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.
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 has five specific phases: assessment, nursing diagnoses, planning (with goals and outcome criteria), implementation, and evaluation.
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?
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.
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.
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 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 in narrative form or in the SOAP (subjective, objective, assessment, planning) notes format
• The right of refusal of medication with proper documentation
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.
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.
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").
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.
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, identification number, 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 newborn nursery 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.
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 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 within normal 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.
• 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!
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:
• Biochemical effects
• Drug history
• Drug origin
• 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.
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 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.
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 is the transport of a drug in the body by the bloodstream to its site of action (Fig. 2-4). 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 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). Some of the chemical reactions by which the liver can metabolize drugs are listed in Table 2-3. 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 in Table 2-4.
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, are listed in Table 2-5.
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 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 retain needed 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 processes of filtration, reabsorption, and secretion are shown in Fig. 2-5.
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.
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.
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.
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.
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 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.
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.
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.
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 often involves more intensive drug therapy and is implemented in the acutely ill (rapid onset of illness) or even critically ill patient. It is often needed 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 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 or replacement therapy supplies the body with a substance needed to maintain normal 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.
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 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.
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.
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 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.
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.
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.
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 (for more information see Chapter 5).
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 (more information on prevention is presented in Chapter 5).
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. Drugs capable of inducing hemolysis in such patients are
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. Local anesthetics. Irritative drugs, astringent agents, adsorbents, slime agents.
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 information not 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.