NURSING PROCESS AND DRUG THERAPY. BASIC PHARMACOLOGY PRINCIPLES. PEDIATRIC, MATERNAL AND GERIATRIC CONSIDERATIONS. LEGAL, ETHICAL AND CULTURAL CONSIDERATIONS. OVER-THE-COUNTER MEDICATIONS AND HERBAL THERAPY. MEDICATION ADMINISTRATION AND DOSAGE CALCULATION

The Nursing Process and Drug Therapy

When you reach the end of this chapter, you should be able to do the following:

1 List the five phases of the nursing process as applicable to drug therapy.

2   Identify the components of the assessment process for patients receiving medications, including collection of subjective and objective data.

3   Discuss the process of formulating nursing diagnoses for patients receiving medications.

4   Identify goals and outcome criteria as related to patients receiving medications.

5   Discuss the evaluation process as it relates to the administration of medications.

6   Apply all phases of the nursing process to the drug administration process.

7   Briefly discuss the “5 Rights” of drug administration and the professional responsibility to patients for safe medication practice.

OVERVIEW

The nursing process is central to all nursing care. It is flexible, adaptable, and adjustable to numerous situations, including the administration of medications.

The nursing process as five specific phases: assessment, nursing diagnoses, planning (with goals and outcome criteria), implementation, and evaluation.

ASSESSMENT

During the assessment phase of the nursing process, subjective and objective data on the patient, drug, and environment are collected. A drug history may include information such as the use of prescription and over-the-counter (OTC) medications, home remedies, herbal and homeopathic treatments (including vitamins); intake of alcohol, tobacco, or caffeine; any current or prior use of “street drugs” (or illegal drug use); past and present health history; and family history. The nursing assessment should include a head-to-toe physical assessment and a collection of information in a holistic framework regarding the religious preferences, health beliefs, sociocultural profile, lifestyle, stressors, socioeconomic status, educational level, motor skill abilities, cognitive ability, and sensory intactness (such as visual and hearing acuity). Objective data may be obtained through physical assessment and include vital signs, weight, height, laboratory studies, and results of diagnostic tests. Creating a thorough medication profile is important to ensure the safe use of medications in patients. The following list is an example of the type of information that would be collected (more specific information in addition to the drug history):

•  OTC medications (e.g., aspirin, vitamins, dietary supplements, acetaminophen products  [Tylenol],  laxatives, cold preparations, sinus medications, antacids,acid reducers, antidiarrheals, minerals, elements) Prescription medications (e.g., birth control pills,hormone replacement therapy, drugs for sexual dysfunction)

•  Street drugs (e.g., marijuana, cocaine, phencyclidine hydrochloride [PCP or “angel dust”], lysergic acid diethylamide [LSD], amphetamines, illegal narcotics such as oxycontin)

•  Herbals and homeopathic substances, plant or animal extracts

•  Problems with drug therapy in the past (e.g., allergies, adverse effects, side effects, diseases or injuries, organ pathology)

•  Growth and development issues as related to the patient’s age and specific expectations (e.g., Erikson’s stages) and tasks for each major age group

It is important for the nurse to have adequate interviewing skills to establish a therapeutic relationship with the patient. The use of open-ended questions is preferred because direct questions that may be answered with a simple “yes” or “no” are not as helpful for collecting thorough patient information. Some of the questions for the nurse to ask the patient, significant other, caregiver, and others involved in the care of the patient include the following:

•  What is the patient’s oral intake? How does the patient tolerate fluids? Can the patient swallow pills and liquids? If not, what difficulty does he or she have?

•  What are the laboratory and diagnostic test values, such as renal and liver function studies, hemoglobin, hematocrit, and protein and albumin levels? What have been the patient’s experiences with medicines, health care professionals, or previous hospitalizations? What are the patient’s vital signs? What medications are ordered and what medications is the patient already taking? How is the patient taking and tolerating the medications? What are the emotional, physical, cognitive, cultural, and socioeconomic factors impacting drug therapy and the nursing process with the patient (for a holistic framework)? What are the drug’s adverse effects, contraindications, appropriate dosages, routes of administration, toxicity, and/or any antidotes and therapeutic levels? What does the particular drug do? Is it really helping the patient? What are the “age-specific” developmental concerns, issues, or implications related to the patient receiving the medication? What are the patient’s cultural origin and racial-ethnic group, and what is their influence on drug therapy? Information collection on the drug or medication must begin by obtaining a complete order from the physician or other licensed individual. The order contains the following six elements:

1  Patient’s name

2  Date order was written

3  Name of medication

4  Dosage (includes size, frequency, and number of doses)

5  Route of delivery

6  Signature of the prescriber

Once these six elements have been verified and transcribed appropriately, the medication should be researched. The use of a current drug handbook, pharmacology textbook, reference such as Mosby’s Drug Consult, or other authoritative source is recommended for the review of drug information. Information to be reviewed includes classification, mechanism of action, dosage, routes, side effects, contraindications, drug incompatibilities, interactions, cautions, and nursing implications. If information is unavailable, the nurse may contact a registered pharmacist for information about the medication. The nurse should document the source of information, including the pharmacist’s name. The nurse should never give a medication with which the nurse is unfamiliar until drug information has been researched and there is complete knowledge about its mechanism of action, cautions, contraindications, drug and/or food interactions, dosage ranges, and routes of administration. The nurse should always assess thoroughly by completing data collection about the patient and the drug.

It is important during the assessment phase of the nursing process to consider the expanded and collaborative role of the nurse. Physicians and dentists are no longer the only health care professionals prescribing and writing medication orders. Nurse practitioners and physician assistants have also gained the professional privilege to legally prescribe medications. Nurses should always be aware of and obtain a copy of their state’s nurse practice acts so that they are informed of role-related responsibilities and for any expanded roles of nurses (e.g., nurse practitioner).

Analysis of Data

Once all of the data regarding the patient, environment, and drug have been collected and reviewed, the nurse must make a critical evaluation of the information (analysis) and make decisions about its importance and implications to the patient. Effort should be made to ensure that all information is obtained and documented at this time.

NURSING  DIAGNOSES

Nurses use nursing diagnoses as a means of communicating information about the patient and the patient experience. Nursing diagnoses are the result of critical thinking, analysis, creativity, and accurate data collection

about the patient. Once the assessment has been completed, the next step is for the nurse to analyze the information before developing appropriate nursing diagnoses. Nursing diagnoses, as related to drug therapy, should be a judgment or conclusion about the risk for problems and actual patient needs or problems but based on an adequate knowledge base.

As mentioned earlier, the major tasks associated with the assessment phase include the collection of subjective and objective data. After assessment, the nursing diagnoses are formulated. Nursing diagnoses related to drug therapy will most likely develop out of data such as deficient knowledge; risk for injury; noncompliance; and various disturbances, excesses, or impairments.

The North American Nursing Diagnosis Association (NANDA) is the formal organization that is recognized by professional groups such as the American Nurses Association (ANA) and individuals as a major contributor to the development of nursing knowledge and is also considered to be the leader in the classification of nursing diagnoses. The purpose of NANDA is to increase the visibility of nursing’s contribution to the care of patients and to further develop, refine, and classify the information and phenomena related to nurses and professional nursing practice. In 1987, NANDA and the ANA developed and endorsed a model or framework for establishing nursing diagnoses. In 1990, Nursing Diagnoses, the official journal of NANDA, was published, and the current resource is titled The International Journal of Nursing Terminologies and Classifications. In 1998 NANDA celebrated its twenty-fifth anniversary. In 2001, and again in 2003, NANDA diagnoses were modified and updated by the organization. New nursing diagnoses are continually submitted for consideration to the Ad Hoc Research Committee within the NANDA organization. This committee articulates with other specialty groups about nursing diagnoses research and provides consultation to NANDA members who wish to generate nursing diagnoses research. One change in the format of nursing diagnoses is the replacement of the phrase “potential for” with the phrase “risk for.” The phrase “risk for” represents the fact that a patient, family, or community may be more vulnerable to developing a particular problem than others in the same situation. Terms in the NANDA Nursing Taxonomy II include impaired, deficient, ineffective, decreased, increased, and imbalanced. The terms altered and alteration are considered to be outdated.

Box 1–

2 provides a list of selected NANDA-approved nursing diagnoses.

PLANNING

After data are collected and nursing diagnoses formulated, the planning phase begins. Planning includes the identification of goals and outcome criteria.

The major aims of the planning phase are to prioritize the nursing diagnoses and to specify the goals and outcome criteria, including when these should be achieved. The planning phase provides time to get special equipment, review the possible procedures or techniques to be rendered, and gather information either for oneself or the patient. This step leads to the provision of safe care if professional judgment making is combined with the acquisition of knowledge about the patient and the medication to be given.

Goals and Outcome Criteria

Goals are objective, measurable, and realistic, with an established time period for achievement of the outcomes, which are specifically stated in the outcome criteria. Patient goals are reflected in expected changes through nursing care. The outcome criteria (descriptions of patient goals) should be succinct, well thought out, and patient focused. They should include behavioral expectations to be met by certain deadlines. The ultimate aim of these crite­ria is the safe and effective administration of medications. They should relate to each nursing diagnosis and guide the implementation of the nursing care plan. Their formulation begins with the analysis of the judgments made about all of the patient data and subsequent nursing diagnoses and ends with the development of a nursing care plan. Outcome criteria provide a standard of measure that can be used to move toward goals. They may address special storage and handling techniques, administration procedures, equipment needed, drug interactions, side effects, and contra indications. In this text specific time frames generally are not included in the goals and outcome criteria because the process of establishing a time frame must be individualized for each patient situation and reflect individual and specific planning and nursing judgment.

Patient-oriented outcome criteria must apply to any medications the patient will receive. The outcome criteria of the 43-year-old man with diabetes mellitus were focused on the administration and general aspects of insulin therapy. In this situation, the patient-oriented outcome criteria include specific patient education about insulin, its side effects, contraindications to its use, and injection techniques. The nurse has the responsibility for being knowledgeable about the medication before it is to be administered. If there are any questions about the order, its appropriateness, or safety in a given patient, the nurse should get answers to these questions and then use professional judgment in the implementation of the order. During the planning phase, if the patient’s condition is changing and could be worsened by the medication or if the physician’s order is unclear or incorrect, the medication should be withheld, the physician should be contacted for clarification or further instructions, and the information should be documented. If the physician is unavailable, the nurse manager or nursing supervisor should be notified immediately about the problem. Nursing policy guidelines should also be checked to find out who else should be contacted.

IMPLEMENTATION

Implementation is guided by the earlier phases of the nursing process (assessment, nursing diagnoses, and planning). Implementation requires constant communication and collaboration with the patient and with members of the health care team who are involved in the patient’s care, as well as with any family, significant others, or other caregivers. Implementation consists of initiation and completion of the nursing care plan as defined by the nursing diagnoses and outcome criteria. When it comes to medication administration, the nurse also needs to know and understand all of the information about the patient and each medication prescribed. It is also important for the nurse always to adhere to the “5 Rights” of medication administration: right drug, right dose, right time, right route, and right patient. In addition, the nurse needs to be aware of the following patient rights:

•  The right to a “double check” and constant systemanalysis (e.g., the system of the drug administration process with regard to everyone involved, including the doctor, the nurse, the nursing unit, and the pharmacy department, and also with regard to patient education)

•  The right to proper drug storage and documentation

•  The right to accurate calculation and preparation of the dosage of medication and proper use of all types of medication delivery systems

•  The right to careful checking of the transcription of medication orders

•  The right to patient safety with correct procedures and techniques of medication administration

•  The right to accurate routes of administration and specific implications

•  The right to the close consideration of special situations (e.g., patient with difficulty swallowing, patient with a nasogastric tube, unconscious patient)

•  The right to having all measures taken with regard to the prevention and reporting of medication errors The right to individualized and complete patient teaching

•  The right to accurate and cautious patient monitoring for therapeutic effects, side effects, and toxic effects The right to continued safe use of the nursing process, with accurate documentation iarrative form or in the SOAP (subjective, objective, assessment, planning) notes format

•  The right of refusal of medication with proper documentation

Right Drug

An important component to the “Right” drug begins with the nurse’s valid license to practice in addition to checking all medication orders and/or prescriptions. To ensure that the right drug is administered, the nurse must pay attention to both the drug orders and the medication labels when preparing medications for administration. In addition, the nurse

should consider whether the drug is appropriate for the patient. The nurse must always clarify the name and indication of the drug, as well as its dosage and route. These orders must be signed by the physician or health care provider within 24 hours or pec the specific facility’s protocol.  Verbal and telephone orders are acceptable only in emergency situations. To be sure that the right drug is being administered and is appropriate, the nurse must obtain information about the patient, such as his or her past and present medical history and a thorough and updated medication history, including OTC medications used. Pertinent laboratory studies should be considered. Information about the drug is also important. As stated earlier, authoritative sources of current (less than 5 years old) information include drug reference books, electronic references including the Internet (e.g., the FDA or USP websites), drug inserts (manufacturer’s information), and licensed pharmacists. It is important for nurses to be familiar with the generic (nonproprietary) drug name and the trade name (proprietary name that belongs to a specific drug manufacturer). The nurse must be careful not to rely on information from peers and co-workers because, as a professional nurse, it is that nurse who is responsible for administering the right drug. Therefore the nurse should always look to the appropriate and current authoritative sources. Before administering any drug by any route, the nurse must know the “particulars” about that drug as well. No matter how busy the nurse may be, it is his or her professional responsibility to check the order and the label on the medication and check for all of the “5 Rights” at least 3 times before giving the medication to the patient. If the nurse has any questions, the physician should be contacted to clarify the order. The nurse should never assume anything when it comes to drug administration.

 

Right Dose

Whenever a medication is ordered, a dosage is also identified and prescribed. The nurse must always check the dose and whether it is appropriate to the patient’s age and size and remember to also always recheck any mathematical calculations. The nurse must pay careful attention to decimal points because an error could cause a tenfold or even greater overdosage. The patient’s age, gender, weight, height, or vital signs may cause the patient to require a different dosage. Remember, the neonate, pedi-atric, and geriatric patients are more sensitive to medications than are younger adult patients and extra caution is warranted.

Right Time

Each health care agency or institution has a policy for routine medication administration times; therefore it is important that the nurse always check this policy. When it comes to the right time for medication administration, often the nurse will be confronted with a conflict between the pharmacokinetic and pharmacodynamic properties of the drugs prescribed and the patient’s lifestyle and likelihood of compliance. For example, the right time for the administration of antihypertensive agents may be four times a day, but for the active, working 42-year-old male patient who is taking a medication associated with the side effect of impotence, a dosage schedule of four times a day may lead to decreased compliance. This emphasis on and teaching to patients  about the right time for the administration of medications must be reflected in the nurse’s own practice. No matter how busy the nurse is, he or she must concentrate on each patient and assess each individually to identify any special time considerations.

In addition, for routine medication orders, medications must be given within Vi hour before or after the actual time specified in the physician’s orders (i.e., if a medication is ordered to be given at 0900 every morning it may be given anytime between 0830 and 0930), except for stat (“to be given immediately”) medications, which must be given within Vi hour of the order. The nurse should always check the hospital or facility policy and procedure for any other specific information concerning the “V2 hour before or after” rule. Most health care facilities use military time when writing medication and other orders. Military time includes the following: 0100 (1 AM), 0200 (2 am), 0300 (3 am), 0400 (4 am), 0500 (5 AM), 0600 (6 am), 0700 (7 am), 0800 (8 am), 0900 (9 am), 1000 (10 am), 1100 (11 am), 1200 (12 noon), 1300 (1 pm), 1400 (2 pm), 1500 (3 pm), 1600 (4 pm), 1700 (5 pm), 1800 (6 pm), 1900 (7 pm), 2000 (8 pm), 2100 (9 pm), 2200 (10 pm), 2300 (11 pm), and 2400 (12 midnight).

Nursing judgment may lead to some variations in timing, but the nurse should be sure to document any change and the rationale for it. If medications are ordered once every day, twice daily, three times daily, and/or even four times daily, the times of administration may be changed if this is not harmful to the patient, if the medication and the patient’s condition do not require adherence to an exact schedule, and with physician approval or notification. For example, an antacid is ordered to be given three times daily at 0900,1300, and 1700, but the nurse has misread the order and gives it at 1100. Depending on the hospital or facility policy, the medication, and the patient’s condition, this may not be considered an error. The dosing times may be changed to be given at 1100, 1500, and 1900 without harm to the patient and without incident to the nurse, prn (pro re nata) medication orders are for the administration of medications with special timing and circumstances.

There are other factors to be considered when it comes to the right time. These include multiple-drug therapy, drug-drug or drug-food compatibility, diag­nostic studies, bioavailability of the drug (such as the need for consistent timing of doses around the clock to maintain blood levels), drug actions, and any bio-rhythm effects such as those that occur with steroids. It is also critical to patient safety to avoid using abbreviations with any component of a drug order (i.e., dosing, time, route). The nurse should spell out all terms (e.g., “three times daily” instead of “tid”).

Right Route

As previously stated, the nurse must know the particulars about each medication before administering it to ensure that the right drug, dose, and route are being used. A complete medication order includes the route for administration. If a medication order does not include the route, the nurse must ask the physician to clarify it. The nurse must never assume the route of administration.

 

 

Right Patient

It is critical to the patient’s safety that the nurse check the patient’s identity before giving each medication dose. The nurse should ask the patient to state his or her name and then check the patient’s identification band or bracelet to confirm the patient’s name, identificatioumber, age, and allergies. With pediatric patients, the parents and/or legal guardians are often the ones who identify the patient. This identification should then be checked against the patient’s identification band or bracelet. In the newborursery and labor and delivery units, the mother and baby have identification bracelets with matching numbers.

Other areas to be assessed in reference to the right patient include the patient’s cultural background, preexisting ideas and attitudes, personal beliefs, and religious af­filiation. Although the standard “5 Rights” of medication administration hold true for safe nursing practice, they do not include all of the variables that affect medication administration. Therefore it is important to also consider a possible sixth right—the process of system analysis. System analysis looks at more than just the “5 Rights.” It also addresses the entire system of medication administration, including ordering, dispensing, preparing, administering, and documenting.

Medication Errors

When discussing the “5 Rights” of medication administration and system analysis, it is important to discuss medication errors. Medication errors are a major problem in all settings of health care today. The National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) defines medication error as

Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.

This definition of medication errors is important for the nurse to understand because it emphasizes that the nurse look not only at the “5 Rights” of medication administration as contributors to a medication error but also at various systems involved in the medication adminis­tration process. Systems may involve any part of the process, from where the order is received to where the medication is administered and include various health care professionals and ancillary personnel, as well as unit stocking, transcription of orders, and how the medication order is verified and interpreted.

EVALUATION

Evaluation occurs after the plan has been implemented, but it is actually an ongoing part of the nursing process and drug therapy. Evaluation in the context of drug therapy is the monitoring of the patient’s responses to the drug—the expected and unexpected responses, therapeutic effects (produced intended effects), side effects, and toxic effects. An example of both a therapeutic effect and an adverse effect is as follows: A patient receives an antihypertensive agent to treat hypertension. A therapeutic effect results if the blood pressure decreases to withiormal limits. An adverse effect results if the blood pressure decreases to less than 100/60 mm Hg with postural hypotension occurring. Documentation is a very important component of evaluation; thus the therapeutic effects and/or adverse or toxic effects to a medication are identified and noted (see the Legal and Ethical Principles box below).

Evaluation is also important in determining the status of educational goals and patient care goals regarding medication administration. Several standards are in place to help in the evaluation of outcomes of care, such as those standards established by nurse practice acts and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). Within the JCAHO, guidelines are established for nursing services policies and procedures. There are even specific standards regarding medication administration, which are established to protect both the patient and the nurse. The evaluation of the patient’s response to previous therapy and other components of his or her medical or surgical regimen is an important facet of safe and effective delivery of drug therapy. The documentation of any findings and cautions regarding medication use and the continual assessment of patients are critical aspects of safe and effective nursing care. The nursing process as it relates to drug therapy is the way in which the nurse organizes and provides drug therapy in the context of prudent nursing care. The nurse’s ability to make astute assessments, formulate sound nursing diagnoses, establish goals and outcome criteria, correctly administer drugs, and continually evaluate the patient’s response to the drug increases with additional experience and knowledge.

Charting “Don’ts”

• Don’t record staffing problems (don’t mention them in a patient’s chart but write a memo instead to the nurse manager).

• Don’t record a peer’s conflicts such as charting possible disputes between a patient and a nurse.

• Don’t mention incident reports in charting because they are confidential and filed separately and not in the patient’s chart. You may document the facts of an incident, but don’t mention the terms.

• Don’t use the following terms: “by mistake,” “by accident,” “accidentally,” “unintentional,” or “miscalculated.”

• Don’t chart other patients’ names because this is a violation in confidentiality.

• Don’t chart anything but facts.

• Don’t chart casual conversations with peers, doctors, or other members of the health care team.

• Don’t use abbreviations.

• Don’t use negative language because it may come back to haunt you!

Pharmacologic Principles

When you reach the end of this chapter, you should be able to do the following:

o   Define common terms used in pharmacology.

o    Understand the role of pharmaceutics, pharmacokinetics, and pharmacodynamics in medication administration and in use of the nursing process.

o   Discuss the application of the four principles of  pharmacotherapeutics to everyday nursing practice as related to drug therapy and with a variety of patients in different health care settings.

o    Apply the phases of pharmacokinetics to drug therapy and the nursing process.

o     Discuss the use of natural drug sources in the development of new drugs

Any chemical that affects the processes of a living organism can broadly be defined as a drug. The study or science of drugs is known as pharmacology. This study may incorporate knowledge from a variety of areas, as follows:

•  Absorption

•  Biochemical effects

•   Biotransformation

•  Distribution

•  Drug history

•  Drug origin

•  Excretion

•  Mechanisms of action

•  Physical and chemical properties

•  Physical effects

•  Therapeutic (beneficial) effects

•  Toxic (harmful) effects

Study in any one of these areas can be defined as pharmacology. Knowledge of these various areas of pharmacology enables the nurse to better understand how drugs affect humans. Without a sound understanding of basic pharmacologic principles, the nurse cannot appreciate the therapeutic benefits and potential toxicity of drugs.

Pharmacology is an extensive science that incorporates five interrelated sciences: pharmacokinetics, pharmacodynamics, pharmacotherapeutics, toxicology, and pharmacognosy. The various pharmacologic agents discussed within each chapter of this text are described from the standpoint of these five sciences. Commonly used terms such as therapeutic index, tolerance, dependence, and dose-response curves are discussed within this chapter.

Throughout the process of development, a drug will acquire at least three different names. The chemical name describes the drug’s chemical composition and molecular structure. The generic name, or nonproprietary name, is given to the drug by the United States Adopted Name (USAN) council. It is often much shorter and simpler than the chemical name. The generic name is used in most official drug compendiums to list drugs. The trade name, or proprietary name, indicates that the drug has a registered trademark and that its commercial use is restricted to the owner of the patent for the drug. The owner is usually the manufacturer of the drug .

Three basic areas of pharmacology—pharmaceutics, pharmacokinetics, and pharmacodynamics—describe the relationship between the dose of a drug given to a patient and the effectiveness of that drug in treating the patient’s disease. Pharmaceutics is the study of how various dosage forms (e.g., injection, capsule, controlled-release tablet) influence pharmacokinetic and pharmacodynamic properties. Pharmacokinetics is the study of what the body does to the drug. Pharmacodynamics is the study of what the drug does to the body. Pharmacokinetics examines four phases of drugs in the body: absorption, distribution, metabolism, and excretion. These four phases and their relationship to drug and drug metabolite concentrations are then determined for various body sites over specified periods. The onset of action, the peak effect of a drug, and the duration of the effect of a drug are also studied by pharmacokinetics. Pharmacodynamics investigates the biochemical and physical effects of drugs in the body. More specifically, it determines a drug’s mechanism of action. Pharmacother-apeutics focuses on the use of drugs and the clinical indications for drugs to prevent and treat diseases. It incorporates the principles of drug actions; therefore an understanding of pharmacotherapeutics is essential for nurses when implementing drug therapy. The study of the adverse effects of drugs on living systems is toxicology. Such toxicologic effects are often an extension of a drug’s therapeutic action. Therefore toxicology often involves overlapping principles of both pharmacotherapy and toxicology. Plants are the source for many drugs, and the study of these natural drug sources (both plants and animals) is called pharmacognosy.

Pharmacology is very dynamic, incorporating several different disciplines (as mentioned earlier). Traditionally chemistry was seen as the primary basis of pharmacology, but pharmacology also relies heavily on the physical, biologic, and social sciences. Different drug dosage forms have different pharmaceutical properties. Drug dosage forms can determine the rate at which drug dissolution and thus absorption occur in the body. Multiple pharmaceutical-related changes in a dosage formulation can affect drug dissolution. When a drug is ingested orally it may come in either a solid form (tablet, capsule, or powder) or a liquid form (solution or suspension). The process of dissolution describes how solid forms of drugs disintegrate, become soluble, and get absorbed into the bloodstream. Oral drugs that are liquids, elixirs, or syrups are already dissolved and are usually absorbed more quickly. Enteric-coated tablets, on the other hand, have a coating that prevents them from being broken down and therefore are not absorbed until they reach the lower pH of the intestines. This pharmaceutical property results in slower dissolution and therefore slower absorption. Sometimes the size of the particles within a capsule can make different capsules containing the same drug dissolve at different rates, get absorbed at different rates, and thus have different onsets of action. A prime example of this is the difference between micronized (Glynase) and nonmi-cronized (DiaBeta and Micronase) forms of glyburide. The micronized formulation of glyburide reaches a maximum concentration peak more quickly than does the nonmicronized formulation.

A variety of dosage forms exist to provide both accurate and convenient drug delivery systems. These delivery systems are designed to achieve a desired therapeutic response with minimal side effects.compliance in mind. Convenience of administration tends to correlate with medication compliance. Many of the extended-release oral dosage forms were designed with this in mind.

The specific characteristics of various dosage forms have a large impact on how and to what extent the drug is absorbed. If a drug is to work at a specific site in the body, it must either be applied directly at that site in an active from or it must have a way of getting to that site. A drug’s dosage form influences this placement. Oral dosage forms rely on gastric and intestinal enzymes and pH to break them down into particles that are small enough to be absorbed into the circulation. Once absorbed through the mucosa of the stomach or intestines, the drug is then transported to the site of action by blood or lymph.

Many topically applied dosage forms work directly on the surface of the skin. Therefore when the drug is applied, it is already in a dosage form that allows it to work immediately. To other topical dosage forms the skin acts as a barrier through which the drug must pass to get to the circulation, which then carries the drug to the site of action.

Dosage forms that are administered via injection are called parenteral dosage forms. They must have certain characteristics to be safe and effective. The arteries and veins that carry drugs throughout the body can easily be damaged if the drug is too concentrated or corrosive. The solutions used in these dosage forms must be very similar to the blood to be safely administered. Parenteral dosage forms that are injected intravenously or intraarte-rially are already in solution and do not have to be dissolved in the body. Their absorption occurs immediately on injection.

PHARMACOKINETICS

A particular drug’s onset of action, time to peak effect, and duration of action are all characteristics defined by pharmacokinetics. Pharmacokinetics is the study of what actually happens to a drug from the time it is put into the body until the parent drug and all metabolites have left the body. Therefore drug absorption into, distribution and metabolism within, and excretion from a living organism represent the combined focus of pharmacokinetics.

Absorption Process

Absorption is the rate at which a drug leaves its site of administration and the extent to which it occurs. A term used to quantify the extent of drug absorption is bioavailability. For example, a drug that is absorbed from the intestine must first pass through the liver before it reaches the systemic circulation. If the drug is metabolized in the liver or excreted in the bile, some of the active drug will be inactivated or diverted before it can reach the general circulation and its sites of action. This is known as the first-pass effect, and it reduces the bioavailability of the drug to less than 100%. Many drugs ad ministered by mouth have a bioavailability of less than 100%, whereas drugs administered by the intravenous (IV) route are 100% bioavailable. If two medications have the same bioavailability, they are said to be bioequivalent. There are various factors affecting the rate of drug absorption. These include the administration route of the drug, food or fluids administered with the drug, dosage formulation, status of the absorptive surface, rate of blood flow to the small intestine, acidity of the stomach, and status of gastrointestinal (GI) motility. Various administration routes and their effects on absorption are now examined in detail, followed by drug distribution, metabolism, and excretion.

Route

How a drug is administered, or its route of administration, affects the rate and extent of

absorption of that drug. Although there are several dosage formulations available for delivering medications to the body, they can all be broken down into three basic categories, or routes of administration: enteral (GI tract), parenteral, and topical. Absorption characteristics vary depending on the dosage form and category.

Enteral. In enteral drug administration the drug is absorbed into the systemic circulation through the oral or gastric mucosa, small intestine, or rectum. The rate of absorption of enterally administered drugs can be altered by many factors. When drugs are taken orally, they are absorbed from the GI tract into the portal circulation (liver). Depending on the particular drug, it may be extensively metabolized in the liver before it reaches the systemic circulation. Normally, orally administered drugs are absorbed from the intestinal lumen into the mesenteric blood system and conveyed by the portal vein to the liver. Once the drug is in the liver, the enzyme systems metabolize it and it is passed into the general circulation. This initial metabolism of a drug and its passage from the liver into the circulation is called the first-pass effect . The drug would have a high first-pass effect (e.g., oral nitrates).

When drugs with a high first-pass effect are administered orally, a large amount of drug may be metabolized before it reaches the systemic circulation. The same drug given intravenously will bypass the liver. This prevents the first-pass effect from taking place, and therefore more of the drug reaches the circulation. Parenteral doses of drugs with a high first-pass effect are much smaller than enteraliy administered oral doses, yet they produce the same pharmacologic response.

Oral. There are many factors that can alter the absorption of orally (enterally) administered drugs, Acid changes within the stomach, absorption changes in the intestines, and the presence or absence of food and fluid can alter the rate and extent of absorption of drugs administered enterally. Various factors that affect the acidity of the stomach are the time of day; the age of the patient; and the presence and types of any medications, foods, or beverages. If food is in the stomach during the dissolution of an orally administered medication, this may interfere with its dissolution and absorption and delay its transit from the stomach to the small intestine, where most drugs are absorbed. On the other hand, food may enhance the absorption of some fat-soluble drugs or drugs that are more easily broken down in an acidic environment.

Before orally administered drugs are passed into the portal circulation of the liver, they are absorbed in the small intestine, which has an enormous surface area. Drug absorption may be altered in patients who have had portions of their small intestine removed because of disease. Anticholinergic drugs may slow down the GI transit time, or the time it takes substances in the stomach to be dissolved and passed into the intestines. This may allow more time for an acid-susceptible drug to be in contact with the acid in the stomach and subsequently broken down, reducing the extent of drug absorption.

The stomach and small intestine are highly vascular-ized. When blood flow to that area is decreased, absorption may also be decreased. Sepsis and exercise are exam ples of conditions in which blood flow to the Gl tract is reduced. With both of these blood tends to be routed to the heart and other vital organs, and in the case of exercise, the skeletal muscles.

Sublingual. Drugs administered by the sublingua] route are absorbed into the highly vascularized tissue under the tongue—the oral mucosa. Sublingual ni-troglycerin is an example. Sublingually administered drugs are absorbed rapidly because the area under the tongue has a large blood supply, and such drugs bypass the liver. Drugs administered by the buccal, sublingual, vaginal, and intravenous routes bypass the liver. By doing so, drugs such as sublingual nitroglycerin are absorbed rapidly into the bloodstream and delivered to their site of action, in the case of nitroglycerin to the coronary arteries. These same characteristics are true for rectally administered medications. Most enemas and suppositories (rectal and vaginal) are absorbed directly into the bloodstream, thus bypassing the liver and the first-pass effect.

 Parenteral. With most medications, the parenteral route is the fastest route by which a drug can be absorbed, followed by the enteral and the topical routes. The term parenteral is a general term that refers to any route of administration other than the Gl tract. Most commonly it refers to injection by any method, though transdermal medications can also be considered parenteral dosage forms. Intravenous injections deliver the drug directly into the circulation, where it is distributed with the blood throughout the body. An intravenous drug formulation is absorbed the fastest. At the other end of the spectrum are transdermal patches, intramuscular (IM) injections, and subcutaneous (SC) injections. These drug formulations are usually absorbed over a period of several hours.

Parenterally administered drugs can be given intrader-mally, subcutaneously, intramuscularly, intrathecally, intra-articularly, and intravenously. The medications that are commonly given by the parenteral route offer the advantage of bypassing the first-pass effect and are in general quickly absorbed. The parenteraJ route of administration offers an alternative route of delivery for those medications that cannot be given orally. The problems posed by acid changes within the stomach, absorption changes in the intestines, and the presence or absence of food and fluid are not then a concern. There are fewer obstacles to absorption in parenteral administration than in enteral administration of drugs. However, drugs that are administered by the parenteral route must still be absorbed into cells and tissues before they can exert their pharmacologic effect.

Subcutaneous and Intramuscular. Parenteral injections under the skin are referred to as subcutaneous injections, and parenteral injections into the muscle are referred to as intramuscular injections. Muscles have a greater blood supply than the skin does; therefore drugs injected intramuscularly are typically absorbed faster than ones injected subcutaneously. Absorption from either of these sites may be increased by applying heat to the injection site or by massaging the site. Both increase the blood flow to the area and therefore enhance absorption. Most intramuscularly injected drugs are absorbed over several hours. However, specially designed long-acting intramuscular dosage forms known as depot forms are designed for slow absorption and may be absorbed over a period of several days to a few months or longer. The intramuscular corticosteroid known as methylprednisolone acetate (Depo-Medrol) can provide antiinflammatory effects for several weeks. The intramuscular contraceptive medrox-yprogesterone acetate (Depo-Provera) normally prevents pregnancy for 3 months per dose. With regard to subcutaneous administration, insulin glargine (Lantus) is a long-acting insulin product that is now in common use.

Absorption can be decreased by administering cold packs to the site of injection. This is typically done to localize an injection, for example when an intravenously administered vasopressor, such as epinephrine, has ex-travasated or leaked out of the vein and into the surrounding tissue and has begun to cause ischemia and tissue damage. Cool compresses produce vasoconstriction, which reduces cellular activity and in turn may limit tissue injury.

Sometimes injections may be given with a vasoconstrictor such as epinephrine to confine an injected drug to the site of injection, thereby limiting its pharmacologic action to that area. A similar principle applies when processes within the patient’s own body, such as hypotension or poor peripheral blood flow, compromise the circulation and therefore reduce drug activity.

Topical. Topical routes of drug administration involve the application of medications to various body surfaces, and several different drug delivery systems exist. Topically administered drugs can be applied to the skin, eyes, ears, nose, and lungs, to name but a few surfaces. As with the enteral and parenteral routes, there are both benefits and drawbacks to using the topical route of administration. A topically applied drug delivers a constant amount of drug over a long period, but the effects of the drug are usually very slow in their onset and very prolonged in their offset. This can be a problem if the patient begins to experience side effects from the drug and there is already a considerable amount of drug in the subcutaneous tissues. Exceptions are some inhaled drugs such as aerolized albuterol for acute treatment of an asthma attack.

Topical ointments, gels, and creams are examples of topically administered drugs. They are commonly used for their local effects, and they include sunscreens, antibiotics, and nitroglycerin paste and ointment. The drawback to their use is that their systemic absorption is very unreliable. Therefore topically applied ointments, gels, and creams are seldom used for the treatment of any systemic illnesses.

Topically applied drugs can also be used in the treatment of various illnesses of the eyes, ears, and sinuses. In such conditions most commonly the required drug is de­livered topically to the actual site of illness and bypasses the first-pass effect in the liver.

Transdermal. Transdermal drug delivery through adhesive drug patches is a topical route of drug administration that is commonly used. Some examples of drugs administered by this route are fentanyl, nitroglycerin, nicotine, estrogen, and clonidine. This method of drug delivery offers the advantage of bypassing the liver and its first-pass effects. It is suitable for patients who cannot tolerate orally administered medications or when it is a practical or convenient method for drug delivery. The various drug delivery systems of specific transdermal patches determine their length of effect. Transdermal drug administration is a more generalized form of topical administration in that the former is a method of systemic drug delivery, whereas the latter focuses on localized skin and soft tissue effects at or near the site of administration.

Inhalation. Inhaled drugs are delivered to the lungs as mcm-size drug particles. This small drug size is necessary to get the drug to the small airways within the lungs (alveoli). Once the small particle of drug is in the alveolus, drug absorption is fairly easy. At this site the thin-walled pulmonary alveolus is in contact with the capillaries, where the drug can be absorbed quickly. Many pulmonary-related diseases can be treated with such topically applied (inhaled) drugs. Examples of inhaled drugs include pentamidine, which is used to treat Pneumocystis carinii infections in the lung; albuterol, which is used for the treatment of bronchial constriction in asthmatics; and vasopressin, which is used to treat diabetes insipidus.

Distribution

Distribution is the transport of a drug in the body by the bloodstream to its site of action. Once a drug enters the bloodstream (circulation), it is distributed throughout the body. At this point it is also beginning to be eliminated by the organs that metabolize and excrete drugs—the liver and the kidney. A drug can be freely distributed to extravascular tissue only if it is not bound to protein. If a drug is bound to protein, it is generally too large to pass through the walls of blood capillaries into tissues. There are three primary proteins that bind to and carry drugs throughout the body: albumin, alpha,-acid glycoprotein, and corticosteroid-binding globulin. By far the most important of these is albumin. When a patient has a low albumin level, for instance when he or she is malnourished or burned, more free, unbound drug results.

When an individual is taking two medications that are highly protein bound, the medications compete for binding to these proteins. This competition results in either less of both or less of one of the drugs binding to the proteins. Consequently, this leaves more free, unbound drug. This process can lead to an unpredictable drug response called a drug—drug interaction. A drug-drug interaction occurs when a drug decreases or increases the response of another concurrently (given at the same time) administered drug. The areas where the drug is distributed first are those that are most extensively supplied with blood. Areas of rapid distribution are the heart, liver, kidneys, and brain. Areas of slower distribution are muscle, skin, and fat.

A theoretic volume, called the volume of distribution, is sometimes used to describe the various areas where drugs may be distributed. These areas, or compartments, can be the blood, total body water, body fat, or other body tissues and organs. Typically a drug that is highly water soluble will have a small volume of distribution and high blood concentrations. The opposite is true for drugs that are highly fat soluble. Fat-soluble drugs have a large volume of distribution and low blood concentrations. Drugs that are water soluble and highly protein bound are more strongly bound to proteins in the blood and less likely to be absorbed into tissues. Because of this, their distribution and onset of action can be slow. Drugs that are highly lipid soluble and poorly bound to protein are easily taken up into tissues and distributed throughout the body. They may even be resorbed back into the circulation from fatty tissue.

There are some sites in the body where it may be very difficult to distribute a drug. These sites typically either have a poor blood supply (e.g., bone) or have barriers that make it difficult for drugs to pass through (e.g., the blood-brain barrier).

Metabolism

Metabolism is also referred to as biotransformation because it involves the biologic transformation of a drug into an inactive metabolite, a more soluble compound, or a more potent metabolite. Biotransformation is the next step after absorption and distribution. The organ most responsible for the biotransformation or metabolism of drugs is the liver. Other tissues and organs that aid in the metabolism of drugs are skeletal muscle, kidneys, lungs, plasma, and intestinal mucosa.

Hepatic biotransformation involves the use of an enormous variety of enzymes known as cytochrome P-450 enzymes (or simply P-450 enzymes) or microsomal enzymes. These enzymes control a variety of chemical reactions that aid in the biotransformation (metabolism) of medications and are targeted against lipid-soluble, nonpolar (no charge) drugs, which are typically very difficult to eliminate. This includes the majority of medications. Those medications with water-soluble (polar) molecules may be more easily metabolized by simpler metabolic reactions such as hydrolysis (metabolism by water molecules). Drug molecules that are the metabolic targets of specific enzymes are said to be substrates of those enzymes. Specific P-450 enzymes are identified by stan­dardized number and letter designations. Some of the most common P-450 enzymes and common drug substrates are listed. The biotransformation capabilities of the liver can vary considerably from patient to patient. Various factors, in-eluding genetics, diseases, conditions, and the presence of other medications that can alter biotransformation.

Delayed drug metabolism results in the accumulation of drugs and a prolonged action of the effects or responses to drugs. Stimulating drug metabolism can thus cause diminishing pharmacologic effects. This is often the case with the repeated administration of some drugs that may stimulate the formation of new microsomal enzymes.

Excretion

Excretion is the elimination of drugs from the body. Whether they are parent compounds or are active or inactive metabolites, all drugs must eventually be removed from the body. The primary organ responsible for this is the kidney. Two other organs that play an important role in the excretion of drugs are the liver and the bowel. Most drugs are metabolized or biotransformed in the liver by various glucuronidases and by hydroxylation and acetylation. Therefore by the time most drugs reach the kidneys, they have been extensively metabolized and only a small fraction of the original drug is excreted as the original compound. Other drugs may circumvent metabolism and reach the kidneys in their original form. Drugs that have been metabolized by the liver become more polar and water soluble. This makes elimination by the kidney much easier. The kidney itself is capable of forming glucuronides and sulfates from various drugs and their metabolites.

The actual act of excretion is accomplished through glomerular filtration, reabsorption, and tubular secretion. Free, unbound water-soluble drugs and metabolites go through passive glomerular filtration, which takes place between the blood vessels of the afferent arterioles and the glomeruli. Many substances present in the nephrons go through active tubular reabsorption. Reabsorption oc­curs at the level of the tubules, where substances are taken back up into the circulation and transported away from the kidney. This is an attempt by the body to retaieeded substances. These substances are actively re-sorbed back into the systemic circulation. Some substances may also be secreted into the nephron from the vasculature surrounding it.

The excretion of drugs by the intestines is another common route of elimination. This is also referred to as biliary excretion. Drugs that are eliminated by this route are taken up by the liver, released into the bile, and elim­inated in the feces. Once certain drugs, such as fat-soluble drugs, are in the bile, they may be resorbed into the bloodstream, returned to the liver, and again secreted into the bile. This process is called enterohepatic recirculation. Enterohepatically recirculated drugs persist in the body for much longer periods. Less common routes of elimination are the lungs and the sweat, salivary, and mammary glands. Depending on the drug, these organs and glands can be highly effective eliminators.

Half-Life

Another pharmacokinetic variable is the half-life of the drug. The half-life is the time it takes for one half of the original amount of a drug in the body to be removed and is a measure of the rate at which drugs are removed from the body. For instance, if the maximum level that a particular dosage could achieve in the body is 100 mg/L, and in 8 hours the measured drug level is 50 mg/L, the estimated half-life for that drug is 8 hours. After about five half-lives, most drugs are considered removed from the body. At that time approximately 97% of the drug has been removed, and what little is remaining is too small to have any beneficial or toxic effects. The concept of half-life is clinically useful for determining when a patient taking a particular drug will be at steady state. Steady state blood levels of a drug refer to a physiologic state in which the amount of drug removedvia elimination (e.g., renal clearance) is equal to the amount of drug absorbed with each dose. This physiologic plateau phenomenon typically occurs after four to five half-lives of administration of a drug. Therefore if a drug has an extremely long half-life, it will take much longer for the drug to reach steady state blood levels. Once an individual has reached steady state blood levels, there are consistent levels of drug in the body that correspond to maximum therapeutic benefits.The pharmacokinetic terms absorption, distribution, metabolism, and excretion are all used to describe the movement of drugs through the body. Drug actions are the cellular processes involved in the drug and cell interaction (e.g., a drug’s action on a receptor). This is in contrast to drug effects, which are the physiologic reactions of the body to the drug. The terms onset, peak, and duration are used to describe drug effects. A drug’s onset of action is the time it takes for the drug to elicit a therapeutic response. A drug’s peak effect is the time it takes for a drug to reach its maximum therapeutic response. Physiologically, this corresponds to increasing drug concentrations at the site of action. The duration of action of a drug is the length of time that the drug concentration is sufficient to elicit a therapeutic response.

The timing of onset, peak, and duration, of action often plays an important part in determining peak (highest blood level) and trough (lowest blood level). If the peak blood level is too high, then toxicity may occur. If the trough blood level is too low, then the drug may not be at therapeutic levels. (A common example involves antibiotic drug therapy with aminoglycoside antibiotics Therefore peak and trough levels are important monitoring parameters for some medications. The processes of drug absorption, distribution, metabolism, and elimination directly determine the duration of action of a drug.

PH ARM ACO DYNAMICS

Pharmacodynamics is the study of the mechanism of drug actions in living tissues. Anatomy and physiology are the study of body structure and why the body functions the way it does. Drug-induced alterations in these normal physiologic functions are explained by the concept of pharmacodynamics. A positive change in a faulty physiologic system is called the therapeutic effect of a drug. This is the goal of drug therapy. Understanding the pharmacodynamk characteristics of a drug can aid in assessing a drug’s therapeutic effect.

Mechanism of Action

There are several ways by which drugs can produce mechanisms of action (therapeutic effects). The effects that a particular drug has depend on the cells or tissue targeted by the drug. Once the drug is at the site of action, it can modify the rate (i.e., increase or decrease) at which that cell or tissue functions, or it can modify the function of that cell or tissue. A drug cannot, however, make a cell or tissue perform a function that it was not designed to perform.

There are three basic ways by which drugs can exert their mechanism of action: receptor, enzyme, and nonse-lective interactions.

Receptor Interaction

If the mechanism of action of a drug is the result of a receptor interaction, then the structure of the drug is essential. This type of drug-receptor interaction involves the selective joining of the drug molecule with a reactive site on the surface of a cell or tissue. This in turn elicits a biologic effect. Therefore a receptor is a reactive site on the surface of a cell or tissue. Once a substance (drug or chemical) binds to and interacts with the receptor, a phar­macologic response is produced . The degree to which a drug attacks and binds with a receptor is called its affinity. The drug with the best “fit” and strongest affinity for the receptor will elicit the greatest response from the cell or tissue. A drug becomes bound to the receptor through the formation of chemical bonds between receptors on the ceil and the active site of the drug. Drugs that bind to receptors interact with receptors in different ways to either elicit or block a physiologic response. Table 2-7 lists the different types of drug-receptor interactions and their definitions. Drugs that are most effective at eliciting a response from a receptor are those drugs that most closely resemble the body’s endogenous substances, which normally bind to that receptor.

Enzyme Interaction

Enzymes are substances that catalyze nearly every biochemical reaction in a cell. The second way drugs can produce effects is by interacting with these enzyme systems. For a drug to alter a physiologic response this way, it must inhibit the action of a specific enzyme. To do this, the drug “fools” the enzyme into binding to it instead of its normal target cell. This protects these target cells from the actions of the enzymes. For example, angiotensin converting enzyme (ACE) causes an enzymatic reaction that results in the production of a substance called angiotensin II, which is a potent vasoconstrictor and mediator of several other processes. The group of drugs called ACE inhibitors fools the ACE into binding to it rather than angiotensin I and thereby prevents the formation of an­giotensin II. This in turn causes vasodilation and helps reduce blood pressure.

Nonspecific Interactions

Nonspecific mechanisms of drug action do not involve a receptor or an enzyme in the alteration of a physiologic or biologic function of the body. Instead, cell membranes and various cellular processes such as metabolic proc­esses are their main sites of action. Such drugs can either physically interfere with or chemically alter these cellular processes. Some cancer drugs and antibiotics have this mechanism of action. By incorporating themselves into the normal metabolic process, they cause the formation of a defective final product. This final product could be an improperly formed cell wall that results in cell death caused by cell lysis, or it could be the lack of a needed en­ergy substrate that leads to cell starvation and death.

PHARMACOTHERAPEUTICS

Before the initiation of a drug therapy, an endpoint or expected outcome of therapy should be established. This desired therapeutic outcome should be patient specific and should be established in collaboration with the patient and, if appropriate, with other members of the health care team. Outcomes must be clearly defined and be either measurable or observable by the patient or caregiver. There should also be a specified time line for these outcomes. The progress being made toward the targeted objective should also be monitored. These outcomes should be realistic and should be prioritized so that drug therapy begins with interventions that are es-

sential to the patient’s acute well-being or those that the patient perceives to be important. Examples of such outcomes are curing a disease, eliminating or reducing a pre­existing symptom, arresting or slowing a disease process, preventing a disease or other unwanted condition, or improving the quality of life.

Assessment

Patient therapy assessment is the process whereby a practitioner integrates his or her

knowledge of medical and drug-related facts with information about a specific patient’s medical and social history. Items that should be considered in the assessment are current medications (prescription, over-the-counter [OTC], and illicit), pregnancy and breast-feeding status, and concurrent illnesses that could contradict starting a medication. A contraindication to a medication is any characteristic about the patient, especially disease state, that makes the use of a given medication dangerous for the patient. Careful attention to this assessment process helps to ensure an optimal therapeutic plan for the patient.

Implementation

The implementation of a treatment plan can involve several types and combinations of therapies. Therapy can be acute, maintenance, supplemental (or replacement), palliative, supportive, or prophylactic.

Acute Therapy

Acute therapy often involves more intensive drug therapy and is implemented in the acutely ill (rapid onset of illness) or even critically ill patient. It is ofteeeded to sustain life. Examples are the administration of vasopres-sors to maintain blood pressure and cardiac output after open-heart surgery, the use of volume expanders in a patient who is in shock, and the use of antibiotics in high-risk trauma patients.

Maintenance Therapy

Maintenance therapy typically does not eradicate problems the patient may have but does prevent progression of the disease. It is used for the treatment of chronic illnesses such as hypertension. Maintenance therapy maintains the patient’s blood pressure within certain limits, which prevents certain end-organ damage. Another example is the use of oral contraception for birth control.

Supplemental Therapy

Supplemental or replacement therapy supplies the body with a substance needed to maintaiormal function. This substance may be needed either because it cannot be made by the body or because it is deficient in quantity. Examples are the administration of insulin to diabetic patients and iron to patients with iron-deficiency anemia.

 

 

Palliative Therapy

The goal of palliative therapy is to make the patient as comfortable as possible. It is typically used in the end stages of an illness when all possible therapy has failed

Examples are the use of high-dose opioid analgesics to re­lieve pain in the final stages of cancer and the use of oxygen in end-stage pulmonary disease.

Supportive Therapy

Supportive therapy maintains the integrity of body functions while the patient is recovering. Examples are providing fluids and electrolytes to prevent dehydration in a patient with influenza who is vomiting and has diarrhea and giving fluids, volume expanders, or blood products to a patient who has lost blood during surgery.

Prophylactic Therapy and Empiric Therapy

Prophylactic therapy is drug therapy provided on the basis of practical experience. It is based on scientific knowledge often acquired during years of observation of a disease and its causes. For example, based on practical experience a surgeon knows that when he or she makes an incision through the skin there is the possibility that skin bacteria are present that can later infect that incision. The surgeon therefore administers an antibiotic before making the incision. Practical experience also dictates which antibiotic is chosen. Prophylactic therapy is also used with dental procedures for patients with mitral valve prolapse or for a patient with prosthetic valves or joints or Teflon grafts. Intravenous antibiotic therapy may also be used to prevent infection during a high-risk surgery and is considered prophylactic.

Unlike prophylactic therapy, empiric therapy is not founded on a scientific or rational basis but instead is the administration of a drug when a certain patho­logic process is suspected on the basis of the patient’s symptoms. For example, acetaminophen is given to a patient who has a fever. The cause of the fever may not be known, but empirically the patient is given acetaminophen because it is believed to lower the body temperature.

Monitoring

Once the appropriate therapy has been implemented, the effectiveness of that therapy must be evaluated. This constitutes the clinical response of the patient to the therapy. Evaluating this clinical response requires that the evaluator be familiar with both the drug’s intended therapeutic action (beneficial effects) and its unintended but potential side effects (predictable, adverse drug reactions).

All drugs are potentially toxic and can have cumulative effects. Recognizing these toxic effects and knowing their effect on the patient are integral components of this monitoring process. A drug accumulates when it is absorbed more quickly than it is eliminated, or when it is administered before the previous dose has been metabolized or cleared from the body. Knowledge of the function of the organs responsible for metabolizing and eliminat­ing a drug, combined with knowledge of how a particular drug is metabolized and excreted, enables the nurse to anticipate problems and treat them appropriately if they occur.

Therapeutic Index

The ratio of a drug’s therapeutic benefits to its toxic effects is referred to as the drug’s therapeutic index. The safety of a particular drug therapy is determined by this index. A low therapeutic index means that the range between a therapeutically active dose and a toxic dose is narrow. Such a drug has a greater likelihood than other drugs of causing an adverse reaction and therefore re­quires closer monitoring. Two drugs with narrow thera­peutic indexes are warfarin and digoxin.

Drug Concentration

Drug concentration in patients can be an important tool for evaluating the clinical response to drug therapy. Certain drug levels correspond to therapeutic responses, whereas others correspond to toxic effects. Toxic drug levels are typically seen when the body’s normal mechanisms for metabolizing and excreting drugs are impaired. This commonly occurs when liver and kidney functions are impaired or in persons such as neonates who have an immature liver or immature kidneys. Dosage adjustments should be made in these patients to appropriately accommodate their impaired metabolism and excretion.

Patient’s Condition

Another patient-specific factor to be considered when monitoring drug therapy is a patient’s concurrent diseases or other medical conditions. A patient’s response to a drug may vary greatly depending on his or her physiologic and psychologic demands. Disease, infection, cardiovascular function, and Gl function are just a few of the physiologic factors that can alter a patient’s therapeutic response. Stress, depression, and anxiety are some of the psychologic factors.

Tolerance and Dependence

The monitoring of drug therapy requires a knowledge of tolerance and dependence and an understanding of the difference between the two. Tolerance is a decreasing response to repetitive drug doses, whereas dependence is a physiologic or psychologic need for a drug. Physical dependence is the physiologic need for a drug (e.g., an opioid in a patient with cancer-related pain). Psychologic dependence is the desire for the euphoric effects of drugs and typically involves the recreational use of various drugs such as benzodiazepines, narcotics, and amphetamines.

Interactions

Drugs may interact with other drugs, foods, or agents administered as part of laboratory tests. Knowledge of drug interactions is vital for the appropriate monitoring of drug therapy. The more drugs a patient receives, the more likely a drug interaction will occur, This is especially true in older adults, who typically have an increased sensitivity to drug effects and are receiving several medications. In addition, OTC medications and herbal therapies can interact significantly with prescribed medications.

The alteration of the action of one drug by another is referred to as drug interaction. A drug interaction can either increase or decrease the actions of another drug and can be either beneficial or harmful. Drug interactions increase in frequency with the number of concomitant drugs taken by a patient. Careful patient care combined with knowledge of all drugs being administered can decrease the likelihood of a harmful drug interaction.

Understanding the mechanisms by which drug interactions occur can help prevent them. There are four phases during which concomitantly administered drugs may interact with each other and alter the pharmacoki-netics of one another: absorption, distribution, metabo­lism, and excretion. Table 2-8 provides examples of these mechanisms for drug interactions. It also illustrates how some drug interactions can be beneficial.

Many terms are used to describe these drug interactions. When two drugs with similar actions are given together, the result is an additive effect. Examples of this are the many combinations of analgesic products, such as aspirin and opioid combinations (aspirin and codeine) or acetaminophen and opioid combinations (acetaminophen and oxycodone). Often drugs are used together for their additive effects so that smaller doses of each drug can be given, thus avoiding toxic effects while maintaining adequate drug action.

Synergistic effects differ from additive effects in that synergism describes a drug interaction that results in combined drug effects that are greater than those that could have been achieved if either drug were given alone. The combination of hydrochlorothiazide with enalapril (Vaseretic) for the treatment of hypertension is an example.

The term used to describe the drug effect that is nearly opposite of the synergistic effect is antagonistic effect. Antagonistic effects result when the combination of two drugs results in drug effects that are less than if the drugs were given separately. These effects are experienced when antacids are given with tetracycline, resulting in decreased absorption of tetracycline.

Incompatibility is a term most commonly used with parenteral drugs. An incompatibility occurs when two parenteral drugs or solutions are mixed together and the result is a chemical deterioration of one or both of the drugs. The combination of these two drugs usually pro­duces a precipitate, haziness, or change in color in the so-lution. The combination of parenteral furosemide (Lasix) and heparin results in this type of incompatibility.

Drug Misadventures

Adverse patient outcomes associated with medication use vary from mild discomfort to death. The most serious outcomes are life-threatening complications, permanent dis­ability, and death. These outcomes are caused by medication misadventures, such as medication errors, drug interactions, drug allergies, and unknown causes. The two broad categories of drug or medication misadventures are adverse drug events (ADEs) and adverse drug reactions (ADRs). ADE is a more general term used to describe any adverse outcome of drug therapy in which a patient is harmed in some way. The cause can be internal to the pa­tient or may be due to an external factor (e.g., staff error, malfunctioning equipment). Medication errors (MEs) are the most common type of ADE and occur during the administration, dispensing, monitoring, or prescribing of a medication, which together are known as the medication use process.

An ADR is one type of ADE that is caused by factors inside the patient’s body (e.g., drug allergy, idiosyncratic reaction). ADRs may be less predictable than ADEs and, therefore, less preventable. However, a drug misadventure could be categorized as both ADR and ADE. For example, if a nurse gives a drug to a patient who on admission reported an allergy to that drug, it might be considered both an ADR (by the patient) and an ADE (by the failure of the nurse to heed the patient’s reported drug allergies). The main reason for an expansion in terminology is the growing realization that harmful consequences associated with medication use and misuse extend beyond ADRs and may include therapeutic appropriateness (or misuse), medication errors, patient compliance, and other problems that result in suboptimal outcomes. Both ADEs and ADRs may or may not be preventable depending on the clinical situation. Good institutional practice involves tracking all ADEs with the intention of preventing those ADEs judged to be preventable.

As mentioned previously, ADRs are not preventable. An ADR is an event occurring in the normal therapeutic use of a drug. An ADR is any reaction to a drug that is unfor prophylaxis, diagnosis, or therapy; and results in hos­pital admission, prolongation of hospital stay, change in drug therapy, initiation of supportive treatment, and complication of diagnosed disease state. Some ADRs can be classified as side effects. Side effects are expected, well-known reactions resulting in little or no change in patient management. They have predictable frequency, and intensity and occurrence are related to the size of the dose. Other ADRs lead to serious adverse events. Serious adverse events are defined as events that are fatal, life threatening, or permanently or significantly disabling; re­quire or prolong hospitalization; cause congenital anomalies; or require intervention to prevent permanent impairment or damage.

Two other more specific types of ADE are potential adverse drug events (PADEs) and adverse drug withdrawal events (ADWEs). A PADE is an elevated laboratory value of a narrow therapeutic index drug known to predispose a patient to increased risk of death or injury but not resulting in an adverse event. A common example of a PADE is an elevated bleeding time (INR) in a patient on warfarin (Coumadin) that has not yet resulted in any adverse outcome. An ADWE is associated with discontinuation of therapy that results in an adverse outcome. An example of an ADWE is hypertension after abrupt discontinuation of clonidine therapy.

ADEs are noxious and unintended. Other terms used for ADE are therapeutic misadventure and medication-related problem. ADEs are also defined as injury resulting from medical intervention related to a drug.

The study of poisons and unwanted responses to therapeutic agents is commonly referred to as toxicology. ADRs can be classified as either side effects or harm­ful effects, and many are extensions of the drug’s normal pharmacologic actions. ADRs can be broken down into four basic categories: pharmacologic reaction, idio­syncratic reaction, hypersensitivity reaction, and drug interaction.

Pharmacologic ADRs are extensions of the drug’s effects in the body. For example, a drug that is used to lower blood pressure in a patient with hypertension causes a pharmacologic ADR when it lowers the blood pressure to the point where the patient becomes unconscious. Idiosyncratic reactions are not the result of a known pharmacologic property of a drug or patient allergy but are peculiar to that patient. Such a reaction is a genetically determined abnormal response to ordinary doses of a drug. Genetically inherited traits that result in the abnormal metabolism of drugs are universally distributed throughout the population. The study of such traits that are solely revealed by drug administration is called phar-macogenetics (see Chapter 48 for fufher information). Idiosyncratic drug reactions are usually caused by abnormal levels of drug-metabolizing enzymes (a complete absence, a deficiency, or an overabundance of the enzyme).

There are many pharmacogenetic disorders. A common one is glucose-6-phosphate dehydrogenase (G6PD) deficiency. This pharmacogenetic disease is transmitted as a sex-linked trait and affects approximately TOO million people. People who lack proper levels of G6PD have idiosyncratic reactions to a wide range of drugs. There are more than 80 variations of the disease, and all produce varying degrees of drug-induced hemolysis.

Hypersensitivity reactions involve the patient’s im­mune system. The patient’s immune system recognizes the drug, a drug metabolite, or an ingredient in a drug formulation as a dangerous foreign substance. This foreign substance is then attacked, neutralized, or de­stroyed by the immune system, causing a hypersensitivity reaction.

The final type of ADR is a drug interaction and results when two drugs interact and produce an unwanted effect. This unwanted effect can be the result of one drug either making the other more potent and accentuating its effects or diminishing the effectiveness of the other. As previously mentioned, in some instances latrogenic Hazards. An iatrogenic hazard is any potential or actual patient harm that is caused by the errant actions of health care staff members. There are a variety of iatrogenic hazards that may occur as a result of drug therapy:

•  Treatment-induced dermatologic responses (e.g., rash, hives, acne, psoriasis, erythema)

•  Renal damage (from, e.g., aminoglycoside antibiotics, nonsteroidal antiinflammatory drugs [NSAIDs], contrast agents)

•  Blood dyscrasias (e.g., a total destruction of all cells produced by the bone marrow, or just a particular cell line such as platelets; most common after therapy with antineoplastic agents)

•  Hepatic toxicity (although not as common as the other iatrogenic responses, the hepatic response will take the form of elevated hepatic enzymes, presenting as a hepatitis-like syndrome)

Other Drug Effects

Other drug-related effects that need to be monitored during therapy are teratogenic, mutagenic, and carcinogenic effects. These can result in devastating patient outcomes and can be prevented in many instances by appropriate monitoring.

Teratogenic Effects. The teratogenic effects of drugs result in structural defects in the unborn fetus. Such agents are called teratogens. There are three major categories of exogenous human teratogens: viral diseases, radiation, and drugs or chemicals. Fetal development involves a delicate programmed sequence of interrelated embryologic events. Any significant disruption in embryogenesis can result in a teratogenic effect. Drugs that are capable of crossing the placenta can act as teratogens and cause drug-induced teratogenesis. Drugs administered during pregnancy can produce different types of congenital anomalies. The period when the fetus is most vulnerable to teratogenic effects begins with the third week of fetal development and usually ends after the third month.

Mutagenic Effects. Mutagenic effects are changes in the genetic composition of living organisms (permanent changes) and consist of alterations in the chromosome structure, the number of chromosomes, and the genetic code of the deoxyribonucleic acid (DNA) mole­cule. Agents capable of inducing mutations are called mutagens. Radiation, chemicals, and drugs can act as mutagenic agents in human beings. The largest genetic unit that can be involved in a mutation is a chromosome; the smallest is a base pair in a DNA molecule. Agents that affect genetic processes are active only during cell reproduction.

Carcinogenic Effects. The carcinogenic effects of drugs cause cancer, and such chemicals and drugs are called carcinogens. There are several exogenous factors that contribute to the development of cancer besides drugs, and the list grows daily. Teratogenic Effects. The teratogenic effects of drugs result in structural defects in the unborn fetus. Such agents are called teratogens. There are three major categories of exogenous human teratogens: viral diseases, radiation, and drugs or chemicals. Fetal development involves a delicate programmed sequence of interrelated embryologic events. Any significant disruption in em-bryogenesis can result in a teratogenic effect. Drugs that are capable of crossing the placenta can act as teratogens and cause drug-induced teratogenesis. Drugs administered during pregnancy can produce different types of congenital anomalies. The period when the fetus is most vulnerable to teratogenic effects begins with the third week of fetal development and usually ends after the third month.

Mutagenic Effects. Mutagenic effects are changes in the genetic composition of living organisms (permanent changes) and consist of alterations in the chromosome structure, the number of chromosomes, and the genetic code of the deoxyribonucleic acid (DNA) molecule. Agents capable of inducing mutations are called mutagens. Radiation, chemicals, and drugs can act as mutagenic agents in human beings. The largest genetic unit that can be involved in a mutation is a chromosome; the smallest is a base pair in a DNA molecule. Agents that affect genetic processes are active only during cell reproduction.

Carcinogenic Effects. The carcinogenic effects of drugs cause cancer, and such chemicals and drugs are called carcinogens. There are several exogenous factors that contribute to the development of cancer besides drugs, and the list grows daily. rently used drugs are salicylic acid, aluminum hydroxide, and sodium chloride. Recombinant DNA techniques provide many laboratory-derived drug products, such as erythropoietin (Epogen and Procrit), granulocyte macrophage-colony stimulating factor (sargramostim), granulocyte-colony stimulating factor (filgrastim), and human insulin (Humulin and Novolin).

Definition of pharmacology, subject assignment, connection with other sciences, history of development

Definitions

Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. These substances may be  chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined as the science of substances used to prevent, diagnose, and treat disease. Toxicology is that branch of pharmacology which deals with the undesirable effects of chemicals on living systems, from individual cells to complex ecosystems.

 

History of Pharmacology

Since time immemorial, medicaments have been used for treating disease in humans and animals. The herbals of antiquity describe the therapeutic powers of certain plants and minerals. Belief in the curative powers of plants and certain substances rested exclusively upon traditional knowledge, that is, empirical informatioot subjected to critical examination.

Claudius Galen (129–200 A.D.) first attempted to consider the theoretical background of pharmacology. Both theory and practical experience were to contribute equally to the rational use of medicines through interpretation of observed and experienced results. “The empiricists say that all is found by experience. We, however, maintain that it is found in part by experience, in part by theory. Neither experience nor theory alone is apt to discover all.”

Theophrastus von Hohenheim (1493– 1541 A.D.), called Paracelsus, began to quesiton doctrines handed down from antiquity, demanding knowledge of the active ingredient(s) in prescribed remedies, while rejecting the irrational concoctions and mixtures of medieval medicine. He prescribed chemically defined substances with such success that professional enemies had him prosecuted

as a poisoner. Against such accusations, he defended himself with the thesis that has become an axiom of pharmacology: “If you want to explain any poison properly, what then isn‘t a poison? All things  are poison, nothing is without poison; the dose alone causes a thing not to be poison.” Early Beginnings

Johann Jakob Wepfer (1620–1695) was the first to verify by animal experimentation assertions about pharmacological or toxicological actions. “I pondered at length. Finally I resolved to clarify the matter by experiments.”

Rudolf Buchheim (1820–1879) founded the first institute of pharmacology at the University of Dorpat (Tartu, Estonia) in 1847, ushering in pharmacology as an independent scientific discipline. In addition to a description of effects, he

strove to explain the chemical properties of drugs. “The science of medicines is a theoretical, i.e., explanatory, one. It is to provide us with knowledge by which our judgement about the utility of medicines can be validated at the bedside.”

Oswald Schmiedeberg (1838–1921), together with his many disciples (12 of whom were appointed to chairs of pharmacology), helped to establish the high reputation of pharmacology. Fundamental concepts such as structure-activity relationship, drug receptor, and selective toxicity emerged from the work of, respectively, T. Frazer (1841– 1921) in Scotland, J. Langley (1852– 1925) in England, and P. Ehrlich (1854–1915) in Germany. Alexander J. Clark (1885–1941) in England first formalized receptor theory in the early 1920s by applying the Law of Mass Action to drug-receptor interactions. Together with the internist, Bernhard Naunyn (1839–1925), Schmiedeberg founded the first journal of pharmacology, which has since been published without interruption. The “Father of American Pharmacology”, John J. Abel (1857–1938) was among the first Americans to train in Schmiedeberg‘s laboratory and was founder of the Journal of Pharmacology and Experimental Therapeutics (published from 1909 until the present). Status Quo After 1920, pharmacological laboratories sprang up in the pharmaceutical industry, outside established university institutes. After 1960, departments of clinical pharmacology were set up at many universities and in industry.

Pharmacokinetics & Pharmacodynamics

The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When a medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective combines the principles of pharmacokinetics with pharmacodynamics to clarify the dose-effect relationship  Pharmacodynamics governs the concentration-effect part of the interaction, whereas pharmacokinetics deals with the dose-concentration part (Holford & Sheiner, 1981). The pharmacokinetic processes of absorption, istribution, and elimination determine how rapidly and for how long the drug will appear at the target organ. The pharmacodynamic concepts of maximum response and sensitivity determine the magnitude of the effect at a particular concentration.

Knowing the relationship between dose, drug concentration and effects allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in responding to a drug. The importance of pharmacokinetics and pharmacodynamics in patient care thus rests upon the improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles.

 

SOURCES OF DRUGS

Where do medications come from? Historically, drugs were mainly derived from plants (eg, morphine), animals (eg, insulin), and minerals (eg, iron). Now, most drugs are synthetic chemical compounds manufactured in laboratories. Chemists, for example, can often create a useful new drug by altering the chemical structure of an existing drug (eg, adding, deleting, or altering a side-chain). Such techniques and other technologic advances have enabled the production of new drugs as well as synthetic versions of many drugs originally derived from plants and animals. Synthetic drugs are more standardized in their chemical characteristics, more consistent in their effects, and less likely to produce allergic reactions. Semisynthetic drugs (eg, many antibiotics) are naturally occurring substances that have been chemically modified. Biotechnology is also an important source of drugs. This process involves manipulating deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and recombining genes into hybrid molecules that can be inserted into living organisms (Escherichia coli bacteria are often used) and repeatedly reproduced. Each hybrid molecule produces a genetically identical molecule, called a clone. Cloning makes it possible to identify the DNA sequence in a gene and produce the protein product encoded by a gene, including insulin and several other body proteins. Cloning also allows production of adequate amounts of the drug for therapeutic or research purposes.

 

DRUG CLASSIFICATIONS AND PROTOTYPES

Drugs are classified according to their effects on particular body systems, their therapeutic uses, and their chemical characteristics. For example, morphine can be classified as a central nervous system depressant, a narcotic or opioid analgesic, and as an opiate (derived from opium). The names of therapeutic classifications usually reflect the conditions for which the drugs are used (eg, antidepressants, antihypertensives, antidiabetic drugs). However, the names of many drug groups reflect their chemical characteristics rather than therapeutic uses (eg, adrenergics, antiadrenergics, benzodiazepines). Many commonly used drugs fit into multiple groups because they have wide-ranging effects on the human body. Individual drugs that represent groups of drugs are called prototypes. Prototypes, which are often the first drug of a particular group to be developed, are usually the standards with which newer, similar drugs are compared. For example, morphine is the prototype of opioid analgesics; penicillin is the prototype of antibacterial drugs. Drug classifications and prototypes are quite stable, and most new drugs can be assigned to a group and compared with an established prototype. However, some groups lack a universally accepted prototype and some prototypes are replaced over time by newer, more commonly used drugs.

DRUG NAMES

Individual drugs may have several different names, but the two most commonly used are

the generic name and the trade name (also called the brand or proprietary name). The generic name (eg, amoxicillin) is related to the chemical or official name and is independent of the manufacturer. The generic name often indicates the drug group (eg, drugs with generic names ending in “cillin” are penicillins). The trade name is designated and patented by the manufacturer. For example, amoxicillin is manufactured by several pharmaceutical companies, some of which assign a specific trade name (eg, Amoxil, Trimox) and several of which use only the generic name. In drug literature, trade names are capitalized and generic names are lowercase unless in a list or at the beginning of a sentence. Drugs may be prescribed and dispensed by generic or trade name.

DRUG MARKETING

A new drug is protected by patent for 14 years, during which it can be marketed only by the pharmaceutical manufacturer that developed it. This is seen as a return on the company’s investment in developing a drug, which may require years of work and millions of dollars, and an incentive for developing other drugs. Other pharmaceutical companies cannot manufacture and market the drug. However, for new drugs that are popular and widely used, other companies often produce similar drugs, with different generic and trade names. For example, the marketing of fluoxetine (Prozac) led to the introduction of similar drugs from different companies, such as citalopram (Celexa), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). Prozac was approved in 1987 and went off patent in 2001, meaning that any pharmaceutical company could then manufacture and market the generic formulation of fluoxetine. Generic drugs are required to be therapeutically equivalent and are much less expensive than trade name drugs.

 

PHARMACOECONOMICS

Pharmacoeconomics involves the costs of drug therapy, including those of purchasing, dispensing (eg, salaries of pharmacists, pharmacy technicians), storage, administration (eg, salaries of nurses, costs of supplies), laboratory and other tests used to monitor client responses, and losses from expiration. Length of illness or hospitalization is also considered. Costs are increasingly being considered a major factor in choosing medications, and research projects that compare costs have greatly increased in recent years. The goal of most studies is to define drug therapy regimens that provide the desired benefits at the least cost. For drugs or regimens of similar efficacy and toxicity, there is considerable pressure on prescribers (eg, from managed care organizations) to prescribe less costly drugs.

PRESCRIPTION AND NONPRESCRIPTION DRUGS

Legally, American consumers have two routes of access to therapeutic drugs. One route is by prescription or order from a licensed health care provider, such as a physician, dentist, or nurse practitioner. The other route is by over-the-counter (OTC) purchase of drugs that do not require a prescription. Both of these routes are regulated by various drug laws. Acquiring and using prescription drugs for nontherapeutic purposes, by persons who are not authorized to have the drugs or for whom they are not prescribed, is illegal.

American Drug Laws and Standards

Current drug laws and standards have evolved over many years. Their main goal is to protect the public by ensuring that drugs marketed for therapeutic purposes, whether prescription or OTC, are safe and effective. The Food, Drug, and Cosmetic Act of 1938 was especially important because this law and its amendments regulate the manufacture, distribution, advertising, and labeling of drugs. It also confers official status on drugs listed in The United States Pharmacopeia. The names of these drugs may be followed by the letters USP. Official drugs must meet standards of purity and strength as determined by chemical analysis or animal response to specified doses (bioassay). The Durham-Humphrey Amendment designated drugs that must be prescribed by a physician and dispensed by a pharmacist. The Food and Drug Administration (FDA) is charged with enforcing the law. In addition, the Public Health Service regulates vaccines and other biologic products, and the Federal Trade Commission can suppress misleading advertisements of nonprescription drugs. Another important law, the Comprehensive Drug Abuse

Prevention and Control Act, was passed in 1970. Title II of this law, called the Controlled Substances Act, regulates the manufacture and distribution of narcotics, stimulants, depressants, hallucinogens, and anabolic steroids. These drugs are categorized according to therapeutic usefulness and potential for abuse and labeled as controlled substances (eg, morphine. The Drug Enforcement Administration (DEA) is charged with enforcing the Controlled Substances Act. Individuals and companies legally empowered to handle controlled substances must be registered with the DEA, keep accurate records of all transactions, and provide for secure storage. Physicians are assigned a number by the DEA and must include the number on all prescriptions they write for a controlled substance. Nurses are responsible for storing controlled substances in locked containers, administering them only to people for whom they are prescribed, recording each dose given on agency narcotic sheets and on the client’s medication administration record, maintaining an accurate inventory, and reporting discrepancies to the proper authorities. In addition to federal laws, state laws also regulate the sale and distribution of controlled drugs. These laws may be more stringent than federal laws; if so, the stricter laws usually apply.

DRUG APPROVAL PROCESSES

The FDA is responsible for assuring that new drugs are safe and effective before approving the drugs and allowing them to be marketed. The FDA reviews research studies

(usually conducted or sponsored by a pharmaceutical company) about proposed new drugs; the organization does not test the drugs.

 

Food and Drug Administration Approval

The FDA approves many new drugs annually. In 1992, procedures were changed to accelerate the approval process, especially for drugs used to treat acquired immunodeficiency syndrome. Since then, new drugs are categorized according to their review priority and therapeutic potential.

“1P” status indicates a new drug reviewed on a priority basis and with some therapeutic advantages over similar drugs already available; “1S” status indicates standard review and drugs with few, if any, therapeutic advantages (ie, the new drug is similar to one already available).

Most newly approved drugs are “1S” prescription drugs. The FDA also approves drugs for OTC availability, including the transfer of drugs from prescription to OTC status, and may require additional clinical trials to determine safety and effectiveness of OTC use. Numerous drugs have been transferred from prescription to OTC status in recent years and the trend is likely to continue. For drugs taken orally, indications for use may be different, and recommended doses are usually lower for the OTC formulation. For example, for OTC ibuprofen, which is available under its generic and several trade names (eg, Advil) in 200-mg tablets and used for pain, fever, and dysmenorrhea, the recommended dose is usually 200 to 400 mg three or four times daily. With prescription ibuprofen, Motrin is the common trade name and dosage may be 400, 600, or 800 mg three or four times daily. FDA approval of a drug for OTC availability involves evaluation of evidence that the consumer can use the drug safely, using information on the product label, and shifts primary responsibility for safe and effective drug therapy from health care professionals to consumers. With prescription drugs, a health care professional diagnoses the condition, often with the help of laboratory and other diagnostic tests, and determines a need for the drug.

DRUG TRANSPORT THROUGH CELL MEMBRANES

Drugs, as well as physiologic substances such as hormones and neurotransmitters, must reach and interact with or cross the cell membrane in order to stimulate or inhibit cellular function. Most drugs are given for effects on body cells that are distant from the sites of administration (ie, systemic effects). To move through the body and reach their sites of action, metabolism, and excretion, drug molecules must cross numerous cell membranes. For example, molecules of most oral drugs must cross the membranes of cells in the gastrointestinal (GI) tract, liver, and capillaries to reach the bloodstream, circulate to their target cells, leave the bloodstream and attach to receptors on cells, perform their action, return to the bloodstream, circulate to the liver, reach drug-metabolizing enzymes in liver

cells, re-enter the bloodstream (usually as metabolites), circulate to the kidneys, and be excreted in urine. Several transport pathways and mechanisms are used to move drug molecules through the body.

 

 

 

PHARMACOKINETICS

Pharmacokinetics involves drug movement through the body (ie, “what the body does to the drug”) to reach sites of action, metabolism, and excretion. Specific processes are absorption, distribution, metabolism (biotransformation), and excretion. Overall, these processes largely determine serum drug levels, onset, peak and duration of drug actions, drug half-life, therapeutic and adverse drug effects, and other important aspects of drug therapy.

Absorption

Absorption is the process that occurs from the time a drug enters the body to the time it enters the bloodstream to be circulated. Onset of drug action is largely determined by the rate of absorption; intensity is determined by the extent of absorption. Numerous factors affect the rate and extent of drug absorption, including dosage form, route of administration, blood flow to the site of administration, GI function, the presence of food or other drugs, and other variables. Dosage form is a major determinant of a drug’s bioavailability (the portion of a dose that reaches the systemic circulation and is available

to act on body cells). An intravenous drug is virtually 100% bioavailable; an oral drug is virtually always less than 100% bioavailable because some is not absorbed from the GI tract and some goes to the liver and is partially metabolized before reaching the systemic circulation. Most oral drugs must be swallowed, dissolved in gastric fluid, and delivered to the small intestine (which has a large surface area for absorption of nutrients and drugs) before they are absorbed. Liquid medications are absorbed faster than tablets or capsules because they need not be dissolved. Rapid movement through the stomach and small intestine may increase drug absorption by promoting contact with absorptive mucous membrane; it also may decrease absorption because some drugs may move through the small intestine too rapidly to be absorbed. For many drugs, the presence of food in the stomach slows the rate of absorption and may decrease the amount of drug absorbed.

Drugs injected into subcutaneous (SC) or intramuscular (IM) tissues are usually absorbed more rapidly than oral drugs because they move directly from the injection site to the bloodstream. Absorption is rapid from IM sites because muscle tissue has an abundant blood supply. Drugs injected intravenously (IV) do not need to be absorbed because they are placed directly into the bloodstream. Other absorptive sites include the skin, mucous membranes, and lungs. Most drugs applied to the skin are given for local effects (eg, sunscreens). Systemic absorption is minimal from intact skin but may be considerable when the skin is inflamed or damaged. Also, a number of drugs have been formulated in adhesive skin patches for absorption through the skin (eg, clonidine, estrogen, fentanyl, nitroglycerin, scopolamine). Some drugs applied to mucous membranes also are given for local effects. However, systemic absorption occurs from the mucosa of the oral cavity, nose, eye, vagina, and rectum. Drugs absorbed through mucous membranes pass directly into the bloodstream. The lungs have a large surface area for absorption of anesthetic gases and a few other drugs.

 

Distribution

Distribution involves the transport of drug molecules within the body. Once a drug is injected or absorbed into the bloodstream, it is carried by the blood and tissue fluids to its sites of pharmacologic action, metabolism, and excretion. Most drug molecules enter and leave the bloodstream at the capillary level, through gaps between the cells that form capillary walls.

Distribution depends largely on the adequacy of blood circulation. Drugs are distributed rapidly to organs receiving a large blood supply, such as the heart, liver, and kidneys. Distribution to other internal organs, muscle, fat, and skin is usually slower. An important factor in drug distribution is protein binding. Most drugs form a complex with plasma proteins, mainly albumin, which act as carriers. Drug molecules bound to plasma proteins are pharmacologically inactive because the large size of the complex prevents their leaving the bloodstream through the small openings in capillary walls and reaching their sites of action, metabolism, and excretion. Only the free or unbound portion of a drug

acts on body cells. As the free drug acts on cells, the decrease in plasma drug levels causes some of the bound drug to be released. Protein binding allows part of a drug dose to be stored and released as needed. Some drugs also are stored in muscle, fat, or other body tissues and released gradually when plasma drug levels fall. These storage mechanisms maintain lower, more even blood levels and reduce the risk of toxicity. Drugs that are highly bound to plasma proteins or stored extensively in other tissues have a long duration of action. Drug distribution into the central nervous system (CNS) is limited because the blood–brain barrier, which is composed of capillaries with tight walls, limits movement of drug molecules into brain tissue. This barrier usually acts as a selectively permeable membrane to protect the CNS. However, it also can make drug therapy of CNS disorders more difficult because drugs must pass through cells of the capillary wall rather than between cells. As a result, only drugs that are lipid soluble or have a transport system can cross the blood–brain barrier and reach therapeutic concentrations in brain tissue. Drug distribution during pregnancy and lactation is also unique. During pregnancy, most drugs cross the placenta and may affect the fetus. During lactation, many drugs enter breast milk and may affect the nursing infant.

Metabolism

Metabolism is the method by which drugs are inactivated or biotransformed by the body. Most often, an active drug is changed into one or more inactive metabolites, which are then excreted. Some active drugs yield metabolites that are also active and that continue to exert their effects on body cells until they are metabolized further or excreted. Other drugs (called prodrugs) are initially inactive and exert no pharmacologic effects until they are metabolized.

Most drugs are lipid soluble, a characteristic that aids their movement across cell membranes. However, the kidneys, which are the primary excretory organs, can excrete only water-soluble substances. Therefore, one function of metabolism is to convert fat-soluble drugs into water-soluble metabolites. Hepatic drug metabolism or clearance is a major mechanism for terminating drug action and eliminating drug molecules from the body.

Most drugs are metabolized by enzymes in the liver (called the cytochrome P450 [CYP] or the microsomal enzyme system); red blood cells, plasma, kidneys, lungs, and GI mucosa also contain drug-metabolizing enzymes. The cytochrome P450 system consists of 12 groups or families, nine of which metabolize endogenous substances and three of which metabolize drugs. The three groups that metabolize drugs are labeled CYP1, CYP2 and CYP3. Of the many drugs metabolized by the liver, the CYP3 group of enzymes is thought to metabolize about 50%, the CYP2 group about 45%, and the CYP1 group about 5%. Individual members of the groups, each of which metabolizes specific drugs, are further categorized. For example, many drugs are metabolized by CYP2D6, CYP2C9, or CYP3A4 enzymes. These enzymes, located within hepatocytes, are complex proteins with binding sites for drug molecules (and endogenous substances). They catalyze the chemical reactions of oxidation, reduction, hydrolysis, and conjugation with endogenous sub-stances, such as glucuronic acid or sulfate. With chronic administration, some drugs stimulate liver cells to produce larger amounts of drug-metabolizing enzymes (a process called enzyme induction). Enzyme induction accelerates drug metabolism because larger amounts of the enzymes (and more binding sites) allow larger amounts of a drug to be metabolized during a given time. As a result, larger doses of the rapidly metabolized drug may be required to produce or maintain therapeutic effects. Rapid metabolism may also increase the production of toxic metabolites with some drugs, (eg, acetaminophen). Drugs that induce enzyme production also may increase the rate of metabolism for endogenous steroidal hormones (eg, cortisol, estrogens, testosterone, and vitamin D). However, enzyme induction does not occur for 1 to 3 weeks after an inducing agent is started, because new enzyme proteins must be synthesized. Rifampin, an antituberculosis drug, is a strong inducer of CYP 1A and 3A enzymes Metabolism also can be decreased or delayed in a process called enzyme inhibition, which most often occurs with concurrent administration of two or more drugs that compete for the same metabolizing enzymes. In this case, smaller doses of the slowly metabolized drug may be needed to avoid adverse reactions and toxicity from drug accumulation. Enzyme inhibition occurs within hours or days of starting an inhibiting agent. Cimetidine, a gastric acid suppressor, inhibits several CYP enzymes (eg, 1A2, 2C, and 3A) and can greatly decrease drug metabolism. The rate of drug metabolism also is reduced in infants (their hepatic enzyme system is immature), in people with impaired blood flow to the liver or severe hepatic or cardiovascular disease, and in people who are malnourished or on low-protein diets. When drugs are given orally, they are absorbed from the GI tract and carried to the liver through the portal circulation. Some drugs are extensively metabolized in the liver, with only part of a drug dose reaching the systemic circulation for distribution to sites of action. This is called the first-pass effect or presystemic metabolism.

Excretion

Excretion refers to elimination of a drug from the body. Effective excretion requires adequate functioning of the circulatory system and of the organs of excretion (kidneys, bowel, lungs, and skin). Most drugs are excreted by the kidneys and eliminated unchanged or as metabolites in the urine. Some drugs or metabolites are excreted in bile, then eliminated in feces; others are excreted in bile, reabsorbed from the small intestine, returned to the liver (called enterohepatic recirculation), metabolized, and eventually excreted in urine. Some oral drugs are not absorbed and are excreted in the feces. The lungs mainly remove volatile substances, such as anesthetic gases. The skin has minimal excretory function. Factors impairing excretion, especially severe renal disease, lead to accumulation of numerous drugs and may cause severe adverse effects if dosage is not reduced.

Serum Drug Levels

A serum drug level is a laboratory measurement of the amount of a drug in the blood at a particular time. It reflects dosage, absorption, bioavailability, half-life, and the rates of metabolism and excretion. A minimum effective concentration (MEC) must be present before a drug exerts its pharmacologic action on body cells; this is largely determined by the drug dose and how well it is absorbed into the bloodstream. A toxic concentration is an excessive level at which toxicity occurs. Toxic concentrations may stem from a single large dose, repeated small doses, or slow metabolism that allows the drug to accumulate in the body. Between these low and high concentrations is the therapeutic range, which is the goal of drug therapy—that is, enough drug to be beneficial, but not enough to be toxic. For most drugs, serum levels indicate the onset, peak, and duration of drug action. When a single dose of a drug is given, onset of action occurs when the drug level reaches the MEC. The drug level continues to climb as more of the drug is absorbed, until it reaches its highest concentration and peak drug action occurs. Then, drug levels decline as the drug is eliminated (ie, metabolized and excreted) from the body. Although there may still be numerous drug molecules in the body, drug action stops when drug levels fall below the MEC. The duration of action is the time during which serum drug levels are at or above the MEC. When multiple doses of a drug are given (eg, for chronic, long-lasting conditions), the goal is usually to give sufficient doses often enough to maintain serum drug levels in the therapeutic range and avoid the toxic range. In clinical practice, measuring serum drug levels is useful in several circumstances:

• When drugs with a low or narrow therapeutic index are

given. These are drugs with a narrow margin of safety

because their therapeutic doses are close to their toxic

doses (eg, digoxin, aminoglycoside antibiotics, lithium,

theophylline).

• To document the serum drug levels associated with particular

drug dosages, therapeutic effects, or possible adverse

effects.

• To monitor unexpected responses to a drug dose. This

could be either a lack of therapeutic effect or increased

adverse effects.

• When a drug overdose is suspected.

Serum Half-Life

Serum half-life, also called elimination half-life, is the time required for the serum concentration of a drug to decrease by 50%. It is determined primarily by the drug’s rates of metabolism and excretion. A drug with a short half-life requires more frequent administration than one with a long half-life. When a drug is given at a stable dose, four or five halflives are required to achieve steady-state concentrations and develop equilibrium between tissue and serum concentrations. Because maximal therapeutic effects do not occur until equilibrium is established, some drugs are not fully effective for days or weeks. To maintain steady-state conditions, the amount of drug given must equal the amount eliminated from the body.

When a drug dose is changed, an additional four to five halflives are required to re-establish equilibrium; when a drug is discontinued, it is eliminated gradually over several half-lives.

PHARMACODYNAMICS

Pharmacodynamics involves drug actions on target cells and the resulting alterations in cellular biochemical reactions and functions (ie, “what the drug does to the body”). As previously stated, all drug actions occur at the cellular level.

 

Receptor Theory of Drug Action

Like the physiologic substances (eg, hormones and neurotransmitters) that normally regulate cell functions, most drugs exert their effects by chemically binding with receptors at the cellular level. Receptors are mainly proteins located on the surfaces of cell membranes or within cells. Specific receptors include enzymes involved in essential metabolic or regulatory processes (eg, dihydrofolate reductase, acetylcholinesterase); proteins involved in transport (eg, sodium–potassium adenosine triphosphatase) or structural processes (eg, tubulin); and nucleic acids (eg, DNA) involved in cellular protein synthesis, reproduction, and other metabolic activities. When drug molecules bind with receptor molecules, the resulting drug–receptor complex initiates physiochemical reactions that stimulate or inhibit normal cellular functions. One type of reaction involves activation, inactivation, or other alterations of intracellular enzymes. Because almost all cellular functions are catalyzed by enzymes, drug-induced changes can markedly increase or decrease the rate of cellular metabolism. For example, an epinephrine–receptor complex increases the activity of the intracellular enzyme adenyl cyclase, which then causes the formation of cyclic adenosine monophosphate (cAMP). cAMP, in turn, can initiate any one of many different intracellular actions, the exact effect depending on the type of cell. A second type of reaction involves changes in the permeability of cell membranes to one or more ions. The receptor protein is a structural component of the cell membrane, and its binding to a drug molecule may open or close ion channels. Ierve cells, for example, sodium or calcium ion channels may open and allow movement of ions into the cell. This usually causes the cell membrane to depolarize and excite the cell. At other times, potassium channels may open and allow movement of potassium ions out of the cell. This action inhibits neuronal excitability and function. In muscle cells, movement of the ions into the cells may alter intracellular functions, such as the direct effect of calcium ions in stimulating muscle contraction. A third reaction may modify the synthesis, release, or inactivation of the neurohormones (eg, acetylcholine, norepinephrine, serotonin) that regulate many physiologic processes. Additional elements and characteristics of the receptor theory include the following:

1. The site and extent of drug action on body cells are determined primarily by specific characteristics of receptors and drugs. Receptors vary in type, location, number, and functional capacity. For example, many different types of receptors have been identified. Most types occur in most body tissues, such as receptors for epinephrine and norepinephrine (whether received from stimulation of the sympathetic nervous system or administration of drug formulations) and receptors for hormones, including growth hormone, thyroid hormone, and insulin. Some occur in fewer body tissues, such as receptors for opiates and benzodiazepines in the brain and subgroups of receptors for epinephrine in the heart (beta1-adrenergic receptors) and lungs (beta2-adrenergic receptors). Receptor type and location influence drug action. The receptor is often described as a lock into which the drug molecule fits as a key, and only those drugs able to bond chemically to the receptors in a particular body tissue can exert pharmacologic effects on that tissue. Thus, all body cells do not respond to all drugs, even though virtually all cell receptors are exposed to any drug molecules circulating in the bloodstream. The number of receptor sites available to interact with drug molecules also affects the extent of drug action. Presumably, a minimal number of receptors must be occupied by drug molecules to produce pharmacologic effects. Thus, if many receptors are available but only a few are occupied by drug molecules, few drug effects occur. In this instance, increasing the drug dosage increases the pharmacologic effects. Conversely, if only a few receptors are available for many drug molecules, receptors may be saturated. In this instance, if most receptor sites are occupied, increasing the drug dosage produces no additional pharmacologic effect.

Drugs vary even more widely than receptors. Because all drugs are chemical substances, chemical characteristics determine drug actions and pharmacologic effects. For example, a drug’s chemical structure affects its ability to reach tissue fluids around a cell and bind with its cell receptors. Minor changes in drug structure may produce major changes in pharmacologic effects. Another major factor is the concentration of drug molecules that reach receptor sites in body tissues. Drugand client-related variables that affect drug actions are further described below.

2. When drug molecules chemically bind with cell receptors, the pharmacologic effects are those due to either agonism or antagonism. Agonists are drugs that produce effects similar to those produced by naturally occurring hormones, neurotransmitters, and other substances. Agonists may accelerate or slow normal cellular processes, depending on the type of receptor activated. For example, epinephrine-like drugs act on the heart to increase

the heart rate, and acetylcholine-like drugs act on the heart to slow the heart rate; both are agonists. Antagonists are drugs that inhibit cell function by occupying receptor sites. This prevents natural body substances or other drugs from occupying the receptor sites and activating cell functions. Once drug action occurs, drug molecules may detach from receptor molecules (ie, the chemical binding is reversible), return to the bloodstream, and circulate to the liver for metabolism and the kidneys for excretion.

3. Receptors are dynamic cellular components that can be synthesized by body cells and altered by endogenous substances and exogenous drugs. For example, prolonged stimulation of body cells with an excitatory agonist usually reduces the number or sensitivity of receptors. As a result, the cell becomes less responsive to the agonist (a process called receptor desensitization or down-regulation). Prolonged inhibition of normal cellular functions with an antagonist may increase receptor number or sensitivity. If the antagonist is suddenly reduced or stopped, the cell becomes excessively responsive to an agonist (a process called receptor upregulation). These changes in receptors may explain why some drugs must be tapered in dosage and discontinued gradually if withdrawal symptoms are to be avoided.

Nonreceptor Drug Actions

Relatively few drugs act by mechanisms other than combination with receptor sites on cells. These include:

1. Antacids, which act chemically to neutralize the hydrochloric acid produced by gastric parietal cells and thereby raise the pH of gastric fluid

2. Osmotic diuretics (eg, mannitol), which increase the osmolarity of plasma and pull water out of tissues into the bloodstream

3. Drugs that are structurally similar to nutrients required by body cells (eg, purines, pyrimidines) and that can be incorporated into cellular constituents, such as nucleic acids. This interferes with normal cell functioning. Several anticancer drugs act by this mechanism.

4. Metal chelating agents, which combine with toxic metals (eg, lead) to form a complex that can be more readily excreted.

VARIABLES THAT AFFECT DRUG ACTIONS

Expected responses to drugs are largely based on those occurring when a particular drug is given to healthy adult men (18 to 65 years of age) of average weight (150 lb [70 kg]). However, other groups of people (eg, women, children, older adults, different ethnic or racial groups, and clients with diseases or symptoms that the drugs are designed to treat) receive drugs and respond differently than healthy adult men. Therefore, current clinical trials are including more representatives of these groups. In any client, however, responses may be altered by both drug- and client-related variables, some of which are described in the following sections.

Drug-Related Variables

Dosage

Although the terms dose and dosage are often used interchangeably, dose indicates the amount to be given at one time and dosage refers to the frequency, size, and number of doses. Dosage is a major determinant of drug actions and responses, both therapeutic and adverse. If the amount is too small or administered infrequently, no pharmacologic action occurs because the drug does not reach an adequate concentration at target cells. If the amount is too large or administered too often, toxicity (poisoning) may occur. Because dosage includes the amount of the drug and the frequency of administration, overdosage may occur with a single large dose or with chronic ingestion of smaller amounts. Doses that produce signs and symptoms of toxicity are called toxic doses. Doses that cause death are called lethal doses. Dosages recommended in drug literature are usually those that produce particular responses in 50% of the people tested.

These dosages usually produce a mixture of therapeutic and adverse effects. The dosage of a particular drug depends on many characteristics of the drug (reason for use, potency, pharmacokinetics, route of administration, dosage form, and others) and of the recipient (age, weight, state of health, and function of cardiovascular, renal, and hepatic systems). Thus, the recommended dosages are intended only as guidelines for individualizing dosages.

Route of Administration

Routes of administration affect drug actions and responses largely by influencing absorption and distribution. For rapid drug action and response, the IV route is most effective because the drug is injected directly into the bloodstream. For some drugs, the IM route also produces drug action within a few minutes because muscles have a large blood supply. The oral route usually produces slower drug action than parenteral routes. Absorption and action of topical drugs vary according to the drug formulation, whether the drug is applied to skin or mucous membranes, and other factors.

Drug–Diet Interactions

Food may alter the absorption of oral drugs. In many instances, food slows absorption by slowing gastric emptying time and altering GI secretions and motility. When tablets or capsules are taken with or soon after food, they dissolve more slowly; therefore, drug molecules are delivered to absorptive sites in the small intestine more slowly. Food also may decrease absorption by combining with a drug to form an insoluble drug–food complex. In other instances, however, certain drugs or dosage forms are better absorbed with certain types of meals. For example, a fatty meal increases the absorption of some sustained-release forms of theophylline. Interactions that alter drug absorption can be minimized by spacing food and medications. In addition, some foods contain substances that react with certain drugs. One such interaction occurs between tyraminecontaining foods and monoamine oxidase (MAO) inhibitor drugs. Tyramine causes the release of norepinephrine, a strong vasoconstrictive agent, from the adrenal medulla and sympathetic neurons. Normally, norepinephrine is active for only a few milliseconds before it is inactivated by MAO. However, because MAO inhibitor drugs prevent inactivation of norepinephrine, ingesting tyramine-containing foods with an MAO inhibitor may produce severe hypertension or intracranial hemorrhage. MAO inhibitors include the antidepressants isocarboxazid and phenelzine and the antineoplastic procarbazine. These drugs are infrequently used nowadays, partly because of this potentially serious interaction and partly because other effective drugs are available. Tyramine-rich foods to be avoided by clients taking MAO inhibitors include beer, wine, aged cheeses, yeast products, chicken livers, and pickled herring. An interaction may occur between warfarin, a frequently used oral anticoagulant, and foods containing vitamin K. Because vitamin K antagonizes the action of warfarin, large amounts of spinach and other green leafy vegetables may offset the anticoagulant effects and predispose the person to thromboembolic disorders. A third interaction occurs between tetracycline, an antibiotic, and dairy products, such as milk and cheese. The drug combines with the calcium in milk products to form an insoluble, unabsorbable compound that is excreted in the feces.

Drug–Drug Interactions

The action of a drug may be increased or decreased by its interaction with another drug in the body. Most interactions occur whenever the interacting drugs are present in the body; some, especially those affecting the absorption of oral drugs, occur when the interacting drugs are given at or near the same time. The basic cause of many drug–drug interactions is altered drug metabolism. For example, drugs metabolized by the same enzymes may compete for enzyme binding sites and there may not be enough binding sites for two or more drugs. Also, some drugs induce or inhibit the metabolism of other drugs. Protein binding is also the basis for some important drug–drug interactions. A drug with a strong attraction to protein-binding sites may displace a less tightly bound drug. The displaced drug then becomes pharmacologically active, and the overall effect is the same as taking a larger dose of the displaced drug.

Increased Drug Effects

Interactions that can increase the therapeutic or adverse effects of drugs are as follows:

1. Additive effects occur when two drugs with similar pharmacologic actions are taken.

Example: ethanol + sedative drug →increased sedation

2. Synergism or potentiation occurs when two drugs with different sites or mechanisms of action produce greater effects when taken together than either does when taken alone.

Example: acetaminophen (non-opioid analgesic) +codeine (opioid analgesic) →increased analgesia

3. Interference by one drug with the metabolism or elimination of a second drug may result in intensified effects of the second drug.

Example: cimetidine inhibits CYP 1A, 2C, and 3A drug-metabolizing enzymes in the liver and therefore interferes with the metabolism of many drugs (eg, benzodiazepine antianxiety and hypnotic drugs, calcium channel blockers, tricyclic antidepressants, some antidysrhythmics, beta blockers and antiseizure drugs, theophylline, and warfarin). When these drugs are given concurrently with cimetidine, they are likely to cause adverse and toxic effects.

4. Displacement of one drug from plasma protein-binding sites by a second drug increases the effects of the displaced drug. This increase occurs because the molecules of the displaced drug, freed from their bound form, become pharmacologically active.

Example: aspirin (an anti-inflammatory/analgesic/antipyretic agent) + warfarin (an anticoagulant) →increased anticoagulant effect

Decreased Drug Effects

Interactions in which drug effects are decreased are grouped under the term antagonism. Examples of such interactions are as follows:

1. In some situations, a drug that is a specific antidote is given to antagonize the toxic effects of another drug.

Example: naloxone (a narcotic antagonist) + morphine (a narcotic or opioid analgesic) →relief of opioidinduced respiratory depression. Naloxone molecules displace morphine molecules from their receptor sites oerve cells in the brain so that the morphine molecules cannot continue to exert their depressant effects.

2. Decreased intestinal absorption of oral drugs occurs when drugs combine to produce nonabsorbable compounds.

Example: aluminum or magnesium hydroxide

(antacids) + oral tetracycline (an antibiotic) →binding of tetracycline to aluminum or magnesium, causing decreased absorption and decreased antibiotic effect of tetracycline

3. Activation of drug-metabolizing enzymes in the liver increases the metabolism rate of any drug metabolized primarily by that group of enzymes. Several drugs (eg, phenytoin, rifampin), ethanol, and cigarette smoking are known enzyme inducers.

Example: phenobarbital (a barbiturate) + warfarin (an anticoagulant) →decreased effects of warfarin

4. Increased excretion occurs when urinary pH is changed and renal reabsorption is blocked.

Example: sodium bicarbonate + phenobarbital →increased excretion of phenobarbital. The sodium bicar-bonate alkalinizes the urine, raising the number of barbiturate ions in the renal filtrate. The ionized particles cannot pass easily through renal tubular membranes. Therefore, less drug is reabsorbed into the blood and  more is excreted by the kidneys.

Client-Related Variables

Age

The effects of age on drug action are most pronounced ieonates, infants, and older adults. In children, drug action depends largely on age and developmental stage. During pregnancy, drugs cross the placenta and may harm the fetus. Fetuses have no effective mechanisms for metabolizing or eliminating drugs because their liver and kidney functions are immature. Newborn infants (birth to 1 month) also handle drugs inefficiently. Drug distribution, metabolism, and excretion differ markedly ieonates, especially premature infants, because their organ systems are not fully developed. Older infants (1 month to 1 year) reach approximately adult levels of protein binding and kidney function, but liver function and the blood–brain barrier are still immature. Children (1 to 12 years) experience a period of increased activity of drug-metabolizing enzymes so that some drugs are rapidly metabolized and eliminated. Although the onset and duration of this period are unclear, a few studies have been done with particular drugs. Theophylline, for example, is cleared much faster in a 7-year-old child than in a neonate or adult (18 to 65 years). After approximately 12 years of age, healthy children handle drugs similarly to healthy adults. In older adults (65 years and older), physiologic changes may alter all pharmacokinetic processes. Changes in the GI tract include decreased gastric acidity, decreased blood flow, and decreased motility. Despite these changes, however, there is little difference in absorption. Changes in the cardiovascular system include decreased cardiac output and therefore slower distribution of drug molecules to their sites of action, metabolism, and excretion. In the liver, blood flow and metabolizing enzymes are decreased. Thus, many drugs are metabolized more slowly, have a longer action, and are more likely to accumulate with chronic administration. In the kidneys, there is decreased blood flow, decreased glomerular filtration rate, and decreased tubular secretion of drugs. All of these changes tend to slow excretion and promote accumulation of drugs in the body. Impaired kidney and liver function greatly increase the risks of adverse drug effects. In addition, older adults are more likely to have acute and chronic illnesses that require multiple drugs or long-term drug therapy. Thus, possibilities for interactions among drugs and between drugs and diseased organs are greatly multiplied.

Body Weight

Body weight affects drug action mainly in relation to dose. The ratio between the amount of drug given and body weight influences drug distribution and concentration at sites of action. In general, people heavier than average need larger doses, provided that their renal, hepatic, and cardiovascular functions are adequate. Recommended doses for many drugs are listed in terms of grams or milligrams per kilogram of body weight.

Genetic and Ethnic Characteristics

Drugs are given to elicit certain responses that are relatively predictable for most drug recipients. When given the same drug in the same dose, however, some people experience inadequate therapeutic effects, and others experience unusual or exaggerated effects, including increased toxicity. These interindividual variations in drug response are often attributed to genetic or ethnic differences in drug pharmacokinetics or pharmacodynamics. As a result, there is increased awareness that genetic and ethnic characteristics are important factors and that diverse groups must be included in clinical trials.

Genetics

A person’s genetic characteristics may influence drug action in several ways.

For example, genes determine the types and amounts of proteins produced in the body. When most drugs enter the body, they interact with proteins (eg, in plasma, tissues, cell membranes, and drug receptor sites) to reach their sites of action, and with other proteins (eg, drug-metabolizing enzymes in the liver and other organs) to be biotransformed and eliminated from the body. Genetic characteristics that alter any of these proteins can alter drug pharmacokinetics or pharmacodynamics. One of the earliest genetic variations to be identified derived from the observation that some people taking usual doses of isoniazid (an antitubercular drug), hydralazine (an antihypertensive agent), or procainamide (an antidysrhythmic) showed no therapeutic effects, whereas toxicity developed in other people. Research established that these drugs are normally metabolized by acetylation, a chemical conjugation process in which the drug molecule combines with an acetyl group of acetyl coenzyme A. The reaction is catalyzed by a hepatic drug-metabolizing enzyme called acetyltransferase. It was further established that humans may acetylate the drug rapidly or slowly, depending largely on genetically controlled differences in acetyltransferase activity. Clinically, rapid acetylators may need larger-than-usual doses to achieve therapeutic effects, and slow acetylators may need smaller-than-usual doses to avoid toxic effects. In addition, several genetic variations of the cytochrome P450 drugmetabolizing system have been identified. Specific variations may influence any of the chemical processes by which drugs are metabolized. As another example of genetic variation in drug metabolism, some people lack the plasma pseudocholinesterase enzyme that normally inactivates succinylcholine, a potent muscle relaxant used in some surgical procedures. These people may experience prolonged paralysis and apnea if given succinylcholine.

Other people are deficient in glucose-6-phosphate dehydrogenase, an enzyme normally found in red blood cells and 20 SECTION 1 INTRODUCTION TO DRUG THERAPY other body tissues. These people may have hemolytic anemia when given antimalarial drugs, sulfonamides, analgesics, antipyretics, and other drugs.

Ethnicity

Most drug information has been derived from clinical drug trials using white men;

few subjects of other ethnic groups are included. Interethnic variations became evident when drugs and dosages developed for white people produced unexpected responses, including toxicity, when given to other ethnic groups. One common interethnic variation is that African Americans are less responsive to some antihypertensive drugs than are white people. For example, angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking drugs are less effective as single-drug therapy. In general, African-American hypertensive clients respond better to diuretics or calcium channel blockers than to ACE inhibitors and beta blockers. Another interethnic variation is that Asians usually require much smaller doses of some commonly used drugs, including beta blockers and several psychotropic drugs (eg, alprazolam, an antianxiety agent, and haloperidol, an antipsychotic). Some documented interethnic variations are included in later chapters.

Gender

Except during pregnancy and lactation, gender has been considered a minor influence on drug action. Most research studies related to drugs have involved men, and clinicians have extrapolated the findings to women. Several reasons have been advanced for excluding women from clinical drug trials, including the risks to a fetus if a woman becomes pregnant and the greater complexity in sample size and data analysis. However, because differences between men and women in responses to drug therapy are being identified, the need to include women in drug studies is evident. Some gender-related differences in responses to drugs may stem from hormonal fluctuations in women during the menstrual cycle. Although this area has received little attention in research studies and clinical practice, altered responses have been demonstrated in some women taking clonidine, an antihypertensive; lithium, a mood-stabilizing agent; phenytoin, an anticonvulsant; propranolol, a beta-adrenergic blocking drug used in the management of hypertension, angina pectoris, and migraine; and antidepressants. In addition, a significant percentage of women with arthritis, asthma, depression, diabetes mellitus, epilepsy, and migraine experience increased symptoms premenstrually. The increased symptoms may indicate a need for adjustments in their drug therapy regimens. Women with clinical depression, for example, may need higher doses of antidepressant medications premenstrually, if symptoms exacerbate, and lower doses during the rest of the menstrual cycle. Another example is that women with schizophrenia require lower dosages of antipsychotic medications than men. If given the higher doses required by men, women are likely to have adverse drug reactions.

Pathologic Conditions

Pathologic conditions may alter pharmacokinetic processes. In general, all pharmacokinetic processes are decreased in cardiovascular disorders characterized by decreased blood flow to tissues, such as heart failure. In addition, the absorption of oral drugs is decreased with various GI disorders. Distribution is altered in liver or kidney disease and other conditions that alter plasma proteins. Metabolism is decreased in malnutrition (eg, inadequate protein to synthesize drugmetabolizing enzymes) and severe liver disease; it may be increased in conditions that generally increase body metabolism, such as hyperthyroidism and fever. Excretion is decreased in kidney disease.

Psychological Considerations

Psychological considerations influence individual responses to drug administration, although specific mechanisms are unknown. An example is the placebo response. A placebo is a pharmacologically inactive substance. Placebos are used in clinical drug trials to compare the medication being tested with a “dummy” medication. Interestingly, recipients often report both therapeutic and adverse effects from placebos. Attitudes and expectations related to drugs in general, a particular drug, or a placebo influence client response. They also influence compliance or the willingness to carry out the prescribed drug regimen, especially with long-term drug therapy.

TOLERANCE AND CROSS-TOLERANCE

Drug tolerance occurs when the body becomes accustomed to a particular drug over time so that larger doses must be given to produce the same effects. Tolerance may be acquired to the pharmacologic action of many drugs, especially opioid analgesics, alcohol, and other CNS depressants. Tolerance to pharmacologically related drugs is called cross-tolerance. For example, a person who regularly drinks large amounts of alcohol becomes able to ingest even larger amounts before becoming intoxicated—this is tolerance to alcohol. If the person is then given sedative-type drugs or a general anesthetic, larger-than-usual doses are required to produce a pharmacologic effect—this is cross-tolerance. Tolerance and cross-tolerance are usually attributed to activation of drug-metabolizing enzymes in the liver, which accelerates drug metabolism and excretion. They also are attributed to decreased sensitivity or numbers of receptor sites.

ADVERSE EFFECTS OF DRUGS

As used in this book, the term adverse effects refers to any undesired responses to drug administration, as opposed to therapeutic effects, which are desired responses. Most drugs produce a mixture of therapeutic and adverse effects; all drugs can produce adverse effects. Adverse effects may produce es sentially any sign, symptom, or disease process and may involve any body system or tissue. They may be common or rare, mild or severe, localized or widespread, depending on the drug and the recipient. Some adverse effects occur with usual therapeutic doses of drugs (often called side effects); others are more likely to occur and to be more severe with high doses. Common or serious adverse effects include the following:

1. CNS effects may result from CNS stimulation (eg, agitation, confusion, delirium, disorientation, hallucinations, psychosis, seizures) or CNS depression (dizziness, drowsiness, impaired level of consciousness, sedation, coma, impaired respiration and circulation). CNS effects may occur with many drugs, including most therapeutic groups, substances of abuse, and over-the-counter preparations.

2. Gastrointestinal effects (anorexia, nausea, vomiting, constipation, diarrhea) are among the most common adverse reactions to drugs. Nausea and vomiting occur with many drugs from local irritation of the gastrointestinal tract or stimulation of the vomiting center in the brain. Diarrhea occurs with drugs that cause local irritation or increase peristalsis. More serious effects include bleeding or ulceration (most often with aspirin and nonsteroidal anti-inflammatory agents) and severe diarrhea/colitis (most often with antibiotics).

3. Hematologic effects (blood coagulation disorders, bleeding disorders, bone marrow depression, anemias, leukopenia, agranulocytosis, thrombocytopenia) are relatively common and potentially life threatening. Excessive bleeding is most often associated with anticoagulants and thrombolytics; bone marrow depression is usually associated with antineoplastic drugs.

4. Hepatotoxicity (hepatitis, liver dysfunction or failure, biliary tract inflammation or obstruction) is potentially life threatening. Because most drugs are metabolized by the liver, the liver is especially susceptible to druginduced injury. Drugs that are hepatotoxic include acetaminophen (Tylenol), isoniazid (INH), methotrexate (Mexate), phenytoin (Dilantin), and aspirin and other salicylates. In the presence of drug- or disease-induced liver damage, the metabolism of many drugs is impaired. Consequently, drugs metabolized by the liver tend to accumulate in the body and cause adverse effects. Besides hepatotoxicity, many drugs produce abnormal values in liver function tests without producing clinical signs of liver dysfunction.

5. Nephrotoxicity (nephritis, renal insufficiency or failure) occurs with several antimicrobial agents (eg, gentamicin and other aminoglycosides), nonsteroidal antiinflammatory agents (eg, ibuprofen and related drugs), and others. It is potentially serious because it may interfere with drug excretion, thereby causing drug accumulation and increased adverse effects.

6. Hypersensitivity or allergy may occur with almost any drug in susceptible clients. It is largely unpredictable and unrelated to dose. It occurs in those who have previously been exposed to the drug or a similar substance (antigen) and who have developed antibodies. When readministered, the drug reacts with the antibodies to cause cell damage and the release of histamine and other intracellular substances. These substances produce reactions ranging from mild skin rashes to anaphylactic shock. Anaphylactic shock is a lifethreatening hypersensitivity reaction characterized by respiratory distress and cardiovascular collapse. It occurs within a few minutes after drug administration and requires emergency treatment with epinephrine. Some allergic reactions (eg, serum sickness) occur 1 to 2 weeks after the drug is given.

7. Drug fever is a fever associated with administration of a medication. Drugs can cause fever by several mechanisms, including allergic reactions, damaging body tissues, increasing body heat or interfering with its dissipation, or acting on the temperatureregulating center in the brain. The most common mechanism is an allergic reaction. Fever may occur alone or with other allergic manifestations (eg, skin rash, hives, joint and muscle pain, enlarged lymph glands, eosinophilia) and its pattern may be low grade and continuous or spiking and intermittent. It may begin within hours after the first dose if the client has taken the drug before, or within approximately 10 days of continued administration if the drug is new to the client. If the causative drug is discontinued, fever usually subsides within 48 to 72 hours unless Sepsis-induced alterations in cardiovascular

function and hepatic blood flow Shock-induced alterations in cardiovascular function and blood flow TABLE 2–1 Effects of Pathologic Conditions on Drug Pharmacokinetics (continued )

SECTION 1 INTRODUCTION TO DRUG THERAPY

drug excretion is delayed or significant tissue damage has occurred (eg, hepatitis). Many drugs have been implicated as causes of drug fever, including most antimicrobials, several cardiovascular agents (eg, beta blockers, hydralazine, methyldopa, procainamide, quinidine), drugs with anticholinergic properties (eg, atropine, some antihistamines, phenothiazine antipsychotic agents, and tricyclic antidepressants), and some anticonvulsants.

8. Idiosyncrasy refers to an unexpected reaction to a drug that occurs the first time it is given. These reactions are usually attributed to genetic characteristics that alter the person’s drug-metabolizing enzymes.

9. Drug dependence may occur with mind-altering drugs, such as opioid analgesics, sedative-hypnotic agents, antianxiety agents, and CNS stimulants. Dependence may be physiologic or psychological. Physiologic dependence produces unpleasant physical symptoms when the dose is reduced or the drug is withdrawn. Psychological dependence leads to excessive preoccupation with drugs and drugseeking behavior.

10. Carcinogenicity is the ability of a substance to cause cancer. Several drugs are carcinogens, including some hormones and anticancer drugs. Carcinogenicity apparently results from drug-induced alterations in cellular DNA.

11. Teratogenicity is the ability of a substance to cause abnormal fetal development when taken by pregnant women. Drug groups considered teratogenic include analgesics, diuretics, antiepileptic drugs, antihistamines, antibiotics, antiemetics, and others.

Toxic Effects of Drugs

Drug toxicity (also called poisoning, overdose, or intoxication) results from excessive

amounts of a drug and may cause reversible or irreversible damage to body tissues. It is a common problem in both adult and pediatric populations. It may result from a single large dose or prolonged ingestion of smaller doses. It may involve alcohol or prescription, over-the-counter, or illicit drugs. Poisoned patients may be seen in essentially any setting (e.g., inpatient hospital units, patients’ homes, long-term care facilities), but are especially likely to be encountered in hospital emergency departments. In some cases, the patient or someone accompanying the patient may know the toxic agent (eg, accidental overdose of a therapeutic drug, use of an illicit drug, a suicide attempt). Often, however, multiple drugs have been ingested, the causative drug or drugs are unknown, and the circumstances may involve traumatic injury or impaired mental status that make the patient unable to provide useful information. Clinical manifestations are ofteonspecific for drug overdoses and may indicate other disease processes. Because of the variable presentation of drug intoxication, health care providers must have a high index of suspicion so that toxicity can be rapidly recognized and treated.

Drug Overdose: General Management

Most poisoned or overdosed clients are treated in emergency rooms and discharged to their homes. A few are admitted to intensive care units (ICUs), often because of unconsciousness and the need for endotracheal intubation and mechanical ventilation. Unconsciousness is a major toxic effect of several commonly ingested substances such as benzodiazepine antianxiety and sedative agents, tricyclic antidepressants, ethanol, and opiates. Serious cardiovascular effects (eg, cardiac arrest, dysrhythmias, circulatory impairment) are also common and warrant admission to an ICU. The main goals of treatment for a poisoned patient are supporting and stabilizing vital functions (ie, airway, breathing, circulation), preventing further damage from the toxic agent by reducing additional absorption or increasing elimination, and administering specific antidotes when available and indicated. General aspects of care are described below; selected antidotes and specific aspects of care are described in relevant chapters.

1. For patient who are seriously ill on first contact, enlist help for more rapid assessment and treatment. In general, starting treatment as soon as possible after drug ingestion leads to better patient outcomes.

2. The first priority is support of vital functions, as indicated by a rapid assessment of the patient’s condition (eg, vital signs, level of consciousness). In serious poisonings, an electrocardiogram is indicated and findings of severe toxicity (eg, dysrhythmias, ischemia) justify more aggressive and invasive care. Standard cardiopulmonary resuscitation (CPR) measures may be needed to maintain breathing and circulation. An intravenous (IV) line is

usually needed to administer fluids and drugs, and invasive treatment or monitoring devices may be inserted. Endotracheal intubation and mechanical ventilation are often required to maintain breathing (in unconscious patients), correct hypoxemia, and protect the airway. Hypoxemia must be corrected quickly to avoid brain injury, myocardial ischemia, and cardiac dysrhythmias. Ventilation with positive end expiratory pressure (PEEP) should be used cautiously in hypotensive patients because it decreases venous return to the heart and worsens hypotension. Serious cardiovascular manifestations often require pharmacologic treatment. Hypotension and hypoperfusion may be treated with inotropic and vasopresssor drugs. Dysrhythmias are treated according to Advanced Cardiac Life Support (ACLS) protocols. Recurring seizures or status epilepticus require treatment with anticonvulsant drugs.

3. For unconscious patients, as soon as an IV line is established, some authorities recommend a dose of naloxone (2 mg IV) for possible narcotic overdose and thiamine (100 mg IV) for possible brain dysfunction due to thiamine deficiency. In addition, a fingerstick blood glucose test should be done and, if hypoglycemia is indicated, 50% dextrose (50 ml IV) should be given.

4. Once the patient is out of immediate danger, a thorough physical examination and efforts to determine the drug(s), the amounts, and the time lapse since exposure are needed. If the patient is unable to supply needed information, interview anyone else who may be able to do so. Ask about the use of prescription, over-the-counter, alcohol, and illicit substances.

5. There are no standard laboratory tests for poisoned patients. The client’s condition and the clinician’s judgment determine which laboratory tests are needed, although baseline tests of liver and kidney function are usually indicated. Specimens of blood, urine, or gastric fluids may be obtained for laboratory analysis. Screening tests for toxic substances are not very helpful because test results may be delayed, many substances are not detected, and the results rarely affect initial treatment. Initial treatment should never be delayed to obtain results of a toxicology screen. Identification of an unknown drug or poison is often based on the patient’s history and signs and symptoms, with specific tests as confirmation. Serum drug levels are needed when acetaminophen, alcohol, digoxin, lithium, aspirin, or theophylline is known to be an ingested drug, to assist with treatment.

6. For orally ingested drugs, gastrointestinal (GI) decontamination has become a controversial topic. For many years, standard techniques for removing drugs from the GI tract included ipecac syrup for alert patients, to induce emesis; gastric lavage for patients with decreased levels of consciousness; activated charcoal to adsorb the ingested drug in the GI tract; and a cathartic (usually 70% sorbitol) to accelerate elimination of the adsorbed drug. More recently, whole bowel irrigation (WBI) was introduced as an additional technique. Currently, there are differences of opinion regarding whether and when these techniques are indicated. These differences led to the convening of a consensus

group of toxicologists from the American Academy of Clinical Toxicology (AACT) and the European Association of Poison Centres and Clinical Toxicologists (EAPCCT). This group issued treatment guidelines that have also been endorsed by other toxicology organizations. Generally, the recommendations state that none of the aforementioned techniques should be used routinely and that adequate data to support or exclude their use are often lacking. Opinions expressed by the consensus group and others are described below:

Ipecac. Usage in hospital settings has declined. Its use may delay administration or reduce effectiveness of activated charcoal, oral antidotes, and whole bowel irrigation. It is contraindicated in patients who are less than fully alert (because of the danger of aspiration). Ipecac may be used to treat mild poisonings in the home, especially in children. Parents should call a poison control center or a health care provider before giving ipecac. If used, it is most beneficial if administered within an hour after ingestion of a toxic drug dose.

Gastric lavage. Its usefulness is being increasingly questioned. It is contraindicated in less than alert patients unless the patient has an endotracheal tube in place (to prevent aspiration). It may be beneficial in serious overdoses if performed within an hour of drug ingestion. If the ingested agent delays gastric emptying (eg, tricyclic antidepressants and other drugs with anticholinergic effects), the time limit may be extended. When used after ingestion of pills or capsules, the tube lumen should be large enough to allow removal of pill fragments.

Activated charcoal. Sometimes called the universal antidote, it is useful in many poisoning situations. It is being used alone for mild or moderate overdoses and with gastric lavage in serious poisonings. It effectively adsorbs many toxins and rarely causes complications. It is most beneficial when given within an hour of ingestion of a potentially toxic amount of a drug known to bind to charcoal. Its effectiveness decreases with time and there are inadequate data to support or exclude its use later than 1 hour after ingestion. Activated charcoal is usually mixed in water (about 50 g or 10 heaping tablespoons in 8 oz. water) to make a slurry, which is gritty and unpleasant to swallow. It is often given by GI tube. The charcoal blackens later bowel movements. Adverse effects include pulmonary aspiration and impaction of the charcoal–drug complex. If used with whole bowel irrigation, activated charcoal should be given before the WBI solution is started. If given during WBI, the binding capacity of the charcoal is decreased.

Cathartic. It is not recommended alone and its use with activated charcoal has produced conflicting data. If used, it should be limited to a single dose to minimize adverse effects.

Whole bowel irrigation (WBI). This technique is most useful for removing toxic ingestions of long-acting, sustained-release drugs (eg, many beta blockers, calcium channel blockers, and theophylline preparations); enteric coated drugs; and toxins that do not bind well with activated charcoal (eg, iron, lithium, lead). It may also be helpful in removing packets of illicit drugs, such as cocaine or heroin. When given, polyethylene glycol solution (eg, Colyte) 1–2 liters/hour to a total of 10 liters is recommended. WBI is contraindicated in patients with serious bowel disorders (eg, obstruction, perforation, ileus), hemodynamic instability, or respiratory impairment (unless intubated).

7. Urinary elimination of some drugs and toxic metabolites can be accelerated by changing the pH of urine (eg, acidifying with amphetamine overdose; alkalinizing with salicylate overdose), diuresis, or hemodialysis. Hemodialysis is the treatment of choice in severe lithium and aspirin (salicylate) poisoning.

8. Administer specific antidotes when available and indicated by the client’s clinical condition. Available antidotes vary widely in effectiveness. Some are very effective and rapidly reverse toxic manifestations (eg, naloxone for opiates, flumazenil for benzodiazepines, specific Fab fragments for digoxin). Others are less effective (eg, deferoxamine for acute iron ingestion) or potentially toxic themselves (eg, physostigmine for tricyclic antidepressant overdose). When an antidote is used, its half-life relative to the toxin’s half-life must be considered. For example, the half-life of naloxone, a narcotic antagonist, is relatively short compared with the half-life of the longer-acting opiates such as methadone. Similarly, flumazenil has a shorter half-life than most benzodiazepines. Thus, repeated doses of these agents may be needed to prevent recurrence of the toxic state.

TABLE 2–2 Antidotes for Overdoses of Selected Therapeutic Drugs (continued)

1.     http://www.youtube.com/watch?v=VuQR3i1LdaQ

2.     http://www.youtube.com/watch?v=7qeoQAybhmo

3.     http://www.youtube.com/watch?v=1UTmL6ubHYs

4.     http://www.youtube.com/watch?v=CPtMa12OEX8

5.     http://www.youtube.com/watch?v=8IqBc8GAQTE

6.     http://www.youtube.com/watch?v=xiuWdJYyIKs

7.     http://www.youtube.com/watch?v=YEYheg3AEWY

8.     http://www.youtube.com/watch?v=6XiuWrgvhyY&NR=1

9.     http://www.zoology.ubc.ca/~biomania/tutorial/solut/pl1fr05.htm

10.                       http://www.youtube.com/watch?v=4G6Rem38aks&feature=related