Description
Adverse Drug Reactions
What is ADRs?
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
• Common Causes of ADRs
• Factors affecting Adverse Drug Reactions
• Classification of ADRs
• Type A (Augmented) reactions
• Type B (Bizarre) reactions
• Type C ( Chronic)
• Type D (Delayed) reactions
• Type E (End of use) reactions
• Types of ADRs
• Classification of ADRs :
• Side effects
• Side effects….(Drug discovery)
• Toxic effect:
An adverse effect of a drug produced by an exaggeration of the effect that produce the therapeutic response.
• Predictable toxic effects
• Unpredictable toxic effects
• Idiosyncrasy
• Drug allergy
• Grading system for hypersensitivity reactions
• Intolerance
• Tachyphylaxis:
• Difference between Tachyphylaxis and Tolerance
• Photosensitivity
• Drug dependence
• Mutagenecity and Carcinogenicity
• Iatrogenic(Physician induced)
• Teratogenicity
• Individual variation in response to
• B) Variation in concentration of an
endogenous receptor ligand
• A) Alteration in concentration of
drug that reaches the receptors
• C) Alteration in number or function
of receptor
• D) Changes in components of
response distal to the receptor
• How to recognize ADRs
• Role of Pharmacist in the management of ADRs
• 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.
•
- Subject:- pharmacology 1
- Course:- B.pharm (pharmacy),
- Semester:- 4th sem , sem :- 4
ADVERSE DRUG
REACTIONS
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What is ADRs?
WHO Definition
Any response to a drug which
is noxious & unintended &
which occurs at doses in man
for prophylaxis, diagnosis or
treatment.
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History about ADRs
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.
. www.remixeducation.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.
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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.
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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.
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Factors affecting Adverse
Drug Reactions
Patient-related factors
Age
Sex
Genetic influences
Concurrent diseases (renal,liver, cardiac)
Previous adverse drug reactions
Compliance with dosing regimen
Total number of medications
Misc. (diet, smoking, environmental exposure)
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Factors affecting Adverse
Drug Reactions
Drug-related factors:
Dose
Duration
Inherent toxicity of the agent
Pharmacodynamic properties
Pharmacokinetic properties
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Classification of ADRs
Depending on
Onset of event: Acute (<60 minutes), Sub-acute (1-24 hrs)
and Latent (>2 days)
Type of reaction: (Wills and brown)
1. A (Augmented)
2. B (Bizarre)
3. C (Chronic)
4. D (Delayed)
5. E (End of treatment)
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Classification of ADRs
Severity: Minor, Moderate, Severe, Lethal ADRs
Others: Side effects, Secondary effects, Toxic
effects, Intolerance, Idiosyncrasy, Drug allergy,
Mutagenicity, Photosensitivity, Drug Dependence,
Drug Withdrawal Reactions, Teratogenicity,
Carcinogenicity, Drug induced disease (Iatrogenic).
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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.
E.g.
• Anticoagulants Bleeding
• Beta blockers Bradycardia
• Nitrates Headache
• Prazosin Postural hypotension www.remixeducation.in
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:
Immunologic An allergic or hypersensitivity reaction
occurs as a result of an immunologic mechanism.
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Type B (Bizarre)
reactions
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 www.remixeducation.in
Type C ( Chronic)
Reactions due to long time exposure.
e.g. Analgesic neuropathy
Dyskinesia with levodopa
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Type D (Delayed) reactions
• Occur due to prolonged exposure.
• Can be due to accumulation.
E.g.
Carcinogenesis, or short term exposure at a critical time
e.g.teratogenesis.
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Type E (End of use) reactions
• Occur on withdrawal especially when drug is stopped
abruptly.
E.g.
• Phenytoin withdrawal Seizures
• Steroid withdrawal Adrenocortical insufficiency.
• opioid causing the withdrawal syndrome.
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Types of ADRs
Type Type of characteristics example
effect
A Augmented Dose dependent Hypoglycaemia-
predicted from the insulin
known
pharmacology of the
drug
B Bizarre Unpredictable Anaphylaxis to
Dose independent penicillin
Rare,fatal
C Chronic Prolong treatment Analgesic neuropathy
D Delayed After years of Antipsycotic –turdive
treatment dyskinesia
E End of use Withdrawal effect GC withdrawal
adrenocortical
Classification of ADRs :
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. www.remixeducation.in
Side effects
Unwanted but often unavoidable, occur at therapeutic
doses
Predicted from the pharmacological profile of a drug
Known to occur in a given percentage of drug recipients
E.g.
Atropine dryness of mouth
Promethazine (anti-allergic) sedation
Codeine(anti-tussive)constipation Used in Traveller’s
diarrhea
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Side effects….(Drug discovery)
Occasionally, “adverse” effects may be exploited to
develop an entirely new indication for a drug.
E.g:
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…
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Toxic effect:
An adverse effect of a drug produced by an
exaggeration of the effect that produce the therapeutic
response.
Predictable Unpredictable
Dose dependent Allergy
Rebound response Idiosyncrasy
Detected during drug Not detected during drug
development development
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Predictable toxic effects
Dose dependent adverse effect may be –
Direct damaging effect to tissue: Paracetamol overdose
leads to hepatotoxicity, Aminoglycoside (Gentamicin) causes
nephrotoxicity.
Rebound response: abrupt withdrawl after chronic use.
Glucocorticoid withdrawal leads to acute adrenal
insufficiency.morphine – due to R supersensitivity.
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Excess pharmacological effect:
Result of excessive pharmacological action of the drug due
to over dosage or prolonged use.
Excess insulin-hypoglycemia even death from
hypoglycemic shock
Antihypertensive - hypotension
Anticoagulant- severe bleeding.
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Unpredictable toxic effects
Dose independent:
Less than therapeutic dose may lead to toxic effect
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Idiosyncrasy
unusual response to a drug due to genetic abnormality.
Drug interacts with some unique feature of the individual,
not found in majority subjects, and produces the
uncharacteristic reaction.
E.g.
Isoniazid: N-Acetylation affects the metabolism of isoniazid
Slow N-Acetylation: Isoniazid is more likely to cause
peripheral neuritis.
Fast N-Acetylation:cause hepatotoxicity in this group.
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Succinylcholine can produce apnea in people with
abnormal serum cholinesterase. Their cholinesterase is
incapable of degrading the succinylcholine, thus it builds up
and depolarization blockade results.
Primaquine, Sulfonamides induce acute hemolytic
anemia in patients with Glucose-6-Phosphate
Dehydrogenase deficiency.
--They have an inability to regenerate NADPH in RBC.G-6-p
deficiency is most prevalent in blacks. It is rare in Asians.
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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,not occurred in all
Occurs on reexposure
E.g. penicillin→1st time →stimulate antibody →Ag-
Ab reaction →allergy
Chief organ: Skin, respiratory tract,GIT,Blood &
blood vessels www.remixeducation.in
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Grading system for
hypersensitivity reactions
Grade
including
Broad clinical features
anaphylaxis
Defining symptoms and signs
1 Cutaneous and Generalized erythema, periorbital
subcutaneous only edema, urticaria, or angioedema
Mild
2 Cardiovascular, Dyspnea, stridor, wheeze, nausea,
respiratory, or vomiting, dizziness, diaphoresis, chest
Modera gastrointestinal or throat tightness, or abdominal
te involvement pain
3 Hypoxia, hypotension, or = 92 % at any stage, hypotension
neurologic compromise (systolic BP < 90 mmHg in adults),
Severe confusion, collapse, loss of
consciousness, or incontinence
Cyanosis or SpO2
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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
E.g.
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
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Tolerance
↓ pharmacological effect on repeated administration of
the drug.
Pharmacokinetic Tolerance: ↑ the enzymes
responsible for metabolizing the drug.
e.g.Phenobarbitone induces metabolism of its own by
increasing its own metabolic enzyme.
Pharmacodynamic Tolerance: Cellular tolerance, due
to down-regulation of receptors.
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Tachyphylaxis:
When responsiveness diminishes rapidly after
administration of a drug, the response is said to be
subject to tachyphylaxis.
Tachyphylaxis to the Action of Topically Applied
Corticosteroids
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Difference between
Tachyphylaxis and Tolerance
Tachyphylaxis is the result of frequent doses over a short
period of time and tolerance is the result of chronic
administration over a long period. It can be predicted from
the word origin. ‘Tachy-‘ means very fast as is used for
tachycardia, ‘-phylaxis’ means defense, and the word is
composed of these, tachyphlaxis, which means rapid
decrease in the response to a drug after repeated doses
(over a short period). A typical example of tachyphyalaxis
is epinephrine’s action on vessels (blood pressure).
Repetitive stimulus over a short time causes the depletion
of a vasoconstricting substance, which results in the
attenuation of response. Tolerance can occur with
morphine or an alcoholic beverage. www.remixeducation.in
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
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Photosensitivity
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
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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
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Drug dependence
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 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.
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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
e.g.
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.
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Iatrogenic(Physician
induced)
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Teratogenicity
Capacity of a drug to cause foetal abnormalities when
administered to the pregnant mother.
Drugs can affect the foetus at 3 stages:
• Fertilization and implantation (Conception to 17
days): failure of pregnancy which often goes
unnoticed.
• Organogenesis (18 days to 55 days): most
vulnerable period, deformities are produced.
• Growth and development (>56 days):
developmental and functional abnormalities can
occur. E.g:
Thalidomide Phocomelia, multiple defects
Anticancer drugs Cleft palate, hydrocephalus,
multiple defects. www.remixeducation.in
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Drugs known to be
teratogenic
Anticancer drugs – Methotrexate – multiple deformity.
Steroid – cleft palate and other.
Oral anticoagulants – bony abnormality (Hypoplastic
nasal structures), optic atrophy, mental retardation.
Oral hypoglycemic agents - multiple deformity.
Androgenic hormone – virilization, hermaphrodite, lid
retraction.
Tetracycline – inhibit bony growth.
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Cont’d
Trimethoprim – cleft palate.
Phenytoin, carbamazepine, valproate -Malformation of
fingers,cleft palate,neural tube defect(spina bifida)
Diethylstilbestrol - Oral contraceptive is no longer used
because it causes reproductive cancers in daughters born
to mothers taking the drug.
Androgen- virulization of female fetus
Aminoglycosides, Chloroquine – Deafness.
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Individual variation in response to
drug
Variation due to age, sex, body weight, surface area,
nutrition, alcoholic, cigarette smoking, pregnancy, genetic
factor, environment, and pathological condition.
4 general mechanism:
A) Alteration in concentration of
drug that reaches the receptors –
rate of absorption of a drug
distributing it through body compartments
clearing the drug from the blood.
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B) Variation in concentration of an
endogenous receptor ligand –
variability in responses to pharmacological antagonist.
propranolol will markedly slow the HR of a patient whose
endogenous catecholamine are elevated (as in
pheochromocytoma), but will not affect the resting HR of
a well trained marathon runner.
C) Alteration in number or function
of receptor –
↑ or ↓ in number or alteration in efficiency of coupling of
receptor to distal effector mechanism – change in
responsiveness.
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e.g.Thyroid hormone increase number of β receptor in
heart and increase sensitivity of cardiac muscle to
catecholamine – tachycardia of thyrotoxicosis.
D) Changes in components of
response distal to the receptor –
Response depend on the functional integrity of
biochemical process in the responding cell and
physiological regulation by interacting organ system.
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How to recognize ADRs
Ensure, medicine received & actually taken by the
patient at the dose advised.
Verify the onset of suspected ADR is after taking the
drug.
Determine the time interval between drug taken – onset
of event.
Evaluate the suspected ADR after discontinuing the
drug / reduced dose, monitor status.
Analyse the alternate cause (other than the drug).
Use relevant literature & experienced physician opinion.
Report the ADR
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Cont’d…
Medicines are supposed to save lives Dying from a disease
is sometimes unavoidable; dying from a medicine is
unacceptable. Lepakhin V. Geneva 2005.
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Cont’d…
Among the Leading cause of death-
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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.
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Role of Pharmacist in the
management of ADRs
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.
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Role of Pharmacist in the
management of ADRs
The pharmacist should facilitate
1. Analysis of each reported ADR.
2. Identification of drugs and patients at high risk for
being involved in ADRs.
3. The development of policies and procedures for the
ADR-monitoring and reporting program.
4. A description of the responsibilities and interactions
of pharmacists, physicians, nurses, risk managers,
and other health professionals in the ADR program.
5. Use of the ADR program for educational purposes.
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Role of Pharmacist in the
management of ADRs
6. Development, maintenance, and evaluation of ADR
records within the organization.
7. The organizational dissemination and use of
information obtained through the ADR program.
8. Reporting of serious ADRs to the FDA or the
manufacturer (or both).
9. Publication and presentation of important ADRs to the
medical community.
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Role of Pharmacist in the
management of ADRs
Direct patient care roles for pharmacists should
include patient counseling on ADRs, identification
and documentation in the patient’s medical record of
high-risk patients, monitoring to ensure that serum
drug concentrations remain within acceptable
therapeutic ranges, and adjusting doses in
appropriate patients (e.g., patients with impaired
renal or hepatic function).
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Thank you
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