3. INTRODUCTION
ADVERSE REACTION:
“ One which is noxious and unintended, and
which occurs at doses normally used in
man for the prophylaxis, diagnosis, or
therapy of disease, or for the modification
of physiological function ”of physiological function ”
The terms “adverse reaction” and “adverse
effect” are interchangeable, except that an
adverse effect is seen from the point of
view of the drug, whereas an adverse
reaction is seen from the point of view of
the patient.
4. The term “adverse effect” encompasses all
unwanted effects; it makes no
assumptions about mechanism, evokes no
ambiguity, and avoids the risk of
misclassification.
The term “adverse effect” is preferable to
other terms such as “toxic effect” or
“side effect”.“side effect”.
6. ADVERSE DRUG EVENT (AE)
Any occurrence or worsening of an
undesirable or unintended sign, symptom
(including an abnormal laboratory
finding), or disease temporally associatedfinding), or disease temporally associated
with the use of a medicinal
product/procedure.
which does not necessarily have a causal
relationship with this treatment
7. • Following scale will be used to estimate
Adverse drug Event grade:
• Grade 1, Mild: Transient or mild
discomfort; no limitation in activity; no
medical intervention/therapy required
• Grade 2, Moderate: Mild to moderate
limitation in activity –some assistance
may be needed; no or minimal medical
intervention/therapy required
8. • Grade 3, Severe: Marked limitation in
activity, some assistance usually
required; medical intervention/therapy
required and hospitalization possible
• Grade 4, Life-Threatening: Extreme
limitation in activity, significant
assistance required; significant medical
intervention/therapy required;
hospitalization or hospice care
9. SIGNAL
• Reported information on a possible causal
relation between an adverse event and a drug,
the relation being previously unknown or
incompletely documented.incompletely documented.
Usually more than a single report is required to
generate a signal,depending on the seriousness
of the event and the quality of the information.
10. PHARMACOVIGILANCE
• Pharmacovigilance (PV) is defined as
the science and activities relating to
the detection, assessment,the detection, assessment,
understanding and prevention of
adverse effects or any other drug-
related problem.
11. HAEMOVIGILANCE
• Monitoring, identification, reporting,
investigation and analysis of adverse events
near-misses and reactions related to blood
transfusion.transfusion.
• Adverse events following immunization (AEFI)
12. PHARMACOVIGILANCE-BENEFITS
Pharmacovigilance plays an important role
in the rational use of medicines by
providing information about ADRs in the
general population.
Knowledge of the adverse effects of drugs Knowledge of the adverse effects of drugs
is important for effective treatment.
Communicating the potential harm of drug-
use to patients is a matter of high priority
and should be carried out by every
prescriber.
14. • Drug use in special situations not studied
in clinical trials (Renal and hepatic failure
patients).
Need of ADR Monitoring
• Most trials assess relatively healthy
patients with only one disease and mostly
exclude specific groups such as pregnant
women, children, and elderly people.
15. • As most drugs are developed in the West,
most of the efficacy data are based on the
Caucasians, with little or no information
available on the Asians.
• Drug interactions may not be studied in• Drug interactions may not be studied in
clinical trials. There is no data on ADRs
that may occur due to the interaction
between the established medicines and
traditional, herbal medicines and vaccines
used locally.
16. Prevalence of ADR
The median proportions of Prevalence of ADR-
related hospitalization in developed and
developing countries was 6.3 % (3.3–11.0) and
5.5 % (1.1–16.9), respectively.
The median proportions of preventable ADRs in The median proportions of preventable ADRs in
developed and developing countries were 71.7 %
(62.3–80.0) and 59.6 % (51.5–79.6), respectively.
Similarly, the median proportions of ADRs
resulting in mortality in developed and
developing countries were 1.7 % (0.7–4.8) and
1.8 % (0.8–8.0), respectively.
18. 27 studies on antipsychotics causing diabetes or other metabolic problems
26 studies on antipsychotics causing heart problems
23 studies on antipsychotics causing weight gain or obesity
22 studies on antipsychotics causing death
8 studies on antipsychotics causing stroke
8 studies on antipsychotics causing involuntary movements
5 studies on antipsychotics causing brain shrinkage and/or structural changes
4 studies on antipsychotics causing cognitive decline or impairment
ANTIPSYCHOTIC DRUG STUDIES:
There are 160 studies from 25 countries
4 studies on antipsychotics causing cognitive decline or impairment
3 studies on antipsychotics causing Parkinson’s Disease
3 studies on antipsychotics having lack of efficacy
3 studies on antipsychotics causing lowered bone mass
3 studies on antipsychotics causing sexual dysfunction
2 studies on antipsychotics causing birth defects
1 study on antipsychotics causing violence and homicidal ideation
1 study on antipsychotics causing psychosis
1 study on antipsychotics causing tumors
1 study on antipsychotics causing coma
19. • 41,000 hospitalizations per year for NSAID-
induced ulcers.
• 16,000 car crashes per year from anti-
psychotics.
Some examples of studies pointing out the results of
adverse drug events
psychotics.
• 32,000 hip fractures per year leading to 1,500
deaths.
• Drug-induced Parkinson’s has developed in
63,000 patients.
20. • 21.3% of the 548 most recently FDA
approved medications were subsequently
withdrawn from the market or given a black
box warning.
• In the recent reports, 51% of new drugs
have serious, undetected adverse effects athave serious, undetected adverse effects at
the time of approval.
• Of the best selling prescription drugs, 148
can cause depression, 133 hallucinations or
psychoses, 105 constipation, 76 dementia,
27 insomnia and 36 parkinsonism.
27. TYPE OF ADVERSE REACTIONS
♠ Type A (Augmented)
♠ Type B (Bizarre)
♠ Type C (Chronic)
♠ Type D (Delayed)
♠ Type E (End of use)
♠ Type F (Therapeutic failure)
♠ Type G (Genetic/genomic)
28. CAN YOU DEFINE THE
VARIATIONS BETWEEN THIS
TYPES OF ADRs?....
29. 11) Type A ADRs) Type A ADRs
Type A (augmented) ADRs are expected
but exaggerated pharmacological or toxic
responses to a drug.
This may be an exaggeration of the This may be an exaggeration of the
intended response to the drug, a
secondary response affecting an organ
other than the target organ but
predictable based on the pharmacology of
the drug, or a toxic response.
30. TypeType AA ADRsADRs contdcontd……......
Most ADRs of this type is due to higher
plasma free drug concentrations
They are usually dose dependent and
avoidable if sufficient drug and patient
information is available.
33. Type A reactions (classes)Type A reactions (classes)
An adverse drug reaction caused by excessive
dosing
I) Toxicity of Overdose (Drug Overdose) :
e.g., Hepatic failure with dose of
paracetamol
Headache with antihypertensives
Hypoglycemia with sulfonylurea;
34. The causes of these types of abnormalities
can be categorized as pharmaceutical,
pharmacokinetic or pharmacodynamic.
35. PharmaceuticalPharmaceutical (dosage(dosage formulationformulation -- related)related):: These
problems cause increased availability of the drug at
the site of delivery due to:
Increased drug quantity - Noncompliance with
pharmacopoeia requirements (BP or USP) during drug
manufacture might increase the amount of activemanufacture might increase the amount of active
agent in the dosage formulation,
Enhanced drug release—Improper formulation can
result in sudden or enhanced release of irritant agents
(eg, potassium chloride and indomethacin) from the
dosage formulation.
36. PharmacokineticPharmacokinetic::
This comprises quantitative alterations in
pharmacokinetic parameters resulting in
abnormally high concentrations of the drug at the
site of action with consequent enhancement of
biological effects. These parameters include ADME.
This is exemplified by the individual variation in
rates of microsomal oxidation due to genetic(eg,
debrisoquine hydroxylation), biological(eg, age and
disease state), or environmental (eg, dietary,
pollutants, alcohol & other interacting drugs)
factors.
37. PharmacodynamicPharmacodynamic::
The organ or tissue responsiveness to toxic actions
might be elevated in some patients leading to ADRs.
This increased sensitivity might reflect:
♠ Enhanced activity or increased number of drug
receptors,
♠ Imbalances of individual homeostatic mechanisms,
for example, the development of severe tachycardia
in some individuals after atropine injection,
♠ Disease states such as the development of
obstructive airway disease precipitated by
propranolol in asthmatic patients.
38. II) Side Effects
Nearly unavoidable secondary drug effect
produced by therapeutic doses
intensity is dose dependent intensity is dose dependent
Occur immediately after initially taking drug or
may not appear until weeks after initiation of
drug use
E.g., sedation with antihistamines
39. III) Drug Interactions
When two drugs taken together & they effect
each other’s response alter
pharmacologically or kinetically
E.g., one drug slow metabolism of 2nd drug
plasma drug conc. toxicity
Theophylline toxicity in presence of
erythromycin
40. 2) Type B reactions or2) Type B reactions or BizzareBizzare
• Type B reactions or Bizzare
– refers to totally abnormal effects,
unrelated from the drug’s known
pharmacological actions.
41. CHARACTERISTICS OF BIZZARE
REACTION
♦ illness is often recognizable as an
immunological reaction.
♦ undetectable during conventional testing.
♦ little or no relation to the usual
pharmacological effects of the drug.
♦ delay between first exposure to the drug
and the occurrence of the subsequent
adverse reaction.
42. Type B Reactions (classes)
I) Hypersensitivity (immunological reaction)
HYPERSENSITIVITY REACTION
I) Hypersensitivity (immunological reaction)
Immune mediated response to a drug agent
in sensitized patient
e.g., anaphylaxis with penicillin
43. Mechanism and types of allergic reactions
A. Humoral
Type-I (anaphylactic) reactions
Reaginic antibodies (IgE) are produced which get
fixed to the mast cells.
Hypersensitivity - I
On exposure to the drug, AG: AB reaction takes
place on the mast cell surface releasing mediators
like histamine, 5-HT, leukotrienes (especially LT-
C4 and D4) prostaglandins, PAF, etc. resulting in
urticaria, itching, angioedema, bronchospasm,
rhinitis or anaphylactic shock.
44. Hypersensitivity -
Mast Cell
Degranulation
Anaphylaxis is usually heralded by paresthesia,
flushing, swelling of lips, generalized itching,
wheezing, palpitation followed by syncope. The
manifestations occur quickly after challenge and
are called immediate hypersensitivity.
Hypersensitivity -
Gell & Coombs Type I
Degranulation
45. Type-II (cytolytic) reactions
Drug + component of a specific tissue cell act as
AG.
The resulting antibodies (IgG, IgM) bind to the
Hypersensitivity - II
target cells; on reexposure AG: AB reaction takes
place on the surface of these cells, complement
is activated and cytolysis occurs, e.g.
thrombocytopenia, agranulocytosis, aplastic
anaemia, haemolysis, organ damage (liver,
kidney, muscle), systemic lupus erythematosus.
46. Hypersensitivity -
Gell & Coombs Type II
NK Cell
Phagocyte
Complement
Removed by
Reticuloendothelial
System
47. Hypersensitivity - III
Type-III (retarded, Arthus) reactions
These are mediated by circulating antibodies
(predominantly IgG, mopping AB). AG: AB complexes
bind complement and precipitate on vascular
endothelium giving rise to a destructiveendothelium giving rise to a destructive
inflammatory response. Manifestations are rashes,
serum sickness (fever, arthralgia, lymph
adenopathy), polyarteritis nodosa, Steven Johnson
syndrome (erythema multiforme, arthritis,
nephritis, mental symptoms). The reaction usually
subsides in 1–2 weeks.
48. Hypersensitivity - IV
B. Cell mediated
Type-IV (delayed hypersensitivity) reactions
These are mediated through production of
sensitized T-lymphocytes carrying receptors for
the AG. On contact with the AG these T cellsthe AG. On contact with the AG these T cells
produce lymphokines which attract granulocytes
and generate an inflammatory response, e.g.
contact dermatitis, some rashes, fever,
photosensitization. The reaction generally takes
> 12 hours to develop.
49. IDIOSYNCRATIC REACTIONS
• An uncommon & abnormal response to drug
• Usually due to genetic abnormality
• Affect drug metabolism & receptor
sensitivity
• Harmful even fatal, appear in low doses
E.g., Anemia (hemolysis) by antioxidant drugs
(G6PD deficiency)
Paralysis due to succinylcholine
(enzyme deficiency)
51. 3) Type C (chronic) Reactions3) Type C (chronic) Reactions
Associated with long-term drug
therapy
Well known and can be anticipated
E.g. opoids, alcohol, barbiturates
52. 4) Type D (delayed) Reactions4) Type D (delayed) Reactions
♦ Carcinogenic & teratogenic effects
♦ Delayed in onset
♦ Very rare
Carcinogenic EffectCarcinogenic Effect
Medication lead to cancer; take >20 y to
develop
Teratogenic Effect
Drug- induced birth defects
53. CURRENT STATUS OFCURRENT STATUS OF
PHARMACOVIGILANCE IN INDIAPHARMACOVIGILANCE IN INDIA
♠ Pharmacovigilance is an integral part of drug therapy.
♠ Still, it is not widely practiced in Indian hospitals. In
various studies, adverse drug reactions have beenvarious studies, adverse drug reactions have been
implicated as a leading cause of considerable
morbidity and mortality
♠ Currently the role of the pharmacist in the reporting
of ADRs is not appreciated everywhere.
