1. Adverse Drug Reactions
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2. What is ADR
WHO definition : Any undesirable effect of a drug beyond its anticipated therapeutic
effects occurring during clinical use
An adverse drug reaction (ADR) is an expression that describes harm associated
with the use of given medications at a normal dosage during normal use. -
ADRs may occur following a single dose or prolonged administration of a drug or result
from the combination of two or more drugs
The meaning of this expression differs from the meaning of "side effect", as it might
also imply that the effects can be beneficial.

3. Why ADR is Important to know
• Over 2 Million serious ADRs yearly.
• 100,000 deaths yearly.
• ADRs 4th leading cause of death ahead of
pulmonary disease, diabetes, AIDS,
pneumonia, accidents and automobile
deaths.
• Ambulatory patients ADR rate—unknown
• Nursing home patients ADR rate— 350,000
yearly.
Institute of Medicine, National Academy Press, 2000 Lazarou J et al. JAMA
1998;279(15):1200–1205 Gurwitz JH et al. Am J Med 2000;109(2):87–94

4. Classification of adverse drug reaction
ABCDE Classification
Rawlins and Thompson devised a classification scheme in 1991, which continues to
be the most frequently used.
• Type A: Predictable, acute, related to mechanism of action
• Type B: Idiosyncratic, unpredictable, acute / sub-acute, not
related to known mechanism
• Type C: Chronic effects (continuous)
• Type D: Delayed effects
• Type E: End-of-treatment effects

5. Classification of adverse drug reaction
Type A
• Dose Related
• 80% of ADR, usually a consequence of the
drug’s primary pharmacological effect (e.g.
bleeding from warfarin, Headache with
glyceryltrinitrate (GTN))
• a low therapeutic index (e.g. nausea from
digoxin)

6. Classification of adverse drug reaction
Type B
• Bizarre effects (or idiosyncratic)
• dose independent and
• Unpredictable (not an extension pharmacological
action of the drug)
• For example: hepatotoxicity due to paracetamol
tinnitus induced by aspirin ototoxicity with
aminoglycosides of main

7. Classification of adverse drug reaction
• Type A less likely to have fatal consequences
than type B reactions
Type
Type A
Type B
Dose Relationship
Yes
No
Frequency
Common
Rarer
Mortality
Low
Higher
Morbidity
High
Lower
Treatment
Stop drug or reduce
dose
Stop drug

8. Classification of adverse drug reaction
Type C
• Results from Chronic or continuous use
• For example, Analgesic nephropathy
• osteoporosis during continued high-dose
glucocorticoid therapy
• tardive dyskinesia during continuous use of
antipsychotic drugs

9. Classification of adverse drug reaction
Type D
These reactions refer to carcinogenic and teratogenic effects.
These reactions are delayed in onset and are very rare since extensive
mutagenicity and carcinogenicity studies are done before drug is licensed.
•
•
•
•
•
•
•
•
Teratogenic Thalidomide - amelia or micromelia or phocomelia
phenytoin -fetal hydantoin syndrome
tetracyclines -teeth malformation and discoloration
aspirin -early closure of ductus arteriosus
carbamazepine -cleft lip and palate, microcephaly
wafarin - saddle nose
sodium valproate - spina bifida
DES - vaginal clear cell adenocarcinoma

10. Classification of adverse drug reaction
Type E
• Rebound adrenal insufficiency
• Withdrawal syndrome (tachycardia on abrupt
discontinuation of β-adrenoceptor blockade)
• Second malignancies following successful
chemotherapy.

11. Physiological, Pharmacological and Toxicological aspects of
metabolism of Drugs

12. Drug- Drug Interactions
Pharmacokinetic and pharmacodynamic
properties of one drug affect either the
pharmacokinetics or pharmacodynamics of
another drug
Pharmacokinetics:“What the body does
to the drug”
Pharmacodynamics:“What the drug does
to the body”

13. Types of Drug Drug Interactions
• Potentiation: Drugs with similar actions cause
an additive effect
• Coumadin and aspirin taken together cause
excessive bleeding
• Sedatives and alcohol cause excessive
sedation

14. Types of Drug Drug Interactions
• Interference: One drug accelerates or slows the
metabolism or excretion of another drug
Erythromycin taken with
– Digoxin = elevated blood levels of digoxin
– Coumadin = enhanced action of Coumadin
Potential for serious adverse effects!

15. Types of Drug Drug Interactions
• Displacement: Two drugs compete for protein
binding sites
– One drug “wins” (is bound to protein)
– Displaced drug is active in greater quantities
– Same effect as taking a higher dose of the
displaced drug!
A major cause of drug-drug interactions!

16. Types of Drug Drug Interactions
• Antagonism: One drug decreases the
effectiveness of another drug because of
divergent actions
– Oral ketoconazole (Nizoral) is absorbed in an
acidic environment
– H2-receptor antagonists or proton pump
inhibitors decrease acidity in the stomach
– Differing action decreases Nizoral
effectiveness

17. Types of Drug Drug Interactions
• CYP450 enzymes and drug-drug interactions
– CYP450 Inhibitors: Drug A inhibits CYP450 enzymes in
the liver; slows metabolism of drug B, toxic levels of
drug B accumulate
– CYP450 Inducers: Drug A stimulates production of
CYP450 enzymes; increases rate of metabolism of drug
B, clears drug B out of the system faster
A major source of drug-drug interactions!

18. Drug Food Interactions
• Food can alter the absorption or metabolism
of medications
• Diets can alter the bacterial flora of the
intestine and may affect the metabolism of
certain drugs
• Iron taken with acidic foods can cause
increased iron absorption
• Acetaminophen or Aspirin taken with or after
alcohol have a high chance for severe liver
damage.

19. Types and Examples of Adverse Reactions

20. Drug Induced liver Injury
• The liver is the main site of metabolism for drugs
and other exogenous compounds.
• vulnerable organ, exposed to parent drug and
metabolite.
• despite this vulnerability, the liver is not the
major target for adverse drug reactions, only
about 9.5% of these involve the liver .
• Overdose of Acetaminophen is a common cause
of hepatic injury, accounting for ~40 % of cases of
acute liver failure in the USA

21. Types of Drug Induced Hepatoxcity
http://ispub.com/IJPHARM/7/1/3723#

22. Case Study on Troglitazone (Rezulin)
• Troglitazone(Thiazolidinediones class)
• Class of Oral Antidiabetics for (peroxisome
proliferator-activated receptor gamma)
• Mechanism:Troglitazone lowers blood glucose
levels through increased glucose uptake by
skeletal muscle, decreased hepatic glucose
production. Approved by FDA 1997

23. Adverse Reaction Study
At Clinical trials , elevations of serum alanine
aminotransferase (ALT) more than three times the
upper limit of normal were observed in 48 out of
2,510 patients (1.9%) treated with troglitazone as
compared to 0.6% in patients who received
placebo. Troglitazone reported to get associated
idiosyncratic hepatotoxicity with some patients
showing severe or fatal liver damage.
Withdrawn from the market in the US and Japan
in March 2000.

24. Troglitazone Metabolites
phenol sulfotransferase, ST1A3
Glucuronosyltransferase
CYP3A4,CYP2C8
Metabolite 1:Troglitazone sulphate
Metabolite 3:Troglitazone quinone
Metabolite 2: Troglitazone glucuronide
Metabolite 4: Hydroxylated Metabolite 1
Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver
microsomes. Drug Metab Dispos. 1999 Nov;27(11):1260-6.

25. Websites for Side Effects and Adverse Drug
Reactions
• FDA : FAERS Systeme Data From 2004-2012
• Sider : The SIDER Side Effect Resource represents
an effort to aggregate dispersed public
information on side
effects(http://sideeffects.embl.de/)
• MedEffect Canada: The Canada Vigilance Adverse
Reaction Online Database contains information
about suspected adverse reactions

26. References
• http://ispub.com/IJPHARM/7/1/3723#
• https://www.med.upenn.edu/gastro/documents/NEJMdrughepatotoxicity
II.pdf
• http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/Buyi
ngUsingMedicineSafely/EnsuringSafeUseofMedicine/GeneralUseofMedici
ne/UCM229033.pdf
• http://www.bmj.com/content/316/7140/1295
• http://www.sciencemag.org/content/321/5886/263
• http://stm.sciencemag.org/content/4/125/125ra31.long