Dr Md Shamshir Alam,

Assistant Professor
Department of Pharmacy
Practice
College of Pharmacy
National University of Science &
Technology, Muscat
 Adverse drug event (ADE)

• Any untoward medical occurrence that may

present during treatment with a medicine, but
which does not necessarily have a causal
relationship with the treatment.
 ADVERSE DRUG REACTION ADR

• Unintended and noxious (harmful)

Loading…
response that occurs at normal doses of
the drug used for prophylaxis, diagnosis
and treatment of diseases.
• All ADRs are ADE but not all ADEs are
ADRs.
 Side effect
• Any effect caused by drug other than the intended
therapeutic effect whether beneficial, neutral or harmful is
called side effect.
• Unwanted & unavoidable PD effects at therapeutic
doses. of
All
immunity
del
atient
Secondary effect -
The
• Indirect consequences of a primary action of a drug.
• Examples: suppression of bacterial flora by
tetracyclines leads to superinfections.
• Corticosteroids weaken host defence mechanisms so
that latent TB gets activated.
 Serious ADR
• An ADR that-
• results in death
- -
-

• is life threatening
•
Loading…
requires inpatient hospitalization or prolonged
hospitalization
• results in persistent or significant disability
• results in congenital anomaly/birth defect
 of
reported (4thaction
ThatType not
- reaction
drug
information
Unexpected ADR in

• An adverse reaction, the nature or severity of which is

not consistent with the applicable product information.

Intolerance
• It is the appearance of characteristic toxic effects
of a drug in an individual at therapeutic doses.
• Indicates low threshold of the individual to the
action of the drug.
• Eg. Chloroquine (vomiting & abdominal pain),
triflupromazine (muscular dystonias),
carbamazepine (ataxia).
 MANIFESTATIONS OF ADRs

• GIT – nausea, vomiting, constipation, diarrhea, gastric mucosal

erosion & ulceration with bleeding.

• HEMATOPOIETIC – bone marrow depression.

• ORGAN TOXICITIES – hepatotoxicity, nephrotoxicity, cardiac

toxicity, ototoxicity, ocular toxicity, CNS toxicity, endocrine &
infertility, dermatological toxicity.

• OTHERS – mask taste & smell.

 TYPES OF ADR
Dose-Dependent
>
-
• Type A (augmented/predictable)
--
> ex
-
: Insuline
produce hypoglusemia

• Type B (bizarre/non-predictable)
°
> ex :
- pensilline produce
hypersenvity
↳ Dose-Independent
• Type C (chronic use)
• Type D (delayed effect)
• Type E (end of use/abrupt withdrawal)
-

• Type F (Failure of treatment)

• Others
 TYPES A (Augmented)

• Usually exacerbation of the pharmacological effects

of a drug.
• Dose dependent.
• Predictable due to known of pharmacology of a
drug
• Preventable
• Incidence of type A is high however, less severe so
associated with less morbidity and mortality.
• Eg: Insulin induced hypoglycaemia, hypotension
caused by antihypertensives, dehydration caused by
diuretics.
 TYPES B (Bizzare)
• Usually hypersensitivity reactions.
• Not dose dependent.
• Drug allergy / allergic reactions.
• Idiosyncratic reactions (pharmacogenomics).
• Often not predictable and not preventable (unless
present with a known past history).
• Incidence of type ABis low however, more severe
so associated with high morbidity and high
mortality.
• Eg: Penicillin induced hypersensitivity reactions.
 TYPE C (Chronic/Continuous)

• Occurs after prolonged exposure to a drug.

• Exact mechanism is unknown.
Loading…
• Eg: Higher frequency of cardiovascular events
among patients exposed to the>COX-2 inhibitor
rofecoxib, osteoporosis caused by corticosteroids.
 TYPES D (Delayed)

• Delayed until long after drug exposure, making

diagnosis difficult.
• Eg: Malignancies that occurs after
immunosuppressive treatment post
transplantation.
• Vaginal cancer occurring many years after
exposure to diethylstilbestrol.
TYPES E (End of treatment)

• Occurring after abrupt drug withdrawal.

• Eg: Alcohol withdrawal– Anxiety, Panic,
delusions, visual and auditory hallucinations.
• Rebound hypertension–clonidine.
• Worsening of angina pectoris beta
blockers.
• Acute adrenal insufficiency
corticosteroids.
• Seizures- antiepileptics.
 TYPE F (Failure of treatment)

• Common to all
• Often caused by drug interactions
Type A Type B Type C Type D Type E Others

Side effects Allergic Drug Teratogenicity Withdrawal Iatrogenic

reactions dependence reactions

Secondary Idiosyncras Cumulative Mutagenicity Photosensiti

effects y toxicity ve reactions

Toxic effects Organ damage Carcinogenicit Masking of

y diseases

Poisoning Immuno Exacerbatio

suppression n of disease

Intolerance
 DIFFERENCE BETWEEN TYPE A ⑤ x33
⑤
⑮

&
TypeB ADRs
A (augmented) Type B (bizarre)
• Due to extension of • Immunological/ genetic basis
pharmacological action

• Predictable • Mostly not predictable

• Quantitative (dose dependent) • Qualitative (dose independent)

• High incidence but low mortality • Low incidence but high mortality

• Dose reduction is needed • Drugs has to be discontinued

• Examples: dryness of mouth & • Anaphylactic reaction due to

blurring of vision due to penicillin G; hemolysis with
atropine; hypoglycemia with primaquine
glibenclamide
 OTHERS

PHOTOSENSITIVITY
• Cutaneous reaction resulting from drug
induced
sensitization of the skin to UV radiation
• Phototoxic (tetracyclines, nalidixic acid,
fluoroquinolones) - short wavelengths(290-
320nm)– shorter duration after exposure ends.
• Photoallergic (sulfonamides, sulfonylureas,
chloroquine) – longer wavelengths (320-400nm)–
persist long after exposure– lesion extend beyond
exposed areas.
 FACTORS PREDISPOSING TO ADR

Age
• Elderly and paediatric patients are more vulnerable
to ADRs.
• Elderly patient are more susceptible due to
physiological changes.
• Eg: Nitrates and ACEI induced postural
hypotension in an elderly patient, grey baby
syndrome with chloramphenicol in children.
 Gender
• Women are reported to be more susceptible to
ADRs than men.
• Eg: Chloramphenicol induced aplastic anemia and
phenylbutazone induced agranulocytosis are twice
and thrice as common in women as compared to
men.

Race and genetic factors

• More prone to ADRs in genetically predisposed
individuals.
• Eg: Patients G6PD deficiency are at higher risk of
developing haemolysis due to primaquine.
 Polypharmacy
• Multiple drug therapy – more prone to develop
ADR.
• Either due to interaction mechanism or by
synergistic effect.

Multiple and inter-current diseases

• Multiple diseases are at increased risk of
developing an ADR.
• Patient with renal and hepatic diseases are also at
high risk.
• Eg: Patient with decreased renal function treated
with normal dose of aminoglycosides is at risk of
developing nephrotoxicity until dose adjustment.
 Drug characteristics
• Some drugs are toxic in nature and patients treated
with those agents are at increased risk of ADRs.
• Eg: Nausea and vomiting with cytotoxic anticancer
drugs.
• Patients treated with narrow therapeutic index
drugs are more at risks of ADRs.
 Managing ADRs
Step 1. Evaluate the nature of the event.
●Obtain a detailed history of the patient.
●Identify and document the clinical reaction. Look up
suspected medicines and known ADRs in the literature
and match them with the reactions described by the
patient
●Classify the severity of the reaction.
● Severe—fatal or life threatening
● Moderate—requires antidote, medical procedure, or hospitalization
● Mild—symptoms require discontinuation of therapy
● Incidental—mild symptoms; patient can chose whether to discontinue
treatment or not
Step 2. Establish the cause.
● Use the Naranjo algorithm (or other system) to assess the
patient’s reaction.

● Evaluate the quality of the medicine.

● Check for a medication error.

Step 3. Take corrective and follow-up action.
Corrective action will depend on cause and severity
●Severe ADRs
● Educate and monitor prescribers.
● Change the formulary or standard treatment guideline if necessary to
substitute a medicine that is safer or that is easier to use by staff.
● Modify patient monitoring procedures.
● Notify drug regulatory authorities and manufacturers.

●All ADRs
● Educate and warn patients.
 PREVENTION OF ADVERSE
EFFECTS

• Avoid inappropriate use of drugs.

• Use appropriate dose, route & frequency of drug administration.
• Take previous history of drug interactions, allergic diseases.
• Rule out drug interactions.
• Adopt correct administration technique.
• Carry out appropriate laboratory monitoring.
 Steps of ADR monitoring
Four Steps of ADR monitoring:
1.Identifying adverse drug reactions

2.Assessing causality 3.Documentation of

ADR

4.Reporting serious ADRs to PV centres/ADR

regulatory authorities
 Assessing causality
• Is there a convincing relationship between the
medicine and the event?

• Did the medicine actually cause the event?

• Is the time to onset of the event compatible with the
suspected cause (plausible time-frame)?
• Did the event occur after the start of some other
medicine or new illness?
Loading…
• Is the event plausible given what is known about the
drug?
• Is there any other possible cause for the event?
• What is the response to withdrawal of the medicine
(dechallenge)?
• What is the response to rechallenge, if applicable?
 Key data elements for causality assessment
• Medical history (incl. concomitant disease).
• Other risk factors (social factors, alcohol use,
substance abuse, etc.).
• Details of drugs taken: names, doses, routes.
• Start and stop dates and indications for use.
• Description of adverse event, including.
clinical description, laboratory results, and
date of onset / end.
• Evolution of event, severity, seriousness,
outcome.
 WHO-UMC Classification of level of
Level Time to Otherrelationship
Recovery Recurrence notes
event explanatio after after
plausible n withdrawal? rechallenge?
? excluded?

Certain Yes Yes Yes Yes Rechallenge not needed

in case of an
anaphylactic reaction

Probable Yes Yes Yes No or ?

Possible Yes No or ? ? No or ?

Unlikely No No or ? No No or ? Suggestive if event

resolves despite
continued exposure

Unclassified No No or ? No No or ? Insufficient data, Can’t

(conditional) assess with the
information available
Unassessable No No or ? No No or ? Can’t be judged
NARANJO ALGORITHM
INTERPRETATION

For assessing the causality-

-definite = 9
-probable = 5-8
-possible = 1-4
-doubtful = 0
 Hartwig and Seigels scale
For assessing the severity-
1.Mild ADRs-are self limiting and do not
contribute to prolongation of length of hospital
stay.
2.Moderate ADRs- require therapeutic
intervention or hospital admission or
prolonged hospital stay by at least one day .
3.Severe ADRs- life threatening, requiring
intensive medical care or produce disability
or lead to death.
 Case study

Case 1
Ravi Kumar, a 50 yrs old male and known case of Type
2 Diabetes Mellitus having a Fasting Blood Glucose-
110mg/dl, HbA1c 7.5% was maintained on Tab
Glibenclamide 5mg twice daily for the last 6 months. 2
days ago he had a binge of alcohol at a party. An hour
later he was brought to emergency with throbbing
headache, palpitations, sweating, vomiting & mental
confusion. On examination he showed disorientation,
flushing, Pulse rate- 104 per min, BP- 120/80 mmHg,
RR- 22 per min, Blood sugar- 112 mg/dl
>
- li

>
-
2 :
temporer relationship

3 : intraction
>
- Drug
Cluvin Calmide and Alchole

>
- 4: Stop take Alchole
Case 2
Lakshman Singh, a 45 yr old man (Wt- 60kg) and
known case of Pulmonary Tuberculosis was stabilized
on intensive regimen of DOTS-ATT (Isoniazid-
10mg/kg/day,Rifampicin-10mg/kg/day, Pyrazinamide-
25mg/kg/day and Ethambutol-20mg/kg/day) since last
one month. Since last 2 weeks he developed persistent
vomiting, loss of appetite and yellow discoloration of
- u
-

urine. On examination, he showed signs of jaundice like

yellowish discoloration of skin and sclera. Investigations
e

revealed Total Serum Bilirubin- 10mg/dl, AST-

500U/ml, ALT- 550U/ml.
① loos of appetite , vomating , yellow discolarition
of orine

② Temporer relationship
Case 3
Adarsh, 19 years old male, presented in emergency with
breathlessness and wheezing. • He had a throbbing
- -
-
- -

headache while he was writing exam in his college. The

invigilator gave him 2 dispersible tablets of Disprin
(Aspirin-350 mg each) to get quick relief. •Past History
- In the past he had been allergic to dust and smoke but
he never took any treatment. He always experienced
throbbing headache when his exams were near, for
which he used to take a tablet of Crocin (Paracetamol-
500mg) and got relieved. -On examination his BP
120/80mmHg and Pulse was 74/min.
1. Which of these events is likely to be associated
with the drug given? Breathleenes and wheezing
2. What could be the factors which can establish a
drug to be the causative agent of an event?
↳ Temporar relationship

.What
3 could be the reasons for patient
current condition ?
have
↳
high dose of Aspirin and
allergy.

Recomindation > of Aspirin with Parcetamol

4 .
-

Replacement
Case 4
• The patient is a 59-year-old male with Type 2 diabetes,
hyperlipidemia, and hypertension. He has no history of liver
disease.
Patient history
• Started Drug X on Feb 10, 2024
• = Medications: simvastatin, lisinopril, bisoprolol, metformin and
E - -
-- - -

glibenclamide
-

• Labs drawn on Feb 10 revealed liver enzymes, INR, creatinine,

and bilirubin all within normal limits
• No alcohol use Emergency
Room
• 8 weeks after starting Drug X, patient presented to ER with 5-day
history ofOce
jaundice, dark urine, and- nausea/vomiting
• He was admitted to ICU and subsequently diagnosed with acute
liver failure
• - Drug X stopped upon- admission
• Viral hepatitis was ruled out
• 7 days after stopping the medication, all lab values returned to
normal
Polypharmacy
=>
means
milty drug take # Answer
DOWD
-
-

Questions
1. List two reasons why this patient may be at risk for
an adverse event. Polyplarmacy-Age&Elderj)E Mliti-diseasee
2. Is a temporal relationship of acute liver failure with
drug X reported in this case? Yes
3. Name two characteristics in this case that support
a causal association of acute liver failure with
Drug X.
4. Based on this case, should regulatory action be
taken to add acute liver failure to the label? Yes
OR No explain your answer. NO ,
 Questions
5. Based on the information on recovery of acute liver
failure reported in this case, the patient
experienced:
A. Positive rechallenge
B. Negative dechallenge
C. Positive dechallenge
D. Negative rechallenge
 Questions
5. Based on the information on recovery of acute liver
failure reported in this case, the patient
experienced:
A. Positive rechallenge
B. Negative dechallenge
C. Positive dechallenge
D. Negative rechallenge
 Questions
5. Based on the information on recovery of acute liver
failure reported in this case, the patient
experienced:
A. Positive rechallenge
B. Negative dechallenge
C. Positive dechallenge
D. Negative rechallenge