• Thalidomide - 1957 - in West Germany
• The German drug company “Grünenthal” developed and sold
• 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.
• became an over the counter drug in Germany around
• 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.
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
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.
Time to withdrawn from market
• Thalidomide was withdrawn from the market
• IT WAS A BIG LESSON FOR THE WHOLE
WORLD CONCERNING WITH DRUG SAFETY
- 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
• 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
• 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
• 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
• 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
• The term ‘side effects’ is often applied to minor type A reactions.
• Bizarre effects (or idiosyncratic)
• dose independent and
pharmacological action of the drug)
• hepatotoxicity due to paracetamol
• tinnitus induced by aspirin
• ototoxicity with aminoglycosides
• Results from Chronic or continuous use
• Analgesic nephropathy
• osteoporosis during continued high-dose
• tardive dyskinesia during continuous use of
- amelia or micromelia or phocomelia
-fetal hydantoin syndrome
-teeth malformation and discoloration
-early closure of ductus arteriosus
-cleft lip and palate, microcephaly
- saddle nose
sodium valproate - spina bifida
- vaginal clear cell adenocarcinoma
• Rebound adrenal insufficiency
• Withdrawal syndrome (tachycardia on abrupt
discontinuation of β-adrenoceptor blockade)
• second malignancies following successful
a. Adverse effects related to the
pharmacological action of the drug
a. Adverse effects unrelated to the main
pharmacological action of the drug
• at least this action is well understood.
• They are sometimes referred to as type A
• postural hypotension occurs with α1-adrenoceptor
• bleeding with anticoagulants,
• sedation with anxiolytics
• intracerebral bleeding caused by anticoagulants,
• hypoglycaemic coma from insulin
• drug dependence produced by opioid analgesics
• 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
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.
• 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.
hypertension and valvular heart disease with fenfluramine,
an appetite suppressant that had been used for several years,
and also with dexfenfluramine.
Eiferman et al.
macroprecipitates in the
J Cataract Refract Surg
2001; 27(10): 1701-2
Brazier et al. Ecstasy
related periodontitis and
mucosal ulceration—a case
report. Br Dent J 2003;
• 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.
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
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.)
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
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
• Introduced in 1964 after Thalidomide tragedy
• Spontaneous reporting system
• Early warning system
• Over 600,000 confidential reports received in UK
Who can report?
Non medical prescribers
Patients also ………..
Where to report?
• www.yellowcard.gov.uk (online completion)
• Or by calling to 0808 100 3352
• Yellow cards can be available in BNF books ..
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.
You don’t need to be completely certain that
what you have seen is ADR. ***
How to get latest informations for
• don’t miss for updates for yourself also.
• DRUG SAFETY UPDATES!!
• Published monthly
• Register for updates ..
• 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
“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: