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wk1PP.pptxNUR 600
Advanced Clinical Pharmacology
Unit 1
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Learning Objectives
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Describe approval process for prescribed drugs in the US
Analyze roles and responsibilities of the Prescribing practitioner
Understand the process of prescribing
Discuss the impact of each of the four pharmacokinetic principles on medications administered to a patient: absorption, distribution, metabolism, and elimination.
Able to identify factors known to cause drug-drug interactions, drug-food interactions, and drug-herb interactions.
Recognize risk factors associated with adverse drug reactions
Describe the differences in pharmacokinetics among pregnancy, neonates, children, and adults.
Describe the various physiological changes that occur in the older adult that affect pharmacokinetic and pharmacodynamics responses.
Identify at least four drugs that are problematic to use in the older adult.
Discuss safe prescribing practices for the older adult.
Discuss factors that may influence the selection of an appropriate antimicrobial regimen.
Role of the U.S. Food and Drug Administration (FDA)
Conducting and monitoring clinical trials
Approving new drugs for market and manufacture
Ensuring safe drugs for public consumption
Stages of development.
Preclinical trials
Phase l
Phase II
Phase lll
Phase lV
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Clinical Trials
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First stage –Preclinical trials
Animal testing
Efficacy, toxic effects, untoward reactions
Phase I
20-100 Healthy human
Absorption, distribution, metabolism, and elimination
Most effective routes and doses of administration determined
Phase II
Several hundred patients with the disease
Monitor effects on people with the disease
Phase III
FDA determines NO apparent Serious Adverse Effects-Dose is appropriate
Double-blind research method
Investigators/patients BLINDED
Several thousand subjects- several years
Drug risks evident
- FDA evaluates data - Accepts/Rejects
Phase IV
Medication on the market (post marketing surveillance)
FDA-Fast Track
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First category
Fast track
Second category
Breakthrough therapy
Third category
Accelerated approval
Fourth category
Priority review
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The purpose of the NPI is to identify all health care providers by a unique number in standard transactions such as health care claims. NPIs may also be used to identify health care providers on prescriptions, in internal files to link proprietary provider identification numbers and other information, in coordination of benefits between health plans, in patient medical record systems, in program integrity files, and in other ways. HIPAA requires that covered entities (i.e., health plans, health care clearinghouses, and those health care providers who transmit health information in electronic form in connection with a transaction for which the Secretary of Health and Human Services has adopted a standard) use NPIs in standard transactions. The NPI is the only health care provider identifier that can be used in standard transactions by covered entities.
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Scheduled Drugs
Schedule
Schedule 1
High potential for abuse; no routine therapeutic use
Schedule
Schedule 2
Valid medical use; high potential for abuse
Schedule
Schedule 3
Potential for abuse is lower than drugs on schedule 2; prescriptions cannot be refilled
Schedule
Schedule 4
Low potential for abuse; limited physiologic dependency
Schedule
Schedule 5
Least potential for abuse; moderate amount of opioids
Efficient and effective
Used by:
Covered health care providers
Health plans
Health care clearinghouse
NPI=Unique 10-digit number
The National Provider Identifier
Controlled substances, DEA and NPI
Prescription versus Nonprescription Drugs
Generic drugs versus brand name drugs
Formulation
FDA approval
Quality
Purity
Strength
Potency
Complementary and alternative medicine (herbal remedies)
First healing system used
Derived from plants (harmless vs harmful)
Do NOT require FDA approval
Use of foreign medications
Unrecognizable names, different dosages/dosage forms, or different active ingredients.
Medication disposal
Potential harm
Safe disposal
Remove of patient identifiers
Drug take-back program
Not to be flushed down the toilet (unless specified)
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Many drugs may now be obtained that were previously available only with a prescription, and at the prescription dosage. Although these drugs are commonly and legally obtained over the counter (OTC) without a prescription, approval for the drug must still be obtained from the FDA for specific uses in specific doses.
These drugs carry user warnings on the labels. Many have the potential for interacting adversely with prescribed drugs or complicating existing disease. The self-prescribed use of OTC drugs may delay diagnosis and treatment of potentially serious problems. On the other hand, the use of OTC drugs can be beneficial for treatment of self-limiting disorders that are not serious.
Generic Drugs versus Brand Name Drugs
Substituting a generic drug for a brand name drug is a common practice. In many states, it is required. When the patent on a brand name drug expires, other drug manufacturers can then produce the same drug formula under its generic name (the generic name and formula of a drug are always the same; only the brand names change). This practice not only benefits the manufacturer but also decreases the cost to the consumer.
To ensure safety, the FDA must grant approval for these drugs, and rigorous testing is again required to ensure that all generic drugs meet specifications for quality, purity, strength, and potency. Generic drugs must demonstrate therapeutic equivalence to the brand name equivalent. They must be manufactured under the same strict standards and meet the same batch requirements for identity, strength, purity, and quality as the brand name drug. To obtain FDA approval, the generic drug is administered in a single dose to at least 18 healthy human subjects. Next, peak serum concentration and the area under the plasma concentration curve (AUC) are measured. The values obtained for the generic drug must be within 80% to 125% of those obtained for the brand name drug. Most generic drugs have a mean AUC within 3% of the brand name drug. There has been no reported therapeutic difference of a serious nature between brand name products and FDA-approved generic products.
Complementary and Alternative Medicine
In the United States, the use of herbal preparations as treatments for disease and disease prevention has increased tremendously. According to the National Center for Complementary and Integrative Health, in 2012 approximately 33% of adults and 11% of children use some form of complementary approach to health care. The findings mirror similar surveys from 2007. The most popular products for adults (7.8%) and children (1.1%) are fish oils/Omega-3 fatty acids. These are followed by glucosamine and/or chondroitin (2.6%), probiotics/prebiotics (1.6%) and melatonin (1.3%) for adults, and for children melatonin (0.7%) (Clarke et al., 2015).
Historically, herbs were the first healing system used. Herbal medicines are derived from plants and thought by many to be harmless because they are products of nature. Some prescription drugs in current use, however, such as digitalis, are also “natural,” which is not synonymous with “harmless.” Before 1962, herbal preparations were considered to be drugs, but now they are sold as foods or supplements and therefore do not require FDA approval as drugs. Hence, there are no legislated standards on purity or quantity of active ingredients in herbal preparations. The value of herbal therapy is usually measured by anecdotal reports and not verified by research. Like synthetic products, herbal preparations may interact with other drugs and may produce undesirable side effects as well.
The Dietary Supplement Health and Education Act (1994) requires labeling about the effect of herbal products on the body and requires the statement that the herbal product has not been reviewed by the FDA and is not intended to be used as a drug. Complementary and alternative medicine (CAM) is discussed further in other chapter.
Disposal of Medications
Many medications can be potentially harmful if taken by someone other than the person for whom they are prescribed. Understand that improperly disposed drugs can leak into the environment, and the best disposal method is through community drug take-back programs. Almost all medicines can be safely disposed of if they are mixed with an undesirable substance, such as cat litter or coffee grounds, and placed in a closed container. Any personal information should be removed from the container by using a black marker or duct tape. Many communities have a drug take-back program for disposal, or drugs can be disposed of when the community collects hazardous material. Drugs should not be flushed down the toilet or drain unless the dispensing directions say this is permitted.
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Role of the Practitioner in the Prescribing Process
Gather data through history and physical examination
Formulate diagnoses and establish treatment plan
Conduct risk–benefit analysis of drug therapy chosen
Consider ethical and practical issues
Educate the patient
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Before prescribing therapy, the practitioner has a responsibility to gather data by taking a thorough history and performing a physical examination. Once the data are gathered and evaluated, one or more diagnoses are formulated and a treatment plan established. As noted, the most frequently used treatment modality is drug therapy, usually with a prescription or OTC drug.
If a drug is deemed necessary for therapy, it is essential for the practitioner to understand the responsibility involved in prescribing that drug or drugs and to consider seriously which class of medication is most appropriate for the patient. The decision is reached based on a thorough knowledge of diagnosis and treatment.
To determine which therapy is best for the patient, the practitioner conducts a risk–benefit analysis, evaluating the therapeutic value versus the risk associated with each drug to be prescribed. The practitioner then selects from a vast number of pharmacologic agents used for treating the specific medical problem. Factors to consider when selecting the drug or drugs are the subtle or significant differences in action, side effects, interactions, convenience, storage needs, route of administration, efficacy, and cost. Another factor in the decision may involve the patient pressuring the practitioner to prescribe a medication (because that is the expectation of many patients at the beginning of a health care encounter). Clearly, many responsibilities are inherent in prescribing a medication, and serious consequences may result if these responsibilities are not taken seriously and the prescription is prepared incorrectly.
Initial questions to ask when selecting drug therapy include “Is there a need for this drug in treating the presenting problem or disease?” and “Is this the best drug for the presenting problem or disease?”
Certain ethical and practical issues must be considered as well. One overriding issue may be the lack of a clinical indication for using a medication. As mentioned, many patients visit a practitioner with the sole purpose of obtaining a prescription. In seeking medical attention, the ill patient expects the health care provider to promote relief from symptoms. In today’s world, an abundance of information available in books, magazines, television, Web sites, and other media suggests that the health care provider can do this by prescribing a special medication. This expectation—that a magic pill or potion—the prescription—is the ticket that will relieve reflux, kill germs, end pain, and restore health—puts pressure on the practitioner to prescribe for the sake of prescribing. A common example of this involves the patient with a cold who seeks an antibiotic, such as penicillin. In such a situation, the practitioner has a responsibility to prescribe only medications that are necessary for the well-being of the patient and that will be effective in treating the problem. In the example of the patient with an uncomplicated head cold, an antibiotic would not be effective, and the responsible practitioner must be prepared to make an ethical and judicious decision not to prescribe an antibiotic and explain it to the patient.
An integral part of the practitioner’s role and responsibility is educating the patient about drug therapy and the intended therapeutic effect, potential side effects, and strategies for dealing with possible adverse drug reactions. This may be explained verbally, with written instructions given, when appropriate. Instructions that are printed and handed to the patient must be readable, in a language that the patient can understand, and at the appropriate health literacy. If side effects are discussed in advance, the patient will know what to expect and will contact the prescriber with symptoms. There may be less likelihood that the patient will discontinue the drug before discussing it with the prescriber.
Medications can also have a placebo effect. Patients must believe that the drug will work for them to be committed to taking it as recommended. If that belief is not instilled in patients, the drug may not be perceived as effective and may not be taken as directed.
The practitioner may want to advise the patient to use only one pharmacy when filling prescriptions. The choice of only one pharmacy has several advantages, which include maintaining a record of all medications that the patient currently receives and serving as a double-check for drug–drug interactions.
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Prescriptive Authority
Regulated by the state in which the practitioner practices
State board of nursing, board of medicine, or board of pharmacy
Practitioner must be aware of procedures required when using drug samples
Practitioner must monitor for adverse drug events
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Prescribing practices of each practitioner are regulated by the state in which he or she practices. Each state determines practice parameters by statutes (laws enacted by the legislature), rules, and regulations (administrative policies determined by regulatory agencies). Each practitioner is responsible for knowing the laws and regulations in the state of practice.
Prescriptive authority is regulated by the State Board of Nursing, Board of Medicine, or Board of Pharmacy, depending on the state. States allow full practice authority, collaborative practice, supervised practice, or delegated practice. Full practice authority has no requirements for mandatory physician collaboration or supervision. Collaborative practice requires a formal agreement with a collaborating physician, ensuring a referral– consultant relationship. Supervised practice is overseen or directed by a supervisory physician. Delegated practice means that prescription writing is a delegated medical act. Regulations can be found at the Division of Professional Regulation for prescribers in each state.
Related to prescriptive authority issues is the issue of drug samples. Most drug companies engage in the promotional practice of distributing sample drugs to practitioners for use by patients. The Prescription Drug Marketing Act (PDMA), which was enacted in 1988 to protect the American consumer from ineffective drugs, also affects the receipt and dispensing of sample drugs. Prescription drugs can be distributed only to licensed practitioners (one licensed by the state to prescribe drugs) and health care entity pharmacies at the request of a licensed practitioner. PDMA protects the public in several ways. It forbids foreign countries to reimport prescription drugs; bans the sale, trade, and purchase of drug samples; prohibits resale of prescription drugs purchased by hospitals, health care entities, and charitable organizations; requests practitioners to ask for drug samples in writing; and regulates wholesale distributors of prescription drugs by requiring licensing in states where facilities are located. There are penalties for violation of the act. This act affects the distribution and use of pharmaceutical samples.
Because these samples are freely available, it might be assumed that they can be distributed by all practitioners, but this is not the case. The practitioner must be aware of the rules that govern requesting, receiving, and distributing these agents because the rules vary from state to state.
Specific procedures are required with drug samples. The pharmaceutical representative’s Sample Request Form must be signed. It includes the name, strength, and quantity of the sample. The sample must be then recorded on the Record of Receipt of Drug Sample sheet. The samples must be stored away from other drug inventory and where unauthorized access is not allowed or in a locked cabinet or closet in a public area. Samples are to be inspected monthly for expiration dates, proper labeling and storage, presence of intact packaging and labeling, and appropriateness for the practice. If a sample has expired, it must be disposed of in a manner that prevents accessibility to the general public. It cannot be disposed into the trash.
When distributing samples, each must be labeled with the patient’s name, clear directions for use, and cautions. All samples are to be dispensed free of charge along with pertinent information. The medication is then documented in the patient’s chart with dose, quantity, and directions.
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Factors Causing Errors in Drug Prescribing
Lack of drug knowledge
Underuse, overuse, misuse of drugs
Lack of patient information
Information on allergies to medications
Herbal preparations used by the patient
Poor communication
Among health care providers, pharmacists, and patients
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Lack of Drug Knowledge
There can be a lack of knowledge about indications and contraindications for drugs. This includes underuse, overuse, and misuse of drugs. An example of underuse is failure to prescribe an inhaled corticosteroid for an asthmatic patient who uses his albuterol daily. An example of overuse is prescribing an antibiotic for a cold or prescribing an antihypertensive drug for someone whose blood pressure is elevated because he is taking pseudoephedrine (Sudafed). An example of misuse is prescribing penicillin to someone for a strep throat who has identified a clear allergy to the drug.
Dosing errors occur when a larger dose is prescribed than needed or the conversion from oral to intravenous is too high. This is especially problematic with pediatrics for antibiotics (Aseeri, 2013). For example, prescribing a dose of Augmentin that is greater than the suggested amount or starting a patient on 30 mg paroxetine instead of 20 mg may increase anxiety.
Lack of knowledge about drug–drug interactions can also cause errors. For example, many drugs interfere with warfarin and cause increased bleeding if taken together. The prescriber must be aware of the potential for drug–drug interactions
Lack of Patient Information
A common error in prescribing is failure to obtain an adequate history from the patient. Often an adequate drug history is not obtained and the provider does not specifically inquire about herbal preparations or OTC medications. Also, information on allergies to medications is not always obtained. In addition to allergies, it is imperative to ascertain the reaction to the medication. Nausea is not considered an allergic reaction. An allergy history should be taken and documented at each visit before a new medication is prescribed. Additionally, asking multiple times about allergies or reactions to drugs during a visit is a safety cross-check to responsible prescribing.
Poor Communication
Poor communication between health care providers, pharmacists, and patients can be a result of poor handwriting, incorrect abbreviations, misplaced decimals, and misunderstanding of verbal prescriptions. These potential errors can be mitigated through the use of electronic health record (EHR); however, new errors can occur if the practitioner does not click on the correct medication. Additionally, there are areas in the United States where providers still handwrite prescriptions. Poor communication also results when the prescriber fails to discuss potential side effects or ask about side effects at subsequent visits.
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Process for Prescribing Medications
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Steps of the Prescribing Process
At each visit, a medication history is obtained with the name of the drug, dosage, and frequency of administration. Information on any allergies should also be obtained. It is also helpful if the patient brings his or her actual drugs to the visit.
Multiple steps (Figure 1.2) are involved in prescribing drugs and evaluating their effectiveness. Again, the first step is determining an accurate diagnosis based on the patient’s history, physical examination, and pertinent test findings.
Next, in selecting the best agent, the practitioner thoroughly evaluates the patient’s condition, taking into consideration the effect that various medications may have on the patient and the disorder, the expected outcomes of therapy, and other variables (Box 1.3). When prescribing any drug therapy, the practitioner must have a solid knowledge and background in the pathophysiology of disease, pharmacotherapeutics, pharmacokinetics, pharmacodynamics, and any interactions
The practitioner needs to be knowledgeable about the best class of drugs for the diagnosed disorder or presenting problem, the recommended dosage, potential side effects, possible interactions with other drugs, and special prescribing considerations, such as required laboratory tests, contraindications, and patient instructions. To select the correct medication, the practitioner must thoroughly understand the pathophysiology of the condition being treated and the natural history of the disease. This information allows the practitioner to decide at which point in the disease process intervention with drug therapy is indicated because in many diseases or disorders, nonpharmacologic therapies are tried before drug therapy is initiated.
Next, the practitioner sets goals for therapy. Goals need to be realistic and outcomes measurable. All interventions, nonpharmacologic and pharmacologic, are initiated to meet these goals, and evaluation of the therapy’s efficacy is based on these goals.
Selecting Most Appropriate Agent
For most disease entities, there is a recommended first-line therapy—that is, research shows certain agents to be more effective than others. Once initiated, the first-line therapy is evaluated and either continued or changed. If the desired goals are not achieved, or if an adverse reaction occurs, second-line therapy is initiated. The second-line therapy is then evaluated. If this therapy is not tolerated or efficacious, a third-line therapy is initiated, and so on. The practitioner continually evaluates the patient’s response to therapy and maintains current therapy or changes it as indicated by the patient’s response. For more information, see the case study outlining the prescribing process. Case studies such as this one are used throughout the text.
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Variables to Consider in Medication Prescribing
Age, sex, race, culture
Weight
Allergies
Pharmacogenomics
Other diseases or conditions, other therapies, and previous therapies
Socioeconomic issues
Health beliefs
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Another step in prescribing drugs is considering specific concerns related to special populations, such as children, pregnant or breast-feeding women, and the elderly. Cultural beliefs are also considered to ensure that the drug regimen honors individual and family customs and preferences. Pharmacogenomics are gaining in popularity when considering which drug to prescribe.
Doses for children are usually based on weight in kilograms. The prescriber has a responsibility to calculate the dose and write the correct dose, rather than relying on the pharmacist to calculate the dose. See Chapter 4 for more information about pediatric drug dosing.
Elderly patients may have some difficulty hearing or reading small print. Additionally, they may be taking multiple prescription medications and OTC medications. The prescriber needs to be specific about when the patient should take each medication and if one drug cannot be taken with others. When the practitioner prescribes for the elderly, he or she must consider renal function because some medications can cause toxicity, even in small doses, with decreased renal function. Chapter 6 reviews the considerations necessary for good prescribing in the elderly.
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Identifying Outcomes of Drug Therapy
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Expected outcomes can include improvement in clinical symptoms or pathologic signs or changes in biochemistry as determined by laboratory tests. To assess whether expected outcomes have been achieved, the practitioner reviews data collected on subsequent visits, evaluates the effectiveness of drug therapy, and investigates any adverse reactions.
The frequency of follow-up visits is determined by the disease and the patient’s response to treatment. While outcomes are being assessed, the practitioner educates the patient about the outcomes of therapy as well. Topics for discussion include drug benefits, side effects, dosage adjustments, and monitoring parameters.
The patient as well as the practitioner must be informed about any undesirable outcomes of therapy with a prescription drug. Reactions that may be expected and must be discussed include side effects, drug or food interactions, and toxicity. Unexpected reactions include allergic reactions or intolerance to a drug. If a patient experiences a serious adverse drug reaction, the practitioner files a report with the FDA’s MedWatch program
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Expected outcomes
Improvement in clinical symptoms or pathologic signs
Changes in biochemistry as determined by lab tests
Undesirable outcomes
Side effects
Drug or food interactions
Toxicity
Standard Components of Prescriptions
Prescribing date
Patient name, address, date of birth
Prescriber’s name, address, and phone number
Name of drug
Dose, dosage regimen, route of administration
Allowable substitutions
Prescriber’s signature and license number
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Once you have determined what medication to prescribe your patient, then you must write the RX. It mut include Date, Name, Address, and Date of Birth. The next components are the name, address, and phone number of the prescriber and the collaborating physician if required by state law or regulations. This enables the pharmacist to contact the prescriber if there is a question about the prescription.
Of course, the name of the drug is the most essential part of the prescription. Ideally, the generic name (with the trade or brand name in parentheses) is used. The name must be legible to avoid errors in filling the prescription correctly. For instance, some drugs have names that are commonly confused or misread, such as Norvasc and Navane, Prilosec and Prozac, carboplatin and cisplatin, and Levoxine and Lanoxin. Severe problems may result if the wrong drug is supplied erroneously. Adding the diagnosis to the prescription, although optional, can help the pharmacist avoid misinterpreting the prescribed drug.
Indication of whether a substitution is allowed is a part of the prescription.
“Brand Medically Necessary” must be written on the prescription.
The signature of the prescriber is required. It should be legible and should be the person’s legal signature. The license number of the prescriber or the collaborating physician is required on the prescription in some, but not all, states depending on the rules and regulations that govern the prescriber. In some instances, the DEA number of the prescriber is also required, especially when prescribing between states or prescribing a controlled substance.
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Advantage of E-Prescribing
Improved legibility of prescriptions and rate of completed prescriptions
Greater patient convenience at pharmacy
Increased compliance with formulary requirements
Decreased drug–drug interactions
Reduced medication errors with use of drug-checking software
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Electronic prescribing has become increasingly popular. Health care technology reduces medication errors with the use of drug-checking software, which checks the medication dose, potential interactions with other medications the patient may be taking, and the patient’s known allergies. This drug-checking software may be part of the EHR or of a freestanding e-prescribing system. Integrated EHRs can calculate dosing based on a patient’s weight and carry out other contextual medication checking against a patient’s laboratory results, age, and disease states. In addition, computer systems provide pick lists of each clinician’s favorite medications with a precalculated dose, frequency, and route, reducing the opportunity for clinicians to order inappropriate amounts of medications with the wrong frequency and route.
E-Prescribing improves the legibility of prescriptions and the rate of completed prescriptions. Patients no longer need to carry paper copies of a prescription to a pharmacy and are more likely to have formulary-compliant medications prescribed for them and to find their prescriptions waiting for them when they arrive at the pharmacy. This leads to greater patient convenience, shorter wait times, and increased compliance with formulary requirements. Electronic prescribing has been said to show a 12% to 20% decrease in ADEs
With electronically generated prescriptions, there are no handwriting misinterpretations and no manual data entry. Correct dosages are built into the software.
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Factors Affecting Patient Adherence to a Drug Regimen
Approachability of health care provider
Perception of respect with which he or she is treated by the practitioner
Belief the therapy is beneficial
Belief the benefits of therapy outweigh the risks or side effects
Degree to which the patient participates in developing the treatment regimen
Cost of the regimen
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A prescribed drug must be used correctly to produce optimal benefits. Patient nonadherence to a prescribed regimen leads to less-than-optimal outcomes, such as progression of the disease state and an increased incidence of hospitalizations. Studies demonstrate that the more complex the treatment regimen, the less likely the patient is to follow it.
Nonadherence was significantly associated with high out-of-pocket costs and clinical response to therapy.
Several variables are associated with improved adherence to a drug regimen. These include variables associated with the patient’s perception of the encounter and of the benefit of the treatment. If a patient is nonadherent to the prescribed regimen, it is important to document that in the chart. The risks of nonadherence are discussed, and that discussion is documented. It is essential to ask why the patient is not following the prescribed treatment, and actions to rectify the problem should be taken. All of this is documented. One issue may be that the patient is unable to swallow the pill. The medicine may be available in liquid form, or the pill may be split or crushed. The practitioner needs to review and understand the factors that affect adherence to a regimen
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Factors Affecting Patient Adherence to a Drug Regimen (cont.)
Simplicity and understanding of the regime
Degree to which the patient feels that expectations are being met
Degree to which the patient perceives his or her concerns are important and being addressed
Degree to which the practitioner motivates the patient to adhere to the regimen
Degree to which the regimen is compatible with the patient’s lifestyle
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Methods of Updating Drug Information
Reference books
Pharmacists
Easy-to-carry drug handbooks
Pocket guides
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Pharmacokinetics versus Pharmacodynamics
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The art and science of clinical practice is based on understanding the relationship between the person and the disease and determining the most appropriate means for alleviating symptoms, curing disease, or preventing severe morbidity or even mortality. Very often, medications are prescribed to accomplish one or more of these goals.
Underpinning this treatment process is the intricate relationship between the body and the medication. Often, practitioners seek to understand the effect a drug has on the body (whether therapeutic or harmful) but neglect to consider the effect that the body has on the drug—even though one cannot be understood without the other. How the body acts on a drug and how the drug acts on the body are the subjects of this chapter.
Pharmacokinetics refers to the movement of the drug through the body—in essence, how the body affects the drug. This involves how the drug is administered, absorbed, distributed, and eventually eliminated from the body.
Pharmacodynamics refers to how the drug affects the body—that is, how the drug initiates its therapeutic or toxic effect, both at the cellular level and systemically. Box 2.1 lists terms and definitions used throughout this chapter.
The purpose of pharmacokinetic processes is to get the drug to the site of action where it can produce its pharmacodynamic effect. There is a minimum amount of drug needed at the site of action to produce the desired effect. Although the amount of drug concentrated at the site of action is difficult to measure, the amount of drug in the blood can be measured. The relationship between the concentration of drug in the blood and the concentration at the site of action (i.e., the drug receptor) is different for each drug and each person. Therefore, measuring blood concentrations is only a surrogate marker, an indication of concentration at the receptor. Figure 2.1 shows the relationship between pharmacokinetics and pharmacodynamics.
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Pharmacokinetics
Refers to the movement of the drug through the body and how the body affects the drug
Drug administration, absorption, distribution, and elimination are involved
Pharmacodynamics
Refers to how the drug affects the body; how the drug initiates its therapeutic or toxic effect at the cellular level and systemically
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Relationship between Pharmacokinetics and Pharmacodynamics
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Therapeutic Window
Range of blood drug concentration that yields a sufficient therapeutic response without excessively toxic reactions
Not considered absolute as it varies from individual to individual
Serves as a guide to the practitioner
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Pharmacokinetics relates to how the drug is absorbed, distributed, and eliminated from the body. In reality, it is the study of the fate of medications administered to a person. It is sometimes described as what the body does to the drug. In theory, pharmacokinetics not only deals with medications, it deals with the disposition of all substances administered externally to any living organism. Pharmacokinetics can help the clinician determine the onset and duration of a drug’s action as well as determine blood levels that would produce therapeutic and toxic effects. As such, one can determine the blood levels necessary to produce a desired effect. This target drug concentration is key to monitoring the effects of many medications. Assuming that the magnitude of the drug concentration at the site of action influences the drug effect, whether desired or undesired, it can be inferred that a range of drug levels produces a range of effects (Figure 2.2). Below a specific level, or threshold, the drug exerts little to no therapeutic effect. Above this threshold, the concentration of drug in the blood is sufficient to produce a therapeutic effect at the site of action. However, as the drug concentration increases in the blood, so does the concentration at the site of action. Above a specific level, an increased therapeutic effect may no longer occur. Instead, an unacceptable toxicity may occur because the drug concentration is too high. Between these two levels—the minimally effective level and the toxic level—is the therapeutic window. The therapeutic window is the range of blood drug concentration that yields a sufficient therapeutic response without excessively toxic reactions. This range should not be considered absolute because it varies from individual to individual and therefore serves only as a guide to the practitioner.
Therapeutic window: concentration versus response. The concentration of the drug in the body produces specific effects. A low concentration is considered subtherapeutic, producing an insufficient response. As the concentration increases, the desired effect is produced at a given drug level. A drug concentration that exceeds the upper limit of the desired response may produce a toxic reaction. The concentration range within which a desired response occurs is the therapeutic window.
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Methods of Absorption
Enteral absorption
Following administration by oral, sublingual, or rectal route
Parenteral absorption
Following administration by inhalation, intravenous, intramuscular, subcutaneous, topical, or transdermal route
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The first aspect of pharmacokinetics to consider is how drugs are administered, how they are absorbed into the body, and how they eventually reach the bloodstream. Merely introducing the drug into the body does not ensure that the compound will reach all tissues uniformly or even that the drug will reach the target site. Commonly recognized methods of absorption include enteral absorption (after the drug is administered by the oral or rectal route) and parenteral absorption (associated with drugs administered intramuscularly [IM], subcutaneously, or topically). The various administration routes and other factors affect a drug’s ability to enter the bloodstream.
The extent to which the drug reaches the systemic circulation is referred to as bioavailability, or F, which is defined as the fraction or percentage of the drug that reaches the systemic circulation. Drugs administered intravenously are 100% bioavailable. Drugs administered by other routes (e.g., oral, IM) may be 100% bioavailable, but more often, they are less than 100% bioavailable. Therefore, bioavailability depends on the route of administration and, equally important, the drug’s ability to pass through membranes or barriers in the body. Box 2.2 discusses the specific case of oral bioavailability.
Drugs given orally may be subject to the first-pass effect, by which drugs are metabolized by the liver before passing into circulation. After absorption from the alimentary canal, drugs go directly to the liver through the portal vein. In the liver, hepatic enzymes act on the drug, reducing the amount of active drug reaching the bloodstream and decreasing the amount available to the body. The fraction (or percentage) of medication reaching systemic circulation after the first pass through the liver is referred to as the drug’s bioavailability (F).
The first-pass effect is not the only factor contributing to the oral bioavailability of a drug. Poorly soluble drugs and drugs adversely affected by gastric pH or other presystemic factors can also have a low bioavailability.
Drugs not usually subject to the liver’s first-pass effect are known as drugs with a low hepatic extraction ratio because the liver does not extract a large percentage of the drug before releasing it into the circulation. Usually, drugs with a low extraction ratio have high oral bioavailability. In contrast, drugs with a high extraction ratio have low oral bioavailability. For example, lidocaine has a hepatic extraction ratio of 0.7; that is, the liver metabolizes 70% of the drug before the drug reaches the circulation and, as such, only 30% remains available systemically. This is one reason lidocaine is administered parenterally. In other words, the first-pass effect for lidocaine is of such magnitude that an alternative route of administration is required. Giving large oral doses of a drug to compensate for the high extraction ratio is often an alternative to parenteral administration. For example, because of the high extraction ratio of propranolol, a 1-mg dose administered intravenously is approximately equivalent to a 40-mg dose administered orally.
Examples of drugs with a high hepatic extraction ratio (70% or more) are imipramine (Tofranil), lidocaine (Xylocaine), and meperidine (Demerol); drugs with intermediate rankings are codeine, nortriptyline (Aventyl), and quinidine (Quinaglute); and some drugs with a low extraction ratio (30% or less) are barbiturates, diazepam (Valium), theophylline (Theo-Dur), tolbutamide (Orinase), and warfarin (Coumadin).
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Factors Affecting Absorption
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A variety of factors affect absorption, such as the presence or absence of food in the stomach, blood flow to the area for absorption, and the dosage form of the drug. The following sections discuss some of the major factors affecting absorption.
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Presence or absence of food in the stomach
Blood flow to the area for absorption
Dosage form of the drug
Movement Through Membranes
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Throughout the body, biologic membranes act as barriers, blocking or permitting the passage of various substances. These membranes protect certain areas of the body from harmful chemicals and allow other areas to be accessed as needed.
Biologic membranes composed of cells serve as barriers primarily because of the structure and function of the cells that make up the membrane. Cell membranes are composed of lipids and proteins, creating a phospholipid bilayer. This bilayer acts as a barrier that is almost impermeable to water, other hydrophilic (water-loving) substances, and ionized substances. However, the bilayer does allow most lipid-soluble (hydrophobic) compounds to pass through readily. Interspersed throughout this bilayer are protein molecules and small openings, or pores. The proteins may act as carrier molecules, bringing molecules through the barrier. The pores allow hydrophilic molecules to pass through if they are small enough. Therefore, drugs and other compounds that pass through membrane barriers can do so by passive or active means.
Passive Diffusion
Drugs can pass through membrane barriers by diffusion. In passive diffusion, molecules move from one side of a barrier to another without expending energy. In passing, the molecules move down a concentration gradient—that is, they move from an area of higher concentration to an area of lower concentration. The rate of diffusion depends on the differences in concentrations, the relative strength of the barrier, the distance that the molecules must travel, and the size of the molecules. This relationship is known as Fick’s law of diffusion. In essence, Fick’s law states that the greater the distance to travel and the larger the molecule, the slower the diffusion.
Another major barrier to the absorption of a drug is its solubility. To facilitate drug absorption, the solubility of the administered drug must match the cellular constituents of the absorption site. Lipid-soluble drugs can penetrate fatty cells; water-soluble drugs cannot. For example, a water-soluble drug such as penicillin cannot easily pass through the barrier between the blood and brain, whereas a highly lipid-soluble drug such as diazepam (Valium) can. The relative strength of the barrier is important because the barrier must be permeable to the diffusing substance. Drugs diffuse more readily through the lipid bilayer if they are in their neutral, nonionized form. Most drugs are weak acids or weak bases, which have the potential for becoming positively or negatively charged. This potential is created through the pH of certain body fluids. In the plasma and in most other fluids, most drugs remain nonionized. However, in the gastric acid of the stomach, weak bases become ionized and are more difficult to absorb. As this weak base progresses through the alkaline environment of the small intestines, it becomes nonionized and therefore more easily absorbed. Similarly, weak acids remain nonionized in the stomach and become ionized in the small intestines. The result is reduced absorption by the intestines.
Active Transport
In active transport, membrane proteins act as carrier molecules to transport substances across cell membranes. The role of active transport in moving drugs across cell membranes is limited. To be carried through by a protein, the drug must share molecular similarities with an endogenous substance the transport system routinely carries. Cells can accomplish this through the process of endocytosis. In this process, the cell forms a vesicle surrounding the molecule, and it is subsequently invaginated in the cell. Once inside the cell, the vesicle releases the molecule into the cytoplasm of the cell.
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Passive diffusion
Molecules move from one side of a barrier to another without expending energy.
Active transport
Membrane proteins act as carrier molecules to transport substances across cell membranes.
Oral Administration of Medications
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The oral route of administration refers to any medication that is taken by mouth (per os or PO). The ability to swallow is implicit in oral administration; however, many practitioners consider local action, in which absorption does not occur, also to be “oral” (e.g., troches for fungal infections of the mouth). Common dosage forms administered by mouth include tablets, capsules, caplets, solutions, suspensions, troches, lozenges, and powders.
Absorption after oral administration usually occurs in the lower GI tract (small or large intestine), is slow, and depends on the patient’s gastric-emptying time, the presence or absence of food, and the gastric or intestinal pH. Variations in one or more of these factors can affect the stability of the drug, the contact time with the intestinal walls, or the blood flow to the GI tract. Most of the absorption occurs in the small intestine, where the large surface area enhances and controls drug entry into the body.
Drugs administered orally must be relatively lipid soluble to cross the GI mucosa into the bloodstream. The diffusion rate, a function of the lipid solubility of a drug across the GI mucosa, is a major factor in determining the rate of absorption of a drug. The acid pH of the stomach and the nearly neutral pH of the intestines can degrade some medications before they are absorbed. In addition, bacteria in various parts of the intestines secrete enzymes that also can break down drugs before absorption.
Although the GI tract is generally resistant to a variety of noxious agents, considerable irritation and discomfort can arise from certain medications in some people. Nausea, vomiting, diarrhea, and less often mucosal damage are common side effects of medications, and the practitioner should monitor all patients for these effects.
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Any medication that is taken by mouth (per os/PO).
Forms include tablets, capsules, caplets, solutions, suspensions, troches, lozenges, and powders.
Absorption usually occurs in the lower GI tract and is slow.
Absorption depends on the patient’s gastric emptying time, presence or absence of food, and intestinal pH.
Sublingual Administration of Medications
Under the tongue (SL)
Relies on absorption through oral mucosa
Drugs are not subject to first-pass effect
Similar to buccal administration
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Sublingual (SL, under the tongue) drug administration relies on absorption through the oral mucosa into the veins that drain those vascular beds. These veins carry the drug to the superior vena cava and eventually the heart. Drugs administered this way are not subject to the first-pass effect (see Box 2.2). This method of administration is limited by the amount of drug that can be placed sublingually and the drug’s ability to pass through the oral mucosa into the venous system. Buccal administration, in which the drug is absorbed through the mucous membranes of the mouth, is similar to SL administration.
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Rectal Administration of Medications
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Drugs administered rectally (PR, per rectum) include suppositories and enemas. Primarily used in the treatment of local conditions (e.g., hemorrhoids) and inflammatory bowel disease, this method is less effective than other enteral routes because of the erratic absorption of most agents. Bowel irritation, early evacuation, and minimal surface area contribute to erratic absorption and poor tolerability of this route. Advantages, however, include the ability to administer a medication to an unconscious or nauseated patient.
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Per rectum (PR)
Primarily used in the treatment of local conditions and inflammatory bowel disease
Less effect than other routes due to erratic absorption
Advantage: can be administered to an unconscious or nauseated patient
Inhalation Administration of Medications
Drugs that are gaseous or sprayable in small particles.
Lungs provide large surface for absorption and quick entry into bloodstream.
Bypasses first-pass effect; high bioavailability.
Examples are anesthetic gases and beta-adrenergic agonists (e.g., albuterol) used in treating asthma.
Disadvantages include irritation to the alveolar space and the need for good coordination during self-administration.
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Drugs that are gaseous or sprayable in small particles may be delivered by inhalation. The lungs provide a large surface area for absorption and quick entry into the bloodstream.
Inhaled medications bypass the first-pass effect and therefore may have a high bioavailability. Examples of inhalants are anesthetic gases and beta-adrenergic agonists (e.g., albuterol) used in treating asthma. Conversely, agents such as inhaled corticosteroids are intended for local action in the lung tissue. Regardless of the intent of inhaled medications, the disadvantages include irritation to the alveolar space and the need for good coordination during self-administration, such as with metered-dose inhalers.
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Intravenous Administration of Medications
IV route provides rapid access to circulatory system.
Drug absorption is considered gold standard with regard to bioavailability.
IV bolus injections allow for large amounts of medication to be administered quickly for a high peak drug level and a rapid effect.
Adverse effects from these high levels of medications also occur.
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Intravenous Administration
The intravenous (IV) route provides rapid access to the circulatory system with a known quantity of drug. Bypassing the first-pass effect and any GI metabolism or degradation, drug absorption by this route is considered the gold standard with regard to bioavailability. IV bolus injections allow for large amounts of medication to be administered quickly for a high peak drug level and a rapid effect. However, adverse effects from these high levels of medications also occur with this form of administration. Repeated bolus doses of medications, at designated intervals, can produce large fluctuations in peak and trough (lowest concentration before next dose) levels. Although over time these peaks and troughs produce average desired concentrations, significant peak and trough fluctuations may not be desirable in some patients. Continuous administration by an infusion can minimize or eliminate these fluctuations and produce a consistent, steady-state concentration.
Like IV administration, intra-arterial administration produces a rapid effect. However, because the drug is directly instilled in an organ, this route is considered more dangerous than the IV route. Therefore, intra-arterial administration is usually reserved for a time when injection into a specific tissue is indicated (e.g., anticancer treatment for a specific tumor).
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Subcutaneous Administration of Medications
SC or SQ
Injected directly beneath the skin
Produces a slower, more prolonged release of medication
Limited by the quantity of the liquid suitable for administration
Dermal irritation, or even necrosis, may occur
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Subcutaneous (SC or SQ) administration produces a slower, more prolonged release of medication into the bloodstream. Injected directly beneath the skin, a drug must diffuse through layers of fat and muscle to encounter sufficient blood vessels for entry into the systemic circulation. This route is limited by the quantity of the liquid suitable for administration (usually 2 to 3 mL). Caution must also be taken because dermal irritation, or even necrosis, may occur. More recent technological advances allow the practitioner to implant drug-releasing mechanisms under the skin, providing a reservoir of drug for long- term absorption. Levonorgestrel (Norplant), a hormonal contraceptive, is administered in this manner.
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Intramuscular Administration of Medications
IM.
Medication is injected into highly vascularized skeletal muscle.
Medications are delivered quickly avoiding changes in plasma levels seen with IV.
Local pain and muscle soreness as well as wide variability in the rate of absorption are drawbacks.
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Injecting medications into the highly vascularized skeletal muscle is a way of administering drugs quickly and avoiding the relatively large changes in plasma levels seen with IV administration. Local pain and muscle soreness are drawbacks to this method, as is the wide variability in the rate of absorption resulting from injections given in different muscles and in different patients. Blood flow to the area is the major factor in determining the rate of absorption. This is considered a safe way to administer irritating drugs, although not all IM injections are truly IM: in grossly obese patients, presumed IM injections may actually be intralipomatous, which decreases the rate of absorption because of the lower vascularity of fatty tissue.
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Topical Administration of Medications
Applying drugs in various vehicles at the site of action.
Involves ointments, creams, drops, and gels.
Gels, the most water-soluble topical dosage form, allow medication to be spread more easily over a larger area.
Creams are water soluble and therefore can be washed from the skin more readily than ointments.
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Topical drug administration involves applying drugs, in various vehicles (e.g., liquids, powders), to the site of action, primarily the skin. Topical ointments, creams, drops, and gels typically produce a local effect. Ointments are occlusive, preventing water absorption or evaporation, and therefore have a hydrating effect and typically produce greater local effects than their cream counterparts. Creams are water soluble and therefore can be washed from the skin more readily than ointments. In hairy areas, creams are preferred over ointments because creams are hydrophilic and hence easier to apply and wash off. Gels, the most water-soluble topical dosage form, allow medication to be spread more easily over a larger area.
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Transdermal Administration of Medications
Across the skin administration.
Systemic delivery of medication through the skin.
Several transdermal drug delivery systems are available for a wide range of medications, including estrogens (Estraderm) and fentanyl (Duragesic).
This method continuously delivers medication to achieve a constant blood level.
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Transdermal (across the skin) administration refers to the systemic delivery of medication through the skin. Several transdermal drug delivery systems are available for a wide range of medications, including estrogens (Estraderm) and fentanyl (Duragesic). In general, this method continuously delivers medication to achieve a constant blood level. The consistent delivery of drug throughout the dosing interval minimizes the peak-to-trough fluctuations seen with other forms of drug administration, thereby minimizing the toxicity associated with high blood levels while maintaining therapeutic concentrations.
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Factors Affecting Distribution of Medications
Blood flow to an area
Lipid or water solubility
Protein binding
Obesity
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A discussion of the routes of administration offers the opportunity to consider the factors affecting drug absorption and bioavailability; once the medication is in the body, however, it must distribute to the site of action to be effective.
Distribution of an absorbed drug in the body depends on several factors: blood flow to an area, lipid or water solubility, and protein binding. For an absorbed drug to distribute from the blood to a specific site of action, there must be adequate blood flow to that area. In patients with compromised blood flow (e.g., from shock), relying on the blood to deliver a drug to a site of action, such as the kidney, may be risky.
In addition, drug distribution may be affected by obesity, both immediately after absorption and after achieving an equilibrium or steady state in the body. Lipid-soluble drugs readily distribute into the fatty tissues, where they may be stored and even concentrated. Water-soluble drugs, however, tend to remain in the highly vascularized spaces of the skeletal muscle. Ideal body weight is usually considered the standard for determining drug dosage, which is often adjusted for obese or cachectic patients.
Protein Binding
After absorption into the blood (and lymph), a drug may circulate throughout the body unbound (free drug) or bound to carrier proteins such as albumin. The extent of drug binding to carrier proteins depends on the affinity of the drug for the carrier protein and the concentrations of both the drug and the protein. Acidic drugs commonly bind to albumin and basic drugs commonly bind to alpha1-acid glycoprotein or lipoproteins.
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Plasma Protein Binding
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Plasma protein binding is typically a reversible phenomenon, with binding and unbinding occurring within milliseconds. Therefore, the bound and unbound forms of the drug can be assumed to be at equilibrium at all times. As such, the degree of binding to plasma proteins can be expressed as a percentage of bound drug to total concentration (bound plus unbound). It is only the unbound or free drug that can exert a pharmacologic effect. If the drug becomes bound, it becomes inactive because it cannot leave the bloodstream or bind to an enzyme or receptor and exert its therapeutic action
Once the free drug is eliminated from the body through metabolism or excretion, the bound drug can be released from the protein to become active. In essence, the bound drug may serve as a storage site or reservoir of the drug. The percentage of the free drug usually is constant for a single drug but varies among drugs. Patient-specific factors, such as nutritional status, renal function, and levels of circulating protein or albumin, can change the percentage of the free drug.
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Calculating the Apparent Volume of Distribution (Vd)
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The amount of drug in the human body can never be directly measured. Observations are made of the concentration of drug in plasma or sometimes in blood. Over time, the concentration of drug in the plasma depends on the rate and extent of drug distribution to the tissues and on how rapidly the drug is eliminated. For most drugs, distribution occurs more rapidly than elimination. The resultant plasma concentration after distribution depends on the dose and the extent of distribution into the tissues. This extent of distribution can be determined by relating the concentration obtained with a known amount of administered drug.
For example, if 100 mg of an IV drug is administered to a person and remains only in the plasma, and if that person’s total plasma volume measures 5 L, the resulting measured concentration of drug would be 20 mg/L [concentration = dose/volume: 100 mg/5 L]. However, in reality, few drugs distribute solely in the plasma, and many bind to plasma proteins. Drugs commonly bind not only to plasma proteins but also to tissue-binding sites on fat and muscle. In addition, drugs translocate into other “compartments” or spaces throughout the body. The volume into which a drug distributes in the body at equilibrium is called the (apparent) volume of distribution (Vd). This volume does not refer to a real
volume; rather, it is a mathematically calculated volume (Box 2.3). The Vd is a direct
measure of the extent of distribution of a drug in the body and represents the apparent volume that a drug must distribute to contain the amount of drug homogenously.
Drugs that are highly water soluble or highly bound to plasma proteins remain in the blood compartment and do not distribute or bind to fatty tissue. These drugs have a low Vd,
usually less than the volume of total body water (approximately 50 L, or 0.7 L/kg). Drugs with a low Vd usually circulate at high levels in the blood. In contrast, drugs that are not
highly protein bound and are highly lipophilic have a high Vd (greater than 150 L, which is
greater than the volume of total body water). These drugs distribute widely throughout the body and may even cross the blood–brain barrier.
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Elimination of Drugs
Methods
Metabolism: liver, kidneys, GI tract
Excretion from the body: kidneys, lower GI tract, lungs, skin
Important concepts in understanding drug elimination
Half-life: time required for elimination of half of drug
Steady state: equilibrium
Clearance: removal of drug from plasma or organ
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All drugs must eventually be eliminated from the body to terminate their effect. Drugs can be eliminated through metabolism (or biotransformation) of the drug from an active form to an inactive form. Drugs can also be eliminated by excretion from the body. Therefore, elimination is a combination of the metabolism and excretion of drugs from the body. Important concepts in understanding drug elimination are half-life, steady state, and clearance. Knowledge of these phenomena in any given patient helps practitioners understand how long a drug will last in the body and how much should be given to maintain therapeutic levels and therefore helps in determining the appropriate dose and dosing intervals.
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Modification of Diet in Renal Disease
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Drug Receptors
The component of the cell (or an enzyme) to which an endogenous substance binds, or attaches, initiating a chain of biochemical events.
The capacity of a drug to bind to a receptor depends on the size and shape of the drug and the receptor.
Commonly classified by the effect they produce.
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Four Types of Receptors
Gated ion channels: open or close channels to allow certain ions to pass through cell membrane
Transmembranous receptors: has its ligand-binding domain on the cell’s surface
G protein–coupled receptors: generate intracellular second messengers
Intracellular receptors: drugs attach to intracellular receptors and initiate direct changes in the cell by affecting DNA transcription
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Drug Receptor Interactions
Affinity: degree to which a drug is attracted to a receptor
Chirality: drugs exist in two forms with mirror-image spatial arrangements called enantiomers or isomers, which affect interaction with receptors
Agonists: drugs that display a degree of affinity for a receptor and stimulate a response
Antagonists: drugs that display an affinity and do not elicit a response
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Dose–Response Relationship
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Factors Affecting Pharmacodynamics
Patient variables
Pathophysiology
Genetics
Age
Sex
Ethnicity
Diet and nutrition
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Four Major Categories of Drug Interactions
Drug–drug interactions
Drug–food interactions
Drug–herb interactions
Drug–disease interactions
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Pharmacokinetic Factors Affecting Drug Therapy
Absorption
Distribution
Metabolism
Excretion
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Pharmacokinetic Drug–Drug Interactions Involving Absorption
Acidity (pH): one drug may alter the acidity of the GI tract
Adsorption: occurs when one agent binds the other to its surface to form a complex
Gastrointestinal motility and rate of absorption: drugs that affect the GI tract can affect the rate of absorption instead of amount of drug absorbed
GI flora: bacteria present in the GI tract are responsible for a portion of the metabolism of some agents
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Distribution of Drugs in Bloodstream
Most are bound to plasma proteins such as albumin or α1-acid glycoprotein.
Only an unbound drug is free to interact with its target receptor site and is therefore active.
The percentage of drug that binds to plasma proteins depends on the affinity of that drug for the protein-binding site.
Clinically significant drug displacement interactions normally occur only when drugs are more than 90% protein bound and have a narrow therapeutic index.
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Metabolism
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Metabolism is a function of the body designed to change substances into water soluble, more readily excreted forms. The liver primarily performs the body’s metabolic functions because of its high concentration of metabolic enzymes. This is why the first-pass effect is significant to the bioavailability of a drug administered orally.
Other organs, such as the kidneys and intestines, as well as circulating enzyme systems, also contribute to the metabolism of drugs. Metabolic processes are used to detoxify drugs and other foreign substances as well as endogenous substances. Drugs may be metabolized from active components into inactive or less active ones. Some drugs, however, may be biologically transformed from an inactive parent drug into an active metabolite. This type of drug is called a prodrug because it is a precursor to the active drug (Table 2.1). Not all drugs are metabolized to the same extent or by the same means. In fact, some drugs, such as the aminoglycosides (e.g., gentamicin [Garamycin]), are not metabolized at all.
Enzyme actions are the primary means for metabolizing drugs, and these actions are broadly classified as phase 1 and phase 2 enzymatic processes. Phase 1 enzymatic processes involve oxidation or reduction, by which a drug is changed to form a more polar or water- soluble compound. Phase 2 processes involve adding a conjugate (e.g., a glucuronide) to the parent drug or the phase 1–metabolized drug to further increase water solubility and enhance excretion.
The oxidative process of phase 1 metabolism is catalyzed by the flavin-containing monooxygenases (FMO), the epoxide hydrolases (EH), and the cytochrome P-450 system (CYP). The FMOs and CYP are composed of superfamilies of more than 100 enzymes each. Three families (about 15 total enzymes) of the CYP enzymes are important contributors to drug metabolism. The common feature of these enzymes is their lipid solubility. Most lipophilic drugs are substrates for one or more of the CYP enzymes (Table 2.2). FMOs are not considered major contributors to drug metabolism at this time.
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Main sites of metabolism
Liver (hepatocytes)
Small intestine (enterocytes)
Kidneys, lungs, brain play minor role
Classification of cytochrome P-450 isoenzymes
Family (>36% homology in amino acid sequence)
Subfamily (77% homology)
Individual gene
Inhibition of Drug Metabolism: Competitive and Noncompetitive
Affinity: the greater the affinity of an inhibiting drug for an enzyme, the more it blocks binding of other drug molecules
Half-life: determines duration of the interaction
Concentration: threshold concentration must be reached or exceeded to inhibit an enzyme
Toxic potential of the object drug
Efficacy: effectiveness of the object drug
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Drug–Drug Interactions Caused by Induction
Result of the action of one drug (inducer) stimulating the metabolism of an object drug (substrate)
Enhanced metabolism produced by an increase in hepatic blood flow or an increase in the formation of hepatic enzymes
Increases the amount of enzymes available to metabolize drug molecules, thereby decreasing the concentration and pharmacodynamic effect of the object drug
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Competitive and Noncompetitive Inhibition
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Renal Excretion of Drugs
Drugs are removed from the bloodstream by the kidneys by filtration or urinary secretion.
Reabsorption from the urine into the bloodstream may also occur.
Absorption may be affected by acidification or alkalinization of the urine and alteration of secretory or active transport pathways.
Although most drugs cross the membrane of the renal tubule by simple diffusion, some drugs are also secreted into the urine through active transport pathways.
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Metabolism eliminates a drug from the body by changing the drug molecule into something else, but drugs also can be eliminated from the body by excretion. Excretory organs include the kidneys, lower GI tract, lungs, and skin. Other structures, such as the sweat, salivary, and mammary glands, are active in excretion as well. Drugs may also be removed forcibly by dialysis.
The primary route of excretion is the kidney. After the drug is metabolized, the resultant metabolite may be filtered by the glomerulus. As the drug continues through the proximal tubule, loop of Henle, and distal tubule, several things may occur: the drug may exert action (as in the case of diuretics), be reabsorbed into the bloodstream, or remain in the nephron, eventually reaching the collecting ducts, from which it ultimately leaves the body in the patient’s urine. This filtration works well for hydrophilic, ionized compounds and is a common route of elimination. Conversely, active secretion of drugs occurs in the proximal tubule. Two different systems exist, one for organic acids (e.g., uric acid) and one for organic bases (e.g., histamine). Once ionized by the acidic pH of the urine, organic bases are not reabsorbed back into the bloodstream. If the pH rises, then more of the organic base becomes nonionized and thus more readily reabsorbed. Similarly, changes in urine pH can alter the reabsorption of organic acids, increasing or decreasing the circulating levels as the pH changes. Drugs such as penicillin are excreted by the organic acid system.
Drugs are excreted by the liver into the gallbladder, resulting in biliary elimination. Biliary elimination can sometimes result in drug reabsorption. For example, if a drug is excreted in the bile, it goes into the GI tract, where it may be reabsorbed and returned to the general circulation. This is called enterohepatic recirculation (Figure 2.4). The result of significant enterohepatic recirculation is a measurable increase in the plasma concentration of a drug and a delay in its elimination from the body.
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Biliary Excretion of Drugs
Biliary excretion allows for the elimination of drugs and their metabolites into the feces.
This route is involved in interactions with drugs that undergo enterohepatic recirculation.
Drugs are excreted into the GI tract through the biliary ducts and have the potential to be reabsorbed through the intestinal wall into the bloodstream.
Some of these drugs depend on enterohepatic recirculation to achieve therapeutic concentrations.
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Pharmacodynamic Interactions
Pharmacodynamic profile: responses or effects produced by a drug’s actions.
Drugs that have a similar characteristic in their pharmacodynamic profile may produce an exaggerated response.
Drugs may also produce opposing pharmacodynamic effects causing the expected drug response to be diminished or even abolished.
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Drug–Food Interactions
Absorption: food can alter extent of drug absorption or change rate of drug absorption.
Metabolism: grapefruit juice inhibits the 3A4 subset of intestinal cytochrome P-450 enzymes and increases the serum concentration of drugs dependent on these enzymes for metabolism; food may also induce drug metabolism and therefore decrease drug efficacy.
Excretion: ingestion of certain fruit juices can alter the urinary pH and affect the elimination and reabsorption of drugs such as quinidine and amphetamine.