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C H A P T E R 4

Drug Development and Safety

OVERVIEW

The arrival of a new drug launched with a massive advertise-ment campaign and clever commercials does little to illu-

minate the highly regulated process that drugs go throughto make it to the market. The overwhelming success inmodern pharmacotherapy in treating disease states atteststo the safety and efficacy of prescribed agents. However,drugs can also be poisons causing unwanted adverse effects ,and drugs can kill. This chapter begins with a descriptionof drug development and the processes for evaluating drugsafety and efficacy and then discusses the various types ofadverse effects and interactions that are caused by drugs.Considerations for specific populations, such as the neonateand the elderly, are highlighted, and the laws relating to druguse and abuse are briefly reviewed.

DRUG DEVELOPMENT

Drug development in most countries has many features incommon, beginning with the discovery and characterizationof a new drug and proceeding through the clinical investiga-tions that ultimately lead to regulatory approval for market-ing the drug. Steps in the process of drug development in theUnited States are depicted in Figure 4–1.

Discovery and Characterization

New drug compounds are either synthesized de novo, isolated from a natural product, or a combination of thetwo as in semi-synthetic compounds. Synthetic drugs maybe patterned after other drugs with known pharmaco-logic activity, or their structure may be designed to binda particular receptor and based on computer modeling

of the drug and receptor. Because the likely activity ofsome new compounds is relatively uncertain, they mustbe submitted to a battery of screening tests to determinetheir effects. There are cases in which a particular pharma-cologic activity of a drug was discovered accidentally afterthe drug was administered to patients for other purposes.For example, the antihypertensive effect of clonidine wasdiscovered when tested for treatment of nasal congestion

and a profound hypotensive episode ensued. This ledto the subsequent development of clonidine for treatinghypertension.

Preclinical Studies

Before a new drug is administered to humans, its pharmaco-logic effects are thoroughly investigated in studies involvinganimals, called preclinical testing . The studies are designedto (a) ascertain whether the new drug has any harmful orbeneficial effects on vital organ function, including cardio-vascular, renal, and respiratory function; (b) elucidate thedrug’s mechanisms and therapeutic effects on target organs;and (c) determine the drug’s pharmacokinetic properties,thereby providing some indication of how the drug wouldbe handled by the human body. Although a few people ob- ject to using animals, there are even fewer willing to refuseall medical treatment and pharmacotherapy that result fromanimal testing.

Federal regulations require that extensive toxicity stud-ies in animals be conducted to predict the risks that will beassociated with administering the drug to healthy humansubjects and patients. The value of the preclinical studiesis based on the proven correlation between drug toxicity inanimals and humans. As outlined in Table 4– 1, the stud-ies involve short-term and long-term administration ofthe drug and are designed to determine the risk of acute,subacute, and chronic toxicity , as well as the risk of tera-togenesis, mutagenesis , and carcinogenesis. After animalsare treated with the new drug, their behavior is assessed andtheir blood samples are analyzed for indications of tissuedamage, metabolic abnormalities, and immunologic effects.Tissues are removed and examined for gross and micro-scopic pathologic changes. Offspring also are studied foradverse effects.

Studies in animals may not reveal all of the adverse effectsthat will be found in human subjects, either because of thelow incidence of particular effects or because of differences insusceptibility among species. This means that some adversereactions may not be detected until the drug is administeredto humans. However, because studies of chronic toxicity ofnew drugs in animals may require years for completion, it isusually possible to begin human studies while animal studies

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C H A P T E R 4



37C H A P T E R 4 ■ Drug Development and Safety

are being completed if the acute and subacute toxicity stud-ies have not revealed any abnormalities in animals.

THE INVESTIGATIONAL NEW

DRUG (IND) APPLICATIONThe Food and Drug Administration (FDA) must approvean application for an investigational new drug (IND) before the drug can be distributed for the purpose of con-ducting studies in human subjects. The IND applicationincludes a complete description of the drug, the results of allpreclinical studies completed to date, and a description of

the design and methods of the proposed clinical studies andthe qualifications of the investigators.

Clinical Trials

Phase I clinical trials seek to determine the pharmacoki-

netic properties and safety of an IND in healthy humansubjects. In the past, most of the subjects were men. Today,women are included in Phase I studies to determine if gen-der has any influence on the properties of the IND. Thesubjects typically undergo a complete history and physicalexamination, diagnostic imaging studies, and chemical andpharmacokinetic analyses of samples of blood and otherbodily fluids. The pharmacokinetic analyses provide a basisfor estimating doses to be employed in the next phase of tri-als, and the other examinations seek to determine if the drugis safe for use in humans.

Phase II clinical trials are the first studies to be per-formed in human subjects who have the particular diseasefor which the IND is targeting. These studies use a smallnumber of patients to obtain a preliminary assessment ofthe drug’s efficacy and safety in diseased individuals and to

establish a dosage range for further clinical studies.Phase III clinical trials are conducted to compare the

safety and efficacy of the IND with that of another sub-stance or treatment approach. Phase III studies employa larger group of subjects, often consisting of hundredsor even thousands of patients and involving multipleclinical sites and investigators. Phase III clinical trials arerigorously designed to prevent investigator bias and in-clude double-blind and placebo-control procedures. In adouble-blind study, neither the investigator nor the patientknows if the patient is receiving the new drug or anothersubstance. Placebo control design includes a group receiv-ing an identical formulation but with no active ingredients.With some diseases, it is unethical to administer a placebobecause of the proven benefits of standard drug therapy.

In such cases, the new drug is compared with the standarddrug for treatment of that disease. Phase III trials often in-volve crossover studies , in which the patients receive onemedication or placebo for a period of time and then areswitched, after a washout period, to the other medicationor placebo.

In many cases, the data are analyzed statistically at vari-ous points to determine whether the IND is sufficiently ef-fective or toxic to justify terminating a clinical trial. Forexample, if a statistically significant greater therapeutic effectcan be demonstrated after 6 months in the group of patientswho are receiving the new drug, it is unethical to continuegiving a placebo or a standard drug to the control group, themembers of which could also benefit from receiving the newdrug. A clinical trial is also stopped if the new drug causes asignificant increase in rate of mortality or serious toxicity.

The New Drug Application (NDA)and Its Approval

After Phase III clinical trials are completed and analyzed,the drug developer may submit a new drug application(NDA) to the FDA to request approval to market the drug.This application includes the results of all preclinical and

Discovery andcharacterizationof new drug

Pre-Clinicalstudies

IND application

Clinical studies

Submission of NDA

Approval of NDA

Postmarketingsurveillance

• Isolate or synthesize a new drug.

• Determine chemical and pharmaceutical properties of

the new drug.

• Report results of all experimental and clinical studies.

• Propose labeling of drug and clinical indications for use.

• Gather and analyze voluntary reports of adverse effects submitted by health care professionals (Phase 4).

• Report results of studies to date.

• Determine pharmacokinetic and pharmacodynamic properties of the drug.

• Test animals for toxicity (acute, subacute, and chronic), teratogenesis, mutagenesis, and carcinogenesis.

• Phase 2: Gather data on efficacy, safety, and proper dosage in a small group of patients.

• Outline properties of the drug.

• Propose clinical studies (sites, investigators, protocols, and methods of data analysis).

• Phase 1: Gather data on drug safety and pharmacokinetics in healthy volunteers.

• Outline properties of the drug.

• Marketing of drug.

• Phase 3: Obtain statistical evidence of drug safety and efficacy.

F igure 4–1 . Steps in the process of drug development in theUnited States. IND = investigational new drug; NDA = new drugapplication.



38 S E C T I O N I ■ Principles of Pharmacology

clinical studies, as well as the proposed labeling and clinicalindications for the drug. The NDA typically constitutes anenormous amount of written material.

The FDA often requires a number of months to review

the NDA before deciding whether to permit the drug to bemarketed. Approved drugs are labeled for specific indica-tions based on the data submitted to the FDA. Some drugsare found to have other clinical uses after the drug has beenintroduced to the market. These indications are knownas unlabeled or “off-label” uses. For example, gabapentin (NEURONTIN ) was initially approved for treating partialseizures but was used “off label” for preventing migraineheadaches and treating chronic pain. In some cases, manu-facturers will seek a revised labeling of an approved drug foranother indication and establish a new trade name. This wasdone for the antidepressant bupropion , the exact same drugmarketed as WELLBUTRIN for treating depression and ZYBAN for use in smoking cessation.

Postmarketing SurveillanceIf a drug is approved for marketing, its safety in the generalpatient population is monitored by a procedure known aspostmarketing surveillance, also considered Phase IV . TheFDA seeks voluntary reporting of adverse drug reactionsfrom health care professionals through its MedWatch pro-gram, and standard forms for this purpose are disseminatedwidely. Postmarketing surveillance is particularly importantfor detecting drug reactions that are uncommon and aretherefore unlikely to be found during clinical trials.

FEDERAL DRUG LAWS AND REGULATIONS IN

THE UNITED STATESThere are two major types of legislation pertaining specifi-cally to drugs. One type concerns drug safety and efficacy and regulates the processes by which drugs are evaluated, la-beled, and marketed. The other type focuses on the preven-tion of drug abuse. In both cases, the laws and regulationsreflect the concern of society with minimizing the harm that

may result from drug use while permitting the therapeuticuse of safe and beneficial agents.

Drug Safety and Efficacy LawsPure Food and Drug Act

The Pure Food and Drug Act of 1906 was the first federallegislation concerning drug product safety and efficacyin the United States. The Act was passed in response tothe sale of patent medicines, often by so-called snake-oilsalesmen, which contained toxic or habit-forming in-gredients. The legislation required accurate labeling ofthe ingredients in drug products and sought to preventthe adulteration of products through the substitution ofinactive or toxic ingredients for the labeled ingredients.Because the Act did not regulate fraudulent advertising,the legislation was only partially successful in eliminatingunsafe drug products.

Food, Drug, and Cosmetic ActThe Food, Drug, and Cosmetic (FD&C) Act of 1938 came inresponse to a tragic incident in which over 100 people diedafter ingesting an elixir that contained sulfanilamide, usedto treat streptococcal infections, in a solution of ethyleneglycol. The legislation, which is still in force today, mademajor strides by requiring evidence of drug safety before adrug product could be marketed, by establishing the FDAto enforce this requirement, and by giving legal authority tothe drug product standards contained in the United StatesPharmacopeia(USP)

First compiled in 1820, the USP has been updated andpublished at regular intervals by a private organization thatis called the United States Pharmacopeial Convention andis composed of representatives of medical and pharmacy

colleges and societies from each state. The USP containsinformation on the chemical analysis of drugs and indicateshow much variance in drug content is allowable for eachdrug product. For example, the USP states that aspirin tab-lets must contain not less than 90% and not more than 110%of the labeled amount of C9 H8 O4 (aspirin). In addition, theUSP outlines standards for tablet disintegration and manyother aspects of drug product composition and analysis.

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T A B L E 4 – 1 . Drug Toxicity Studies in Animals

Type of Study Method Observations

Acute toxicity Administer a single dose of the drug in two species viatwo routes.

Behavioral changes, LD50 ,* and mortality.

Subacute toxicity Administer the drug for 90 days in two species via aroute intended for humans.

Behavioral and physiologic changes, blood chemistrylevels, and pathologic findings in tissue samples.

Chronic toxici ty Administer the drug for 6–24 months, depending on thetype of drug.

Behavioral and physiologic changes, blood chemistrylevels, and pathologic findings in tissue samples.

Teratogenesis Administer the drug to pregnant rats and rabbits duringorganogenesis.

Anatomic defects and behavioral changes inoffspring.

Mutagenesis Perform the Ames test in bacteria. Examine culturedmammalian cells for chromosomal defects.

Evidence of chromosome breaks, gene mutations,chromatid exchange, trisomy, or other defects.

Carcinogenesis Administer the drug to rats and mice for their entirelifetime.

Higher than normal rate of malignant neoplasms.

* The LD50 (the median lethal dose) is the dose that kills half of the animals in a 14-day period after the dose is administered.




PROVISIONS OF THE FOOD, DRUG, AND COSMETIC ACT. The FD&CAct prohibits the distribution of drug products that areadulterated , misbranded (mislabeled), or that do not havean approved NDA . The Act requires that drug productlabels contain the name, dosage, and quantity of ingredi-ents, as well as warnings against unsafe use in children or

in persons with medical conditions for whom use of thedrug might be dangerous. A drug product is said to beadulterated if it does not meet USP standards or if it is notmanufactured according to defined “good manufacturingpractices.”

AMENDMENTS TO THE, DRUG, AND COSMETIC ACT. The FD&C Acthas been amended many times. The Durham-HumphreyAmendment was passed in 1952 and created a legal dis-tinction between nonprescription and prescription drugs.Prescription drugs are labeled “Rx Only.” Agents that areclassified as prescription drugs are those that are deter-mined to be unsafe for use without the supervision of adesignated health care professional. After a new drug hasbeen marketed for a period of time or if it is found to besafe enough to be used without physician supervision, the

FDA may reclassify the drug as a nonprescription drug,known as an over-the-counter (OTC) drug . For example,topical cortisone products, antifungal drugs for treatingcandidiasis, proton pump inhibitors for treating acid refluxsuch as omeprazole (PRILOSEC ), and antihistamines suchas loratadine (CLARITIN ) were originally classified as pre-scription drugs but are now classified as nonprescriptiondrugs.

The Kefauver-Harris Amendments were passed in 1962,largely in response to reports of severe malformations inthe offspring of women in Europe who took thalidomide ,for sedation, during their pregnancy. In fact, thalidomidehad not been marketed in the United States, because afemale scientist at the FDA, Frances Kelsey, held up ap-proval of thalidomide. Nevertheless, the shocking pictures

from Europe of deformed babies spurred Congress to morestrongly regulate drug development; as a result, Congresspassed amendments that required the demonstration ofboth safety and efficacy in studies involving animals andhumans before a drug product could be marketed. Althoughthe processes of new drug development and testing have notchanged substantially since this amendment was passed, theFDA review of new drugs has been streamlined in recent years.

The Orphan Drug Amendments were passed in 1983 toprovide tax benefits and other incentives for drug manufac-turers to test and produce drugs that are used in the treat-ment of rare diseases and are therefore unlikely to generatelarge profits. The Act appears to have been successful, asseveral hundred orphan drugs are now available. Examplesare drugs used for the treatment of urea cycle enzyme defi-

ciencies, Gaucher’s disease, homocystinuria, and other raremetabolic disorders.

Drug Price Competition and Patent Restoration Act

The Drug Price Competition and Patent Restoration Act of1984 extended the patent life of drug products (which at thattime was 17 years) by adding the amount of time requiredfor regulatory review of an NDA. It also accelerated the

approval of generic drug products by allowing investigatorsto submit an abbreviated NDA in which the generic productis shown to be therapeutically equivalent to an approvedbrand name product. Therapeutic equivalence is demon-strated on the basis of a single-dose oral bioavailability study that compares the generic drug with the brand name

drug. If the variance is within a specified range (usually±20%), the generic drug may be approved for marketing.The cost of such a study is relatively small compared withthe millions of dollars required for the development of acompletely new drug.

In 1992, accelerated drug approval was authorized fornew drugs to treat life-threatening conditions such asacquired immunodeficiency syndrome (AIDS) and cancer.Under the new regulations, patients with these conditionscan be treated with an investigational drug before clinicaltrials have been completed.

Drug Abuse Prevention Laws

Harrison Narcotics Act

The Harrison Narcotics Act of 1914 was the first major drug abuse legislation in the United States. It wasprompted by the growing problem of heroin abuse, whichfollowed the synthesis of this potent and rapid-acting de-rivative of morphine. The Act sought to control narcoticsthrough the use of tax stamps on legal drug products, apractice similar to the use of tax stamps on alcoholic bever-ages today. The Harrison Narcotics Act had a profound andcontroversial effect on the treatment of substance abuse inthat it prohibited physicians from administering opioiddrugs to drug-dependent patients as part of their treatmentprogram.

Comprehensive Drug Abuse Preventionand Control Act

During the 1960s, the prevalence of drug abuse increased ,especially among adolescents and young adults, who wereusing a wide range of drugs that included prescriptionsedatives and stimulants as well as substances such aslysergic acid diethylamide (LSD), marijuana, and otherhallucinogens. Believing that the drug abuse problem re-quired a new approach, members of Congress passed theComprehensive Drug Abuse Prevention and Control Actof 1970. This law is often called the Controlled SubstancesAct (CSA) .

The CSA classified drugs with abuse potential into fiveschedules, based on their degree of potential for abuse andtheir clinical usage. Schedule I drugs were classified as highabuse potential and no legitimate medical use, and their dis-tribution and possession are prohibited. Schedule II drugs have high abuse potential but a legitimate medical use, and

their distribution is highly controlled through requirementsfor inventories and records and through restrictions onprescriptions. Schedule III, IV, and V drugs have lowerabuse potential and decreasingly fewer restrictions on distri-bution. The CSA requires that all manufacturers, distribu-tors, physicians, and medical researchers using controlleddrugs register with the Drug Enforcement Agency , which isresponsible for enforcing the Act.




ADVERSE EFFECTS OF DRUGS

Adverse effects , or side effects , can be classified with respectto their mechanisms of action and predictability. Those dueto excessive pharmacologic activity are the most predictableand are often the easiest to prevent or counteract. Organ

toxicity caused by other mechanisms is often unpredictable,because its occurrence depends on the drug susceptibility ofthe individual patient, the drug dosage, and numerous otherfactors. Hypersensitivity reactions are responsible for a largenumber of adverse organ system effects. These reactions oc-cur frequently with some drugs but only rarely with others.

Excessive Pharmacologic Effects

Drugs often produce adverse effects by the same mechanism that is responsible for their therapeutic effect on the targetorgan. For example, atropine may cause dry mouth and uri-nary retention by the same mechanism that reduces gastricacid secretion in the treatment of peptic ulcer, namely, bymuscarinic receptor antagonism. This type of adverse effectmay be managed by reducing the drug dosage or by substi-

tuting a drug that is more selective for the target organ.

Hypersensitivity Reactions

Hypersensitivity reactions , or drug allergies , are respon-sible for a large number of organ toxicities that range inseverity from a mild skin rash to major organ system fail-ure. An allergic reaction occurs when the drug, acting as ahapten , combines with an endogenous protein to form anantigen that induces antibody production. The antigen andantibody subsequently interact with body tissues to producea wide variety of adverse effects.

In the Gell and Coombs classification system , allergicreactions are divided into four general types, each of which canbe produced by drugs. Type I reactions are immediate hyper-

sensitivity reactions that are mediated by immunoglobulinE (IgE) antibodies. Examples of these reactions are urticaria

(hives), atopic dermatitis, and anaphylactic shock . Type IIreactions are cytolytic reactions that involve immunecomplement and are mediated by immunoglobulins G andM. Examples are hemolytic anemia, thrombocytopenia,and drug-induced lupus erythematosus. Type III reactions are mediated by immune complexes . The deposition of

antigen-antibody complexes in vascular endothelium leadsto inflammation, lymphadenopathy, and fever (serum sick-ness). An example is the severe skin rash seen in patientswith a life-threatening form of drug-induced immune vas-culitis that is known as Stevens-Johnson syndrome . TypeIV reactions are delayed hypersensitivity reactions that aremediated by sensitized lymphocytes. An example is the am-picillin-induced skin rash that occurs in patients with viralmononucleosis.

Adverse Effects on Organs

In some cases, the adverse effects and therapeutic effects ofa drug are caused by different mechanisms. For example,in patients taking aspirin , the adverse reaction such as hy-perventilation that leads to respiratory alkalosis is caused

by adverse effects that do not appear to be mediated bythe drug’s primary mechanism of action, which is inhibi-tion of prostaglandin synthesis. A variety of drugs (Table4–2) produce toxicity of the liver, kidneys, or other vitalorgans, and this toxicity may not be readily apparent untilsignificant organ damage has occurred. Patients receivingthese drugs should be monitored with appropriate labora-tory tests. For example, hepatotoxicity may be detected bymonitoring serum transaminase levels, while hematopoi-etic toxicity may be detected by periodically performingblood cell counts.

Hematopoietic Toxicity

Bone marrow toxicity, one of the most frequent types of

drug-induced toxicity, may present as agranulocytosis,anemia, thrombocytopenia , or a combination of these

T A B L E 4 – 2 . Drug-Induced Organ Toxicities

Organ Toxicity Examples of Adverse Effects Examples of Drugs

Cardiotoxicity Cardiomyopathy Inflammatory fibrosis Daunorubicin, doxorubicin, and idarubicin, methysergideHematopoietic toxici ty Agranulocytosis* Captopril, chlorpromazine, chlorpropamide, clozapine,

and propylthiouracilAplastic anemia* Chloramphenicol and phenylbutazoneHemolytic anemia* Captopril, levodopa, and methyldopaThrombocytopenia* Quiniaine, rifampin, and sulfonamides

Hepatotoxicity Cholestatic jaundice* Erythromycin estolate and phenothiazinesHepatitis* Amiodarone, captopril, isoniazid, phenytoin, and sulfonamides

Nephrotoxicity Acute tubular necrosis Aminoglycoside antibiotics, amphotericin B, and vancomycinInterstitial nephritis* Nonsteroidal anti-inflammatory drugs (NSAIDs) and penicillins

(especially methicillin)Ototoxicity Vestibular and cochlear disorders Aminoglycoside antibiotics, furosemide, and vancomycinPulmonary toxicity Inflammatory fibrosis Methysergide

Pulmonary fibrosis Amiodarone, bleomycin, busulfan, and nitrofurantoinSkin toxicity All forms of skin rash* Antibiotics, diuretics, phenytoin, sulfonamides, and sulfonylureas

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*Immunologic mechanisms known or suspected.




(pancytopenia). The effects are often reversible when thedrug is withdrawn, but they may have serious consequencesbefore toxicity can be detected. For example, patients whodevelop agranulocytosis may succumb to a fatal infectionbefore the problem is recognized.

Many drugs, such as chloramphenicol , are believed to

cause hematopoietic toxicity by triggering hypersensitivityreactions directed against the stem cells in bone marrow ortheir derivatives. Chloramphenicol also produces a revers-ible form of anemia by blocking the action of the enzymeferrochelatase and thereby preventing the incorporation ofiron into heme.

The most serious form of hematopoietic toxicity is aplas-tic anemia , which may be associated with several types ofblood cell deficiencies and lead to pancytopenia . Aplasticanemia is probably due to a hypersensitivity reaction andis often irreversible, although it has recently been treatedby administration of hematopoietic growth factors (seeChapter 17).

Hepatotoxicity

A large number of drugs produce liver toxicity, either viaan immunologic mechanism or via their direct effect on thehepatocytes. Liver toxicity can be classified as cholestatic orhepatocellular. Cholestatic hepatotoxicity is often causedby a hypersensitivity mechanism producing inflammationand stasis of the biliary system. Hepatocellular toxicity issometimes caused by a toxic drug metabolite. For exam-ple, acetaminophen and isoniazid have toxic metabolitesthat may cause hepatitis. With many hepatotoxic drugs,elevated serum transaminase levels may provide an earlyindication of liver damage and levels should be monitoredduring the first 6 months of therapy and at longer intervalsthereafter. Many authorities believe that if transaminaselevels exceed 2 times the upper normal limit, a physi-cian should consider alternative drug therapy or frequent

monitoring of enzyme levels. If transaminase levels exceed3 times the upper normal limit, the drug should be dis-continued. Unfortunately, some patients have developedacute hepatic failure even when serum transaminase levelshave been monitored appropriately. In recent years, severaldrugs such as troglitazone , used to treat diabetes, wereremoved from the market as a result of excessive cases offatal hepatic failure.

Nephrotoxicity

Renal toxicity is caused by various drugs, including severalgroups of antibiotics. The forms of renal toxicity can beclassified according to site and mechanism and includeinterstitial nephritis, renal tubular necrosis , and crys-talluria (the precipitation of insoluble drug in the renal

tubules). Nephrotoxicity often reduces drug clearance ,thereby elevating plasma drug concentrations and leadingto greater toxicity. With some drugs that routinely causerenal toxicity, such as the antineoplastic agent cisplatin,the kidneys can be protected by means of forced diuresis,in which the drug is administered with large quantities ofintravenous fluid so as to lower the drug concentration inthe renal tubules.

Bladder toxicity is less common than renal toxicity, butit may occur as an adverse effect of a few drugs. One ex-ample is cyclophosphamide, an antineoplastic drug whosemetabolite causes hemorrhagic cystitis. This disorder canbe prevented by administering mesna , a sulfhydryl-releasingagent that conjugates the toxic metabolite in the urine.

Other Organ Toxicities

Pulmonary toxicity occurs through a variety of mechanisms.Some drugs, such as opioid analgesics, cause respiratorydepression via their effects on the brain stem respiratorycenters. The drugs bleomycin and amiodarone producepulmonary fibrosis , so patients who are being treated withthese agents should have periodic chest x-rays and blood gasmeasurements to detect early signs of fibrosis.

Relatively few drugs produce cardiotoxicity. Anthracy-cline anticancer drugs, such as doxorubicin (ADRIAMYCIN ), pro-duce adverse cardiac effects that resemble congestive heartfailure. HMG-CoA (3-hydroxy-3-methylglutaryl–coenzyme A)reductase inhibitors such as lovastatin (MEVOCOR ) maycause skeletal muscle damage evidenced by muscle pain and

sometimes leading to rhabdomyolysis.Skin rashes of all varieties, including macular, papular,

maculopapular, and urticarial rashes, may be produced bydrug hypersensitivity reactions. A mild skin rash may disap-pear with continued drug administration. Nevertheless, be-cause rashes may lead to more serious skin or organ toxicity,they should be monitored carefully.

Idiosyncratic Reactions

Idiosyncratic reactions are unexpected drug reactions cau-sed by a genetically determined susceptibility. For example,patients who have glucose-6-phosphate dehydrogenasedeficiency may develop hemolytic anemia when they areexposed to an oxidizing drug such as primaquine or to a

sulfonamide.

DRUG INTERACTIONS

A drug interaction is defined as a change in the pharmaco-logic effect of a drug that results when it is given concur-rently with another drug or with food. Drug interactionsmay be caused by changes in the pharmaceutical, pharma-codynamic, or pharmacokinetic properties of the affecteddrug (Table 4–3).

Pharmaceutical Interactions

Pharmaceutical interactions are due to a chemical reactionbetween drugs prior to their administration or absorption.

Pharmaceutical interactions occur most frequently whendrug solutions are combined before they are given intra-venously. For example, if a penicillin solution and an ami-noglycoside solution are mixed, they will form an insolubleprecipitate, because penicillins are negatively charged andaminoglycosides are positively charged. Many other drugsare incompatible and should not be combined before theyare administered.

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Pharmacodynamic Interactions

Pharmacodynamic interactions occur when two drugs haveadditive, synergistic, or antagonistic effects on a tissue, or-gan system, microbe, or tumor cells. An additive effect isequal to the sum of the individual drug effects, whereas a

synergistic effect is greater than the sum of the individualdrug effects. Some pharmacodynamic interactions occurwhen two drugs act on the same receptor, and others occurwhen the drugs affect the same physiologic function throughactions on different receptors. For example, epinephrine andhistamine affect the same function but have antagonistic ef-fects. Epinephrine activates adrenergic receptors to causebronchial smooth muscle relaxation, whereas histamineactivates histamine receptors to produce bronchial smoothmuscle contraction.

Pharmacokinetic Interactions

In pharmacokinetic interactions, a drug alters the absorp-tion, distribution, biotransformation, or excretion of anotherdrug or drugs. Mechanisms and examples of pharmacoki-

netic interactions are provided in Tables 4-3 and 4–4.

Altered Drug Absorption

There are several mechanisms by which a drug may affect theabsorption and bioavailability of another drug. One mecha-nism involves binding to another drug in the gut and pre-venting its absorption. For example, cholestyramine , a bile

acid sequestrant, binds to digoxin and prevents its absorp-tion. Another mechanism involves altering gastric or intes-tinal motility so as to affect the absorption of another drug.Drugs tend to be absorbed more rapidly from the intestinesthan from the stomach. Therefore, a drug that slows gastricemptying, such as atropine, often delays the absorption of

another drug. A drug that increases intestinal motility, suchas a laxative, may reduce the time available for the absorptionof another drug, thereby causing its incomplete absorption.

Altered Drug Distribution

Many drugs displace other drugs from plasma proteins andthereby increase the plasma concentration of the free (un-bound) drug, but the magnitude and duration of this effectare usually small. As the free drug concentration increases,so does the drug’s rate of elimination, and any change in thedrug’s effect on target tissues is usually short-lived.

The enterohepatic cycling of some drugs is dependent onintestinal bacteria that hydrolyze drug conjugates excretedby the bile and thereby enable the more lipid-soluble parentcompound to be reabsorbed into the circulation. Antibiotics

administered concurrently with these drugs may kill the bac-teria and reduce the enterohepatic cycling and plasma drugconcentrations. When antibiotics are taken concurrentlywith oral contraceptives containing estrogen, for example,they may reduce the plasma concentration of estrogen andcause contraceptive failure (Fig. 4–2).

Altered Drug Biotransformation

In some cases, biotransformation is affected by drugs that al-ter hepatic blood flood. In many cases, it is affected by druginteractions that either induce or inhibit drug-metabolizingenzymes (see Table 4–4).

Inducers of cytochrome P450 enzymes include barbitu-rates, carbamazepine, and rifampin, which bind to regulatory

domains of cytochrome P450 (CYP) genes and increase genetranscription. These agents induce the CYP1A2, CYP2C9,CYP2C19, and CYP3A4 isozymes, whereas the CYP2D6 andCYP2E1 isozymes are not readily induced by commonlyused drugs. The rate of induction depends on the dose andfrequency of administration. Enzyme induction is usuallymaximal after several days of continuing drug administra-tion. Enzyme induction increases the clearance and reducesthe half-life of drugs biotransformed by the enzyme. Whenthe inducing drug is discontinued, the synthesis of P450enzymes gradually returns to the pretreatment level.

A large number of drugs bind to and inhibit CYP iso-zymes. CYP3A4 is selectively inhibited by erythromycin,itraconazole, and doxycycline, whereas other drugs such ascimetidine, ketoconazole, and fluoxetine inhibit several CYPisozymes. Significant interactions occur when these drugs

reduce the clearance and increase the plasma concentra-tion of other drugs. For example, itraconazole inhibits thebiotransformation of HMG-CoA reductase inhibitors, suchas lovastatin and atorvastatin, by CYP3A4. This inhibitionincreases plasma levels several fold, sometimes leading tosevere muscle inflammation and lysis (rhabdomyolysis).Grapefruit juice has been found to contain bioflavo-noid compounds that inhibit CYP3A4 and thereby elevate

T A B L E 4 – 3 . Types and Mechanismsof Drug Interactions

Type Mechanism

Drug Interactions with

Food

Altered drug absorption

PharmaceuticalInteractions (DrugIncompatibilities)

Chemical reaction between drugsprior to their administration orabsorption

PharmacodynamicInteractions

Additive, synergistic, or antagonisticeffects on a microbe or tumor cells

Additive, synergistic, or antagonisticeffects on a tissue or organ system

PharmacokineticInteractions

Eltered drug absorption Altered gut motility or secretionBinding or chelation of drugsCompetition for active transport

Altered drug distribution Displacement from plasmaprotein–binding sites

Displacement from tissue-bindingsites

Altered drug

biotransformation

Altered hepatic blood flow

Enzyme inductionEnzyme inhibition

Altered drug excretion Altered biliary excretion orenterohepatic cycling

Altered urine pHDrug-induced renal impairmentInhibition of active tubular secretion




concentrations of drugs such as felodipine (PLENDIL ) that aremetabolized by this enzyme.

Altered Drug Excretion

Drugs can alter the renal or biliary excretion of other drugsby several mechanisms. A few drugs, such as carbonic anhy-drase inhibitors , alter the renal pH. This in turn can change

the ratio of another drug’s ionized form to its non-ionizedform and affect its renal excretion. Probenecid competeswith other organic acids, such as penicillin, for the activetransport system in renal tubules. Quinidine and verapamil decrease the biliary clearance of digoxin and thereby increaseserum digoxin levels. Potentially nephrotoxic drugs, such asthe aminoglycoside antibiotics , may impair the renal excre-tion of other drugs via their effect on renal function.

T A B L E 4 – 4 . Management of Clinically Significant Pharmacokinetic Drug Interactions

Examples of Inducersor Inhibitors

Examples of Affected Drugs Management

Inducers of Drug Biotransformation Barbiturates, carbamazepine,

and rifampinWarfarin Increase warfarin dosage as indicated by prothrombin time

(international normalized ratio).Carbamazepine Theophylline Monitor plasma theophylline concentration and adjust dosage

as needed.Rifampin Phenytoin Monitor plasma phenytoin concentration and adjust dosage as

needed.

Inhibitors of Drug AbsorptionAluminum, calcium, and iron Tetracycline Give tetracycline 1 hour before or 2 hours after giving the other

agent.Cholestyramine Digoxin and warfarin Give digoxin or warfarin 1 hour before or 2 hours after giving

cholestyramine.

Inhibitors of Drug BiotransformationCimetidine Benzodiazepines, lidocaine,

phenytoin, theophylline,and warfarin

Instead of giving cimetidine, substitute a histamine blocker thatdoes not inhibit drug metabolism.

Disulfiram Ethanol Make sure the patient understands that disulfiram is used thera-peutically to promote abstinence from alcohol (ethanol).

Erythromycin Carbamazepine and theophylline Lower the dose of the affected drug during erythromycin therapy.Erythromycin, itraconazole,

and ketoconazole

Lovastatin and atorvastatin Avoid concurrent therapy and thereby avoid myopathy.

Monoamine oxidase inhibi tors Levodopa andsympathomimetic drugs

Avoid concurrent therapy, if possible; otherwise, give a subnor-mal dose of the affected drug.

Inhibitors of Drug ClearanceDiltiazem, quinidine, and verapamil Digoxin Give a subnormal dose of digoxin and monitor the plasma

drug concentration.Probenecid Cephalosporins and penicillin Advise the patient that the combination of drugs is intended to

increase the plasma concentration of the antibiotic.Thiazide diuretics Lithium Give a subnormal dose of lithium and monitor the plasma drug

concentration.

Antibioticeliminatesbacteria andinterruptsenterohepaticcycling

Excretion via bileLiver

Reabsorptionvia circulation

IntestinesEstrogenglucuronide

Estrogen

Bacterialenzymes

Estrogenglucuronide

Estrogen

F igure 4–2 . Interaction ofantibiotics with estrogens foundin oral contraceptives. Estrogen isconjugated with glucuronate andsulfate in the liver, and the conju-gates are excreted via the bile intothe intestines. Intestinal bacteriahydrolyze the conjugates, and es-trogen is reabsorbed into the circu-lation. The enterohepatic cycling isinterrupted if concurrently adminis-tered antibiotics destroy the intesti-nal bacteria. Contraceptive failuremay result.




Clinical Significance of DrugInteractions

The clinical significance of drug interactions varies widely.In some cases, toxicity is severe and can be prevented only byavoiding the concurrent administration of drugs. In other

cases, toxicity can be avoided by proper dosage adjustment andother measures (see Table 4 – 4). For example, when quinidineand digoxin are administered concurrently, a subnormaldose of digoxin should be used to prevent adverse effects.Fortunately, many drug interactions are of minor signifi-cance, and the interacting drugs can usually be administeredconcurrently without affecting their efficacy or the patient’ssafety. Drug interactions are more likely to occur if the af-fected drug has a low therapeutic index or is being used totreat a critically ill patient. However, polypharmacy , whichrefers to the use of multiple medications by a patient, islinked to many adverse effects and toxicity due to drug in-teractions in the elderly.

FACTORS AFFECTING DRUG

SAFETY AND EFFICACYAge, disease, pregnancy, and lactation are important bio-logic variables that can alter the response to drugs in par-ticular patients.

Age

Factors affecting drug disposition in different age popula-tions are summarized in Table 4–5.

In neonates, and especially in premature infants, thecapacity to metabolize and excrete drugs is often greatlyreduced because of low levels of drug biotransforma-tion enzymes. Oxidative reactions and glucuronate conjugation occur at a lower rate in neonates than in adults,

whereas sulfate conjugation is well developed in neonates.Consequently, some drugs that are metabolized primarilyby glucuronate conjugation in adults (drugs such as acet-aminophen) are metabolized chiefly by sulfate conjugationin neonates. Nevertheless, the overall rate of biotransforma-tion of most drugs is lower in neonates and infants than itis in adults.

In comparison with children and young adults, elderlyadults also tend to have a reduced capacity to metabolizedrugs. Biotransformation via oxidative reactions usuallydeclines more than biotransformation via drug conjugation.Therefore, it may be safer to use drugs that are conjugatedwhen the choice is available. For example, benzodiazepines

that are metabolized by conjugation, such as lorazepam and temazepam , are believed to be safer for treatment ofthe elderly than are benzodiazepines that undergo oxidativebiotransformation (e.g., diazepam).

Renal function is lower in neonates and elderly adultsthan it is in young adults, and this affects the renal excretionof many drugs. For example, the half-lives of aminoglycosideantibiotics are greatly prolonged in neonates. Glomerularfiltration declines 35% between the ages of 20 and 90 years,with a corresponding reduction in the renal elimination ofmany drugs.

Because the very young and the very old tend to have in-creased sensitivity to drugs, the dosage per kilogram of bodyweight should be reduced when most drugs are used in thetreatment of these populations.

Disease

Hepatic and renal disease may reduce the capacity of theliver and kidneys to biotransform and excrete drugs, therebyreducing drug clearance and necessitating a dosage reduc-tion to avoid toxicity. Heart failure and other conditionsthat reduce hepatic blood flow may also reduce drug bio-transformation. Oxidative drug metabolism is usually im-paired in patients with hepatic disease, whereas conjugationprocesses may be little affected.

Guidelines for dosage adjustment in patients with hepaticor renal disease are available and can be found in clinicalreferences. Dosage adjustments are made by reducingthe dose, increasing the interval between doses, or both.Adjustments for individual patients are usually based on

laboratory measurements of renal or hepatic function andon plasma drug concentration.

Pregnancy and Lactation

Drugs taken by a woman during pregnancy or lactation cancause adverse effects in the fetus or infant.

T A B L E 4 – 5 . Factors Affecting Drug Disposition in Different Age Populations

Process of DrugDisposition

POPULATION

Neonates and Infants Children Elderly Adults

Absorption Altered absorption of some drugs. No major changes, but first-passinactivation may be increased.

No major changes.

Distribution Incomplete blood-brain barrier; highervolumes of distribution forwater-soluble drugs.

No major changes. Higher volumes of distribution forfat-soluble drugs.

Biotransformation Lower rate of oxidative reactions andglucuronate conjugation.

Biotransformation rate for somedrugs higher than in adults.

Reduced oxidative metabolism;relatively unchanged conjuga-tion metabolism.

Excretion Reduced capacity to excrete drugs. No major changes. Reduced capacity to excrete drugs.




The risk of drug-induced developmental abnormali-ties known as teratogenic effects is the greatest during theperiod of organogenesis from the 4th to the 10th week ofgestation. After the 10th week, the major risk is to the de-velopment of the brain and spinal cord. An estimated 1% to5% of fetal malformations are attributed to drugs. Although

only a few drugs have been proven to cause teratogenic ef-fects (Table 4–6), the safety of many other drugs has not yetbeen determined.

The FDA has divided drugs into five categories, basedon their safety in pregnant women . Drugs in CategoriesA and B are relatively safe. Drugs in Category A havebeen shown in clinical studies to pose no risk to the fe-tus, whereas those in Category B may have shown riskin animal studies but not in human studies. For drugsin Category C, adverse effects on the fetus have beendemonstrated in animals, but there is insufficient data inpregnant women, so risk to the fetus cannot be ruled out.Drugs in Category D show positive evidence of risk to thefetus, and drugs in Category X are contraindicated duringpregnancy.

Drugs of choice for pregnant women are listed in

clinical references and are selected on the basis of theirsafety to the fetus as well as their therapeutic efficacy. Forexample, penicillin, cephalosporin, and macrolide anti-biotics (all Category B drugs) are preferred for treatingmany infections in pregnant women, whereas tetracycline

antibiotics (Category D) should be avoided. Acetaminophen(Category B) is usually the analgesic of choice in pregnancy,but ibuprofen and related drugs are also in Category B andmay be used when required. For the treatment of nauseaand vomiting of pregnancy, the combination of pyridoxine(Category A) in combination with doxylamine (Category B)

is the only medication specifically labeled for this indicationby the FDA. Other drugs considered relatively safe for usein pregnancy include insulin and metformin (GLUCOPHAGE )for treating diabetes mellitus (both Category B drugs),famotidine (PEPCID ) and omeprazole (PRILOSEC ) for reduc-ing gastric acidity (Category B drugs), diphenhydramine(BENADRYL ) for treating allergic reactions (Category B), andtricyclic antidepressants such as desipramine (NORPRAMIN )for treating mood depression (Category B). Most antiepi-leptic drugs pose some risk to the fetus, and the selectionof drugs for treating epilepsy in pregnant women requirescareful consideration of the risks and benefits of suchmedication.

Some drugs can be taken by lactating women withoutposing a risk to their breast-fed infants. Other drugs placethe infant at risk for toxicity. As a general rule, breast-

feeding should be avoided if a drug taken by the motherwould cause the infant’s plasma drug concentration to begreater than 50% of the mother’s plasma concentration.Clinical references provide guidelines on the use of specificdrugs by lactating women.

T A B L E 4 – 6 . Examples of Teratogenic Drugs and Their Effects on the Fetus or Newborn Infant*

Drug Adverse Effects

Alkylating agents and antimetabolites(anticancer drugs)

Cardiac defects; cleft palate; growth retardation; malformation of ears, eyes, fingers,nose, or skull; and other anomalies.

Carbamazepine Abnormal facial features; neural tube defects, such as spina bifida; reduced head size;and other anomalies.

Coumarin anticoagulants Fetal warfarin syndrome (characterized by chondrodysplasia punctata, malformationof ears and eyes, mental retardation, nasal hypoplasia, optic atrophy, skeletaldeformities, and other anomalies).

Diethylsti lbestrol (DES) Effects in female offspring: clear cel l vaginal or cervical adenocarcinoma; irregular menses;and reproductive abnormalities, including decreased rate of pregnancy and increasedrate of preterm deliveries. Effects in male offspring: cryptorchidism, epididymal cysts,and hypogonadism.

Ethanol Fetal alcohol syndrome (characterized by growth retardation, hyperactivity, mentalretardation, microcephaly and facial abnormalities, poor coordination, and otheranomalies).

Phenytoin Fetal hydantoin syndrome (characterized by cardiac defects; malformation of ears, lips,palate, mouth, and nasal bridge; mental retardation; microcephaly; ptosis; strabismus;and other anomalies).

Retinoids (systemic) Spontaneous abortions. Hydrocephaly; malformation of ears, face, heart, limbs, and liver;microcephaly; and other anomalies.

Tetracycline Hypoplasia of tooth enamel and staining of teeth.Thalidomide Deafness, heart defects, limb abnormalities (amelia or phocomelia), renal abnormalities,

and other anomalies.Valproate Cardiac defects, central nervous system defects, lumbosacral spina bifida, and microcephaly.

*Other substances known to be teratogenic include lead, lithium, methyl mercury, penicillamine, polychlorinated biphenyls, and trimethadione. Otherdrugs that should be avoided during the second and third trimester of pregnancy are angiotensin-converting enzyme inhibitors, chloramphenicol,indomethacin, prostaglandins, sulfonamides, and sulfonylureas. Other drugs that should be used with great caution during pregnancy include antithyroiddrugs, aspirin, barbiturates, benzodiazepines, corticosteroids, heparin, opioids, and phenothiazines.




Review Questions1. An advertisement in a local newspaper seeks to enroll

20 patients with arthritis in a medical study that would bethe first time that a new drug would be tested in persons withthis disease. The study would therefore be classified as a

(A) Phase I clinical study(B) Phase II clinical study(C) Phase III clinical study(D) Phase IV clinical study(E) Phase V clinical study

2. Which one of the following schedules of controlled sub-stances is for drugs with the highest abuse potential thathave a legitimate medical use?

(A) Schedule I(B) Schedule II(C) Schedule III

(D) Schedule IV(E) Schedule V

3. The 4th to the 10th week of gestation is the period of timewhen there is the greatest concern about drug-induced

(A) fetal cardiac arrest(B) fetal hemorrhage(C) fetal malformations(D) labor(E) fetal jaundice

4. Which of the following drug interaction mechanisms ismost likely to lead to sustained elevations of plasma drugconcentrations and drug toxicity?

(A) induction of CYP2C19(B) inhibition of CYP3A4

(C) displacement of a drug from plasma albuminbinding sites

(D) inhibition of the P-glycoprotein carrier protein(E) acceleration of gastric emptying by a “prokinetic”

drug

5. Elderly persons may have altered drug dispositionbecause of

(A) markedly reduced absorption of many drugs(B) higher volumes of distribution for water-soluble

drugs(C) accelerated renal excretion of ionized drugs(D) increased permeability of the blood-brain barrier(E) reduced capacity to oxidize drugs

Answers and Explanations1. The answer is B: Phase II study. Phase II studies are done

in a small group of test subjects that have the disease statetargeted by the new drug. Phase I studies are done to es-tablish safety and pharmacokinetics in healthy subjects,often students in the health professions. Phase III studiesare large, multicenter studies in patients with the diseasestate. Phase IV studies are post-marketing surveillance, inwhich physicians report adverse effects to the FDA. Thereis no Phase V in the drug development process.

2. The answer is B: Schedule II. Schedule II controlled drugshave a high degree of abuse potential but are still used bythe medical profession. These drugs may still be abused bydiversion, the act of illegally obtaining prescription drugs

by sale or theft. Schedule I lists the most abused and illegaldrugs, including marijuana, mescaline, LSD, and MDMA(“ecstasy”). Note that cocaine, although much abused in theform of powder (“coke”) and free base (“crack”) is listed asSchedule II as it does have a limited medical use, as a localanesthetic and vasoconstricting agent in ear, nose, and throatprocedures. Schedules III–V controlled drugs have some de-gree of abuse potential but less than those of Schedule II.

SUMMARY OF IMPORTANT POINTS

■ The process of drug development includes chemicaland pharmacologic characterization, experimentalstudies to test for toxicity in animals, and clinical studiesto determine efficacy and safety in humans.

■ Drug development is regulated by the FDA. An INDapplication must be completed before clinical studies canbe started, and an NDA must be submitted and approvedbefore the drug can be marketed.

■ Phase I studies provide data about drug safety andpharmacokinetics in healthy subjects; Phase II studiesprovide data about the proper dosage and potentialefficacy in a small group of patients; and Phase III studiesprovide statistical evidence of efficacy and safety in acontrolled clinical trial.

■ The Food, Drug, and Cosmetic Act established the FDAto regulate the development, manufacturing, distribution,and usage of drugs. Amendments have established theprescription class of drugs, stricter requirements for

human drug testing, incentives for developing orphandrugs for rare diseases, and abbreviated procedures formarketing generic drug products.

■ The Comprehensive Drug Abuse Prevention andControl Act, also called the Controlled Substances Act(CSA), classifies potentially abused drugs in five catego-ries (Schedules I–V), requires registration of legitimatedrug distributors and health care professionals, and limitsthe prescription and distribution of controlled substances.

■ The adverse effects of drugs may be due to excessivepharmacologic effects, hypersensitivity reactions, orother mechanisms responsible for organ toxicities. Thebone marrow, liver, kidney, and skin are frequent sites ofdrug toxicity.

■

Drug interactions occur when one drug alters thepharmacologic properties of another drug. Mostinteractions are due to pharmacokinetic effects, particularlyinhibition or induction of drug biotransformation.

■ Age, disease, pregnancy, and lactation are factors thatmust be considered in drug selection and dosage. Thevery young and the very old tend to have an increasedsensitivity to therapeutic agents, usually because of areduced capacity to eliminate drugs. Target organs mayalso be more sensitive to drugs in these populations.




3. The answer is C: fetal malformations. The 4th to 10thweek of gestation is the period when fetal organs aredeveloped. Teratogenic drugs may cause fetal malforma-tions if taken by a pregnant woman during this interval.These malformations include cleft palate, malformationof fingers and toes, heart defects, facial abnormalities,

and skeletal deformities. Drug-induced labor or jaundiceis primarily of concern during the last trimester of preg-nancy. Drug-induced cardiac arrest and hemorrhage arenot specifically associated with the 4th to 10th week ofgestation.

4. The answer is B: inhibition of CYP3A4. Inhibition ofdrug-metabolizing enzymes will increase the half-life andplasma concentrations of affected drugs, thereby posinga risk of toxicity. Induction of these enzymes will reducehalf-life and plasma levels. Displacement of a drug fromplasma proteins or inhibition of P-glycoprotein mightincrease plasma levels temporarily until the rate of elimi-nation increases. Acceleration of gastric emptying mightincrease the rate of drug absorption but would not perma-nently increase plasma drug levels.

5. The answer is E: reduced capacity to oxidize drugs. Con- jugative metabolism is relatively unchanged in the elderly,but oxidative drug metabolism is usually reduced. Theelderly tend to have a higher percentage of body fat than younger adults and therefore have increased volumesof distribution of fat-soluble drugs. Drug absorption is

not typically altered in the elderly, and their blood-brainbarrier is not noticeably impaired in most cases.

SELECTED READINGS

Bahna, S.L., B. Khalili. New concepts in the management of adverse drugreactions. Allergy Asthma Proc 28:517–524, 2007.

Gee, D. Establishing evidence for early action: the prevention of repro-ductive and developmental harm. Basic Clin Pharmacol Toxicol 102: 257–266, 2008.

Hajjar, E.R., A.C. Cafiero, and J.T. Hanlon. Polypharmacy in elderly pa-tients. Am J Geriatr Pharmacother 5:345–351, 2007.

Sakata, T., and E.A. Winzeler. Genomics, systems biology and drug devel-opment for infectious diseases. Mol Biosyst 3:841–848, 2007.

Zwillich, T. US lawmakers tackle safety reforms at the FDA. Lancet369:1989–1990, 2007.

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