Adverse drug reactions

1. Adverse Drug Reaction
• The negative and undesirable effects of drug therapy are known as
adverse drug reaction.
• These reactions may be caused by the drug
metabolites; from an interaction between two
itself or one of its
or more drugs or
between a drug and food; or may be caused by an excipient in the
product, such as dye or preservative.
• According to WHO, adverse drug reaction is defined as:
“A response to a drug that is noxious and unintended, and that occurs
at doses normally used in human for the prophylaxis, diagnosis or
therapy of disease or for the modification of physiological function.”

2. Classification of ADRs
Rawlins and Thompson classification: In this classification, the ADRs
are categorized into two classes; type A and type B reactions
Type-A Reaction (95%)
• Type-A reactions are common and predictable with most identified
prior to marketing.
• These are dose related and result directly from the pharmacological
action of the drug, but can be due to
– drug-drug interactions,
– drug-food interactions,
– This represent approximately 70 to 80% of all ADRs

3. Examples of Type-A Reaction:
– Excessive effects of the pharmaclological action of
a drug,
• Example: haemorrhage with anticoagulants.
– Unwanted pharmacological actions of a drug,
tricyclic
blurred
urinary
• Example: antimuscarinic effects of
antidepressants which can result in
vision, tachycardia, dry mouth and
retention.
– Withdrawal reactions, which may occurs with
abrupt withdrawal of some drugs after prolonged
use,
• Example: insomnia with hypnotics.

4. Type-B Reaction (5%)
• Type B reactions are unexpected effects which are
unrelated to the known pharmacological action of
the drug.
• This type of ADRs is uncommon, cannot be
predicted, is not dose-related, and has no relation to
the pharmacological action of the drug.
• In most cases, the mechanism involved in type-B
reactions is unknown.

5. • These reactions predominantly affect
– The liver
– Skin, and
– Hematopoietic system.
• This class of ADRs
(hypersensitivity
includes drug allergies
reactions) such as
anaphylaxis from penicillin,
• Type-B ADRs may influence by genetic and
environmental factors and are frequently not
discovered until after a drug is marketed.

7. Wills and Brown classification: To overcome the limitations of Rawlins and
Thompson classification, adverse reactions are classified into nine categories
based on their mechanism:
1.Type A (Augmented ) Dose related
• Pharmacologically predictable
• Improves if medication is withdrawn
• Common
2.Type B (Bugs) Non- dose related
• Pharmacologically predictable
• Involves reaction with microorganism
• Improves if medicine withdrawn
3.Type C (Chemical/Chronic) Dose related & time related
• They are not pharmacologically predictable, but may be seen based on the
knowledge of physicochemical characteristics of the drug. Type C reactions
are irritant reaction that is related to drug concentration. eg: contact
dermatitis.

8. 4.Type D (Delivery/Delayed) Time related
• Type D reactions are independent of the chemical as well as
pharmacological properties of the drug. Instead, they occur due to method
of administration or nature of the drug formulation. It can be improved if
medicine withdrawn or method of delivery changed. eg: infection at the
site of injection
5.Type E (Exit/End of use) Withdrawal
• The reactions are pharmacologically predictable and begin only when the
drug is withdrawn or the dose is reduced. The condition of the patient
improves when the drug therapy is reintroduced. eg: withdrawal seizure
when anticonvulsants like Phenytoin is withdrawn
6.Type F (Familial/Failure) Failure of therapy
• They only occur in genetically predisposed patient. It can be improved if
medicine withdrawn. eg: hemolytic anemia with primaquin in G6PD
deficient individuals.

9. 7.Type G (Genotoxicity)
• Irreversible genetic damage is caused by this Type G adverse
reaction. eg: teratogenic agent like Thalidomide causes genetic
damage to the developing fetus.
8.Type H (Hypersensitivity)
• They are also known as drug allergy and is often immune
mediated response.
9.Type U (Unclassified)
• This includes those reactions in which the mechanism is
unclear. eg: taste disturbances associated with Simvastatin.

10. Severity of ADR
1. Minor: no need of therapy, antidote or hospitalization
2. Moderate: requires drug change, specific treatment,
hospitalization
3. Severe: potentially life threatening, permanent damage,
prolonged hospitalization
4. Lethal: directly or indirectly leads to death

11. ADR Categories
1. Side effects
2. Secondary effects
3. Toxic effects
4. Intolerance
5. Idiosyncrasy
6. Drug allergy
7. Photosensitivity
8. Drug dependence
9. Drug withdrawal reactions
10. Teratogenicity
11. Mutagenicity & carcinogenicity

12. Anaphylaxis
• Anaphylaxis is a severe life threatening allergic reaction.
• Common anaphylactic reactions are to foods, insect stings,
medications, etc
• It occurs due to reaction of antigen with a specific class of antibody
(IgE) bound to the surface of mast cells & basophils. When antigen
reacts with antibody, the cell membrane permeability increases that
leads to influx of calcium ions into cells. This causes degranulation of
mast cells & basophils with the liberation of histamine & other
mediators.
• This reaction may sometime lead to acute circulatory failure known as
anaphylactic shock.
• Treatment: Adrenaline injection (Life saving drug)

13. Treatment of anaphylaxis
• Airway management; supplemental oxygen
• Apply tourniquet to obstruct blood flow from antigen source
• Intravenous fluids; glucocorticoids, antihistaminic drugs,
bronchodilators
• Adrenaline injection i.m. or s.c.; adrenaline is physiological
antagonist of histamine, quick reversal of hypotension,
bronchospasm, laryngeal edema is seen

14. Organ specific adverse drug effects
Hepatotoxicity
• Venous blood from stomach & intestine flows into the portal vein &
then through liver before entering systemic circulation. The liver is the
first organ to encounter ingested food & drugs.
• All of the major functions of liver are affected by the adverse drug
reactions like hepatic transport & synthetic process.
• Major liver functions affected by adverse drug reactions are:
o Homeostasis
o Filtration of particulates
o Protein synthesis
o Bioactivation & detoxification
o Formation of bile & biliary secretion

15. Major adverse drug reaction of liver are:
• Fatty liver: ethanol, valproic acid
• Hepatocyte death: paracetamol, ethanol
• Bile duct damage: amoxicillin, methylene
• Sinusoidal disorders: steroids, cyclophosphamide
• Fibrosis & cirrhosis: ethanol, vitamin A

16. Nephrotoxicity
Kidney plays important role in maintaining:
• Total body homeostasis
• Excretion of metabolic wastes
• Regulation of extracellular fluid volume
• Electrolyte composition
• Acid-base balance
• Synthesis & release of renin & erythropoietin
• Activation of vitamin D3
Thus adverse drug reaction to kidney can disrupt all of these functions &
effect body metabolism. Major adverse drug reaction of kidney are:
• Acute renal failure: NSAIDS, amphotericin B, cyclosporine
• Chronic kidney failure: aminoglycosides, cisplatin, lithium

17. Reasons for Adverse Reactions
1.Dispensing & Medication administration errors
– Over prescription by Physician as well as self medication by patients
may lead to adverse drug reactions.
2.Failure to set therapeutic end point
– Physicians unable to set therapeutic end point for potent drugs or misuse
of drugs like digitalis, corticosteroids, diuretics, etc may cause adverse
drug reactions

18. 3.Bioavailability Differences
– Changes in formulation of drugs from
bioavailability & leads to adverse effects
different brands affects
4.Patient Factors
– Physiological & disease status of patients affects adverse drug
reaction. Different age group like child, adult & elderly have difference
in metabolism, excretion which affects drug response & adverse drug
reactions.

19. 5.Multiple Drug Therapy
– Digoxin and beta-blockers may cause increased risk of bradycardia
6.Age and Sex
– Neonates have reduced drug clearance, resulting in increased risk of
ADRs,
– Elderly taking a greater number of medicine so multiple drug therapy may
influence the elder groups.
– Some ADRs appear to occur more frequently in females
7.Multiple disease states
– Patients with peptic ulcer disease being at increased risk of bleeding when
prescribed NSAID,
– Those with asthma who may suffer bronchospasm with beta-
adrenoceptor blocking drugs.

20. 8.Types of Drug Prescribed
– ADRs may be more likely to occur when the drug regimen includes
medicines with a narrow therapeutic index such as, digoxin,
anticoagulants and insulin
9.Dosage
– Drowsiness with antiepileptic drugs such as, phenytoin, Phenobarbital
and carbamazepine
10.Route of Administration
– Rapid IV injection of digoxin for heart disease may cause nausea and
arrhythmias

21. 11.Formulation
– ADRs can be due to excipients in pharmaceutical formulation, e.g.,
coloring agents, sweeteners and preservatives.
– Changes in formulation of digoxin resulting in changes in particle size
which affected bioavailability lead to toxicity
12.Patient Compliance
– ADRs more frequently occur if the patient does not follow the
prescribed regimen.
– Taking too much of a drug may lead to adverse effects)

22. Prevention/Management of Adverse drug reaction
Since many ADRs are preventable, a major part of the nurse role
in ADRs should be to reduce the occurrence of the problem
through:
1. Identifying potential side effects of drug therapy and advising
a safe course of action.
2. Avoiding
carrying
patients.
unnecessary poly-pharmacy by
out review of therapy and by
encouraging and
compliances to
3. Choosing the least toxic drugs where possible.

23. 4. Checking the history of allergy or previous reaction to a
drug
5. Checking the drug interaction and advising on what
action to take
6. Encouraging the patients to complete the course of
medication
7. Encouraging patients to report any new symptoms
8. Advising on simplifying dose and drug regimens to
encourage good compliance

24. Adverse Drug Reaction Reporting System
• Pharmacovigilance is the study of the safety of marketed drugs
under the practical conditions of clinical use in large communities.
• As per WHO Pharmacovigilance ‘is the science and activities
relating to the detection, assessment, understanding and
prevention of adverse drug reactions or any other possible drug
related problems’.
• The ultimate goal of this activity is to improve the safe and rational
use of medicines, thereby improving patient care and public health.

25. • Why PV is required ?
The numbers of patients in clinical safety analysis remain far too
small to detect uncommon or rare adverse drug reactions (ADRs),
even if these are serious.
• Pharmacoepidemiology is the study of the use of, and effects of,
drugs in large numbers of people. As the term implies, this form of
enquiry uses the methods of epidemiology; it is concerned with all
aspects of the benefit–risk ratio of drugs in populations.
• Pharmacolovigilance Centres are present in hospitals to report
adverse drug reactions. They are centrally governed by Uppsala
Monitoring Centre (UMC), Sweden.
• In UK, Yellow Card Scheme is used to report adverse drug reactions
by MHRA.