Pharmacovigilance AND ADVERSE DRUG REACTIONS. MONITORING REPORTING ROLE OF PHARMACIST. CLASSIFICATION OF ADR. MECHANISM OF ADR ROLE OF PHARMACIST IN MANAGING ADR. AUGMENTED, BIZZARE, CONTINOUS, DELAYED, END OF TREATMENT, ABCD, ABCDE.

1. PHARMACOVIGILANCE
AND
ADVERSE DRUG REACTIONS
AKHIL JOSEPH
PHARM.D 5TH YEAR

2. DEFINITION
• PHARMACOVIGILANCE (PV) ALSO CALLED AS DRUG SAFETY
• PHARMAKON------- IN GREEK ----DRUG
• VIGILARE ----------- IN LATIN ------TO KEEP WATCH
• Pharmacovigilance is the science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other
drug related problem.

3. HISTORY
 FROM THE EARLIEST TIMES, PHARMACEUTICAL FORMULATIONS HAVE BEEN RECOGNIZED
AS BEING POTENTIALLY DANGEROUS.
 PUBLIC AND PROFESSIONAL CONCERN ABOUT THESE MATTERS FIRST AROSE IN THE LATE
19TH CENTURY.
 IN 1922, THERE WAS AN ENQUIRY INTO THE JAUNDICE ASSOCIATED WITH THE USE OF
SALVARSAN, AN ORGANIC ARSENICAL USED IN THE TREATMENT OF SYPHILLIS.
 IN 1937 IN THE USA, 107 PEOPLE DIED FROM TAKING AN ELIXIR OF SULFANILAMIDE
THAT CONTAINED THE SOLVENT DIETHYLENE GLYCOL
 THIS LED TO THE 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.
 MAJOR MODERN CATASTROPHE THAT CHANGED PROFESSIONAL AND PUBLIC OPINION
TOWARDS MEDICINES WAS THE THALIDOMIDE INCIDENT.

4.  IN 1961, IT WAS REPORTED IN WEST GERMANY THAT THERE WAS AN OUTBREAK OF
PHOCOMELIA (HYPOPLASTIC AND APLASTIC LIMB DEFORMITIES) IN THE NEW BORN
BABIES.
 IT WAS SHOWN SUBSEQUENTLY THAT
• THALIDOMIDE, A NON BARBITURATE HYPNOTIC, WAS
• TO BLAME.
 THE CRUCIAL PERIOD OF PREGNANCY DURING WHICH THALIDOMIDE IS TERATOGENIC IS
THE FIRST THREE MONTHS.
 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.

5. Drug Year Adverse Reaction Outcome
Sulfanilamide 1937 Liver damage due to
diethylene glycol
Solvent changed; FDA
established
Thalidomide 1961 Congenital Malformations Withdrawn
Chloramphenicol 1966 Blood Dyscrasias Uses restricted
Benoxaprofan 1982 Liver damage Withdrawn
Aspirin 1986 Reye’s syndrome Uses restricted
Flecainide 1989 Cardiac Arrhythmias Uses restricted
Noscapine 1991 Gene toxicity Withdrawn
Triazolam 1991 Psychiatric disorders Withdrawn
Temafloxacin 1992 Various serious adverse
effects
Withdrawn
Co-trimoxazole 1995 Serious allergic
reactions
Uses restricted
Terfenadine 1997 Interactions (e.g. with
grapefruit juice)
Withdrawn from OTC sale
Sotalol 1997 Cardiac
arrhythmias
Uses restricted
Astemizole 1998 Interactions Withdrawn
Cisapride 2000 Cardiac
arrhythmias
Withdrawn
Cerivastatin 2001 Rhabdomylosis Withdrawn
DRUGS THAT HAVE BEEN WITHDRAWN OR HAVE HAD THEIR USES
RESTRICTED BECAUSE OF ADR

6. AIMS
• To improve patient care and safety in relation to the use of medicines, and all medical and
paramedical interventions;
• To improve public health and safety in relation to the use of medicines;
• To contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging
their safe, rational and more effective (including cost-effective) use;
• To promote understanding, education and clinical training in pharmacovigilance and its effective
communication to health professionals and the public.
• To promote rational and safe use of medicines.

7. GOALS
The ultimate goals of pharmacovigilance are:
• The rational and safe use of medical drugs.
• The assessment and communication of the risks and benefits of drugs on the
market.
• Educating and informing of patients.

8. Why do we need pharmacovigilance ?
1. Humanitarian concern
-Animal toxicology is often not a good predictor for human effects.
-Evidence of safety from clinical trials is insufficient due to some limitations
• LIMITATIONS (phase 1-3): limited size ,
• Narrow population (age &sex specific),
• Narrow indications (only specific disease),
• Short duration

9. 2. Safe use of medicines
• Medicines are supposed to save lives.
• Dying from a disease is sometimes unavoidable; dying from a medicine is unacceptable.
• It has been find that ADR’s may cause 5700 deaths per year in U.K.
• ADR’s were 4th-6th commonest cause of death in the us in 1994.
3. ADR’s ARE EXPENSIVE
• 6.5% of admissions are due to ADR’s
• Cost £446 million per annum in U.S.
4. Promoting rational use of medicines
5. Ensuring public confidence
6. To protect patients from unnecessary harm
6. Ethical concern
• To know of something that is harmful to another person who does not know, and not telling, is unethical.

10. ADVERSE DRUG REACTIONS
• 'A response to a drug 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 modifications of physiological function’ is called as an
ADR.
• An adverse event (ae) is any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product and which does not necessarily have a causal relationship with this
treatment.
• An adverse event (ae) can therefore be any unfavourable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product,
whether or not related to the medicinal (investigational) product.
• Serious adverse event or reaction is any untoward medical occurrence that at any dose; – results in death, life
threatening, requires inpatient hospitalization or prolongation of existing hospitalization – results in persistent of
significant disability or incapacity.
• Thus all adr are adverse events but all adverse events are not ADR.

11. PREDISPOSING FACTORS
1. RACE:
Certain population in Africa and south east Asia have people who are deficient in glucose ‐ 6 ‐ phosphate
dehydrogenase, such individuals are at substantial risk of developing haemolytic crises after the use of anti
malarial drugs like primaquine. The rate at which drugs are acetylated varies considerably between ethnic
groups. Rapid acetylators predominate among eskimos and slow acetylators among jews. Slow acetylators are
likely to suffer from peripheral neuropathy due to INH.
2. GENDER:
Women are likely to suffer from certain ADR than men. Agranulocytosis caused by phenylbutazone or
chloramphenicol is 3 times more potent in women than in men.
3. AGE:
The elderly over the age of 60 years are more susceptible for adr than the younger groups. It is well known
that elderly are more sensitive to analgesics and become more confused with barbiturates. After a standard IV
dose of pethidine, the plasma concentration is higher and half life is longer in older than in younger patients.

12. In younger patients , neonates when premature, some enzymes involved in drug metabolism and elimination are
poorly developed and consequently the risk of ADR is high. HAZARDOUS DRUGS: chloramphenicol,
sulphonamides, barbiturates.
4. ALLERGIC DISORDER:
patients with allergic disorder and hyper sensitivity reaction are more likely to develop from ADR.
5. RENALAND HEPATIC DISEASES:
impaired renal and hepatic function predisposes ADR to those drugs that are wholly or mainly excreted unchanged in
urine.
6. PLASMA PRITEIN BINDING:
The pharmacological action and toxicity of certain drugs are influenced by degree to which they bind to plasma
protein, mainly to albumin. A decrease in plasma albumin level due to age, malnutrition or disease and metabolism of
drugs that are highly protein bound. Example : WARFARIN.
7. FORMULATION OFTHE DRUG:
Epidemics of particular drug ADR occur because of toxic vehicles or change in formulation when pharmaceutical
manufacturer change the excipients present in some capsules of phenytoin in the form of calcium sulphate dihydrate
to lactose, many patients develop symptoms of phenytoin toxicity.

13. CLASSIFICATION
• Type A : ‘Augmented’: on-target (too much of a good thing) - predictable.
• Type B : ‘Bizzare’: idiosyncratic, vary from patient to patient - unpredictable.
• Type C : ‘Continuous’: adverse effects which arise from long-
term use of a drug. They may be perfectly safe and effective in the short term, but can become un
favourable with chronic use, die to physiological adaptations / accumulation of adverse effects.
• Type D : ‘Delayed’: adverse drug effects long after the drug is gone.

14. Type A : ‘Augmented’: DOSE-RELATED ADVERSE DRUG REACTIONS:
a) PHARMACEUTICAL VARIATION
b) PHARMACOKINETIC VARIATION
i. PHARMACOGENETIC VARIATION
ii. HEPATIC DISEASE
iii. RENAL DISEASE
iv. CARDIAC DISEASE
v. THYROID DISEASE
vi. DRUG INTERACTIONS
C. PHARMACODYNAMIC VARIATION
i. HEPATIC DISEASE
ii. ALTERED FLUID AND ELECTROLYTE BALANCE
iii. DRUG INTERACTIONS

15. Type B : ‘Bizzare’: NON-DOSE RELATED ADVERSE DRUG REACTIONS
a) IMMUNOLOGICAL REACTIONS
b) PSEUDO ALLERGIC REACTIONS
c) PHARMACOGENETIC VARIATION
Type C : ‘Continuous’: LONG-TERM ADVERSE DRUG REACTIONS
a) ADAPTIVE CHANGES
b) REBOUND PHENOMENA
Type D : ‘Delayed’: DELAYED ADVERSE DRUG REACTIONS
a) CARCINOGENESIS
b) EFFECTS CONCERNED WITH REPRODUCTION
i. IMPAIRED INFERTILITY
ii. TERATOGENESIS
iii. DRUGS IN BREAST MILK
Type E : ‘End of treatment effect’ :

16.  Dose related adverse reactions have led to the concept of the
THERAPEUTIC INDEX, or the TOXIC:THERAPEUTIC
RATIO.
 This indicate the margin between the therapeutic dose and
the toxic dose.
 The bigger the ratio, the better.
 Examples of drugs with a low TOXIC:THERPEUTIC RATIO:
• Anticoagulants (warfarin, heparin)
• Hypoglycemic drugs (insulin, sulfonylurea) Antiarrythmic
drugs (lidocaine, amiodarone)

17. • Cardiac glycosides
• (digoxin, digitoxin)
• Amino glycoside antibiotics (gentamicin,
netilmicin)
• Oral contraceptives
• Cytotoxic and immunosuppressive drugs (cyclosporine, methotrexate,
azathioprine)
• Antihypertensive drugs ( beta adrenoceptors antagonists, ACE
inhibitors)
 Dose-related adverse reactions can occur because of variations in the
Pharmaceutical, Pharmacokinetic, or
Pharmacodynamic properties of a drug, often due to Pharmacogenetic
characteristic of a patient.

18.  Adverse drug reactions occur because of alterations
in the systemic availability of a formulation
EXAMPLE:
Phenytoin Intoxication, by a change in one of the
excipients in the phenytoin capsules from calcium
sulfate to lactose, which increase the systemic
availability of phenytoin.
 Adverse reaction can occur because of the
presence of a contaminant
EXAMPLE:
Pyrogens or even Bacteria in intravenous
formulations.

19.  Out of date formulations can sometimes cause
adverse reactions, because of degradation
products
EXAMPLE:
out-dated Tetracycline can cause Fanconi’s
Syndrome.

20.  There is much variation among normal
individuals in the rate of elimination of
drugs.
 This variation is most marked for drugs that
are cleared by hepatic metabolism.
 It is determined by several factors, which
may be GENETIC, ENVIRONMENTAL, or
HEPATIC.

21. Acetylation
Oxidation
Succinylcholine hydrolysis
Acetylation:
 Acetylation shows genetic variability.
 There are Fast and Slow acetylators.
 Several drugs are acetylated by N- ACETYL
TRANSFERASE.
 Fast Acetylation is autosomal dominant and
Slow Acetylation is autosomal recessive.

22.  Drugs whose Acetylation is genetically
determined are:
• Isoniazid
• Hydralazine
• Procainamide
• Dapsone
• Some sulfonamides
Increased incidence of PERIPHERAL
NEUROPATHY is observed in slow acetylators of
Isoniazid

23. OXIDATION:
 Oxidation also shows genetic variability.
 There are individuals with impaired oxidation
and with normal oxidation.
 Impaired oxidation ones are called as POOR
METBOLIZERS and the ones with normal are
called EXTENSIVE METABOLIZERS.
Debrisoquine type:
 CYP2D6 is a cytochrome P450 enzyme and
carries out Debrisoquine hydroxylation.
 Impaired hydroxylation of Debrisoquine is an
AUTOSOMAL RECESSIVE DEFECT of this
cytochrome.

24.  Drugs that are affected besides Debrisoquine
are:
• Captopril
• Metoprolol
• Phenformin
• Perhexitine
• Nortryptine
 Poor hydroxilators are more likely to show
dose related adverse effect of these drugs.
 In case of toxic metabolites risk would be
greater in extensive hydroxilators.

25. Succinylcholine Hydrolysis:
 Succinylcholine is hydrolyzed by
PSEUDOCHOLINESTRASE.
 In some individuals pseudocholinestrase is abnormal and
does not metabolize succinylcholine rapidly.
 In such cases drug persist in blood and continue to produce
neuro muscular blockade for several hours. This result in
respiratory paralysis called SCOLINE APNOEA.
 There are three types of abnormalities of
pseudocholinestrase each inherited in an AUTOSOMAL
RECESSIVE FASHION.
Dibucaine resistant type
Fluoride resistant type
Silent gene type

26.  Adverse drug reaction due to impaired
hepatic metabolism are not so common.
 Hepatocellular dysfunction, as in several
hepatitis or advanced cirrhosis, can reduce the
clearance of drugs like phenytoin, theophylline
and warfarin.
 A reduction in hepatic blood flow, as in heart
failure, can reduce the hepatic clearance of drugs
that have an high extraction ratio for
e.g. propranolol, morphine and pethidine.
 Reduced production of plasma proteins (for
e.g. albumin) by the liver in cirrhosis can lead
to reduced protein binding of drugs.

27.  If a drug or active metabolite is excreted by glomerular
filtration or tubular secretion, it will accumulate in renal
insufficiency and toxicity will occur.
 Cardiac failure, particularly congestive cardiac
failure, can alter the pharmacokinetic properties of
drugs by several mechanisms:
1) Impaired absorption, due to intestinal mucosal edema
and a poor splanchnic circulation, can alter the efficacy
of some oral diuretic, such as FUROSEMIDE;

28. 2) Hepatic congestion and reduced liver blood
flow may impair the metabolism of some
drugs (e.g. Lidocaine).
3) Poor renal perfusion may result in reduced renal
elimination (e.g. Procainamide).
4) Reduction in the apparent volumes of distribution of
some cardio active drugs, by mechanisms that are not
understood cause reduced loading dose requirements
(e.g. Procainamide, Lidocaine, Quinidine)

29.  Hepatic disease can alter pharmacodynamic
responses to drugs in several ways;
1. Reduced Blood Clotting:
 In cirrhosis and acute hepatitis, production of
clotting factor is impaired and patients bleed
more readily.
 Drugs that impair blood clotting, that impair
homeostasis, or that predispose to bleeding by
causing gastric ulceration should be avoided or
used with care for e.g. Anticoagulants and
NSAIDS.

30. 2. Hepatic Encephalopathy:
 In patients with, or on the border line of,
hepatic encephalopathy, the brain is more
sensitive to the effects of drugs with sedative
actions. If such drugs are used, coma can
result. It is therefore wise to avoid Opioids &
other Narcotic Analgesics and Barbiturates.
3. Sodium and Water Retention:
 In hepatic cirrhosis, sodium and water
retention can be exacerbated by certain
drugs. Drugs that should be avoided or used
with care include NSAIDS, Corticosteroids,
Carbamazepine and formulations containing
large amount of sodium.

31.  The pharmacodynamic effects of some drugs
are altered by changes in fluid and
electrolyte balance.
Example:
 The toxic effect of cardiac glycosides are
potentiated by both Hypokalaemia and
Hypercalcaemia.
 The Class1 of Antiarrhythmic drugs such as
Quinidine, Procainamide and Disopyramide
are more arrhythmogenic if there is
hypokalaemia.

32.  Include
a) IMMUNOLOGICAL and
b) PHARMACOGENETIC mechanisms of adverse
reactions.
There is no relationship to the usual
pharmacological effects of the drug;
There is often a delay between the first exposure to the
drug and the occurrence of the subsequent adverse
reaction;
There is no formal dose-response curve;
The illness is often recognizable as a form of
immunological reaction like rash, serum sickness,
urticaria etc.

33.  Factors involved in drug allergy concern the
Drug and Patients:
THE DRUG:
 Macromolecules such as PROTEINS (vaccines
and enzymes such as streptokinase),
POLYPEPTIDES (insulin and dextrans) can
themselves be immunogenic.
THE PATIENTS:
 There are genetic factors that make some
patients more likely to develop allergic
reactions than others:
 A history of allergic disorders
 HLA status(antigens on human lymphocytes)

34.  Classified acc. to the classification of
hypersensitivity reactions, i.e. into four
types, TYPES I-IV.
Type 1 Reactions
(anaphylaxis; immediate hypersensitivity):
 The drug or metabolite interacts with IgE
molecules fixed to cells, particularly tissue
mast cells and basophiles leukocytes.
 This triggers a process that lead to the
release of pharmacological mediators like
histamine, 5-HT, kinins, and arachidonic acid
derivatives, which cause allergic response.

35.  Manifest as Urticaria, Rhinitis, Bronchial
Asthma, Angio-oedema and Anaphylactic Shock.
 Drugs likely to cause type 1 are
Penicillins, Streptomycin, Local Anaesthetics
etc.
Type II Reactions (Cytotoxic
Reactions):
 A circulating antibody of the IgG, IgM, or IgA class
interact with an antigen formed by hapten.
 Complement is then activated and cell lysis
occurs.
Example: Thrombocytopenia, Haemolytic Anaemia

36. Type III Reactions
(Immune Complex Reactions):
 Antibody (IgG) combines with antigen i.e. the
hapten-protein complex in circulation
 Complex thus formed is deposited in the
tissues, complement is activated, and damage
to capillary endothelium results.
 Serum sickness is the typical drug reaction
of this type.
 Penicillins, Sulfonamides &
Antithyroiddrugs may be responsible.

37. Type IV reactions (Cell Mediated):
 T-lymphocytes are sensitized by a hapten- protein
antigenic complex.
 Inflammatory response ensues when lymphocytes come
in contact with the antigen.
 E.g. Dermatitis caused by local anesthetic creams,
topical antibiotics and antifungal creams.
Pseudo Allergic Reactions:
 Term applied to reactions that resemble allergic
reactions clinically but for which no immunological
basis can be found.
 Asthma and Skin Rashes caused by aspirin are
the examples.

38.  Mechanistic approach does not fit in the
clinical presentation so a clinical approach.
Fever:
 Drug fever as an isolated phenomenon can
occur with penicillin, phenytoin, hydralazine
and quinidine.
Rashes:
 Different types of rashes are shown in the
table given.

39. Type of rash Description Examples of
drugs causing
it
Erythema
multiform
Target like lesions on the
extensor surface of the limbs.
Penicillamine
Penicillin
Sulphonamides
Erythema nodosum Tender red nodules, sometimes
with bruising on the extensor
surface of the limbs.
Phenobarbitals
Sulphonamides
Oral
contraceptives
Exfoliative
dermatitis
Red, scaly, Exfoliative lesions
sometimes involving extensive
areas of skin
Carbamazepine
Gold salts
Phenylbutazone
Pemphigus Widespread blistering Penicillamine
Rifampicin
Urticaria Red raised lesions surrounded
by oedema often confluent
Codiene
Dextrans
Penicillin

40. BLOOD DISORDERS:
 Thrombocytopenia, Neutropenia, Hemolytic
Anaemia, and Aplastic Anaemia can all occur
as adverse drug reactions.
RESPIRATORY DISORDERS:
 Asthma occurring as a pseudo allergic
reaction to Aspirin, other NSAIDS and
Tartarzine is an e.g. adverse drug reaction.

41. Red cell enzyme defects
Porphyria
Malignant hyperthermia
 RED CELL ENZYME DEFECTS:
 Unusual drug reaction occur in individuals whose
erythrocytes are deficient in any one of three
different but functionally related enzymes.
 Glucose-6-phosphate dehydrogenase
 Glutathione reductase
 Methaemoglobin reductase

42. Methaemoglobin reductase
G6PD
Glutathione reductase

43. Glucose-6-phosphate dehydrogenase deficiency:
 G6PD deficient erythrocytes when exposed
to oxidizing agents undergoes Haemolysis.
 The prevalence of this defect varies with race.
 There are two varieties of deficiency:
 Black variety
 Mediterranean variety
 Blacks have normal G6PD production but its
degradation is accelerated.
 Mediterranean have abnormal G6PD production.

44. Glutathione reductase deficiency
 Deficiency is autosomal dominant.
 Deficiency of enzyme directly cause
deficiency of reduced glutathione.
Methaemoglobin reductase
deficiency
 If Methaemoglobin is not reduced to
Haemoglobin continously accumulation of
Methaemoglobin takes place resulting in
impairment of O2 delivery to tissues, causing
HYPOXAEMIA.
 Inheritance of defect is autosomal recessive.

45. PORPHYRIA:
 Porphyrias constitute a group of disorders of
haem-biosynthesis.
 Different types of porphyrias are there:
 Acute intermittent porphyrias
 Variegate porphyria
 Porphyria cutanea tarda
 Erythropoietic Porphyria
 Each type of Porphyria is associated with a
different abnormality of an enzyme in haem-
biosynthetic pathway.
 Drugs to be avoided in porphyria :
Barbiturates, Dapsone, Chloramphenicol,
Diclofenac etc.

46. MALIGNANT HYPERTHERMIA:
 It is an autosomal dominant generic disorder of skeletal
muscles that occurs in susceptible individuals
undergoing General Anesthesia with inhaled agents
(halogenated) and muscle relaxants like
Succinylcholine.
 This rare condition of uncontrolled release of calcium
by sarcoplasmic reticulum of skeletal muscles leads to
muscles spasm, hyperthermia and autonomic liability.
 Dantrolene is indicated in life threatening situations.

47.  Examples include development of tolerance
to and physical dependence on the
NARCOTIC ANALGESICS and the occurrence
of TARDIVE DYSKINESIA in some patients
receiving long term neuroleptic drug therapy
for schizophrenia.
 During long term therapy sudden withdrawal
of the drug can result in rebound reactions.

48. Examples :
 Typical Syndromes occurring after sudden
withdrawal of narcotic analgesic or of alcohol
(delirium tremens).
 Sudden withdrawal of Barbiturates result in
restlessness , mental confusion and
convulsions.
 Sudden withdrawal of β-adrenoceptors
antagonists result in rebound tachycardia
which can precipitate myocardial ischemia.
 Sudden withdrawal of corticosteroids results
in syndrome of adrenal insufficiency.

49.  There are three major mechanisms of
carcinogenesis:
i. Hormonal:
 Incidence of VAGINAL ADENOCARCINOMA is
increased in daughters of women who have
taken STILBOESTROL during pregnancy for
the treatment of threatened abortions.
 Increased risk of BREAST CANCERS is about
50% and woman taking HORMONE
REPLACEMENT THERAPY (HRT) for more than
five years.

50. ii. Gene Toxicity:
 Occurs when certain molecules bind to
nuclear DNA and produce changes in gene
expressions.
Examples:
 BLADDER CANCER in patient taking long term
CYCLOPHOSPHAMIDE
 Carcinomas of RENAL PELVIS associated with
PHENACETIN abuse.
 Non lymphocytic LEUKEMIA in patients
receiving ALKYLATING AGENTS such as
melphalan, chlorambucil etc.

51. iii. Suppression of immune
responses:
 Patients taking immunosuppressive drugs
such as AZATHIOPRINE with
CORTICOSTEROIDS have increased risk of
developing LYMPHOMAS.

52. a. Impaired Fertility
b. Teratogenesis
Impaired Fertility:
 Cytotoxic drugs can cause female infertility
through ovarian failure with amenorrhea.
 Male fertility can be reduced by impairment
of spermatozoal production or function and
can be either reversible or irreversible:

53.  REVERSIBLE IMPAIRMENT can be caused by
sulfasalazine, nitrofurantoin, MAO inhibitors
and antimalarial drugs;
 IRREVERSIBLE IMPAIRMENT, due to azospermia,
can be caused by cytotoxic drugs, such as
alkylating agents cyclophosphamide and
chlorambucil.

54. Teratogenesis:
 Teratogenesis occurs when a drug taken
during early stages of pregnancy causes a
developmental abnormality in a fetus.
 Drugs can affect fetus at 3 stages:
1) FERTILIZATION AND IMPLANTATION:
 Conception to 17 days
 Failure of pregnancy which often goes
unnoticed.
2) ORGANOGENESIS:
 18 to 55 days of gestation
 Most vulnerable period, deformities are
produced

55. 3) GROWTH AND DEVELOPMENT:
 55 days onwards
 development and functional abnormalities
can occur
 ACE inhibitors can cause HYPOPLASIA of
organs
 NSAIDs may induce PREMATURE CLOSURE OF
DUCTUS ARTERIOSUS
 Different teratogenic drugs are:
 Thalidomide, Methotrexate, Warfarin,
Phenytoin, Phenobarbitone, Valproate
Sod.,Lithium, etc.

56. CAUSALITY ASSESSMENT
WHO-UMC CAUSALITY ASSESSMENT SCALE

57. NARANJO’S CAUSALITY ASSESSMENT CRITERIA

58. ROLE OF PHARMACIST IN THE MANAGEMENT OF ADRS
• A pharmacist plays a pivotal role in the identification, detection, prevention, and management of
drug-drug interactions, drug-food interactions and adrs.
• Pharmacist can carry out such activities in inpatient setting, while taking part in viewing charts
during ward rounds, and during medication management while dealing with prescriptions.
• Since pharmacists have a vast knowledge on drugs and therapeutics, their ability to discover and
deal with adrs is quite important.
• Keeping in view the reporting of adrs, a pharmacist’s participation enhances reporting rate with
higher calibre.

59. • The intervention of pharmacists by organising lectures and group discussions thus providing
information about the importance, seriousness, preventability and necessity of reporting shows
heightened improvement of knowledge, attitude and perception about adrs.
• All health professionals play their respective roles in balancing between benefits and risks of
medication when it is introduced in the market.
• However, the expertise of a pharmacist about a drug, especially if newly marketed, play a more
important role in adrs reporting to the authorities which helps in either withdrawing the product
from the market or cause labelling changes.
• Pharmacists working in community pharmacy have an added advantage of detecting and
reporting adrs while dealing with on the counter prescriptions and herbal products.
• In a community pharmacy, a pharmacist may not have direct and definite patient list but the
patients coming to the same pharmacy to refill their prescription gives the pharmacist an
opportunity to detect a possible adr that the patient might be experiencing and can help in the
management and the reporting of the said adr.