ADVERSE DRUG REACTIONS

WHAT IS ADR?

WHO Definition
Any response to a drug which is
noxious & unintended & which
occurs at doses in man for
prophylaxis, diagnosis or
treatment.
 HISTORY ABOUT ADRS

In 1922: JAUNDICE associated with the use of SALVARSAN, an organic

arsenical used in the treatment of Syphillis.

In 1937: In USA, 107 people died from taking an ELIXIR OF SULFANILAMIDE

that contained the SOLVENT DIETHYLENE GLYCOL.

Establishment of the FOOD AND DRUG ADMINISTRATION (FDA), which was

given the task of enquiring into the safety of new drugs before allowing them
to be marketed.
In 1958: Thalidomide marketed in West Germany as a non barbiturate
hypnotic & for morning sickness during pregnancy. In 1959 - 1961,
it was reported in that there was an outbreak of PHOCOMELIA
(hypoplastic and aplastic limb deformities) in the new born babies.
The THALIDOMIDE INCIDENT led to a public outcry, to the institution all
round the world of DRUG REGULATORY AUTHORITIES, to the
development of a much more sophisticated approach to the preclinical
testing and clinical evaluation of drugs before marketing, and to a greatly
increased awareness of adverse effect of drugs and methods of
detecting them.
 COMMON CAUSES OF ADRS

• Failing to take the correct dosages at the correct times.

• Overdosing.
• Allergies to chemical components of the medicine.
• Combining the medicine with alcohol.
• Taking other drugs or preparations that interact with the
medicine.
• Taking a medicine that was prescribed for someone
else.
 FACTORS AFFECTING ADVERSE
DRUG REACTIONS

Patient-related factors: Drug-related factors:

• Age
• Sex • Dose
• Genetic influences • Duration
• Concurrent diseases (renal, liver,
cardiac) • Inherent toxicity of the agent
• Previous adverse drug reactions
• Pharmacodynamics properties
• Compliance with dosing regimen
• Total number of medications • Pharmacokinetic properties
• Misc. (diet, smoking, environmental
exposure)
 CLASSIFICATION OF ADRS
Depending on
1-Onset of event: Acute (<60 minutes), Sub-acute (1-24 hrs) and
Latent (>2 days)
2-Type of reaction: (Rawlins and Thompson)
i. A (Augmented)
ii. B (Bizarre)
iii. C (Chronic)
iv. D (Delayed)
v. E (End of treatment)
3-DoTS Classification:
4-Severity: Minor, Moderate, Severe, Lethal ADRs

5-Others: Side effects, Secondary effects, Toxic effects, Intolerance,

Idiosyncrasy, Drug allergy, Mutagenicity, Photosensitivity, Drug
Dependence, Drug Withdrawal Reactions, Teratogenicity,
Carcinogenicity, Drug induced disease (Iatrogenic).
 TYPE A: (AUGMENTED) REACTIONS
Reactions which can be predicted from the known pharmacology
of the drug
 Dose dependent
 Can be alleviated by a dose reduction
 Common
 Skilled management reduces their incidence.
Example#
• Anticoagulants  Bleeding
• Beta blockers  Bradycardia
• Nitrates  Headache
• Prazosin  Postural hypotension
 TYPE B: (BIZARRE) REACTIONS
A type B reaction is one that is not due to an extension of the active
pharmacologic properties of the drug; the B indicates bizarre. They are
called pharmacologically unexpected, unpredictable, or
idiosyncratic adverse reactions.
There are two subclasses:
1-Immunologic: An allergic or hypersensitivity reaction occurs as a
result of an immunologic mechanism.
2-Idiosyncratic: The term idiosyncratic is often used in a broad sense
to designate qualitatively abnormal adverse reactions that occur in a
given individual and whose mechanism is not yet understood.
 Characteristics of Bizarre Reactions

 Reaction disappears on discontinuation of the drug

 Recognizable as an immunological reaction
 Undetectable during conventional testing
 Little or no relation to the usual pharmacological effects
of the drug
 TYPE C: ( CHRONIC)
Reactions due to long time exposure.
Example#
 Analgesic nephropathy
 Dyskinesia with levodopa

TYPE D: (DELAYED) REACTIONS

Occur due to prolonged exposure. Can be due to accumulation.
Eample#
 Carcinogenesis, or short term exposure at a critical time .
 Teratogenesis
TYPE E: (END OF USE) REACTIONS

Occur on withdrawal especially when drug is stopped abruptly.

Example#
 Phenytoin withdrawal  Seizures
 Steroid withdrawal  Adrenocortical insufficiency.
 Opioid causing the withdrawal syndrome.
 Depending on Severity

Minor ADRs: No therapy, antidote or prolongation of

hospitalization is required.

Moderate ADRs: Requires change in drug therapy, specific

treatment or prolongs hospital stay by atleast 1 day.

Severe ADRs: Potentially life threatening, causes permanent

damage or requires intensive medical treatment.

Lethal: Directly or indirectly contributes to death of the patient.

 SIDE EFFECTS

Unwanted but often unavoidable, occur at therapeutic doses

Predicted from the pharmacological profile of a drug
Example#
 Atropine dryness of mouth
 Promethazine (anti-allergic) sedation
 Codeine(anti-tussive)constipation Used in
Traveller’s diarrhea
SIDE EFFECTS….(DRUG DISCOVERY)

Occasionally, “adverse” effects may be exploited to develop an

entirely new indication for a drug.
Example#
• Unwanted hair growth during Minoxidil treatment of severely
hypertensive patients  development of the drug for hair growth.
• Sulfonamides used as antibacterials were found to produce
hypoglycemia and acidosis as side effects  development of
Hypoglycemic Sulfonylureas.
 IDIOSYNCRASY
Unusual drug response that occurs in a small minority of individuals
within therapeutic dose is called idiosyncrasy. Or, Inherited abnormal
response to drugs mediated by single gene is called idiosyncrasy and
cause increased, decrease and bizarre response to drugs.
• It is a qualitatively abnormal, harmful effect of drug.
• Reaction may occur with low doses.
• Genetic factor may be responsible.
Example of idiosyncrasy
• Anti-malarial drug primaquine causes haemolysis of 5-10% of black
males.
• Sulphonamide causes haemolysis in Glucose-6-PO4 dehydrogenase
deficient patient.
 TOLERANCE

Decrease pharmacological effect on repeated administration of

the drug.
 Pharmacokinetic Tolerance: ↑ the enzymes responsible for
metabolizing the drug.
Example: Phenobarbitone induces metabolism of its own by
increasing its own metabolic enzyme.
 Pharmacodynamics Tolerance: Cellular tolerance, due to down-
regulation of receptors.
 Depletion of stores Example: Amphetamine
 INTOLERANCE
Appearance of characteristic toxic effects of a drug in an individual at
therapeutic doses
Converse of tolerance
Indicates a low threshold of the individual
Example#
• Triflupromazine (single dose)  Muscular dystonias in some
individuals
• Carbamazepine (few doses) Ataxia in some individuals
• Chloroquine (single tablet)  Vomiting and abdominal pain in some
individuals.
 PHOTOSENSITIVITY
Cutaneous reaction resulting from drug induced sensitization of the skin to UV
radiation. The reactions are of two types
Phototoxic: Drug or its metabolite accumulates in the skin, absorbs light
and undergoes a photochemical reaction resulting in local tissue damage
(sunburn-like, i.e., erythema, edema, blistering, hyper pigmentation)
E.g. Tetracyclines (esp. Demeclocycline), and Tar products,
Nalidixic acid, Fluoroquinolones, Sulfones etc.
Photoallergic: Drug or its metabolite induces a cell mediated immune
response which on exposure to light (longer wave length) produces a papular
or eczematous contact dermatitis like picture.
E.g. Sulfonamides, Sulfonylureas, Griseofulvin, Chloroquine,
Chlorpromazine.
 DRUG DEPENDENCE
Drugs capable of altering mood and feelings are liable to repetitive use
to derive euphoria, withdrawal from reality, social adjustment, etc.
Psychological dependence: Individual believes that optimal state of
well being is achieved only through the actions of the drug.
E.g. Opioids, Cocaine.
Physical dependence: Altered physiological state produced by
repeated administration of a drug which necessitates the continued
presence of the drug to maintain physiological equilibrium.
Discontinuation of the drug results in a characteristic withdrawal
(abstinence) syndrome.
E.g. Opioids, Barbiturates, Alcohol, Benzodiazepines
Drug abuse: Use of a drug by self medication in a manner and amount,
that deviates from the approved medical and social patterns in a given
culture at a given time.
Drug abuse refers to any use of an illicit (against the law) drug.

Drug addiction: Compulsive drug use characterized by overwhelming

involvement with the use of a drug.

Drug habituation: Less intensive involvement with the drug, withdrawal

produces only mild discomfort.
Habituation and addiction imply different degrees of psychological
dependence.
 MUTAGENECITY AND
CARCINOGENICITY
Capacity of a drug to cause genetic defects and cancer respectively.
Chemical carcinogenesis generally takes several (10-40) years to
develop.
Unpredictable
Example#
 Estrogen- Endometrial carcinoma.
 OCP- Ca cervix, breast Ca
 Iron S/C or I/M – blackening of area – increase incidence of
sarcoma (cause is unknown).
 Anticancer drug.
 DRUG ALLERGY

• Acquired, altered reaction of the body to drug.

• Immunologically mediated reaction.
• occur even with much smaller doses
• Also called Drug hypersensitivity
• Not genetic and not occurred in all
• Occurs on re-exposure
• E.g. penicillin→1st time →stimulate antibody →Ag-Ab reaction
→allergy
• Chief organ: Skin, respiratory tract, GIT, Blood & blood vessels
 TACHYPHYLAXIS

When responsiveness diminishes rapidly after administration of

a drug, the response is said to be subject to tachyphylaxis.

 Tyramine can cause depletion of all NE (Norepinephrine) stores if

you use it long enough, resulting in tachyphylaxis.
 SECONDARY EFFECTS

Indirect consequences of a primary action of the drug

Example#
 Tetracycline Suppression of bacterial flora Superinfections
 Corticosteroids Weaken host defense Activation of latent
tuberculosis
 TOXIC EFFECTS
Result of excessive pharmacological action of the drug due to over
dosage or prolonged use.
Over dosage may be
1. Absolute (Accidental, homicidal, suicidal)
2. Relative (Gentamycin in Renal failure)
Result from
1. Extension of therapeutic effect:
E.g. Barbiturates  Coma,
Digoxin  Complete A-V block,
Heparin  Bleeding
2. Functional alteration:
E.g. Atropine  Delirium
3. Drug induced tissue damage:
E.g. Paracetamol  Hepatic necrosis
 TERATOGENICITY
Capacity of a drug to cause foetal abnormalities when
administered to the pregnant mother
Drugs can affect the foetus at 3 stages:
1. Fertilization and implantation (Conception to 17 days):
failure of pregnancy which often goes unnoticed.
2. Organogenesis(18 days to 55 days): most vulnerable
period, deformities are produced.
3. Growth and development (> 56 days): developmental and
functional abnormalities can occur. E.g:
Thalidomide Phocomelia, multiple defects
Anticancer drugs  Cleft palate, multiple defects
 AIMS OF KNOWING ADRS

 To improve patient care and safety.

 To improve public health and safety.

 To contribute to the assessment of benefit, harm,

effectiveness and risk of medicine.
 TEN COMMANDMENTS TO REDUCE
ADVERSE DRUG REACTIONS
1. Critically review the total condition of the patient. Be particularly
careful when you prescribe to children, elderly, seriously ill,
pregnant patients and those with renal, cardiac or liver
diseases.
2. Use as few drugs as possible. Balance the seriousness of
possible reactions against the beneficial effects of each drug
that is being considered.
3. Know well the drugs that you use. Compare the efficacy and
safety of each of the available competitive medications that
appear to be worthy of consideration for the patient.
4. Do not change too readily from one drug you know to one you do
not know. If you decide to use a new drug, know that drug.
5. Do not hesitate to use textbooks and other references providing
information on drug reaction and interaction.
6. Be especially careful when prescribing drugs known to exhibit a
large variety of reactions/ interactions.
7. Be aware of interactions with certain foods, alcohol and even with
household chemicals.
8. Regularly make an inventory of the drugs your patient is receiving.
9. Review your patient regularly for all the drugs used and especially
those bought without prescriptions.
10. If your patient shows signs and symptoms not clearly explained by
the course of illness, think of adverse drug reaction.
 ROLE OF THE PHARMACIST
Pharmacists should exert leadership in the development,
maintenance, and ongoing evaluation of ADR programs. They
should obtain formal endorsement or approval of such
programs through appropriate committees (e.g., a pharmacy
and therapeutics committee and the executive committee of
the medical staff) and the organization’s administration. In
settings where applicable, input into the design of the program
should be obtained from the medical staff, nursing staff, quality
improvement staff, medical records department, and risk
managers. The pharmacist should facilitate.
• Analysis of each reported ADR.
• Identification of drugs and patients at high risk for
being involved in ADRs.
• The development of policies and procedures for the
ADR-monitoring and reporting program.
• A description of the responsibilities and interactions of
pharmacists, physicians, nurses, risk managers, and
other health professionals in the ADR program.
• Use of the ADR program for educational purposes.
• Development, maintenance, and evaluation of ADR
records within the organization.
• The organizational dissemination and use of information
obtained through the ADR program.
• Reporting of serious ADRs to the FDA or the
manufacturer (or both).
• Publication and presentation of important ADRs to the
medical community.