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

2 Chapter 3 Outline  Adverse reactions  Definitions and classifications  Clinical manifestations of adverse reactions  Toxicologic evaluation of drugs

3Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Reactions  Haveles (p. 28)  Drugs may act on biologic systems to accomplish a desired effect, but they lack absolute specificity  They can act on many different organs or tissues  This is the reason for undesirable or adverse drug reactions cont’d…

4Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Reactions  No drug is free from producing some adverse effects in a certain number of patients  Estimates indicate that between 5% and 10% of patients hospitalized in the Unite States are admitted because of adverse reactions to drugs

5Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Definitions and Classifications  Haveles (pp ) (Fig. 3-1)  Every drug has more than one action  Therapeutic effects are clinically desirable actions  Adverse effects are clinically undesirable reactions Not desired, potentially harmful, and occurs at usual therapeutic doses Not desired, potentially harmful, and occurs at usual therapeutic dosescont’d…

6Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Definitions and Classifications  Adverse reactions may be divided into the following categories  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 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 The drug acts on nontarget organs to produce an undesirable effectcont’d…

7Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Definitions and Classifications  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 Neither predictable nor dose related  Interference with natural defense mechanisms The drug reduces body’s ability to fight infection The drug reduces body’s ability to fight infection

8Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Clinical Manifestations of Adverse Reactions  Haveles (pp )  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…

9Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Clinical Manifestations of Adverse Reactions  Haveles (p. 29)  Before a drug is used, its risk against its benefits must be assessed  The beneficial effect must be weighed against its potential for adverse reactions

10Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Exaggerated Effect on Target Tissues  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  Occasionally, this may result from liver or kidney disease

11Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Effect on Nontarget Tissues  Haveles (p. 29)  Caused by the nontherapeutic action of the drug  Reactions can occur at usual doses but appear more often at higher doses  A reduction in dose usually reduces these adverse reactions

12Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Effect on Fetal Development (Teratogenic Effect)  Haveles (pp , 491) (Table 25-2)  The relationship between drugs and congenital abnormalities has been recognized since the middle of the twentieth century  “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  They are A, B, C, D, and X (from least to most risky) cont’d… cont’d…

13Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Effect on Fetal Development (Teratogenic Effect)  Although no drug can be considered “safe” for administration to a pregnant woman, many of the drugs used in dentistry are among the safest  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

14Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Local Effect  Haveles (p. 30)  Local reactions are characterized by local tissue irritation  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

15Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Drug Interactions  Haveles (p. 30)  A drug interaction can occur when the effect of one drug is altered by another drug  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

16Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Hypersensitivity (Allergic Reaction)  Haveles (pp )  Occurs when the immune system of an individual responds to the drug administered or applied  The drug must act as an antigen and stimulate antibody production in a previously sensitized patient  Neither dose dependent nor predictable cont’d…

17Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Hypersensitivity (Allergic Reaction)  An ingested drug may be metabolized to a reactive metabolite known as a hapten  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…

18Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Hypersensitivity (Allergic Reaction)  Haveles (pp ) (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

19Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Type I (Immediate)  Mediated by immunoglobulin E (IgE) antibodies  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 Bronchioles, resulting in anaphylactic shock Respiratory system, resulting in rhinitis and asthma Respiratory system, resulting in rhinitis and asthma Skin, resulting in urticaria and dermatitis Skin, resulting in urticaria and dermatitiscont’d…

20Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Type I (Immediate)  Because these reactions can occur quickly after drug exposure, they are known as immediate hypersensitivity reactions  Anaphylaxis is an acute, life-threatening allergic reaction characterized by hypotension, bronchospasm, laryngeal edema, and cardiac arrhythmias

21Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Type II (Cytotoxic/Cytolytic)  Complement-dependent reactions involving either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies  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

22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Type III (Immune complex/Arthus/Serum sickness)  Mediated by IgG antibodies  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

23Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Type IV (Delayed Hypersensitivity)  Mediated by sensitized T lymphocytes and macrophages  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

24Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Idiosyncrasy  Haveles (p. 31)  A reaction that is neither the drug’s side effect nor an allergic reaction  Some are genetically determined abnormal reactions; others may be the result of an immunologic mechanism

25Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Interference with Natural Defense Mechanisms  Haveles (p. 31)  A drug’s effect on the body’s defense mechanisms can result in an adverse reaction  Long-term systemic administration of corticosteroids can result in decreased resistance to infection

26Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Toxicologic Evaluation of Drugs  Haveles (pp )  Evaluations of the toxic effects of drugs are based on experiments performed with lower animals and clinical trials conducted in humans  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…

27Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Toxicologic Evaluation of Drugs  Haveles (p. 31) (Fig. 3-2)  The median lethal dose (LD 50 ) is the dose the kills 50% of experimental animals  The median effective dose (ED 50 ) is the dose required to produce a specified intensity of effect in 50% of the animals  The ratio LD 50 /ED 50 is the therapeutic index (TI) of a drug cont’d…

28Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Toxicologic Evaluation of Drugs  Haveles (pp ) (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