Pharmacy Practice for Final Year B.Pharmacy Sem-VII, As per PCI Syllabus Adverse Drug Reaction

1. Adverse Drug Reaction
Prepared By:- Miss.Mali S.M.
Asst.Professor
Subject- Pharmacy Practice
Sahyadri College of Pharmacy,Methwade,
Tal-Sangola,Dist-Solapur ,Maharashtra, India.
1
UNIT-I

2.  INTRODUCTION:-
Drugs are prescribed with specific intension and a physician
would expect a drug to act effectively and selectively
without any undesirable phenomenon in the organism.
Thus,when a physician prescribed a drug for cardiac
dysfunction, he would very much like to select a drug which
acts only on heart. and on no other physiological system.
• DEFINITION AND SIGNIFICANCE OF ADVERSE DRUG
REACTIONS:-
The WHO defined as adverse drug reaction as: ‘Any noxious
and unintended effect of drug which occurs at doses
normally used in man for the prophylaxis diagnosis or
therapy of disease or for the modification of physiological
functions'. It includes the documented and accepted
adverse drug effects
2

3. Adverse drug reactions are more frequent in patients taking
large number of drugs. In general, 3 % of the admissions to
medical wards occur because of the adverse drug reactions.
It has been estimated that an average medical hospital
patient receives between 5-10 different drugs during a ten
day stay in a hospital.
In this period around 25% of the patient's experiences one or
more adverse drug effects and 1% experience a life-
threatening event due to drugs.
√ Reasons For Adverse Reactions:-
①Dispensing and medication administration errors
②Failure to set therapeutic end point
③Bioavailability differences
④Patient factors 3

4. • CLASSIFICATION OF ADVERSE DRUG REACTlONS:-
1.Predictable:-
√ Excessive Pharmacological Effects.
√ Secondary Pharmacological Effects.
√ Rebound Response on Discontinuation.
2. Unpredictable:
√ Aliergic reactions and anaphylaxis.
√ Idiosyncrasy.
√ Geneticaily determined effects.
4

5. √ Excessive pharmacological Effects:-
It is the most common adverse drug reaction which may
occur due to excessive pharmacological effect of the drug.
Excessive pharmacological effect generally appears due to
over dosage of a drug.
This is particularly troublesome with cardioactive.,
hypotensive, hypogiycemia and central nervous system
depressive agents.
√ Secondary Pharmacologlcal Effects
No drugs have a single pharmacological effect. Any effects
which are associated with a drug besides the desired effects
are called as Secondary Effects.
Drugs have several pharmacological actions at usual
therapeutic dose but it is Prescribed solely for one of these
be. 5

6. √ Idiosyncracy:-
• The term IDIOSYNCRASY (Greek idios, means "one's own;
and synkrasis, a mixing together") has long been used to
denote both quantitative and qualitative abnormal drug
response.
• Idiosyncrasy covers unusual, bizzare or unexpected drug
effects which cannot be explained or predicted in individual
recipient.
• It also includes drug induced foetal abnormalities.
eg. Phocomelia, which developed in the Offspring's of in
other exposed to thalidomide. Drug induced cancer is also
an Idiosyncratic reactian. 6

7. Sr. No. Idiosyncrasy Allergy Toxicity
1. Occurs in genetically
abnormal subjects.
For few % of subjects In all subjects at high
doses
2. It arises for few
drugs.
Aries for many drugs All drugs
3. Prior drug exposure
unnecessary
Prior drug exposure
unnecessary/
essential
Prior drug exposure
unnecessary
4. Response is dose
dependent.
Dose independent
erratic response
Dose dependent
5. Mechanism
explained by drug-
receptor interaction.
Antigen-Antibody
reaction
Drug-receptor
interaction
Table No.1:- Characteristics Comparison between
Idiosyncrasy, Allergy and Toxicity
7

8. √ Allergic Drug Reactions:-
Allergy is an adverse response to a foreign substance
resulting from a previous exposure to that substance. It is
manifested only after a second or subsequent exposure.
Only a small proportion of the population exposed to the
drug exhibit allergic reactions.
• Characteristics of allergic adverse drug reactions are as
follows:-
∆ The reaction does not resemble the expected
pharmacological action of the drug.
∆ There is delay between the first exposure to the drug and
the development of a reaction. 8

9. ∆ Mechanism of allergic drug reaction can be explained an
immunological basis. Drug or its metabolite which is a small
molecule having simple structure generally combine with body
proteins.
∆ This stable drug-protein complex act as an antigen. Simple
chemicals which are capable of binding firmly with a protein to
form antigen product, are termed as 'haptens'.
∆ When an individual comes in contact with antigenic complex,
there occurs formation of antibodies; i.e. sensitized.Such
sensitized individual when re-exposed to the drug or hapten,
antigen react with antibodies.
∆ Common are allergic drug reactions in human are expresses in
following table : 9

10. Site of Reaction Symptoms Drugs
Skin Urticaria, itching,rashes Penicillin, aspirin,
Sulfonamide, barbiturates,
streptomycin
Dermatitis. Tetracycline
Respiratory Tract Difficulty in breathing Penicillin,local anaesthetic,
heroin
Vascular System Decrease in B.P. Penicillin, aspirin
Blood Haemolytic anaemia Penicillin, methyl-dopa,
quinidine.
Leucopenia Phenylbutazone, thiouracil
Table No.2:- Common Allergic Drug Reactions in Human
10

11. √ Genetically Determined Toxicity:-
• Patients of selected genetic makeup are at substantially greater
than average risk for some specific drug toxicities.
E.g. :- glucose-G-phosphate dehydrogenase is involved in
degradation of glucose for producing energy.
• Certain population in Africa and South East Asia are deficient in
glucose-G-phophate dehydrogenase and, therefore, there are
substantial risk of developing haemolytic disease after the use of
antimalarial drug- primaquine. sulphonamides, guanidine and
nitrofurantoin.
• Similarly ,there is other genetically determined toxicity. This
include:
=Patients with porphyria are susceptible to CNS depression agents
like barbiturates.
=Individual with pseudocholinesterase deficiency is highly susceptible
to succinyicholine. They may develop paralysis and often apnoea.
11

12. • Toxicity Followlng Sudden Withdrawal of Drugs:-
∆ Tolerance occurs after prolong use of variety of drugs of narcotic
analgesics, ethyl alcohol, some hypotensive agents (clonidine) and
corticosteroids drugs. Sudden Withdrawal of such drugs shows severe
adverse effects.
∆ In patients habituated to central nervous depressant such as; ethyl
alcohol, barbiturate and some benzodiazepines, withdrawal of the usual
dose may produce marked agitation tachycardia, confusion, delirium
and convulsions. Clonidine is used in hypertension but Sudden
withdrawal may cause severe hypertension.
∆ Long term of corticosteroids therapy is less common because it may
cause atrophy of recipient's adrenal glands. Therefore, sudden
withdrawal can precipitate an acute adrenal crisis in which the patients
become profoundly weak, hypotension are collapsed.
12

13. √ Drug Interaction:-
• Drug interaction may be defined as an alteration of the effects of
one drug by prior or concurrent administration of another drug. A
part from interaction of drug with another drug (drug-drug
interaction), with food (drug-food interaction) and disease state
(drug-disease' interaction) it also includes.
• Drug interaction becomes clinically more signiticant in patients
with renal
impairment,alcoholics, and patients receiving chronic medication or
having metabolic abnormalities.
• Drug interaction may become harmful to the patient by increasing
efficacy or toxicity or by decreasing the therapeutic effect of an
administered drug. But sometimes interactions may prove beneficial;
when it allows reduction in dose by enhanced efficacy without
increase the toxicity. 13

14. √ Classification of Drug Interaction:-
A) Consequence Wise:-
They are classified into two categories:
1)Beneficial
2)Adverse drug interaction
Some drugs interactions may be desirable and intended as
when a combination of medications produces improved
therapy, perhaps greater margin of safety, more appropriate
onset or duration of action, lowered toxicity or enhanced
potency with diminished side effects. Such an interaction is
also termed as Intentional Drug Interactions.
14

15. Beneficial interaction are not frequently reported but in
certain conditions they have been used to minimise the risk
of a particular form of therapy or to improve therapeutic
efficacy,
E.g.
1] Combination of sulphamethoxazole with trimothoprim is
used to enhance the antibacterial effect of either
therapeutic effect.
B) Site Wise:-
On the basis of site, adverse reaction may be classified into
Two Types,
1.External
2. Internal 15

16. C) Mechanism Wise:-
Drug interactions can be classified on the basis of their
mechanism i.e. pharmacokinetic drug interaction and
pharmacodynamic drug interaction.
1} Pharmacokinetic Drug Interaction:-
It occurs as a Result of altered drug absorption, distribution,
metabolism and Excretion.
•Altered Drug Absorption: It may be due to :
✓ Physiochemical Interaction: Change in gastric pH by one drug
(e.g. antacidscimetidine, ranitidine) which affects the ionization
of another drug and so absorption of aspirin remains unionized
at the stomach pH. so drug is rapidiy absorbed from stomach
but use of antacid with aspirin reduces the absorption due to
alteration of PH.
16

17. ✓ Altered Gastrointestlnal Motility: It affects the rates of
drug absorption. E.g.; Propanthelin which delays gastric
emptying and 'reduces intestinal motility will cause
hinderance in absorption of many drugs,
E.g. digoxin .
✓ Change in Bacterlal Flora: Intestinal flora may play
important role in synthesizing Vitamin K. essential for normal
blood clotting or may reactivate some inactive drug metal
excreted via bile by deconjugating them.
✓ Change In Mucosal Function: Drugs with specific GIT may
damage the gastrointestinal mucosa or block active transport
& so alter the absorption rate of the drug.
✓ Blood Flow: The better the blood supply to an area where
a drug being absorbed, the greater the concentration
gradient and faster the absorption rate. 17

18. • Altered Drug Distribution:
Some drugs are highly bound to plasma proteins” example
coumarins, sulphonyl ureas and phenytoin. Co-
administration of a a which can displace the former from
their binding sites, will cause an increa. pharmacological
activity and possible toxicity. Trichloroacetic acid, a
metabolite chloral hydrate, may displace warfarin from its
binding sites (plasma proteins) and increases the
anticoagulant activity which results in bleeding tendency.
Similarly, methotrexate, an anticancer drug, is displaced by
some sulphonamidesa a granulocytosis may result.
18

19. ✓ Altered Drug Metabolism:-
• Induction of Hepatic Microsomal Enzymes:-
Certain drugs, e.g. barbiturd alcohol, phenylbutazone and
some anticonvulsants are potent inducers of the microsomal
enzymes.
The simultaneous use of these drugs with any other drug
which is normally metabolized by this route, will result in
increased metabolism or clearance of the latter with reduced
therapeutic efficacy if the parent compound is the effect
mediator but possibly increased if effect is due to a
metabolite.
• Inhibition of Hepatic Microsomal Enzymes:-
Some drugs inhibit the activity of microsomal enzymes and
so the metabolism of other drugs. 19

20. ✓Alterated Drug Excretion:-
• Competition for Active Tubular Secretion:-
Active tubular secretion of many drugs occurs in proximal limb
of the loop of Henle. If two drugs, which are normally secreted
in this way, are co-administered in large doses, competition
may lead to an interaction whereby greater than expected
amount of one or other are retained in the body.
• Change in Urine pH:-
Reabsorption of drug is decreased in renal tubule by
changing the pH of urine. It is most likely encouraged as,
for example, in salicylate or phenobarbitone poisoning
where alkalization of the urine will increase elimination of
these drugs,
20

21. 2} Pharmacodynamic Drug Interaction:-
✓ Drugs Having Similar Pharmacological Effect: A patient receiving
hypnotics may develop an allergic skin reaction and for this, he
receives an antihistamine which itself has central nervous system
depressed effect. The combined effects may be sufficient to produce
serious sedation which cannot be obtained from either of these drugs.
✓ Drugs Having Opposite Pharmacological Effect: When patient is
receiving pilocarpine (cholinergic drug) for glaucoma (eye disease) and
at the same time for abdominal pain may be prescribed with an
anticholinergic drug, then interocular pressure may be altering by the
anticholinergic drug.
✓ Change in Electrolytic and Fluid Balance: Drugs, e.g. diuretic, that
cause potassium depletion may potentiate the effect of digitalis and
nonpolarizing muscle relaxant but antagonize the effect of lignocaine,
quinidine and procainamide.
21

22. • METHODS FOR DETECTING ADVERSE DRUG REACTIONS:-
° Many factors are responsible for the adverse effects of drugs in
patients receiving it. The adverse effects of the drug depend on its
dose, duration, toxicity and other individual factors such as sex, age,
genetics, compliance of patients and total number of drugs
administered. Whether a patient experiences the toxicity of drug
depends on its dose.
° The pharmacokinetics of the drug may also affect the drug toxicity.
Alteration in pharmacokinetic of drug may result in abnormally
higher concentration of drug at receptor Site, resulting in adverse
effect.
° Therapeutic index of a drug is also responsible for the adverse
effects. The drug with small therapeutic index is more prone to
produce adverse effects than with large therapeutic index. 22

23. • Spontaneous Case Reports:-
It is the common method of affecting doubts about drug
related diseases; A prescribed suspects that a condition
arising in a patient may be drug related. He therefore reports
either in a ietter to the medical journals or to the
manufacturer of drug. By this means other prescribers are
alerted to the possibility of drug-disease relationship.
"Spontaneous Reporting Agencies" are set up to collect and
gather such case reports. Although the resulting information
collected gives no idea of the frequency with which a given
event is caused by a drug, it indicates that a number of
prescribers feel that the event is possibly drug -related.
23

24. Most of the physician fail to report many adverse
drug reactions which may be due to the following
reasons:-
∆ The misconception that ADR reflects poor
therapeutic agent selection.
∆ Lack of interest.
∆ Lack of understanding of what to report.
∆ Belief that the reaction is unimportant or has
been previously reputed in the literature.
24

25. √ Vital Statlatlce and Record Linkage Studies:-
The details of cause of death or of hospitalization are routinely
collected and analyzed. It gives early warning of an epidemic of
drug related disease. Record linkage studies may be used to great
effect in th search for drug-induced disease.
Cohort Studies:-
∆ The "Cohort" means identifying a group of recipients of drug of
interest and observing these patients for varying lengths of time
for what happens to them.
∆ This type of study is used for short term clinical trial of new
drug.Cohort studies involving long term clinical trials are more
difficult to organize.
∆ Thus,this method is of great value for detecting predictable
adverse effects due to excessive pharmacotogical effects arising
during/ immediately after short term treatment.
25

26. √ Case Control Studies:-
∆ It Invotves the comparison of group of patients with a disease
which is thought to be due to drug (the 'cases’) with h group of
patients who do not have the disease (the ‘control).
∆ The drug histories of the cases and controis are obtained and
compared,if a drug is causing the disease then its use amongst the
cases will be far in excess of that found in the controls.
∆ Case control studies can be conducted rapidly and efticientiy at
relatively low cost, However. It must be conducted correctly and
resulting data must be interpreted correctly.
26

27. √ Precautions should be taken while concluding
case control studies:
1)The case must be selected carefully.
2) The controls obtained should be from similar
population of cases with the exception that controls do
not have the disesase of interest.
3) The method used to describe drug use must be
identical in cases and controls.
4) Interpretation of results must be accurate.
27

28. √ REPORTING AND MANAGEMENT OF ADVERSE DRUG
REACTION:-
• The truism "the harder you look, the more you find” is
best illustrated in the area of adverse drug reaction. Life
threatening emergencies like haemorrhage,hypogiycemic
coma, cardiac arrhythmias, convulsion or hypertensive
crisis may occur.
• It is important to recognize and prevent such
catastrophies, for which certain guideiines would be
helpful.
1)The more potent the drug, higher is the risk of toxicity.
2) Authentic manuals on drug interactions must be readily
available for consultation.
28

29. Pharmacist should involve in the following steps of
identifcation and monitoring of adverse drug reactions.
✓ Patient History:-
∆ Pharmacist should check whether the patient have a
history of allergic disorder. It is anticipated that 10% to 25%
of patient’s population is hypetsensitive to one drug or
another.
∆ The pharmacist may reduce the likelihood of these
reactions by asking the patient whether or not he has ever
experienced an allergic reaction to a drug.
∆ If the answer is "yes", the pharmacist should then
inquire as to the type of ADR and the drug that supposed
induced it.
29

30. ✓ Drug Profile Records:-
The patient profIle or complete family health record can
assist in controlling and preventing adverse drug
reactions. The pharmacist is capable of knowing all of the
medications used by these patients by maintaining a
health Realrecords.
✓ Literature Review:-
Pharmacist and physician should check properly
published literature and package insert information of
drugs and given the proper attention regarding the
suspected adverse drug effect of drugs.
30

31. ✓ Drug Level Studies:-
∆ If the adverse drug reaction is dose dependent then the
pharmacist should check the drug levels in biological
fluids.
∆ Computer software's can be used for checking drug
levels as well as drug-drug. drug-diet and drug-disease
interaction.
✓ Therapeutic Decision Making:-
∆ The advice of the pharmacist is very valuable
regarding the immediate discontinuation of therapy in
case of ADRs.
∆ Pharmacist should check the risk/benefit ratio of the
continued administration of drug against the availability
of other drugs. 31

32. REFERENCES:-
1. A Text book of Pharmacy Practice by the author Sourabh
Kosey Nirali Prakashan. Page No.3.1-3.16
2. A Text book of Pharmacy Practice by the author Dr. Sachin V.
Tembhurne, Dr. Ashwini R. Madgulkar, Dr. Virendra S.
Ligade Nirali Prakashan. Page No.3.1-3.20
3. www.Google.com
32

33. Thank You.....
33