Transcript Therapeutics Week 3

Chapter 3:
Adverse Reactions
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Chapter 3 Outline
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Adverse reactions
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Definitions and classifications
Clinical manifestations of adverse reactions
Toxicologic evaluation of drugs
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
2
Adverse Reactions
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Haveles (p. 28)
Drugs may act on biologic systems to
accomplish a desired effect, but they lack
absolute specificity
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They can act on many different organs or tissues
This is the reason for undesirable or adverse drug
reactions
cont’d…
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3
Adverse Reactions

No drug is free from producing some adverse
effects in a certain number of patients
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Estimates indicate that between 5% and 10% of
patients hospitalized in the Unite States are
admitted because of adverse reactions to drugs
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4
Definitions and Classifications
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Haveles (pp. 28-29) (Fig. 3-1)
Every drug has more than one action
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Therapeutic effects are clinically desirable actions
Adverse effects are clinically undesirable reactions
• Not desired, potentially harmful, and occurs at usual
therapeutic doses
cont’d…
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5
Definitions and Classifications
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Adverse reactions may be divided into the
following categories
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Toxic reaction: an extension of the pharmacologic
effect resulting from a drug’s effect on the target
organs
• The amount of the desired effect is excessive
Side effect: a dose-related reaction that is not part
of the desired therapeutic outcome
• The drug acts on nontarget organs to produce an
undesirable effect
cont’d…
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6
Definitions and Classifications
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Idiosyncratic reaction: a genetically related
abnormal drug response
Drug allergy: an immunologic response to a drug
resulting in a reaction such as rash or anaphylaxis
• Neither predictable nor dose related
Interference with natural defense mechanisms
• The drug reduces body’s ability to fight infection
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7
Clinical Manifestations of
Adverse Reactions
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Haveles (pp. 29-31)
Exaggerated effect on target tissues
Effect on nontarget tissues
Effect on fetal development (teratogenic effect)
Local effect
Drug interactions
Hypersensitivity (allergic reaction)
Idiosyncrasy
Interference with natural defense mechanisms
cont’d…
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8
Clinical Manifestations of
Adverse Reactions
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
Haveles (p. 29)
Before a drug is used, its risk against its
benefits must be assessed
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The beneficial effect must be weighed against its
potential for adverse reactions
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9
Exaggerated Effect on Target
Tissues
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
Haveles (p. 29)
An extension of therapeutic effect caused by
the overreaction of a sensitive patient or by a
dose that is too large for that patient
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Occasionally, this may result from liver or kidney
disease
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10
Effect on Nontarget Tissues
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
Haveles (p. 29)
Caused by the nontherapeutic action of the
drug
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Reactions can occur at usual doses but appear
more often at higher doses
A reduction in dose usually reduces these adverse
reactions
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11
Effect on Fetal Development
(Teratogenic Effect)
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The relationship between drugs and congenital
abnormalities has been recognized since the
middle of the twentieth century
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Haveles (pp. 29-30, 491) (Table 25-2)
“Although more information is now available about the
safety of drugs in pregnant women, sufficient
information is still lacking”
The U.S. Food and Drug Administration (FDA)
has attempted to address concerns about the
lack of adequate knowledge of drugs by defining
five FDA pregnancy categories
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They are A, B, C, D, and X (from least to most risky)
cont’d…
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12
Effect on Fetal Development
(Teratogenic Effect)
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Although no drug can be considered “safe”
for administration to a pregnant woman,
many of the drugs used in dentistry are
among the safest
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These drugs include penicillin and erythromycin,
acetaminophen, and the local anesthetic lidocaine
Drugs used in dentistry contraindicated for
pregnant women include tetracycline,
nonsteroidal antiinflammatory agents,
benzodiazepines, and metronidazole
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13
Local Effect
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Haveles (p. 30)
Local reactions are characterized by local
tissue irritation
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Occasionally, injectable drugs can produce
irritation, pain, and tissue necrosis at the site of
injection
Topically applied agents can produce irritation at
the site of application
Drugs taken orally can produce gastrointestinal
symptoms such as nausea or dyspepsia
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14
Drug Interactions
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A drug interaction can occur when the effect
of one drug is altered by another drug
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Haveles (p. 30)
Interactions may result in toxicity or lack of efficacy
Interactions may also produce beneficial effects
The likelihood that a drug interactions would
occur increases with the number of drugs a
patient is taking
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15
Hypersensitivity (Allergic
Reaction)
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
Haveles (pp. 30-31)
Occurs when the immune system of an
individual responds to the drug administered
or applied
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The drug must act as an antigen and stimulate
antibody production in a previously sensitized
patient
Neither dose dependent nor predictable
cont’d…
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16
Hypersensitivity (Allergic
Reaction)
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An ingested drug may be metabolized to a
reactive metabolite known as a hapten
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The hapten can act as an antigen after combining
with proteins in the body
The antigen formed then stimulates the production
of an antibody
With subsequent exposure to the drug, the
antibodies formed will react with the antigen
(drug or metabolite) administered and elicit
an antigen-antibody reaction
cont’d…
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17
Hypersensitivity (Allergic
Reaction)
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Haveles (pp. 30-31) (Table 3-1)
Drug allergy can be divided into four types of
reactions, depending on the type of antibody
produced or the cell mediating the reaction
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18
Type I (Immediate)
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Mediated by immunoglobulin E (IgE)
antibodies
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When a drug antigen binds to IgE antibody,
histamine, leukotrienes, and prostaglandins are
released, producing vasodilation, edema, and
inflammation
The targets of this reaction are
• Bronchioles, resulting in anaphylactic shock
• Respiratory system, resulting in rhinitis and asthma
• Skin, resulting in urticaria and dermatitis
cont’d…
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Type I (Immediate)
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Because these reactions can occur quickly
after drug exposure, they are known as
immediate hypersensitivity reactions
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Anaphylaxis is an acute, life-threatening allergic
reaction characterized by hypotension,
bronchospasm, laryngeal edema, and cardiac
arrhythmias
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20
Type II (Cytotoxic/Cytolytic)
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Complement-dependent reactions involving
either immunoglobulin G (IgG) or
immunoglobulin M (IgM) antibodies
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The antigen-antibody complex is fixed to a
circulating red blood cell, resulting in lysis
Examples are penicillin-induced hemolytic anemia
and methyldopa-induced autoimmune hemolytic
anemia
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21
Type III (Immune
complex/Arthus/Serum sickness)
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Mediated by IgG antibodies
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The drug antigen-antibody complex fixes
complement and deposits in the vascular
endothelium
Manifested as serum sickness; includes urticarial
skin eruptions, arthralgia, arthritis,
lymphadenopathy, and fever
Can be caused by penicillins and sulfonamides
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22
Type IV (Delayed
Hypersensitivity)
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Mediated by sensitized T lymphocytes and
macrophages
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When the cells contact the antigen, an
inflammatory reaction is produced by
lymphokines, neutrophils, and macrophages
An example is contact dermatitis caused by topical
application of drugs
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23
Idiosyncrasy
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
Haveles (p. 31)
A reaction that is neither the drug’s side effect
nor an allergic reaction
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Some are genetically determined abnormal
reactions; others may be the result of an
immunologic mechanism
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24
Interference with Natural Defense
Mechanisms
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
Haveles (p. 31)
A drug’s effect on the body’s defense
mechanisms can result in an adverse
reaction
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Long-term systemic administration of
corticosteroids can result in decreased resistance
to infection
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25
Toxicologic Evaluation of Drugs
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
Haveles (pp. 31-32)
Evaluations of the toxic effects of drugs are
based on experiments performed with lower
animals and clinical trials conducted in humans
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Animal experiments can often elicit adverse
reactions that could occur in humans, but drug
reactions in animals do not always predict reactions
in humans
cont’d…
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26
Toxicologic Evaluation of Drugs
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
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
Haveles (p. 31) (Fig. 3-2)
The median lethal dose (LD50) is the dose the
kills 50% of experimental animals
The median effective dose (ED50) is the dose
required to produce a specified intensity of
effect in 50% of the animals
The ratio LD50/ED50 is the therapeutic index
(TI) of a drug
cont’d…
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27
Toxicologic Evaluation of Drugs
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
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
Haveles (pp. 31-32) (Fig. 3-3)
If the value of the TI is small (narrow TI), then
toxicity is more likely
If the TI is large (wide TI), then the drug will
be safer
A TI of greater than 10 is usually needed to
produce a therapeutically useful drug
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