ADVERSE DRUG REACTION

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.
TERMINOLOGIES

- Adverse Drug Event (ADE)

o Any untoward occurrence that may present during treatment with a pharmaceutical product but that does
not necessarily have a causal relation to the treatment (WHO)

- Adverse Drug Reaction (ADR)

o A response to a drug that is noxious and unintended and occurs at doses normally used in man for the
prophylaxis, diagnosis, or therapy of disease or for modification of physiological function (WHO)

- Medication Error
o Any preventable event that may cause or lead to inappropriate medication use or patient harm while the
medication is in the control of the health care professional, patient, or consumer (NCC MERP)
o Inappropriate use of a drug that may or may not result in harm (Nebeker)

- Side effect
o Any unintended effect of a pharmaceutical product occurring at normal doses, related to the
pharmacology of the drug

- Unexpected Adverse Reaction

a. An adverse reaction, the nature or severity of which is not consistent with domestic labeling or market
authorization, or expected from characteristics of the drug (Cobert)

- Serious Adverse Effect

a. Any untoward medical occurrence that at any dose results in death, requires hospital admission or
prolongation of existing hospital stay, results in persistent or significant disability/incapacity, or is life
threatening (Edwards)

- Signal
a. Reported information on a possible causal relation between an adverse event and a drug, the relation being
previously unknown or incompletely documented (Edwards)

CLASSIFICATION ACCORDING TO SEVERITY

CLASSIFICATION DESCRIPTION EXAMPLES

MILD No antidote or treatment required, hospitalization is Digestive disturbances, headaches,

not prolonged fatigue

MODERATE Change in treatment is required but not Visual disturbance, Muscle tremor,
discontinued, hospitalization may be prolonged or Difficulty with urination, Mood or
a specific treatment is required Mental Alteration

AMMDacanayRPh©2020

Saint Louis University – Department of Pharmacy

 SEVERE Severe reactions include those that may be life Liver failure, Abnormal heart rhythm,
threatening that result in persistent or significant Certain types of allergic reactions
disability or hospitalization, and that cause a birth
defect.

LETHAL Lethal reactions are those in which a drug reaction Bleeding from anticoagulants
directly or indirectly caused death. These reactions
are typically severe reactions that were not
detected in time or did not respond to treatment.

TYPES OF ADVERSE DRUG REACTIONS

Type A: AUGMENTED
- Dose-related reactions
- It can occur either as an extension effect or part of the therapeutic effect or can occur as not part of the intended
therapeutic effect (as a side-effect).
- It has usually a dose-dependent mechanism.
- Subtypes
a. Augmented extension effect
- bradycardia seen in this hypertensive patient was less than 60 and the patient feels some discomfort, then
this is a form of beta-blocker augmented extension effect.
- It is expected, and can be managed with dose reduction or shifting to another class of hypertensive agent.
b. Augmented side effect
- let us say that the same patient experienced bronchospasm as a result of beta-blocker use, this is a form of
an augmented Side-effect.
- The management in this ADR case will have to be shifting to another class of hypertensive agent.
- Phenothiazines or haloperidols used to treat psychiatric conditions may induce extra-pyramidal side
reactions that can be managed with small doses of benztropine or diphenhydramine.
- Anti-cancer drugs that induce nausea and vomiting can be given anti-emetic agents.

Type B: BIZARRE
- Non-dose-related reactions
- this effect can be likened to a hypersensitivity or idiosyncratic reactions.
- It is often unpredictable.
- Unknown mechanism and casualty
- Subtypes:
- Idiosyncratic
a. Unknown Mechanism; Influenced by genetic and environmental factor.
b. Example:
- Sulfonamides causing Stevens-Johnson Syndrome
- Halothane causing acute hepatic necrosis
- Anesthetic drugs causing hyperthermia
- Immunologic Reaction Mechanism

AMMDacanayRPh©2020

Saint Louis University – Department of Pharmacy

 TYPE MEDIATORS EXAMPLES

TYPE I Occurs after antigen binds onto igE found on the Anaphylaxis , hay fever,
ANAPHYLACTIC REACTION
surfaces of mast cells. The re-exposure of the asthma, urticaria
same allergen could cause cross-linking of the cell-
bound igE -> degranulation (release of histamines,
leukotrienes & prostaglandins)

TYPE II involve the binding of IgG and IgM antibodies to Hemolytic transfusion reactions
CYTOTOXIC REACTION antigens on cell surfaces. and hemolytic disease of
newborns (hemolytic anemia
This induces a cascade of events that leads to cell death and aplastic anemia)
(complement-mediated lysis).

TYPE III result from the formation of antigen-antibody complexes Serum sickness, rheumatoid
IMMUNOCOMPLEX that settle on tissues and organs. In an attempt to arthritis and SLE (Hydralazine,
REACTION remove these complexes, underlying tissue is also Phenytoin, INH, Procainamide)
damaged.

regulated by T cells and are delayed reactions to Tuberculin reactions, and

TYPE IV
antigens associated with cells contact dermatitis
DELAYED REACTIONS

T-lymphocytes sensitized by an antigen release

lymphokines after subsequent contact with the same
antigen.

Lymphokines induce inflammation and activate

macrophages

Type C: CONTINUOUS / CHRONIC

- Dose and time-related reactions,
- This ADR happens after a prolonged use of a drug even at normal dosage.
- It affects organ systems.
- Subtypes:
o Addiction
§ Condition where a person takes a drug compulsively, despite potential harm to themselves of their
desire to stope
§ Example: Marijuana, Opiates
o Dependence
§ Compulsion to take the drug repeatedly and experiences unpleasant symptoms if discontinued.
§ Examples: BZD, Caffeine, Cocaine
• Physical dependence- body
• Psychological dependence- mind
o TOLERANCE
§ larger doses required to produce the same effect.
o TACHYPHYLAXIS

AMMDacanayRPh©2020

Saint Louis University – Department of Pharmacy

 § a rapid decrease in response to repeated doses over a short period of time
§ Drug Holiday

Type D: DELAYED
- Time related reactions
- this is seen when a drug used at some earlier time has some adverse effects are observed much later on, such as
affecting the next generation
- Subtypes:
o Carcinogenesis
§ Initiation of cancer formation
o Teratogenesis
§ Congenital malformations
§ Teratogens and its complications
• Methotrexate – CNS and limb malformations
• ACE inhibitors- prolonged renal failure in neonates, decreased skull ossification, renal tubular
dysgenesis
• Anticholinergic drugs – neonatal meconium ileus
• Methimazole- aplasia cutis
• Carbamazepine – neural tube defects
• Cyclophosphamide – CNS malformations, secondary cancer
• Danazol- masculinization of female fetuses
• NSAIDs- constriction of ductus arteriosus, necrotizing enterocolitis
• Lithium- Ebstein anomaly
• Warfarin – Skeletal and CNS defects, Dandy- Walker syndrome
- Pregnancy Categories

CATEGORY DEFINITIONS CLINICAL APPLICATION

CATEGORY A "Controlled studies in women fail to For all practical purposes, there are no
demonstrate a risk to the fetus in the Category A drugs.
first trimester (and there is no evidence
of a risk in later trimester), and the
possibility of fetal harm appears
remote."

CATEGORY B "Either animal-reproduction studies Category B drugs include prenatal

have not demonstrated a fetal risk but vitamins, acetaminophen and several
there are no controlled studies in other medications used routinely and
pregnant women or animal- safely during pregnancy. If there is a
reproduction studies have shown an clinical need for a Category B drug, it
adverse effect (other than a decrease is considered safe to use it.
in fertility) that was not confirmed in
controlled studies in women in the first
trimester (and there is no evidence of
a risk in later trimesters)."

AMMDacanayRPh©2020

Saint Louis University – Department of Pharmacy

CATEGORY C "Either studies in animals have revealed
adverse effects on the fetus
(teratogenic or embryocidal or other)
and there are no controlled studies in
women or studies in women and
animals are not available. Drugs should
be given only if the potential benefit
justifies the potential risk to the fetus."
Category C drugs have not been
shown to be harmful to fetuses (if they
had been, they wouldn't be Category
C drugs). However, there are some
reasons to be more concerned about
these drugs than Category B drugs. If
the pregnant patient will benefit from
a Category C drug, it is generally used,
although most obstetricians would
prefer a Category B drug if it will give
equivalently good results.

CATEGORY D "There is positive evidence of human Category D drugs have some

fetal risk, but the benefits from use in significant risks. They should be used
pregnant women may be acceptable during pregnancy only when the
despite the risk (e.g., if the drug is alternatives are worse.
needed in a life-threatening situation
or for a serious disease for which safer
drugs cannot be used or are
ineffective.)"

CATEGORY X "Studies in animals or human beings Category X drugs should not be used
have demonstrated fetal during pregnancy.
abnormalities or there is evidence of
fetal risk based on human experience
or both, and the risk of the use of the
drug in pregnant women clearly
outweighs any possible benefit. The
drug is contraindicated in women who
are or may become pregnant."

Type E: END OF USE

- Withdrawal reactions
- this is when a drug that was used on long term is suddenly stopped, the patient suffers a form of withdrawal reaction.
- These drugs exhibit tolerance phenomenon or have some dependency potential.
- Examples include:
o rebound hypertension following sudden cessation of clonidine,
o adrenal insufficiency after stopping prolonged steroid use,
o seizures from acutely ceasing anticonvulsants,
o and uncomfortable withdrawal syndromes from benzodiazepines and narcotics.

Type F: FAILURE OF THERAPY

- Unexpected failure of therapy, where a drug undesirably increases or decreases in efficacy
- Examples include:
o Drug-Drug interactions
o Use of counterfeit drugs
o Drug instability
o Poor patient compliance
o Wrong route of administration
o Drug resistance

AMMDacanayRPh©2020

Saint Louis University – Department of Pharmacy