Chapter 3: Adverse Drug Reactions

Compendium of 80 flashcards covering adverse drug reactions, classifications, clinical manifestations, teratogenicity, and toxicologic evaluation based on Chapter 3.

What is the primary reason for undesirable or adverse drug reactions?

The drug's lack of absolute specificity in biologic systems.

According to the text, what percentage of annual U.S. hospital admissions are due to adverse drug reactions?

Approximately $5\%$.

What is the reported frequency of hospitalized patients experiencing at least one adverse drug reaction during their stay?

A minimum of $15\%$.

What is the fundamental objective in pharmacotherapeutics?

To select the drug and dosage that provides maximal therapeutic effects and minimal adverse effects.

What are the four general groups used to classify adverse drug effects?

Toxic reactions, allergic reactions, idiosyncrasies, and interference with natural defense mechanisms.

How are toxic effects defined?

Adverse effects of an unexpected nature resulting from the direct action of the drug on the tissue or organ systems.

Why does penicillin G have low toxicity despite a high incidence of adverse reactions?

It has little effect on tissue/organ systems directly but has a high potential for allergic reactions.

How are side effects defined in this text?

Expected, predictable, and generally mild actions that occur in addition to the therapeutic effect.

At what dosage levels do side effects typically occur?

They can occur in every patient given an adequate dose.

What specific side effect is associated with the use of anticholinergics for ulcer treatment?

Dryness of the mouth (xerostomia).

A glaucoma-like effect from a large dose of an anticholinergic would be categorized as what?

A toxic effect.

According to Figure 3-1, what are the two main characteristics of side effects and toxic reactions?

Predictable and dose-related.

What are the two main characteristics of allergic reactions?

Not predictable and not dose-related.

How do exaggerated effects on target organs relate to therapeutic effects?

They are considered an extension of the therapeutic effects produced by an overdose or in a sensitive patient.

What is a patient-related factor that might prolong drug action and lead to toxicity?

Liver or kidney disease that inhibits drug metabolism or excretion.

At what dosage do effects on nontarget organs or tissues usually appear?

Higher doses or with more prolonged administration.

What term describes the clinical manifestation resulting from large doses of salicylates?

Salicylism.

List four symptoms of salicylism.

Headache, dizziness, tinnitus, and mental confusion.

What field of study examines genetic variations in how patients react to drugs?

Pharmacogenetics.

A deficiency in which enzyme causes some patients to experience red blood cell hemolysis when taking sulfonamides?

Glucose-6-phosphate dehydrogenase.

Which antimalarial drug is cited as a cause of hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency?

Primaquine.

What is the etymology of the word teratogenic?

Derived from the Greek prefix terato, meaning monster.

What does the term teratogenic mean?

The production of a malformed fetus.

Exposure to which infectious disease in $1941$ was first recognized for its association with birth defects?

German measles.

Which tranquilizer released in $1961$ was associated with an increase in infants born with phocomelia?

Thalidomide.

What is phocomelia?

A rare condition characterized by the presence of short or absent limbs.

What was the established critical period of gestation for thalidomide's teratogenic effect?

Between $21$ and $36$ days.

Which animal species developed typical limb malformations on retesting with thalidomide?

Certain species of white rabbits and monkeys.

What was the postulated reason for why rats did not show abnormalities during initial thalidomide tests?

Differences in metabolic pathways between species.

Name one potent teratogen used to treat acne that contains a "black box" warning.

Isotretinoin (Accutane).

What is the clinical definition of FDA Pregnancy Category A?

Adequate studies have failed to demonstrate a risk to the fetus in the first trimester, and fetal harm appears remote.

What characterizes FDA Pregnancy Category B?

Animal studies show no risk and there are no human studies, or animal studies show risk but human studies fail to demonstrate harm.

What characterizes FDA Pregnancy Category C?

Animal studies show adverse effects but human studies are lacking, or no studies are available. Potential benefits may warrant use.

What characterizes FDA Pregnancy Category D?

Positive evidence of human fetal risk exists, but benefits may warrant use in serious situations.

What characterizes FDA Pregnancy Category X?

Studies in animals or humans demonstrate fetal abnormalities, and risks clearly outweigh any potential benefits.

Name an example of a drug in FDA Pregnancy Category A.

Potassium chloride.

Identify a category X drug related to epilepsy treatment mentioned in the text.

Trimethadione.

Which four drugs are generally considered the safest for use in pregnant women in dentistry?

Lidocaine, codeine, penicillin, and erythromycin.

When is aspirin specifically contraindicated for use in pregnant women?

Near-term.

Which drug groups used in dentistry carry specific warnings about use during pregnancy?

Nonsteroid antiinflammatory agents, tetracyclines, and benzodiazepines.

What are the symptoms of a local reaction to injectable drugs?

Tissue irritation, pain, induration, and tissue necrosis at the injection site.

What gastrointestinal symptoms may result from local reactions to oral drugs?

Nausea, vomiting, and dyspepsia.

To produce an allergic reaction, what must a drug act as?

An antigen.

What is the reactive drug metabolite that combines with protein to form an antigen in an allergic reaction?

A hapten.

Which antibody mediates Type I (immediate) hypersensitivity reactions?

Immunoglobulin E (IgE).

What chemical mediators are released when a drug antigen binds to IgE antibodies?

Histamine, leukotrienes, and prostaglandins.

What are the major symptoms of anaphylaxis?

Hypotension, bronchospasm, laryngeal edema, and cardiac arrhythmias.

How quickly does anaphylaxis usually occur after drug administration?

Within $5$ to $30$ minutes.

What is the estimated death rate for penicillin-induced anaphylaxis?

$1$ to $10$ deaths per $10$ million injections.

Which local anesthetic is cited in a case of death after use of a throat lozenge?

Benzocaine.

Which antibodies mediate Type II (cytologic) allergic reactions?

IgG and IgM.

Give an example of a Type II allergic reaction.

Penicillin-induced hemolytic anemia.

What antibody mediates Type III (Arthus) reactions?

IgG.

What are the manifestations of a Type III allergic reaction?

Serum sickness, including urticarial eruptions, arthralgia, arthritis, lymphadenopathy, and fever.

How is an idiosyncratic reaction defined?

A reaction that cannot be explained by any known pharmacologic or biochemical mechanisms.

Provide an example of an idiosyncrasy involving barbiturates.

Excitement in some geriatric patients.

Phenothiazine-induced obstructive jaundice is considered which type of adverse reaction?

Idiosyncrasy.

How do antibiotics interfere with natural defense mechanisms?

By causing an overgrowth of intestinal flora with nonphysiologic bacteria and fungi.

How does long-term systemic administration of corticosteroids affect natural defense?

It results in a reduced resistance to infection.

What does the term LD50 represent?

The dose of a drug that kills $50\%$ of treated animals.

How is the LD50 usually expressed?

Milligrams per kilogram ($mg/kg$).

What is the formula for the therapeutic index of a drug?

$$\text{Therapeutic Index} = \frac{\text{LD}_{50}}{\text{ED}_{50}}$$

What are the three major phases of preclinical safety testing in animals?

Acute, subacute (prolonged), and chronic.

What happens during the acute phase of preclinical testing?

The $LD_{50}$ is determined using single doses in two species (one being a rodent).

What is the typical duration of the subacute phase of toxicity testing?

$2$ to $13$ weeks.

What is the primary purpose of the subacute phase of testing?

To determine dosages at which physiologic and specific toxicologic effects appear.

What is the duration of chronic toxicity tests?

$90$ days to $2$ years.

What application must be approved by the FDA before clinical trials can begin?

An Investigational New Drug (IND) application.

How many phases of clinical trials must be completed for an NDA to be approved?

The first three phases (Phase I, II, and III).

What is the focus of Phase I clinical trials?

Determining biologic effects, metabolism, and safe dosage ranges in humans using small numbers of volunteers.

What is the purpose of Phase II clinical trials?

Determining potential therapeutic usefulness and final dose ranges in small numbers of selected patients.

What technique is used in Phase II and III to compare testing drugs with placebos?

A double-blind technique.

What happens during Phase III clinical trials?

Broad trials involving a large sample of patients to determine overall safety and efficacy.

What is Phase IV of a clinical study?

The stage where limited marketing occurs while efficacy and safety are monitored under supervision.

How long does it typically take to complete the first three phases of clinical testing?

$6$ to $8$ years.

Which toxicity phase tests drug effects through several generations of animals?

The chronic phase.

What specific studies are often included in chronic testing protocols?

Carcinogenicity, teratogenicity, and mutagenicity.

Which two animal species are typically used in subacute toxicity testing?

Rats and dogs.

Toxic reactions result from the influence of drugs on which two areas?

Target organs/tissues and nontarget organs/tissues.

In addition to the drug's antigen, what else is required to elicit a response in an allergic reaction?

The production of other compounds (antibodies).