Clinical Pharmacy 4th Pharm D

1. SCOPE,DEFINITION AND AIMS OF
PHARMACOVIGILANCE
PHARM-D 4TH YEAR
CLINICAL PHARMACY
Dr. Pradeepthi.k
Assistant Professor
Department of Pharmacy Practice

2. MECHANISM OF ADRS
 Karch and Lasagna described various mechanisms for
adverse drug reactions. The mechanisms are related to the
pharmacologic or pharmacodynamic aspects of drugs can be
used to classify the type of reaction that occurs.
 Intolerance
 Drug intolerance or drug sensitivity refers to an inability to
tolerate the adverse effects of a medication, generally at
therapeutic or subtherapeutic doses. Conversely, a patient is
said to be "tolerating" a drug when they can tolerate its
adverse effects.
 It is not to be confused with a drug allergy, which is a form of
drug intolerance, but requires an immune-mediated
component. It is also not to be confused with drug tolerance
("drug resistance," or tachyphylaxis) which refers to a lack of
adverse effects

3.  even at higher than average doses.
 Some instances of drug intolerance are known to result
from genetic variations in drug metabolism.
 Example: Tinnitus after a normal dose of aspirin -
exacerbated respiratory disease, Muscle pain or
weakness due to statin therapy
 Liver failure/kidney failure after a normal dose of
acetaminophen .
 Fatal poisoning in breastfed newborn baby due to use of
codeine by the mother.
 Tinnitus Tinnitus is a condition that causes ringing or
other noises in your ears without an external sound.

5. DRUG ALLERGY
 A drug allergy is the abnormal reaction of your
immune system to a medication. Any medication
over-the-counter/ prescription or herbal is capable
of inducing a drug allergy.
 However, a drug allergy is more likely with certain
medications.
 The most common signs and symptoms of drug
allergy are hives, rash or fever. A drug allergy may
cause serious reactions, including a life-threatening
condition that affects multiple body systems
(anaphylaxis).

6. HIVES REACTION

7. ANAPHYLAXIS
 This is a severe life-threatening, generalized or systemic
hypersensitivity reaction which may be IgE or non-IgE
mediated.
 It is usually characterized by one or more of the
following: generalized erythema, or flushing, urticaria,
angioedema of the face, lip, tongue or uvula, stridor,
rhonchi and/or hypotension.
 Anaphylaxis is a clinical diagnosis for which drug-
induced anaphylaxis is one of the most easily avoidable
causes. A drug allergy is not the same as a drug side
effect, a known possible reaction listed on a drug label.
 A drug allergy is also different from drug toxicity caused
by an overdose of medication.

8.  Stridor is a high-pitched sound you make when you
breathe through a narrow or partly blocked airway.
It can be a sign of various conditions, from birth
defects to infections to tumors.
 Rhonchi are gurgling or bubbling sounds in the
lungs, caused by accumulated fluids or
secretions blocking the airways.
ANGIOEDEMA

9.  The term "drug hypersensitivity" refers to
objectively reproducible symptoms or signs initiated
by exposure to a drug at a dose normally tolerated
by non-hypersensitive persons.
 "Drug allergy" refers to immunologically mediated
drug hypersensitivity reactions. These may be
either immunoglobulin E (IgE)-mediated
(immediate) or non-IgE-mediated (delayed)
hypersensitivity reactions.
 "Nonallergic hypersensitivity reactions" refer to
ADRs that are not immunologically mediated.

10. MECHANISM OF DRUG ALLERGY
 Drug allergy may be IgE or non-IgE mediated.
 In IgE-mediated reactions, (e.g., urticaria, angioedema,
anaphylaxis). drug allergens bind to IgE antibodies, which are
attached to mast cells and basophils, resulting in IgE cross-
linking, cell activation and release of preformed and newly
formed mediators.
 In non-IgE-mediated drug allergy, the mechanisms include
 Cytotoxic/cytolytic reactions involving the interaction of IgG or
IgM antibodies and complement with a drug allergen
associated with cell membranes (e.g., immune hemolytic
anemia, thrombocytopenia),
 Drug immune complex reactions (e.g., serum sickness and
drug- induced lupus), and
 T-cell-mediated reactions.
 By far, T-cell-mediated reactions are generally the most
prevalent type of reaction. There are three main processes by
which T cells are stimulated by drugs:

11. SERUM SICKNESS
 Serum sickness in humans is a reactionto proteins
in antiserum derived from a non-human animal
source, occurring 5–10 days after exposure.
Symptoms often include a rash, joint pain, fever,
and lymphadenopathy. It is a type
of hypersensitivity, specifically immune comple
hypersensitivity (type III). The term serum
sickness–like reaction(SSLR) is occasionally used
to refer to similar illnesses that arise from the
introduction of certain non-protein substances, such
as penicillin.

12. HAPTEN CONCEPT
 Haptens are chemically reactive small compounds
(<1000 daltons) that bind to proteins/peptides and
modify them covalently.
 These subsequently may Stimulate the innate
immune system by covalently binding to cellular
proteins, thereby transmitting a danger signal,
which in turn results in stimulation; or Stimulate the
specific immune system by forming hapten-carrier
complexes, which in turn can form neoantigens.
 The hapten-protein 6 complexes are processed and
then presented as hapten-modified peptides to T
cells, which can react with these peptides

13. PRO-HAPTEN CONCEPT
 Pro-haptens are not chemically reactive and cannot
form a covalent bond with a peptide. To become
chemically reactive, they must first be converted
into a hapten by being metabolized into a
compound that is chemically reactive.

14. PI (PHARMACOLOGIC INTERACTION WITH IMMUNE
RECEPTORS) CONCEPT
 A chemically inert drug, unable to covalently bind to
proteins, is still able to "fit" to some of the many
immune receptors (as it does to other proteins/
receptors).
 Under certain circumstances, this reversible drug-
receptor interaction can activate immune cells
specific for peptide antigens, which then expand
and cause inflammatory reactions of different types.
 A primary immune response to the drug is not
necessary for such a reaction to occur, but an
expansion of drug-reactive cells may be required
before symptoms appear.

15. DRUGS CAUSING ALLERGY
 Antibiotics, such as penicillin, cephalosporins,
sulfonamaides, tetracyclines, quniolones.
 Pain-relievers, such as aspirin, ibuprofen,
salicylates and naproxen sodium.
 Chemotherapy drugs for treating cancer
 Medications for autoimmune diseases, such as
rheumatoid arthritis
 Loacal anaesthics

16. PHOTOSENSITIVITY
 Photosensitivity, sometimes referred to as a sun
allergy, is an immune system reaction that is
triggered by sunlight/UV radiations.
 Photosensitivity reactions include solar urticaria,
chemical photosensitization, and polymorphous
light eruption and are usually characterized by an
itchy eruption on patches of sun-exposed skin.
 People may inherit a tendency to develop these
reactions. Certain diseases, such as systemic lupus
erythematosus and some porphyrias, also may
cause more serious skin reactions to sunlight.
There are two types of chemical photosensitivity:
phototoxicity and photoallergy

17.  Porphyria is a group of disorders in which
substances called porphyrins build up in the
body, adversely affecting the skin or nervous
system.

18. PHOTO TOXICITY
 In phototoxicity, people have pain and develop redness,
inflammation, and sometimes brown or blue-gray
discoloration in areas of skin that have been exposed to
sunlight for a brief period. These symptoms resemble
those of sunburn, but the reaction differs from sunburn
in that it occurs only after the person has swallowed
certain drugs (such as tetracyclines or diuretics) or
chemical compounds or has applied them to the skin
(such as perfume and coal tar). Some plants (including
limes, celery, and parsley) contain compounds called
furocoumarins that make some people's skin more
sensitive to the effects of UV light. This reaction is called
phytophotodermatitis.
 All phototoxic reactions appear only on areas of skin
that have been exposed to the sun. They usually
develop within hours after sun exposure.

19. PHOTO ALLERGY
 In photoallergy, an allergic reaction causes
redness, scaling, itching, and sometimes blisters
and spots that resemble hives. This type of reaction
can be caused by aftershave lotions, sunscreens,
and sulfonamides.
 Substances that cause photoallergy are capable of
doing so only after the person has been exposed to
both the substance and sunlight (because sunlight
is what makes the substance capable of triggering
photoallergy).
 Photoallergic reactions can also affect areas of skin
that have not been exposed to the sun. They
usually develop 24 to 72 hours after sun exposure

20. SOME DRUGS THAT SENSITIZE THE SKIN TO
SUNLIGHT
 Antianxiety drugs- Alprazolam, Chlordiazepoxide
 Antibiotics- Quinolones, Sulfonamides,
Tetracyclines, Trimethoprim
 Antidepressants- Tricyclic antidepressants
 Antifungal drugs (taken by mouth)- Griseofulvin
 Antihyperglycemics- Sulfonylureas
 Antimalarial drugs- Chloroquine, Quinine
 Antipsychotics- Phenothiazines
 Chemotherapy drugs- Dacarbazine, Fluorouracil,
Methotrexate, Vinblastine

21.  Diuretics- Furosemide, Thiazides
 Drugs used to treat acne (taken by mouth)-
Isotretinoin
 Heart drugs- Amiodarone, Quinidine
 Pain-relief drugs (analgesics)- NSAIDs (especially
piroxicam and ketoprofen)
 Skin preparations- Antibacterials (such as
chlorhexidine and hexachlorophene), Coal tar,
Fragrances, Furocoumarin-containing plants, such
as limes, celery, and parsley, Sunscreens

22. DRUG DEPENDENCE
 Drug dependence is the body's physical need, or
addiction, to a specific agent. Over the long term,
this dependence results in physical harm, behavior
problems, and association with people who also
abuse drugs.
 Stopping the use of the drug can result in a specific
withdrawal syndrome. There is therefore virtually no
difference between dependency and addiction.
Addiction encompasses both a mental and physical
reliance on a given substance.

23. MENTAL AND PHYSICAL DEPENDENCE
 Mental dependence is when use of a substance is a
conditioned response to an event or feeling.
 These are known as "triggers." Triggers can be
emotional responses to events, certain people, places or
anything a person associates with using a substance.
Something as simple as driving can trigger a desire to
use.
 These triggers set off biochemical changes in a person's
brain that strongly influence addictive behavior. When
the symptoms of mental and physical dependence are
apparent, an addiction is usually present.
 However, the main characteristic that distinguishes
addiction from dependence is the combination of mental
and physical dependence with uncontrollable behavior
in obtaining and using a substance.

24. TYPES OF DRUG DEPENDENCE
 Morphine-type:
 Psychological dependence severe
 Physical dependence severe; develops quickly
 Tolerance marked
 Cross-tolerance with related drugs
 Naloxone induces abstinence syndrome.
 Barbiturate-type:
 Physical dependence very severe; develops
 Slowly at high doses
 Tolerance less marked than with morphine
 Cross-tolerance with alcohol and benzodiazepines

25.  Amphetamine-type
 Psychological dependence severe
 Physical dependence slight: psychoses occur
 During use
 Tolerance occurs.
 Cannabis-type
 Psychological dependence
 Physical dependence dubious (no characteristic
abstinence syndrome)
 Cocaine-type
 Physical dependence slight
 Tolerance slight (to some actions).
 Alcohol-type
 Psychological dependence severe

26.  Physical dependence with prolonged heavy use
 Cross-tolerance with other sedatives.
 Tobacco-type Psychological dependence Physical
dependence.
 Drug mixtures
 Barbiturate-amphetamine mixturesinduce a characteristic
alteration of mood that does not occur with either drug
alone
 Psychological dependence
 strong Physical dependence occurs .
 Tolerance occurs.
 Heroin-cocaine mixtures: similar characteristics.

27. DRUG ABUSE
 Drug abuse refers to an individual who continues to
use drugs even though they know it is having an
adverse affect on their health and well being.
 Drug abusers will continue to use even though their
social life is falling apart and their financial stability
is collapsing. Drug abuse is an intense desire to
use increasing amounts of a particular substance or
substances to the exclusion of other activities

28. DRUG WITHDRAWAL REACTIONS
 Drug withdrawal is the group of symptoms that occur
upon the abrupt discontinuation or decrease in intake of
medications or recreational drugs. In order for the
symptoms of withdrawal to occur, one must have first
developed a form of drug dependence. This may occur
as physical dependence, psychological dependence or
both. Drug dependence develops from consuming one
or more substances over a period of time. Dependence
arises in a dose-dependent manner and produces
withdrawal symptoms that vary with the type of drug that
is consumed.
 Example: Benzodiazepines withdrawal symptoms-
hallucinations, seizures, psychosis and increased risk of
suicide Opiates Withdrawal symptoms - anxiety,
sweating, vomiting, and diarrhea.

29.  Alcohol withdrawal symptoms - irritability, fatigue, shaking,
sweating/nausea.
 Nicotine withdrawal symptoms - irritability, fatigue,
insomnia, headache, and loss concentration.
 Many prescription and legal nonprescription substances
can also cause withdrawal symptoms when individuals
stop consuming them, even if they were taken as directed
by a physician.

30. IDIOSYNCRASY
 Idiosyncrasy is defined as an individual's unique
abnormal or peculiar response to a particular drug.
Idiosyncratic drug reactions(IDRs) are not the most
common type of adverse drug reaction (ADR), but
they are unpredictable but often life threatening.
 It is thought to result from genetic enzymatic
deficiencies or other unique physiological variables
and leading to abnormal mechanisms of drug
metabolism or altered physiological effects of drug.
It has no relation to the pharmacology, amount or
concentration of the drug.

31. CHARACTERISTICS OF IDRS
 Unpredictable and very uncommon.
 Delay in onset, which varies with the type of IDR
and even the drug.
 On re-exposure, typically the IDR occurs
immediately but there are many exceptions.
 The same drug can often cause more than one type
of IDR.
 There may be no increase in incidence with
increasing dose within the therapeutic range, but
IDRs are not dose independent.

32. EXAMPLES OF DRUG IDIOSYNCRASY
 A single dose of Triflupromazine induces muscular
dystonia in some individuals specially children.
 One tablet of Chloroquine may cause vomiting and
abdominal pain.
 Aminoglycoside Antibiotics induced deafness.
 Drugs and Chemicals Unequivocally Demonstrated to
Precipitate Hemolytic Anemia (e.g. Acetanilide,
Nitrofurantoin, Primaquine, Methylene Blue,
Sulfacetamide, Nalidixic Acid, Naphthalene,
Sulfanilamide, Sulfamethoxazole, Sulfapyridine etc.
 Nevirapine causes skin rash in 8-16% of patients and
can also cause severe liver toxicity.
 Only few doses of Carbamazepine may cause ataxia in
some people.

33. TERATOGENICITY
 The terms "teras" meaning "malformation" and
Teratogen is defined asany chemical, substance, or
exposure given to the pregnant mother that may
cause birth defects to the developing fetus.
Teratogenesis is the formation of an abnormal
embryo.
 The Teratogenicityis refers to capacity of a
exogenous agents to cause foetal abnormalities
when administered to the mother at any stage of
pregnancy. The placenta does not strictly constitute
a barrier and any drug can cross it to a greater or
lesser extent.

34. FACTORS THAT DETERMINE THE EFFECTS OF
TERATOGENS
 Dose reaching fetus Time of pregnancy during
which drug exposure occurs Duration of exposure.
 Effects of Teratogens on the Fetus
 Spontaneous abortion
 Malformations (major or minor)
 Intrauterine growth retardation
 Mental retardation
 Carcinogenesis
 Mutagenesis (causing genetic mutation)

36.  Thalidomide cause Phocomelia means 'seal limbs'. Consists of
an absence of development of the long bones of the arms and
legs.
 Phenytoin cause Fetal Hydantoin syndrome, Cleft lip/palate,
Microcephaly and Mental retardation.
 Valproate cause Neural Tube defects.
 Isotretinoin cause mental retardation and learning disabilities
Eye & ear deformities Cleft lip, cleft palate & other facial
abnormalities Heart defects Microcephaly & Hydrocephaly
 Alcohol cause fetal alcohol syndrome
 Warfarin cause fetal warfarin syndrome, Saddle nose,
Retarded growth, Defects of limbs, eyes and central nervous
system
 Tetracycline cause teeth and bone damage, Yellow staining,
Enamel hypoplasia, Caries and pigmentation of permanent
teeth

37. MUTAGENICITY
 Mutagenicity refers to the induction of permanent
transmissible changes in the amount or structure of
the genetic material of cells or organisms.
 These changes may involve a single gene or gene
segment, a block of genes or chromosomes. The
genetic change is referred to as a mutation and the
agent causing the change as a mutagen.
 Genotoxicity is similar to mutagenicity except that
genotoxic effects are not necessarily always
associated with mutations. All mutagens are
genotoxic, however, not all genotoxic substances
are mutagenic.

38.  Mutations can either occur in germ cells or somatic
cells. If the mutation occurs in a germ cell the effect is
heritable.
 There is no effect on the exposed person, rather the
effect is passed on to future generations.
 If the mutation occurs in a somatic cell, it can cause
altered cell growth (e.g. cancer) or cell death (e.g.
teratogenesis) in the exposed person.
 Germ cells are those cells that are involved in the
reproductive process and can give rise to a new
organism.
 Male germ cells give rise to sperm and female germ
cells develop into ova. Toxicity to germ cells can cause
effects on the developing fetus (such as birth defects,
abortions).

39.  Somatic cells are all body cells except the
reproductive germ cells. They have two sets (or
pairs) of chromosomes. Toxicity to somatic cells
causes a variety of toxic effects to the exposed
individual (such as dermatitis, death, and cancer).
 Carcinogenicity Carcinogenicity is the ability or
tendency of a chemical to induce tumors (benign or
malignant), increase their incidence or malignancy,
or shorten the time of tumor occurrence when it is
inhaled, ingested, dermally applied, or injected.

40.  A carcinogen is any substance, radionuclide, or radiation that
promotes carcinogenesis, the formation of cancer. This may
be due to the ability to damage the genome or to the
disruption of cellular metabolic processes.
 Several radioactive substances are considered carcinogens,
but their carcinogenic activity is attributed to the radiation, for
example gamma rays and alpha particles, which they emit.
 Common examples of non-radioactive carcinogens are inhaled
asbestos, certain dioxins, and tobacco smoke. Although the
public generally associates carcinogenicity with synthetic
chemicals, it is equally likely to arise in both natural and
synthetic substances.
 Carcinogens are not necessarily immediately toxic; thus, their
effect can be insidious. Co-carcinogens are chemicals that do
not necessarily cause cancer on their own, but promote the
activity of other carcinogens in causing cancer.

41. DRUG INDUCED DISEASE (LATROGENIC)
 Drug-induced diseases also called as iatrogenic
diseases or physician induced diseases, are well know n
but least studied entity. They represent functional
disturbances t diseases) caused by drugs which persist
even after the offending remedy has been withdrawn
and largely eliminated.
 Some of the risk factors of Drug-induced diseases are
multiple chronic diseases. multiple physicians,
hospitalization, medical or surgical procedures, long
duration of medicine use, advancing age, female sex
and a particular class of drugs.
 Most of these Drug-induced diseases are largely
preventable, if strict vigilance and proper periodic clinical
and diagnostic monitoring are undertaken.

42. EXAMPLES:
 Parkinsonism by phenothiazine and other
neuroleptics
 Hepatitis by isoniazid
 Peptic ulcer by salicylates, glucocorticoids or
reserpine
 Aplastic anaemia by chloramphenicol etc.

43. PREDISPOSING FACTORS OF ADRS
 1. Stopping in Mid-way: Patients often stop taking
medicines due to various reasons like cost,
ignorance, non-availability, etc. There is a
possibility of ADR if drugs like steroids and
hormones are suddenly withdrawn.
 2. Factors like age, idiosyncrasy, and disease
conditions also cause unwanted reactions in some
patients.

44.  3. Bioavailability Problems: Due to the poor
formulation of drugs, blood concentration is affected
and hence they may reach a toxic level in some
patients, subsequently leading to ADR.
 4. Intake of drugs should be stopped at an
appropriate time. It should not be continued
indefinitely unless otherwise indicated. Failure to
set therapeutic endpoint is one of the reasons for
ADR to occur. Intake of drugs like digitalis,
diuretics, steroids, and antibiotics should be
stopped when their continuation is not necessary.
 5. Self-medication by patients and over prescription
by doctors may also produce ADR. If any mishap or
disease arises under a doctor's treatment, it is
known as Iatrogenic or a Drug- Induced Disease

45.  6. Sex: It is a general perception that women are more
susceptible to ADR than men. Though the reason is not
established yet, it is suspected that it could be owed to
hormonal, pharmacokinetic or immunological factor. One
known example to justify this argument is the adverse
effect of Chloramphenicol [Blood Dyscrasias] which is
more common in the female population.
 7. Age: The chances of drugs producing ADR on infants,
young children as well as on elderly people are more
due to underdevelopment of internal organs in the
farmer and improper functioning of them in the later.
Chloramphenicol produces 'gray baby syndrome' on the
neonates whereas nitrates and ACE inhibitors cause
hypotension in geriatric cases.
 8. Apart from above, drug interactions is one of the
major reasons for ADR

46. THANK YOU