4. Drug induced diseases (iatrogenic diseases) are common.
About 3-5% hospital admissions are due to ADR worldwide.
ADR increases duration of stay in hospital and cost of
treatment.
Most of the adverse effects are reversible initially e.g. visual
disturbance due to ethambutol, hepatotoxicity due to INH and
bone marrow depression (dose dependent) due to
chloramphenicol.
By knowing specific side effect, it is possible to differentiate
weather symptoms reported by the patient are due to the drug
or something new.
5. Historical background
A principle appreciated by Paracelsus (founder of
chemical therapeutics) 500 years ago stated
“All things are poisons and there is
nothing that is harmless ; the dose alone decides
that some-thing is no poison.” (Bennet, Brown,
2012)
6. 1922- Jaundice associated with use of SALVARSAN an
organic arsenical used in treatment of syphilis.
1937- In USA, 107 people died from taking elixin which
contained the solvent DEG, Diethylene Glycol.
1938- FDA established, task was to enquire into
the safety of new drugs before marketing.
1958- Thalidomide marketed in West-Germany used for
the treatment of morning sickness during pregnancy.
7. 1959-61- There was an outbreak of Phocomelia in
newborn babies.
The Thalidomide incident led to a public outcry to the
institutions all around the world of drug regulatory
authorities and led to the development of much more
sophisticated approach to the preclinical testing and
clinical evaluation of drugs before marketing, and to a
greatly increased awareness of adverse effects of drugs
and to methods of detecting them.
11. Adverse Drug Reaction
(ADR)1
Response to a drug that is noxious, Undesirable and unintended
and that occurs at therapeutic doses used in humans for
prophylaxis, diagnosis, or therapy of disease, or for the
modification of physiologic function.
Excludes therapeutic failures, overdose, poisoning, drug abuse,
misuse, overuse, noncompliance, and medication errors.
WHO
12. Side effects are pharmacological effects produced with
therapeutic dose of drug, e.g. dryness of mouth with
atropine. These are neither harmful nor damaging and
recovery is quick on stopping the drug or reducing the dose.
Secondary effects are due to indirect consequences of a
primary action of drug, e.g. tetracyclines leads to suppression
of bacterial flora and leads to superinfections.
Untoward effects These also develop with therapeutic dose
of drug, but are undesirable and, if severe may necessitate
the cessation of treatment, e.g. potassium loss due to
diuretics drugs.
13. Toxic effects
These are seen usually when a drug is administered
repeatedly and/or in large doses.
Highly significant for drugs with narrow therapeutic index,
e.g. digoxin, phenytoin etc.
Sometimes drug is safe but metabolite is toxic, e.g.
Paracetamol, Isoniazid.
Mutagenicity, Carcinogenicity, Teratogenicity.
14. ADVERSE DRUG EVENT (ADE)
VS
ADVERSE DRUG REACTION (ADR)
Adverse Drug Event (ADE): Any untoward medical
occurrence that may be present during treatment with a
pharmaceutical product but which does not necessarily
have a casual relationship with this treatment.
Adverse drug reaction (ADR): Any noxious change which is
suspected to be due to a drug, occurs at a doses normally
used in man, requires treatment or decrease in dose or
indicates caution in future use of the same drug.
15. Every ADR is an AE but only some
AEs will be ADRs
16. SAE (Serious Adverse Event)
FDA
Any untoward medical occurrence that
Results in death or
Is life threatening or
Requires hospitalization or
Causes persistent or significant disability or
Is a birth defect or
Requires medical intervention to prevent one of the
above outcomes
18. Grades of ADR based on severity
MILD – Subsides by itself, no need of any
intervention.
MODERATE – Needs discontinuation and change of
drug, specific treatment, prolonged
hospitalization.
SEVERE – Potentially life threatening, permanent
disability or needs intensive care.
FATAL – Results into death (direct or indirect).
19. Classification of ADRs
(Wills & Brown)
Type A (Augmented)
Type B (Bizarre)
Type C (Continuous use)
Type D (Delayed)
Type E (Exit/End of treatment)
20. Type A (Augmented)
Reactions which can be predicted from known
pharmacology of drug.
Dose dependent.
Can be alleviated by dose reduction.
e.g.
Anticoagulant's Bleeding,
Beta blockers Bradycardia,
Nitrates Headache,
Prazosin Postural hypotension,
21. Type B (Bizarre) Reactions
Cannot be predicted from pharmacology of drug
Not dose dependent
Host dependent factors important in
predisposition
e.g.
Penicillin Anaphylaxis
Anticonvulsant Hypersensitivity
23. Idiosyncratic Reactions
(Pharmacogenetics)
Hemolysis in G6PD deficiency- Primaquine, Dapsone,
Nitrofurantoin, Sulfamethoxazole etc.
INH acetylation
Allergic Reactions
Penicillin's, Sulfonamides, Quinolones, Iodine
containing agents, Vancomycin etc.
24. Comparison Between Type A AND
Type B ADR
Type A Type B
Nature of ADR Augmented/normal
response
Totally abnormal
bizarre response
Mechanism Hyper-response Genetic,
immunological/unkno
wn
Pharmacologically
predictable
Largely yes No
Dose dependent Yes No
Incidence and
morbidity
High Low
Mortality Low High
Treatment Adjust dose Stop the drug
25. Type C (Continuous use)
Reactions
These are both time and dose related.
e.g.
Paracetamol Hepatotoxicity
Hyperglycemia Glucocorticoids
Tardive dyskinesia Neuroleptics
26. Type D (Delayed) Reactions
Mostly occurs after many years of treatment.
Can be due to accumulation.
e.g.
Mutagenicity
Carcinogenicity
Teratogenicity
27. Type E (End of treatment/
Due to abrupt withdrawal)
Occur on withdrawal especially when the drug is
stopped abruptly
e.g.
Phenytoin withdrawal Seizures
Steroid withdrawal Adrenocortical
insufficiency
Beta blocker withdrawal Worsening of angina
28. FACTORS CAUSING ADR
1. Patients factor: Age (more at extreme of ages), genetic
constitution, environmental hazard and allergy.
2. Drug factor: Type A or type B or others.
3. Clinician / prescriber factor: It may be due to
prolonged use which is inappropriate, abrupt
discontinuation, prescribing the unsafe drugs during
pregnancy.
29. Recognition of ADR
1. Experimental (Cohort studies) – phase 1-3
clinical trials
Only common drug effects are noticed (small
population)
2. Observational studies (Pharmacoepidemiology)
Post marketing surveillance
Prospective and retrospective studies are done
30. ADR Monitoring
Pharmacovigilance is a science and activities relating
to the detection assessment, understanding and
prevention of drug effects or any other drug related
problem (WHO).
PvPI is a great initiative in this regard.
AEFI is an important component of PvPI which has
great relevance as per as immunization drive for
covid-19 is concerned.
31. How To Prevent ADR
Use drugs rationally
Take drug history
and history of drug
reactions
Check for possibility
of interaction of
drug with food,
disease and other
drugs used
simultaneously.
Check the signs of
overdose and toxicity
especially using drugs
by IV route
Perform TDM if
applicable
Assess risk benefit
ratio
Give adequate
information to the
patient
