Chapter 3: Adverse Reactions Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All...

Chapter 3:Chapter 3:

Adverse ReactionsAdverse Reactions

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 3 OutlineChapter 3 Outline

Adverse reactionsAdverse reactions Definitions and classificationsDefinitions and classifications Clinical manifestations of adverse reactionsClinical manifestations of adverse reactions Toxicologic evaluation of drugsToxicologic evaluation of drugs


Adverse Reactions Adverse Reactions

Haveles (p. 28)Haveles (p. 28) Drugs may act on biologic systems to Drugs may act on biologic systems to

accomplish a desired effect, but they lack accomplish a desired effect, but they lack absolute specificityabsolute specificity They can act on many different organs or tissuesThey can act on many different organs or tissues This is the reason for undesirable or adverse drug This is the reason for undesirable or adverse drug

reactionsreactions

cont’d…cont’d…


Adverse ReactionsAdverse Reactions

No drug is free from producing some adverse No drug is free from producing some adverse effects in a certain number of patientseffects in a certain number of patients Estimates indicate that between 5% and 10% of Estimates indicate that between 5% and 10% of

patients hospitalized in the Unite States are patients hospitalized in the Unite States are admitted because of adverse reactions to drugsadmitted because of adverse reactions to drugs


Definitions and ClassificationsDefinitions and Classifications

Haveles (pp. 28-29) (Fig. 3-1)Haveles (pp. 28-29) (Fig. 3-1) Every drug has more than one actionEvery drug has more than one action

Therapeutic effectsTherapeutic effects are clinically desirable actions are clinically desirable actions Adverse effectsAdverse effects are clinically undesirable reactions are clinically undesirable reactions

• Not desired, potentially harmful, and occurs at usual Not desired, potentially harmful, and occurs at usual therapeutic dosestherapeutic doses



Definitions and ClassificationsDefinitions and Classifications

Adverse reactions may be divided into the Adverse reactions may be divided into the following categoriesfollowing categories Toxic reaction: an extension of the pharmacologic Toxic reaction: an extension of the pharmacologic

effect resulting from a drug’s effect on the target effect resulting from a drug’s effect on the target organsorgans• The amount of the desired effect is excessiveThe amount of the desired effect is excessive

Side effect: a dose-related reaction that is not part Side effect: a dose-related reaction that is not part of the desired therapeutic outcomeof the desired therapeutic outcome• The drug acts on nontarget organs to produce an The drug acts on nontarget organs to produce an

undesirable effectundesirable effect



Definitions and ClassificationsDefinitions and Classifications Idiosyncratic reaction: a genetically related Idiosyncratic reaction: a genetically related

abnormal drug responseabnormal drug response Drug allergy: an immunologic response to a drug Drug allergy: an immunologic response to a drug

resulting in a reaction such as rash or anaphylaxisresulting in a reaction such as rash or anaphylaxis• Neither predictable nor dose relatedNeither predictable nor dose related

Interference with natural defense mechanisms Interference with natural defense mechanisms • The drug reduces body’s ability to fight infectionThe drug reduces body’s ability to fight infection


Clinical Manifestations of Clinical Manifestations of Adverse ReactionsAdverse Reactions

Haveles (pp. 29-31)Haveles (pp. 29-31) Exaggerated effect on target tissuesExaggerated effect on target tissues Effect on nontarget tissuesEffect on nontarget tissues Effect on fetal development (teratogenic effect)Effect on fetal development (teratogenic effect) Local effectLocal effect Drug interactionsDrug interactions Hypersensitivity (allergic reaction)Hypersensitivity (allergic reaction) IdiosyncrasyIdiosyncrasy Interference with natural defense mechanismsInterference with natural defense mechanisms



Clinical Manifestations of Clinical Manifestations of Adverse ReactionsAdverse Reactions

Haveles (p. 29)Haveles (p. 29) Before a drug is used, its risk against its Before a drug is used, its risk against its

benefits must be assessedbenefits must be assessed The beneficial effect must be weighed against its The beneficial effect must be weighed against its

potential for adverse reactionspotential for adverse reactions


Exaggerated Effect on Target Exaggerated Effect on Target TissuesTissues

Haveles (p. 29)Haveles (p. 29) An extension of therapeutic effect caused by An extension of therapeutic effect caused by

the overreaction of a sensitive patient or by a the overreaction of a sensitive patient or by a dose that is too large for that patientdose that is too large for that patient Occasionally, this may result from liver or kidney Occasionally, this may result from liver or kidney

diseasedisease


Effect on Nontarget TissuesEffect on Nontarget Tissues

Haveles (p. 29)Haveles (p. 29) Caused by the nontherapeutic action of the Caused by the nontherapeutic action of the

drugdrug Reactions can occur at usual doses but appear Reactions can occur at usual doses but appear

more often at higher dosesmore often at higher doses A reduction in dose usually reduces these adverse A reduction in dose usually reduces these adverse

reactionsreactions


Effect on Fetal Development Effect on Fetal Development (Teratogenic Effect)(Teratogenic Effect)

Haveles (pp. 29-30, 491) (Table 25-2)Haveles (pp. 29-30, 491) (Table 25-2) The relationship between drugs and congenital The relationship between drugs and congenital

abnormalities has been recognized since the abnormalities has been recognized since the middle of the twentieth centurymiddle of the twentieth century ““Although more information is now available about the Although more information is now available about the

safety of drugs in pregnant women, sufficient safety of drugs in pregnant women, sufficient information is still lacking”information is still lacking”

The U.S. Food and Drug Administration (FDA) The U.S. Food and Drug Administration (FDA) has attempted to address concerns about the has attempted to address concerns about the lack of adequate knowledge of drugs by defining lack of adequate knowledge of drugs by defining five FDA pregnancy categoriesfive FDA pregnancy categories They are A, B, C, D, and X (from least to most risky)They are A, B, C, D, and X (from least to most risky)

cont’d… cont’d…


Effect on Fetal Development Effect on Fetal Development (Teratogenic Effect)(Teratogenic Effect)

Although no drug can be considered “safe” Although no drug can be considered “safe” for administration to a pregnant woman, many for administration to a pregnant woman, many of the drugs used in dentistry are among the of the drugs used in dentistry are among the safestsafest These drugs include penicillin and erythromycin, These drugs include penicillin and erythromycin,

acetaminophen, and the local anesthetic lidocaineacetaminophen, and the local anesthetic lidocaine Drugs used in dentistry contraindicated for Drugs used in dentistry contraindicated for

pregnant women include tetracycline, pregnant women include tetracycline, nonsteroidal antiinflammatory agents, nonsteroidal antiinflammatory agents, benzodiazepines, and metronidazolebenzodiazepines, and metronidazole


Local EffectLocal Effect

Haveles (p. 30)Haveles (p. 30) Local reactions are characterized by local Local reactions are characterized by local

tissue irritationtissue irritation Occasionally, injectable drugs can produce Occasionally, injectable drugs can produce

irritation, pain, and tissue necrosis at the site of irritation, pain, and tissue necrosis at the site of injectioninjection

Topically applied agents can produce irritation at Topically applied agents can produce irritation at the site of applicationthe site of application

Drugs taken orally can produce gastrointestinal Drugs taken orally can produce gastrointestinal symptoms such as nausea or dyspepsiasymptoms such as nausea or dyspepsia


Drug InteractionsDrug Interactions

Haveles (p. 30)Haveles (p. 30) A drug interaction can occur when the effect A drug interaction can occur when the effect

of one drug is altered by another drugof one drug is altered by another drug Interactions may result in toxicity or lack of Interactions may result in toxicity or lack of

efficacyefficacy Interactions may also produce beneficial effectsInteractions may also produce beneficial effects

The likelihood that a drug interactions would The likelihood that a drug interactions would occur increases with the number of drugs a occur increases with the number of drugs a patient is takingpatient is taking


Hypersensitivity (Allergic Hypersensitivity (Allergic Reaction)Reaction)

Haveles (pp. 30-31)Haveles (pp. 30-31) Occurs when the immune system of an Occurs when the immune system of an

individual responds to the drug administered or individual responds to the drug administered or appliedapplied The drug must act as an antigen and stimulate The drug must act as an antigen and stimulate

antibody production in a previously sensitized antibody production in a previously sensitized patientpatient

Neither dose dependent nor predictableNeither dose dependent nor predictable



Hypersensitivity (Allergic Hypersensitivity (Allergic Reaction)Reaction)

An ingested drug may be metabolized to a An ingested drug may be metabolized to a reactive metabolite known as a reactive metabolite known as a haptenhapten The hapten can act as an antigen after combining The hapten can act as an antigen after combining

with proteins in the bodywith proteins in the body The antigen formed then stimulates the production The antigen formed then stimulates the production

of an antibodyof an antibody With subsequent exposure to the drug, the With subsequent exposure to the drug, the

antibodies formed will react with the antigen antibodies formed will react with the antigen (drug or metabolite) administered and elicit (drug or metabolite) administered and elicit an antigen-antibody reactionan antigen-antibody reaction



Hypersensitivity (Allergic Hypersensitivity (Allergic Reaction) Reaction)

Haveles (pp. 30-31) (Table 3-1)Haveles (pp. 30-31) (Table 3-1) Drug allergy can be divided into four types of Drug allergy can be divided into four types of

reactions, depending on the type of antibody reactions, depending on the type of antibody produced or the cell mediating the reactionproduced or the cell mediating the reaction


Type I (Immediate) Type I (Immediate)

Mediated by immunoglobulin E (IgE) antibodiesMediated by immunoglobulin E (IgE) antibodies When a drug antigen binds to IgE antibody, When a drug antigen binds to IgE antibody,

histamine, leukotrienes, and prostaglandins are histamine, leukotrienes, and prostaglandins are released, producing vasodilation, edema, and released, producing vasodilation, edema, and inflammationinflammation

The targets of this reaction are The targets of this reaction are • Bronchioles, resulting in anaphylactic shockBronchioles, resulting in anaphylactic shock

• Respiratory system, resulting in rhinitis and asthmaRespiratory system, resulting in rhinitis and asthma

• Skin, resulting in urticaria and dermatitisSkin, resulting in urticaria and dermatitis



Type I (Immediate)Type I (Immediate)

Because these reactions can occur quickly Because these reactions can occur quickly after drug exposure, they are known as after drug exposure, they are known as immediate hypersensitivity reactionsimmediate hypersensitivity reactions Anaphylaxis is an acute, life-threatening allergic Anaphylaxis is an acute, life-threatening allergic

reaction characterized by hypotension, reaction characterized by hypotension, bronchospasm, laryngeal edema, and cardiac bronchospasm, laryngeal edema, and cardiac arrhythmiasarrhythmias


Type II (Cytotoxic/Cytolytic) Type II (Cytotoxic/Cytolytic)

Complement-dependent reactions involving Complement-dependent reactions involving either immunoglobulin G (IgG) or either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodiesimmunoglobulin M (IgM) antibodies The antigen-antibody complex is fixed to a The antigen-antibody complex is fixed to a

circulating red blood cell, resulting in lysiscirculating red blood cell, resulting in lysis Examples are penicillin-induced hemolytic anemia Examples are penicillin-induced hemolytic anemia

and methyldopa-induced autoimmune hemolytic and methyldopa-induced autoimmune hemolytic anemiaanemia


Type III (Immune Type III (Immune complex/Arthus/Serum sickness)complex/Arthus/Serum sickness)

Mediated by IgG antibodiesMediated by IgG antibodies The drug antigen-antibody complex fixes The drug antigen-antibody complex fixes

complement and deposits in the vascular complement and deposits in the vascular endotheliumendothelium

Manifested as serum sickness; includes urticarial Manifested as serum sickness; includes urticarial skin eruptions, arthralgia, arthritis, skin eruptions, arthralgia, arthritis, lymphadenopathy, and feverlymphadenopathy, and fever

Can be caused by penicillins and sulfonamidesCan be caused by penicillins and sulfonamides


Type IV (Delayed Type IV (Delayed Hypersensitivity)Hypersensitivity)

Mediated by sensitized T lymphocytesMediated by sensitized T lymphocytes and and macrophagesmacrophages When the cells contact the antigen, an When the cells contact the antigen, an

inflammatory reaction is produced by lymphokines, inflammatory reaction is produced by lymphokines, neutrophils, and macrophagesneutrophils, and macrophages

An example is contact dermatitis caused by topical An example is contact dermatitis caused by topical application of drugsapplication of drugs


IdiosyncrasyIdiosyncrasy

Haveles (p. 31)Haveles (p. 31) A reaction that is neither the drug’s side effect A reaction that is neither the drug’s side effect

nor an allergic reactionnor an allergic reaction Some are genetically determined abnormal Some are genetically determined abnormal

reactions; others may be the result of an reactions; others may be the result of an immunologic mechanismimmunologic mechanism


Interference with Natural Defense Interference with Natural Defense MechanismsMechanisms

Haveles (p. 31)Haveles (p. 31) A drug’s effect on the body’s defense A drug’s effect on the body’s defense

mechanisms can result in an adverse mechanisms can result in an adverse reactionreaction Long-term systemic administration of Long-term systemic administration of

corticosteroids can result in decreased resistance corticosteroids can result in decreased resistance to infectionto infection


Toxicologic Evaluation of DrugsToxicologic Evaluation of Drugs

Haveles (pp. 31-32)Haveles (pp. 31-32) Evaluations of the toxic effects of drugs are Evaluations of the toxic effects of drugs are

based on experiments performed with lower based on experiments performed with lower animals and clinical trials conducted in humansanimals and clinical trials conducted in humans Animal experiments can often elicit adverse Animal experiments can often elicit adverse

reactions that could occur in humans, but drug reactions that could occur in humans, but drug reactions in animals do not always predict reactions reactions in animals do not always predict reactions in humansin humans




Haveles (p. 31) (Fig. 3-2)Haveles (p. 31) (Fig. 3-2)

The median lethal dose (LDThe median lethal dose (LD5050) is the dose the ) is the dose the

kills 50% of experimental animalskills 50% of experimental animals The median effective dose (EDThe median effective dose (ED5050) is the dose ) is the dose

required to produce a specified intensity of required to produce a specified intensity of effect in 50% of the animalseffect in 50% of the animals

The ratio LDThe ratio LD5050/ED/ED5050 is the therapeutic index is the therapeutic index

(TI) of a drug(TI) of a drugcont’d…cont’d…



Haveles (pp. 31-32) (Fig. 3-3)Haveles (pp. 31-32) (Fig. 3-3) If the value of the TI is small (narrow TI), then If the value of the TI is small (narrow TI), then

toxicity is more likelytoxicity is more likely If the TI is large (wide TI), then the drug will If the TI is large (wide TI), then the drug will

be saferbe safer A TI of greater than 10 is usually needed to A TI of greater than 10 is usually needed to

produce a therapeutically useful drugproduce a therapeutically useful drug

Chapter 3: Adverse Reactions Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All...

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