Dr.

Badar Uddin Umar

Drugs have:
Beneficial effects
Harmful effects

Facts
Drugs save life & improve health
Drugs also threaten life
Curd yesterday of my disease
I died last night of my physician
- Mathew Prior: 17th Century
From, the remedy worse than the disease

So, the important question is ALWAYS:

Do the potential benefits of the medication
outweigh the potential risks for the individual?
Definition
An adverse drug reaction is any undesirable effect of a
drug beyond its anticipated therapeutic effects occurring
during clinical use.

The term (ADR) usually excludes-

nontherapeutic overdosage (e.g. toxicities due to
accidental exposure or attempted suicide) and
lack of efficacy of drug
WHO definition:
Any response to a drug that is noxious and
unintended and that occurs at doses used in
humans for prophylaxis, diagnosis, or therapy of
disease, or for the modification of physiologic
function.

It excludes therapeutic failures, overdose, drug

abuse, noncompliance, and medication errors
 Injuryresulting from the medical use of a drug.
Includes Medication Error & ADR

Medication error: An injury resulting from an

error in preparing, procuring, prescribing,
dispensing, administering, or monitoring.

Adverse drug reaction (ADR): An injury

resulting from the medical use of a drug where
no error is involved.
ADRs are a common clinical problem.
Causes adverse consequences to
patients
From mere inconvenience to death and
Have very high incidence in clinical
practice
For marketed drugs in USA
Occur in 5% of all hospital admissions
10-20% of hospital inpatients
About 25% in general practice
Significant cause of death (0.5-0.9%)
 In the UK Non Steroidal Anti-Inflammatory Drug
(NSAID) use alone accounts for1
65,000 emergency admissions/year
12,000 ulcer bleeding episodes/year
2,000 deaths/year

1Blower et al. Emergency admissions for upper gastrointestinal

disease and their relation to NSAID use. Aliment Pharmacol Ther
1997; 11: 283-291
Consequences of ADRs:
Adversely affects patients quality of life
Complicate drug therapy
Decrease compliance and delay cure
Increase cost of patient care
Cause patients to lose confidence in their
doctors
May mimic disease, resulting in unnecessary
investigations and delay in treatment
ADRs are usually classified depending on
Onset
Severity
Type
 ADR: Onset of event:

Acute
Within 60 minutes

Sub-acute
1 to 24 hours

Latent
> 2 days
 ADR: Severity of event:
Mild
Do not require an antidote, therapy, or prolongation of
hospitalization
Commonly known as side-effects

Moderate
Require a change in, but not necessarily cessation of the
drug and may prolong hospitalization or require special
treatment
Severe
Are potentially life threatening, requiring
discontinuation of the drug and specific treatment of
the adverse reaction

Lethal
Directly or indirectly contributes to the patient's
death
FDA: Serious ADR

Result in death
Life-threatening
Require hospitalization
Prolong hospitalization
Cause disability
Cause congenital anomalies
Require intervention to prevent permanent
injury
2 main types:
Type A (Augmented)
Type B (Bizarre)

3 other sub-types:
Type C, D & E
Type A (known pharmacological adverse drug
reactions)

TypeA reactions represent an Augmentation of

the pharmacological actions of a drug

Predictable & dose-dependent

Readily reversible on reducing the dose or
withdrawing the drug.

Commonest type of ADRs (accounting for over

80% of all ADRs)

Not usually life threatening.

Type A adverse reactions:

Are of 2 types:

A) Extension of primary effect

B) Secondary effect
 Effects due to extension of the primary
pharmacological actions of the drug

Augmentation of the drug's therapeutic

actions

Example: Bradycardia with Propranolol

(due to effect on desirable beta1 blocking effect)
Effects due to the secondary pharmacology of the
drug
The action different from the drug's therapeutic
actions
The action still rationalisable from the known
pharmacology of the drug

Example: Bronchospasm with propranolol (due to

effect on undesirable beta2 blocking effect)
Thus, for propranolol:
Bradycardia is primary pharmacological adverse
effects
Bronchospasm is a secondary pharmacological
adverse effect.

More emphasis is now placed on the secondary

pharmacology of new drugs during preclinical
evaluation to anticipate problems that might arise once
the drug is given to humans.
Type B adverse reactions: (unknown
pharmacological adverse drug reactions)
These are Bizarre
Not predictable i.e., cannot be predicted
from the known pharmacology of the drug.
Not dose dependent
Cant be readily reversed
Less common but often serious
Life threatening
Type B ADRs may be:

1) Idiosyncrasy
2) Drug Allergy or Hypersensitivity
Idiosyncrasy: (Pharmacogenetics)
Inherent qualitative abnormal response to a drug
Due to genetic abnormality, mainly due to
deficiency of enzymes in the body
Also may be due to abnormal receptor activity
Incidence:
Happens to very small population
Rare but serious
Idiosyncrasy due to enzyme abnormality
Hemolysis with primaquine

if glucose 6-phosphate dehydrogenase (G6PD)

enzyme deficiency in any person

If primaquine given

Hemolysis leading to hemolytic anemia
Idiosyncrasy due to receptor abnormality
Malignant hyperthermia with general anesthetics
(Halothane)

Sudden huge rise in IC calcium concentration

Increase in muscle contraction
Increase in metabolic activities
Rise of body temperature
Drug allergy
Also known as hypersensitive reaction
Due to antigen-antibody interactions
1st dose acts as an antigen
Antibody is produced against the antigen in the body
Subsequent dose causes antigen-antibody reaction

e.g. Penicillin induced anaphylaxis

(Type 1 hypersensitivity reaction)
Types of allergic reactions
Type I - immediate, anaphylactic (IgE)
e.g., anaphylaxis with penicillins
Type II - cytotoxic antibody (IgG, IgM)
e.g., methyldopa and hemolytic anemia
Type III - serum sickness (IgG, IgM) antigen-antibody
complex
e.g., procainamide-induced lupus
Type IV - delayed hypersensitivity (T cell)
e.g., contact dermatitis
Type C or Continuous type:
Happens due to long term chronic use of a drug
Involves dose accumulation
e.g. Analgesic nephropathy with Paracetamol /
NSAIDs
Type D
Delayed effect
ADRs are found long term after use of drug
Teratogenesis
Carcinogenesis

Teratogenesis: birth defect that is evident after birth

but the drug taken during 1st trimester of pregnancy
Carcinigenesis: carcinoma detected long after use of a
drug
Teratogenesis
Teratogenesis is the abnormal congenital
malformation of fetus due to use of some drugs in 1st
trimester of pregnancy
(4-10 weeks: period of organogenesis)

Teratogenic drugs:
1st detected teratogenic drug is thalidomide
It causes phocomelia--flipper-like limb defect (like
penguin)
Thalidomide disaster in early 60s
Other teratogenic drugs:

Cytotoxic (anticancer) drugs

Vitamin A (retinoid)
Antithyroid drugs
Steroid preparations
OAHs
oral anticoagulants etc.

In general, all drugs should be avoided in 1st

trimester of pregnancy to avoid teratogenic risk
Type E
Ending of drug use
ADRs are manifested after withdrawal of a drug which
was used for a long period
When glucocorticoid is abruptly
withdrawn/discontinued after prolonged use
Adrenocortical insufficiency
Suddenly body suffers from glucocorticoid crisis
Who might get an ADR?

Anyone who takes a medicine

Differential diagnosis should include the
possibility of an ADR if the patient is taking any
form of medication
Who is most at risk from ADRs?

Patients who;
are young, or old or female
are taking multiple therapies
50% of patients on 5 drugs or more
have more than one medical problem
have a history of allergy or a previous reaction to
drugs
What should raise suspicion of an ADR?

A symptom that.
appears soon after a new drug is started
appears after a dosage increase
disappears when the drug is stopped
reappears when a drug is restarted
ADEs: Most Commonly Involved Drugs:

Antibiotics
Antineoplastics
Cardiovascular drugs
Hypoglycemics
NSAID/Analgesics
CNS drugs
Most Common ADEs:

Gastrointestinal tract events 22.1%

Electrolyte/renal 16.7%
Hemorrhagic 12.7%
Metabolic/endocrine 9.5%
Dermatologic (skin) /allergic 7.9%
Common Symptoms From ADEs:

Confusion
Nausea
Decreased balance
Change in bowel pattern
Sedation
Orthostatic hypotension
What conditions are often drug related?
Anaphylaxis
antibiotics, iron dextran injection
Stevens Johnson Syndrome
associated with carbamazepine, antibiotics
Blood dyscrasias
neutropenia with methotrexate and gold salts
thrombocytopenia with heparin
What questions should be asked if suspect an ADR?

Does the patient have a history of other drug-

induced problems?
ask the patient

Does the patient take more than one drug ?

could an interaction be causing the ADR?
long term medication is unlikely to cause new
problems
What else ...?
When did the reaction or symptoms begin?
timings are useful

Have any of the clinical measurements or lab

results recently become abnormal?

Does the patient have any medical problems?

that could be causing the symptoms?
some diseases predispose patients to ADRs
Causes of ADRs

ADRs may be due to:

Drug cause
Patient cause
Prescribers error---
Type C D & E
Polypharmacy
Factors predisposing to ADRs
A) Dose factor:
Due to administration more than therapeutic dose

excessive insulin

hypoglycaemia
B) Pharmaceutical factor:
Due to wrong pharmaceutical preparation

Slow release NSAID

Release in high concentration due to faulty
preparation

GIT bleeding
C) Pharmacokinetic factor:
Due to decrease kinetic activities

Sulfonylurea

Decreased elimination in renal insufficiency

Hypoglycaemia
D) Pharmacodynamic factor:
Due to drugs mechanism of action
NSAID

LVF due to salt & water retention

E) Polypharmacy: Drug-drug interaction factor:

Erythromycin + terfenadine= Arrhythmia
Other factors:
age
gender
multiple disease
allergy
Prevention of ADRs
Whenever a drug is given a risk is taken
Risks may be avoidable or unavoidable

30-50% ADRs are preventable

Drug interaction
Inappropriate medication
Unnecessary medication
Reduction of ADRs can be achieved by:
Better knowledge of diseases
Better knowledge of drugs
Site-specific delivery
Informed, careful and responsible prescribing
Management of ADRs:
Mild ADRs can often be recognized before they
become serious.
If an ADR occurs, the type and precipitating factors
must be determined immediately if possible.
Discontinue the offending agent if:
it can be safely stopped
the event is life-threatening or intolerable
there is a reasonable alternative

Continue the medication (modified as needed) if:

it is medically necessary
there is no reasonable alternative
the problem is mild and will resolve with time
Discontinue non-essential medications
Administer appropriate treatment
e.g., atropine, antihistamines, epinephrine,
corticosteroids, glucagon etc
Provide supportive or palliative care
e.g., hydration, glucocorticoids, warm / cold
compresses, analgesics etc
Consider desensitization
Generally,
For dose-related ADRs:
Modify the dose or reduce precipitating factors

For ADRs unrelated to dose:

The drug usually should be withdrawn and re-
exposure should be avoided.
Thank you very much