Thalidomide was a sedative that was prescribed to pregnant women in the late 1950s to treat morning sickness. It was later found to cause severe birth defects in over 10,000 babies worldwide, with malformed limbs being the most common defect. Thalidomide was withdrawn from the market in 1961 after the link to birth defects was established. This tragedy highlighted the need for rigorous safety testing of drugs, especially for teratogenic effects, and led to the establishment of regulatory frameworks for drug approval and pharmacovigilance systems like the Yellow Card Scheme to monitor adverse drug reactions.

1. Dr Htet Htet
MBBS, MMedSc (Pharmacology)
Lecturer
Clinical Pharmacology

2. Thalidomide Tragedy

3. History
• Thalidomide - 1957 - in West Germany
• The German drug company “Grünenthal” developed and sold
the drug.
• Primarily prescribed as a sedative or hypnotic, to cure “anxiety,
insomnia, gastritis, and tension".
• Afterwards it was used against nausea and to alleviate morning
sickness in pregnant women.

4. • became an over the counter drug in Germany around
1960, and
• could be bought without a prescription.
• Shortly after the drug was sold, in Germany, between 5,000
and 7,000 infants were born with malformation of the
limbs (phocomelia). Only 40% of these children survived.

5. Time to Investigate
•
statistic - “50 % of the mothers with deformed children had taken thalidomide during
the first trimester of pregnancy.”
•
Throughout Europe, Australia, Canada and some part of America - cases were reported
of infants with phocomelia; only 50% of them survived.
•
Those subjected to thalidomide while in the womb experienced- limb deficiencies -
long limbs either were not developed or presented as stumps.
•
Other effects - deformed eyes, hearts, alimentary, and urinary tracts, and blindness and
deafness.
•
During that time period the use of medications during pregnancy was not strictly
controlled, and drugs were not thoroughly tested for potential harm to the fetus.

6. Time to withdrawn from market
• Thalidomide was withdrawn from the market
in 1961
• IT WAS A BIG LESSON FOR THE WHOLE
WORLD CONCERNING WITH DRUG SAFETY
AND REGULATION

11. - 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.

13. • 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
Data from
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

15. • Type A:
– Augmented pharmacologic effects - dose dependent and predictable
• Type B:
– Bizarre effects (or idiosyncratic) - dose independent and unpredictable
• Type C: Chronic effects (continuous)
• Type D: Delayed effects
• Type E: End-of-treatment effects
• Types A and B were proposed in the 1970s,and the other types were
proposed subsequently when the first two proved insufficient to classify
ADRs.

16. • 80% of ADR,
• usually a consequence of the drug’s primary pharmacological effect (e.g.
bleeding from warfarin)or
• a low therapeutic index (e.g. nausea from digoxin), and
• predictable
• dose-related, usually mild,
• But may be serious or even fatal (e.g. intracranial bleeding from warfarin).
• usually due to inappropriate dosage, especially when drug elimination is
impaired.
• The term ‘side effects’ is often applied to minor type A reactions.

17. • 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

18. • 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

19. • 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

20. • Rebound adrenal insufficiency
• Withdrawal syndrome (tachycardia on abrupt
discontinuation of β-adrenoceptor blockade)
• second malignancies following successful
chemotherapy.

21. a. Adverse effects related to the
pharmacological action of the drug
main
a. Adverse effects unrelated to the main
pharmacological action of the drug

23. • predictable,
• at least this action is well understood.
• They are sometimes referred to as type A
('augmented‘)

24. Examples:
• postural hypotension occurs with α1-adrenoceptor
antagonists,
• bleeding with anticoagulants,
• sedation with anxiolytics
• intracerebral bleeding caused by anticoagulants,
• hypoglycaemic coma from insulin
• drug dependence produced by opioid analgesics

26. Examples
• paracetamol hepatotoxicity
• aspirin-induced tinnitus
when susceptibility is increased
• eg. during pregnancy
Or if the patient has some predisposing conditions,
• glucose 6-phosphate dehydrogenase deficiency
• mutation in the mitochondrial DNA that predisposes to
aminoglycoside ototoxicity

27. Unpredictable idiosyncratic reactions
– drug-induced hepatic or renal necrosis,
– bone marrow suppression,
– carcinogenesis and
– disordered fetal development.
– aplastic anaemia from chloramphenicol
– anaphylaxis in response to penicillin
idiosyncratic reactions are termed type B ('bizarre')
in the Rawlins & Thomson (1985) classification.

28. • such reactions cannot be excluded by preapproval clinical
trials (which might typically expose only a few thousand
individuals to the drug), and
• the association may come only after years of use,
• so there is a need for continued monitoring by regulatory
authorities after drugs have been licensed and marketed.
• An
example
is
the
association
between
pulmonary
hypertension and valvular heart disease with fenfluramine,
an appetite suppressant that had been used for several years,
and also with dexfenfluramine.

29. Erythematous maculopapular eruption due to penicillin: rashes of this kind are by far the
most common reactions to drugs.
Vervloet D , and Durham S BMJ 1998;316:1511-1514
©1998 by British Medical Journal Publishing Group

30. Erythema multiforme due to sulphonamide treatment, showing characteristic target-like
lesions.
Vervloet D , and Durham S BMJ 1998;316:1511-1514
©1998 by British Medical Journal Publishing Group

31. Fixed drug eruption, so called because the lesion recurs at the same site after each
administration—in this case, due to barbiturates.
Vervloet D , and Durham S BMJ 1998;316:1511-1514
©1998 by British Medical Journal Publishing Group

32. Exfoliative dermatitis—a severe complication in this case due to co-trimoxazole.
Vervloet D , and Durham S BMJ 1998;316:1511-1514
©1998 by British Medical Journal Publishing Group

33. Eiferman et al.
Ciprofloxacin
microprecipitates and
macroprecipitates in the
human corneal
epithelium.
J Cataract Refract Surg
2001; 27(10): 1701-2

34. Brazier et al. Ecstasy
related periodontitis and
mucosal ulceration—a case
report. Br Dent J 2003;
194(4): 197-9

41. • toxicity testing in animals and humans are important for seeking
approval to market a new drug.
• Nevertheless, harmful effects are often encountered during
therapeutic use, often the result of misprescribing, but also due to
the emergence of toxic effects not detected in animals.
• These harms are usually referred to as 'adverse drug reactions'
(ADRs) and are of great concern to drug regulatory authorities,
• For establishing the safety as well as the efficacy of drugs.

43. 1. Listen to your patient (Patients may tell you about
symptoms they have experienced since taking a
new medicine and it is important to listen to the
patient’s own concerns regarding their drug
therapy.)
2. Alert by yourself (some adverse reactions may not
be apparent to the patient, you will need to be
alert to the possible occurrence of ADRs.)

44. 3. Trust your own observations and initiative
- vital in this respect, in linking a sign or
symptom to either current or previous
therapy. (Remember these can include overthe-counter (OTC) drugs and unlicensed
herbal remedies).

45. Other things to be alert for include:
• Abnormal clinical measurements
(e.g. temperature, pulse, blood pressure, blood
glucose, body weight) while on drug therapy
• Abnormal biochemical or haematological
laboratory results while on drug therapy. For
example, plasma drug concentrations or liver biopsy
where drug-induced hepatitis is suspected

48. • Introduced in 1964 after Thalidomide tragedy
• Spontaneous reporting system
• Early warning system
• Over 600,000 confidential reports received in UK

49. Who can report?
•
•
•
•
•
•
•
•
•
Doctors
Dentists
Pharmacists
Nurses
Midwives
Health visitors
Non medical prescribers
Now
Patients also ………..

50. Where to report?
• www.yellowcard.gov.uk (online completion)
• http://yellowcard.mhra.gov.uk/
• Or by calling to 0808 100 3352
• Yellow cards can be available in BNF books ..

51. When to report?
•
•
•
•
•
If you suspect ADR,
Do not assume someone else will be reported.
Only 2-4% of ADR are reported.
Only 10% of serious ADR are reported.
“No”
You don’t need to be completely certain that
what you have seen is ADR. ***

52. How to get latest informations for
yourself?
• don’t miss for updates for yourself also.
• DRUG SAFETY UPDATES!!
• Published monthly
• Register for updates ..
• http://www.mrha.gov.uk/publications/safetyg
uidance/DrugSafetyUpdate/index.htm

61. • Vigabactrin – visual field defects
• Cyproterone acetate – hepatotoxicity
• Alendronate – severe oesophageal toxicity
• sibutramine – (Meridia (sibutramine):
– Market Withdrawal Due to Risk of
Serious Cardiovascular Events) 2010-2011

63. “All health care professionals have a responsibility to
inform colleagues about clinically important drug
reactions that they detect, even if a well
recognized or causal link is uncertain”.
Edwards IR and Aroson JK. Adverse Drug Reactions:
Definitions, Diagnosis and Management. Lancet 2000; 356:

64. References

65. • http://en.wikipedia.org/wiki/Thalidomide
• http://www.who.int/bulletin/volumes/91/8/BLT12-111609-table-T1.html
• http://www.fda.gov/Drugs/DevelopmentApprova
lProcess/DevelopmentResources/DrugInteraction
sLabeling/ucm114848.htm
• http://www.mhra.gov.uk/Safetyinformation/How
wemonitorthesafetyofproducts/Medicines/TheYe
llowCardScheme/Informationforhealthcareprofes
sionals/Adversedrugreactions/index.htm
• http://www.docstoc.com/docs/57017777/TheYellow-Card-Scheme-Reporting
• British National Formularly (61st Edition)