Adverse Drug Effects V

Drug Toxicity in Pregnancy and
Lactation
Drugs taken by the mother can be
passed on transplacentally or via breast
milk and adversely affect the unborn or
the neonate.
Pregnancy
Limb malformations induced by the
hypnotic, thalidomide, first focused attention
on the potential of drugs to
cause malformations (teratogenicity).
Drug effects on the unborn fall into two
basic categories:
1. Predictable effects that derive from
the known pharmacological drug
properties. Examples are: masculinization
of the female fetus by androgenic
hormones; brain hemorrhage
due to oral anticoagulants; bradycardia
due to !-blockers.
2. Effects that specifically affect the developing
organism and that cannot
be predicted on the basis of the
known pharmacological activity profile.
In assessing the risks attending
drug use during pregnancy, the following
points have to be considered:
a) Time of drug use. The possible sequelae
of exposure to a drug depend on
the stage of fetal development, as
shown in A. Thus, the hazard posed
by a drug with a specific action is limited
in time, as illustrated by the tetracyclines,
which produce effects on
teeth and bones only after the third
month of gestation, when mineralization
begins.
b) Transplacental passage. Most drugs
can pass in the placenta from the maternal
into the fetal circulation. The
fused cells of the syncytiotrophoblast
form the major diffusion barrier.
They possess a higher permeability to
drugs than is suggested by the term
“placental barrier”.
c) Teratogenicity. Statistical risk estimates
are available for familiar, frequently
used drugs. For many drugs,
teratogenic potency cannot be demonstrated;
however, in the case of
novel drugs it is usually not yet possible
to define their teratogenic hazard.
Drugs with established human teratogenicity
include derivatives of vitamin
A (etretinate, isotretinoin [used
internally in skin diseases]), and oral
anticoagulants. A peculiar type of damage
results from the synthetic estrogenic
agent, diethylstilbestrol, following its
use during pregnancy; daughters of
treated mothers have an increased incidence
of cervical and vaginal carcinoma
at the age of approx. 20.
In assessing the risk: benefit ratio, it is
also necessary to consider the benefit
for the child resulting from adequate
therapeutic treatment of its mother. For
instance, therapy with antiepileptic
drugs is indispensable, because untreated
epilepsy endangers the infant at least
as much as does administration of anticonvulsants.
Lactation
Drugs present in the maternal organism
can be secreted in breast milk and thus
be ingested by the infant. Evaluation of
risk should be based on factors listed in
B. In case of doubt, potential danger to
the infant can be averted only by weaning.

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Adverse Drug Effects IV

Type 2, cytotoxic reaction. Drugantibody
(IgG) complexes adhere to the
surface of blood cells, where either circulating
drug molecules or complexes already
formed in blood accumulate.
These complexes mediate the activation
of complement, a family of proteins that
circulate in the blood in an inactive
form, but can be activated in a cascadelike
succession by an appropriate stimulus.
“Activated complement” normally
directed against microorganisms, can
destroy the cell membranes and thereby
cause cell death; it also promotes phagocytosis,
attracts neutrophil granulocytes
(chemotaxis), and stimulates other
inflammatory responses. Activation
of complement on blood cells results in
their destruction, evidenced by hemolytic
anemia, agranulocytosis, and
thrombocytopenia.
Type 3, immune complex vasculitis
(serum sickness, Arthus reaction).
Drug-antibody complexes precipitate on
vascular walls, complement is activated,
and an inflammatory reaction is triggered.
Attracted neutrophils, in a futile
attempt to phagocytose the complexes,
liberate lysosomal enzymes that damage
the vascular walls
. Symptoms may include fever,
exanthema, swelling of lymph
nodes, arthritis, nephritis, and neuropathy.
Type 4, contact dermatitis. A cutaneously
applied drug is bound to the
surface of T-lymphocytes directed specifically
against it. The lymphocytes release
signal molecules (lymphokines)
into their vicinity that activate macrophages
and provoke an inflammatory
reaction.

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Adverse Drug Effects III

Drug Allergy
The immune system normally functions
to rid the organism of invading foreign
particles, such as bacteria. Immune responses
can occur without appropriate
cause or with exaggerated intensity and
may harm the organism, for instance,
when allergic reactions are caused by
drugs (active ingredient or pharmaceutical
excipients). Only a few drugs, e.g.
(heterologous) proteins, have a molecular
mass (> 10,000) large enough to act
as effective antigens or immunogens,
capable by themselves of initiating an
immune response. Most drugs or their
metabolites (so-called haptens) must
first be converted to an antigen by linkage
to a body protein. In the case of penicillin
G, a cleavage product (penicilloyl
residue) probably undergoes covalent
binding to protein. During initial contact
with the drug, the immune system
is sensitized: antigen-specific lymphocytes
of the T-type and B-type (antibody
formation) proliferate in lymphatic tissue
and some of them remain as socalled
memory cells. Usually, these processes
remain clinically silent. During
the second contact, antibodies are already
present and memory cells proliferate
rapidly. A detectable immune response,
the allergic reaction, occurs.
This can be of severe intensity, even at a
low dose of the antigen. Four types of
reactions can be distinguished:
Type 1, anaphylactic reaction.
Drug-specific antibodies of the IgE type
combine via their Fc moiety with receptors
on the surface of mast cells. Binding
of the drug provides the stimulus for the
release of histamine and other mediators.
In the most severe form, a lifethreatening
anaphylactic shock develops,
accompanied by hypotension,
bronchospasm (asthma attack), laryngeal
edema, urticaria, stimulation of gut
musculature, and spontaneous bowel
movements .

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Adverse Drug Effects I

Adverse Drug Effects
The desired (or intended) principal effect
of any drug is to modify body function
in such a manner as to alleviate
symptoms caused by the patient’s illness.
In addition, a drug may also cause
unwanted effects that can be grouped
into minor or “side” effects and major or
adverse effects. These, in turn, may give
rise to complaints or illness, or may
even cause death.
Causes of adverse effects: overdosage
. The drug is administered in
a higher dose than is required for the
principal effect; this directly or indirectly
affects other body functions. For instances,
morphine , given in the
appropriate dose, affords excellent pain
relief by influencing nociceptive pathways
in the CNS. In excessive doses, it
inhibits the respiratory center and
makes apnea imminent. The dose dependence
of both effects can be graphed
in the form of dose-response curves
(DRC). The distance between both DRCs
indicates the difference between the
therapeutic and toxic doses. This margin
of safety indicates the risk of toxicity
when standard doses are exceeded.
“The dose alone makes the poison”
(Paracelsus). This holds true for both
medicines and environmental poisons.
No substance as such is toxic! In order to
assess the risk of toxicity, knowledge is
required of) the effective dose during
exposure) the dose level at which
damage is likely to occur) the duration
of exposure.

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