of

which are serious
30% to 60% are preventable

80 -90% of total drug usage is issued by GPs. ADRs in GPs?

90% of ADRs caused by digitalis, antimicrobials, insulin and diuretics

Reference: Lazarou j, Pomeranz BH, Corey PN., JAMA, 1998; 279: 1200-5
Clavenna A, Bonati M. Arch Dis Child. 2009 Sep; 94(9):724-8. 4
“Poison is in everything, and no thing is without
poison. The dosage makes it a poison or a
remedy” - Parecelcus
Risk factors for ADR
• Patient factor
Age, genetic factors,
physiological conditions,
allergies, comorbidities
• Drug factor
Drug-drug interaction,
synergistic effects
Patient
factor
 Age: Very young

Infants and very young children:

capacity to metabolize the drug is not
fully developed
• Neonates have immature renal tubular function
when they are below the age of 8 weeks, avoiding
digoxin, aminoglycosides, ACE inhibitors, NSAIDs is
a must
• Physiologic hypoalbuminemia in neonates affects
drug dosing. Caution is recommended when
dealing with high protein binding drugs such as
NSAIDs
• Increased anesthetic effects due to immature
blood brain barrier at < 8 weeks of age
Age: Elderly
Multiple health problems leading to polypharmacy

Reduced liver function with age

Changes in body composition- decreased body water and relative increase of fat tissue

• drugs that dissolve in water reach higher concentrations

• drugs that dissolve in fat accumulate more

Reduced kidney function with age

• Type A reactions were more common among elderly adults (85.9%) and type B reactions were more common in
adults (35%) compared to other age groups

Because of all age-related changes, many drugs tend to stay in an older person’s body much
longer than they would in a younger person’s body, prolonging the drug’s effect and increasing
the risk of side effects
Gender

Physical & physiological differences

• Women have lower bodyweight and organ size, more body fat, different gastric
motility and lower glomerular filtration rate  PK differences

Slower renal clearance in women

• Digoxin, may require a dosage adjustment; prone for adverse effect

Hepatic drug reactions

• More common in females. It was estimated that the female gender is a risk
factor for hepatotoxicity more than men

PD dffferences
• Women: greater sensitivity to and enhanced effectiveness of beta blockers,
opioids, selective serotonin reuptake inhibitors, and typical antipsychotics.
• More prone to adverse effects
Physiological states: Pregnancy,
breastfeeding

Changes in pregnancy causes changes in PK & PD

• Increase in blood volume: decreases plasma concentration
of some drugs
• Increased renal blood flow & GFR  increased excretion of
some drugs

Teratogenic effect
• Especially during organogenesis, eg ACE inhibitors, ARBs
(birth defect)
• For drugs taken during the second and third trimesters,
ADRs are usually manifested in the neonate (birth to 1
month) or infant (1 month to 1 year) as growth
retardation, respiratory problems, infection, or bleeding
 Genetics
Drug/drug class Pharmacogenetic Additional susceptibility Example of clinical context
marker factors
Carbamazepine HLA B*15:02 (in the Han-Chinese, Thai and Marker for carbamazepine-induced Stevens-Johnson
populations listed) Malaysian populations syndrome and toxic epidermal necrolysis

Simvastatin SLCO1B1 (solute Advanced age, untreated Statin-induced rhabdomyolysis (rare) whose risk is four
carrier organic anion hypothyroidism, excess times greater with single defective allele, 16 times
transporter 1B1) physical activity, concomitant greater with two defective alleles
medications (eg fibrates)

Abacavir HLA-B*57:01 Higher CD8 cell count at start Marker for abacavir-induced hypersensitivity reactions
of therapy with fever, rash, lethargy and abdominal and acute
respiratory symptoms

Thiopurines TPMT activity N/A 1 in 10 individuals are heterozygous (50% normal TPMT

(Azathioprine activity) and 1 in 300 have completely deficient activity.
mercaptopurine) Thiopurine-induced myelosuppression is associated with
TPMT activity.
Allergy

Drug independent cross-reactive antigens can induce

sensitizations, manifest as drug allergy
• After primary sensitization to a causative drug, a second exposure causes
affected T cells and antibodies to enter the elicitation phase,
corresponding to the type I to IV immune reactions
Allergy to penicillin is the most commonly reported medication
allergy
• IgE mediated: immediate (within minutes)
• Flushing, urticarial, angioedema, laryngeal oedema, GI symptoms, hypotension
• Due to B-lactam or R-side chain UpToDate 2016. Penicillin Allergy: Immediate Reactions
Comorbidities

Concomitant host disease may also influence

susceptibility to adverse reactions

Diseases may alter physical & physiological conditions

to affect PK & PD
• Eg: HIV disease increases the frequency of idiosyncratic toxicity with
anti-infective drugs such as co-trimoxazole
• Glutathione deficiency has been suggested by some to be responsible
Drug factor
Polypharmacy and ADR: Drug Interaction
The term lacks universal consistent definition but generally refers to – Multiple
medications (> 4-5 types) – Commonly in older patients (~40% with this issue)

Increasing number of drugs taken and risk of ADR (Goldberg et al, 1996)

• 2 drugs 13% risk

• 4 drugs 38% risk
• 7 > drugs 82% risk

May be seen more common in

• Old age, comorbidities, hospitalisation, number of doctors etc.

Managing polypharmacy

Always review the patient’s medications

Good doctor-patient relationship allows you to obtain more

information about drugs a patient is taking – those non-prescribed
ones

For polypharmacy, consider if all drugs are needed

The process (skill) of discontinuing some drugs: de-prescribing

ADR
classificatio
n
Type A

Type A (Augmented)
• Relatively common

Features
• Pharmacologically predictable
• Dose related
• Improves if medication is withdrawn

Example
• Hypoglycaemia with SU
• Bradycardia with β blockers, etc
Type B
Type B (Bizarre/Idiosyncratic)
• Less common
• important because they are often serious
and account for many deaths

Features
• Less predictable (usually)
• Occur in susceptible individuals (genetics)

Example
• Anaphylaxis to antibiotics, etc
• SJS, TENs with allopurinol, carbamazepine,
antibiotics
Type C

Type C (Chronic/Continuing)

Feature
• Reaction after long term use

Example
• Methotrexate  toxicity
• Bisphosphonate  osteonecrosis
• NSAIDS  nephropathy
Type D

Type D (Delayed)

Features
• Apparent after sometime using the drug.
Timing makes it difficult to be detect
• Mutagenesis/carcinogenesis after chronic
use

Example
• Teratogenesis after short term use at a
critical time
• E.g. Thalidomide
Type E

Type E (End of use)

Features
• Occurs when a drug is abruptly withdrawn

Example
Opiates withdrawal  withdrawal syndrome
Benzodiazepine withdrawal  insomnia,
anxiety, perceptual disturbance
Type F

…some also
include Type
F (Failure of
therapy)
ADR Reporting: Why report?
To detect unknown and unpredictable safety problems
that may surface only after a drug is in the market

Drug related problems such as ADRs may differ from

country to country due to:
• diseases and prescribing practices
• genetics
• diet
• traditions
• drug manufacturing process
• drug distribution
• use of traditional and complementary drugs
What should be reported?
An event or reaction that may
result in the following outcomes:
• Results in Death (cause of death
important)
• Life-threatening
• Requires/prolongs hospitalization
• Causes significant disability/incapacity
• Congenital anomaly
…and also these circumstances:
ADR for innovator ADR due to health
ADR in generics
products (labeled supplement
medicine
or unlabeled) administration

Adverse Events
ADR due ADR due
Following
traditional unregistered
Immunisation
medicine usage medicine
(AEFI)

Drug used in
Drug interaction
special population
Non-prescription medicines
Quality defects can also lead to ADRs e.g. Dioxin
contamination in Cod Liver Oil preparations resulting in
product withdrawals in UK (2006)

Patients can develop ADRs to food supplements, “health

products”

Overuse of supplements
How to minimize ADR
Necessary vs
Good prescribing Know the drug
unnecessary
behaviour / skills ADR profile
drug

Assess individual risk for patient:

predisposing factors, Comorbidity,
Advise patient of
concurrent drug use, drug history etc risk

If an ADR predictive test

Arrive at an agreed decision about
is available, make good
the prescription
use of it
Traditional & Complementary Medicine

Minimal information available on traditional medicines

• ADRs
• Drug interactions
• At risk groups e.g. alfalfa and exacerbation of SLE

Misnomer of “because it is natural, it is safe

• Association of Black Cohosh with liver problems

Health professionals should try to get as much information as possible

• Name of product
• Indication
• Place of purchase (esp for unregistered products)
ADR due to Adulterated Food Products
Adulterant in Malay Traditional Medicine
(Makjun/Tonik)
Adulterant in Traditional Chinese
Medicine: Dexamethasone
Popular adulterants

Antihistamine -
Erectile dysfunction
Corticosteroid - Chlorpheniramine, NSAIDs -
drugs - Sildenafil,
Dexamethasone dextromethorphan, Phenylbutazone
tadalafil dan analog
promethazine

Slimming Agents - Antidiabetic -

Analgesic - Sibutramine, N- Metformin,
Statin - Lovastatin
Paracetamol desmethylsibutramin Glibenclamide,
e Ripaglinide
Thank you!