ADVERSE EFFECTS OF

DRUGS
Types of Adverse Drug Reaction
• An adverse drug reaction: ‘any
undesired or unintended effect of drug
treatment’
• Two types: those related to the main
pharmacological action of the drug, and
those unrelated to the main
pharmacological action
• Clinically significant adverse drug
reactions are common, costly and
avoidable
• Adverse drug reactions range from mild to
severe, and from non-serious to serious and
life-threatening effects resulting in death or
disabilities
• Therefore, of great concern to drug
regulatory authorities (e. g. FDA, TFDA,
EMEA) charged to establish the safety and
efficacy of drugs before they are licensed for
marketing hence protecting the public
• Events that are unpredictable and those
masked by a high background incidence
unrelated to drug exposure are of particular
concern
• Adverse effects related to the main
pharmacological action of the drug
– Time course of the event shadows drug
administration and discontinuation
– When the main pharmacological action of the
drug is well understood, event reasonably
predictable
– They are also known as type A (augmented)
adverse reactions
 – Type A adverse events are often reversible
and respond to dose reduction (? Drug
dependence)
– Sometimes serious e. g. intracebral
haemorrhage from anticoagualnts or
hypoglycaemic coma from insulin
• Eamples:
– Postural hypotension with alpha-adrenoceptor
antagonisit
– Bleeding with anticoagulants
– Sedation with anxiolytics
• Adverse effects unrelated to the main
pharmacological action of the drug
• Generally no plausible temporal
relationship with drug administration and
thus unpredictable
• May first appear months or years after start
of treatment
• A huge challenge in terms of initial
recognition especially if event may be a
symptom or sign of the disease or if
masked by a common condition such as
malignancy or myocardial infarction.
• These idiosyncratic reactions are also
termed as type B (‘bizarre’) adverse
reactions
• Often initiated by a chemically reactive
metabolite rather than the parent drug
(direct or immunological)
• Usually severe (otherwise would go
unrecognized)
• Their existence is important in
establishing the safety of medicines
• May be predictable when:
– A drug is taken in excessive dose ( e.g.
paracetamol hepatotoxicity)
– A drug is taken during pregnancy (e.g.
thalidomide teratogenicity
– A drug is taken by patients with a predisposing
disorder (e.g. primaquine-induced haemolysis
in patients with glucose 6-phosphate deficiency
• Sometimes a predictable subsidiary
pharmacological effect may have
serious implications for rare susceptible
individuals (e. g. QT interval
prolongation)
• Examples of rare but unpredictable
severe adverse effects
– Aplastic anaemia from chloramphenicol
– Anaphylaxis in response to penicillin
 Drug Toxicity
• Toxicity testing in drug development
• Done in animals on new drugs before they are
administered to humans
• A wide range of tests is used in different species
involving
• Long-term administration of the drug
• Regular monitoring for physiological or
biochemical changes
• Detailed postmortem examination at the end of
the trial to detect any gross or histological
abnormalities
• Toxicity testing is performed with does
well above the expected therapeutic
range
• Establishes which tissues or organs are
likely ‘targets’ of toxic effects of the drug
• Recovery studies are performed to
assess whether toxic effects are
reversible
• Particular attention is paid to irreversible
changes e. g. carcinogenesis or
neurodegeneration
• The basic assumption is that toxic effect
caused by a drug is similar in humans and
animals. However, there are species
variation e. g. in drug metabolism
• Therefore, toxicity testing in animals is not
always a reliable guide
• Toxic effects can range from negligible to so
severe as to preclude any further
development
• Intermediate levels of toxicity are more
acceptable in drugs intended for severe
illnesses (e. g. AIDS or cancers)
• Safety of a drug (as opposed to toxicity)
can be established only during use in
humans
General mechanisms of toxicin-
induced cell damage and cell
death

• Toxic concentrations of drugs or

metabolites may cause necrosis
• Increasingly, programmed cell death
(apoptosis) is recognized as of
paramount importance especially in
chronic toxicity
• Chemically reactive drug metabolites
can form covalent bonds with target
molecules or alter target molecules by
non-covalent bonding
• Non-covalent interactions
• lipid peroxidation:
– Can be initiated by reactive metabolites or
oxygen species
– A peroxidative cascdade is activated which
may affect much of the membrane lipid
– Cell damage results from alteration of
membrane permeability
– Defense mechanisms e. g. GSH peroxidase,
and vitamin E protect against this
• Reactive oxygen species
– Reduction of molecular oxygen to superoxide
anion may be followed by enzymatic
conversion to hydrogen peroxide,
hydroperoxy and hydroxyl radicals
– These are cytotoxic both directly and through
lipid peroxidation
– Are important in excitotoxicity and
neurodegeneration
• Depletion of glutathione
– The GSH redox cycle protects cells from
oxidative stress
– GSH can be depleted by accumulation of
normal oxidative products or by action of toxic
chemicals
– GSH normally maintained in redox couple with
its disulfide, GSSG
– Oxidising species convert GSH to GSSG,
GSH being regenerated by NADPH-
dependent GSSG reductase
– when cellular GSH fall to 20 - 30 % of
normal cellular defense against toxic
compounds is impaired and cell death can
result
• Modification of sulffhydryl groups
– Can be produced either by oxidising species
that alter sulfhydryl groups reversibly or by
covalent interaction
– Free sulfhydryl groups are critical in the
catalytic activity of many enzymes
– Important targets sulfhydryl
modification by reactive metabolites
include
• cytoskeleton protein actin
• GSH reductase
• Calcium transporting ATPase im plasma
membarane and endoplasmic reticulum
• Covalent interactions
• Targets for covalent interactions include
DNA, proteins/peptides, lipids and
carbohydrates
• Covalent bonding to DNA is a basic
mechanism of mutagenic chemicals
• Several non-mutagenic chemicals also
form covalent bonds with
macromolecules, but relationship with
cell death is not well understood
– e. g. cholinestrase inhibitor paraoxon binds
acetylcholinesterase at the neuromuscular
junction and causes necrosis of skeletal
muscle
 Figure 53-1 Potential mechanisms of liver cell
death resulting from the metabolism of
paracetamol to N-acetyl-p-benzoquinone imine
(NAPBQI). GSH, glutathione. (Based on data
from Boobis A R et al. 1989 Trends Pharmacol
Sci 10: 275-280 and Nelson S D, Pearson P G
1990 Annu Rev Pharmacol Toxicol 30: 169.)
 Mutagenesis and
carcinogenicity
• Mutagenesis involves modification of DNA
• Mutation of pro-oncogenes or tumour
supressor genes leads to carcinogenesis
• More than one mutation is usually required
• Drugs are relatively uncommon (but not
unimportant) causes of birth defects and
cancers
 Carcinogens
• Carcinogens can be:
– Genotoxic, i.e. causing mutations directly
(primary carcinogens) or after conversion
to reactive metabolites (secondary
carcinogens)
– Epigenetic, i. e. increasing the possibility
that a mutagen will cause cancer, although
not themselves muatagenic
• Epigenetic carcinogens include:
– ‘Promoters’ which increase cancer rate if
given after the mutagen
– ‘Cocarcinogens’ which increase cancer rate
if given with the mutagen
• New drugs are tested for mutagenicity
and carcinogenicity
• The main test for mutagenicity measures
back-mutation (in histidine-free-medium)
of a mutant Salmonella typhimurium,
which unlike the wild type, cannot grow
without histidine) in the presence of:
 – The chemical to be tested
– A liver microsomal enzyme preparation for
generating reactive metabolites
• Colony growth indicates that mutagenesis
has occurred
• The test is rapid and inexpensive but
some false positives and negatives occur
 Measurement of mutagenicity
and carcinogenicity
• Assays have been developed to detect
mutagenicity and carcinogenicity and
can be divided as follow:
• In vitro tests for mutagenicity suitable
for screening large numbers of
compounds (...but problem of sensitivity
and specificity for carcinogenicity)
• Whole-animal tests for carcinogenicity,
expensive and time-consuming but
required by regulatory authorities before
new drugs are licensed for use in
humans
– Main limitation of the test is the important
species differences in metabolism
(formation of reactive metabolites)
• Whole-animal tests for teratogenesis
(reproductive toxicicity testing)
– Tests in pregnant animals
– Required for drugs to be used by women of
reproductive potential
– Similar limitations as with carcinogenicity
testing
 In vitro tests for genotoxic
carcinogens
• Bacteria have great advantages as a
test system for measuring mutagenicity
because of their high replication rate
• The most widely used assays are
variations of the Ames test, which
measure the rate of back-mutation
(reversion from mutant to wild-type
form) in S. typhimurium
In vivo test for carcinogenicity
• Entail detection of tumours in groups of
test animals
• Inevitably slow ( there is usually a
latency of months or years before
tumuors develop)
• Results often provide only equivocal
eveidence (…tumours can develop
spontaneously in control animals)
 Teratogenesis and drug-
induced fetal damage
• Teratogenesis means production of
gross structural malformations of the
fetus (e.g. Absence of limbs after
thalidomide)
• Less comprehensive damage can be
produced by several drugs (table 53.2,
Rang and Dale’s Pharmacology 6E
pg759)
• Less than 1 % of congenital fetal defects
are attributed to drugs given to the
mother
• Gross malformations are produced only if
teratogens act during organogenesis
(days 17 – 60)
• This occurs during the first 3 months of
pregnancy but after blastocyst formation
• Drug-induced fetal damage is rare during
blastocyst formation
• The mechanism of action of teratogens
are not clearly understood, although
DNA damage is a factor but not the only
factor
• The control of morphogenesis is poorly
understood: Vit A derivatives (retinoids)
are involved and a potent teratogens

• New drugs are usually tested in

pregnant females of at least one rodent
and one non-rodent (e.g. rabbit) species
• Known teratogens also include several
drugs that do not react directly with DNA
but which inhibit its synthesis by their
effects on folate metabolism
• Examples include methotrexate and
phenytoin
• Administration of folate during pregnancy
reduces the frequency of both
spontaneous and drug-induced
malformations, especially neural tube
effects
• The fetus depends on adequate supply
of nutrients during the final stage of
histogenesis and functional maturation
• During this time development is
regulated by a variety of hormones
• Drugs that interfere with the supply of
nutrients or hormonal milieu may have
deleterious effects on growth and
development
• Angiotensin II plays an important part of
in the later stages of fetal development
and in renal function
• ACE inhibitors and angiotensin receptor
antagonists (sartans) cause
ologohydramnios and renal failure if
administered during later stages of
pregnancy
• They have been associated with skull
defects in experimental animals
 Testing for teratogenicity

• The thalidomide disaster brought the need for

routine teratogenicity studies on new
therapeutic drugs
• Assessment in humans is difficult
• Spontaneous malformation rate is high (3 – 10
%) and highly variable between regions, age
groups and social class
• Large studies, which must ran for years are
required and usually give suggestive rather
than conclusive results
• Studies using embriyonic stem cells in
assessing developmenttal toxicity are
showing some promise
• In vitro methods based on culture of cells,
organs or whole embryos are still not able
to satisfactorily predict teratogenesis in
vivo
• Most regulatory authorities require
teratogenicity testing in a rodent plus in
one non-rodent species
• Pregnant females are dosed at various
levels during the critical period of
organogenesis, and the fetuses are
examined for structural abnormalities
• However, there is poor cross-species
correlation, which means that these
tests are not reliably predictive in
humans
• Therefore, recommended that new
drugs are not used in pregnancy unless
it is essential
 Some definite and probable
human teratogens
• Relatively few drugs are known to be
teratogenic in humans
• The following are the more important
– Thalidomide
– Cytotoxic drugs (e.g. Chlorambucil,
cyclophosphamide) and antimetabolites
(e.g. Azathioprine, mercaptopurine) folate
antagonists (e.g. Methotrexate)
– Retinoids (e.g. Etretinate, Vit A derivative
and metabolite, acitretin) causes high
propotion of serious skeletal deformities
– Heavy metals, lead, cadmium and mecury
all cause fetal malformations in humans,
evedence from Minamata disease (CP,
mental retardation, often with
microcephaly). Inactivate many enzymes
by forming covalent bonds with sulfhydrl
and other groups
• Antiepileptic drugs

– Congenital malformations increased 2 – 3

fold in babies of epileptic mothers

– All existting antiepileptic drugs have been

implicated. Phenytoin (cleft palate),
valporate (neural tube defects) and
carbamazepine (spina bifida, hypospadias)
• Warfarin
– Administration in the first trimester
associated with nasal hypoplasia and
various CNS abnormalities in about 25 %
of exposed babies

– Must not be used in last semester because

of risk of intracranial haemorrhage in the
baby during delivery
• Antiemetics
– Widely used to treat morning sickness in
early pregnancy

– Some are teratogenic in animals

– Results in humans are inconclusive

– Even so, prudent to avoid the use of these

drugs in pregnant patients if possible
 Assessment of genotoxic
potential
• Registration of pharmaceuticals requires
a comprehensive assessment of their
genotoxic potential
• No single test is adequate
• Approach recommended by International
Conference on Harmonization is a battery
of in vitro and in vivo tests
• The following is often used
– A test for gene mutation in bacteria
– An in vitro test with cytogenetic evaluation of
chromosomal damage
– An in vivo test for chromosomal damage
using rodent haematopoietic cells
– Reproductive toxicity testing
– Carcinogenenicity testing
 Allergic reactions to drugs
• Drugs or their reactive metabolites can
bind covalently to proteins to form
immunogens (Penicillin is an important
example and can also form
immunogenic polymers)
• Drug-induced allergic (hypersensitivity)
reactions may be antibody-mediated
(types I, II, III) or cell-mediated (type IV)
• The main criteria that are suggestive of
an immune response are as follows
– The time course differs from the main action
of the drug; either delayed in onset or occurs
only with repeated exposure to the drug
– Allergy may result from doses that are too
small to elicit pharmacodynamic effects
– The reaction conforms to one of the clinical
syndromes associated with allergy – types I,
II, III and IV of the Gell and Combs
classification and is unrelated to the
pharmacodynamic effect of the drug
• Important clinical types of allergic
responses to drugs
– Anaphylactic shock (type I): many drugs can
cause this, and most deaths are caused by
penicillin
• Other drugs that can cause anaphylaxis
include
– Various enzymes (streptokinase,
asparaginase)
– Hormones (corticotropin)

– Heparin

– Dextrans, radiological contrast agents

– Vaccines and other serological products

Haematological reactions (type II, III or
IV) including haemolytic anaemia (e.g.
Methyldopa); agranulocytosis (e.g. Carbimazole);
thrombocytopenia (e.g. Quinine, heparin); and
aplastic anaemia (e.g. Chloramphenicol)

Allergic liver damage

Most results from direct toxic effect of drugs or their
Metabolites
However, hypersentivity are sometimes involved
– Hepatitis (types II, III): e.g. halothane,
phenytoin
Other hypesensitivity reactions
– Rashes (types I, IV) are usually mild but
can be life-threatening (e.g. Stevens-
Johnson syndrome)
– Drug-induced systemic lupus
erythematosis (mainly type II): antibodies
to nuclear material are formed (e.g.
hydralazine)
 Balancing the risk and benefit of
drugs
• Merit assessment for drugs should be based
on concepts that are clinically useful and can
be used on both sides of the balance
• Three main concepts related to any effect of a
drug on the body
– How great the effect is
– Its duration (how long does it stay?)
– What is its incidence
• Three main aspects of risk:
– The seriousness and severity of the adverse
reaction
– The duration of the adverse reaction
– The frequency of occurrence
• Three main aspects of benefit
– The seriousness of the disease being
treated, consider against the likely extent
of improvement
– The chronicity of the disease, against the
probable reduction in duration produced by
treatment
– The frequency of the disease (in an
individual 100 %), against the frequency of
improvement
• The concepts can be used in a general
sense, for example to compare drugs
used in the same indication, and applied
to individual patients
• However, considerable judgment is still
required in the application of the
concepts
• Example:
• We have a patient with a serious infection
with about 80% mortality and which may
last for weeks if the patient doesn’t die.
Chloramphenicol is curative in 90 % of
cases and patients usually improve within
days. Aplastic anaemia is the main AR
with an incidence of about 1 in 18,000 and
a mortality of 30 % and protracted
morbidity of months
• What would be the simple clinical decision
here?