Pharmacology_Katzung

Pharmacology_Katzung. Elements [12] to [14] of the prescription include refill information, waiver of the requirement for childproof containers, and additional labeling instructions (eg, warnings such as “may cause drowsiness,” “do not drink alcohol”). Pharmacists put the name of the medication on the label unless directed otherwise by the prescriber, and some medications have the name of the drug stamped or imprinted on the tablet or capsule. Pharmacists must place the expiration date for the drug on the label. If the patient or prescriber does not request waiver of childproof containers, the pharmacist or dispenser must place the medication in such a container. Pharmacists may not refill a prescription medication without authorization from the prescriber. Prescribers may grant authorization to renew prescriptions at the time of writing the prescription or over the telephone or electronically. Elements [15] to [17] are the prescriber’s signature and other identification data such as National Provider


Pharmacology_Katzung

Pharmacology_Katzung. at the time of writing the prescription or over the telephone or electronically. Elements [15] to [17] are the prescriber’s signature and other identification data such as National Provider Identification (NPI), Drug Enforcement Administration (DEA) number, or State License number.


Pharmacology_Katzung

Pharmacology_Katzung. Unfortunately, prescribing errors are common. Several groups provide online information regarding practices designed to reduce or document such errors, eg, Institute for Safe Medication Practices (ISMP; http://www.ismp.org/) and National Coordinating Council for Medication Error Reporting and Prevention Program (MERP; http://www.nccmerp.org/about-medication-errors). TABLE 65–1 Abbreviations used in prescriptions and chart orders. agit shake, stir D5W, D5W dextrose 5% in water disp, dis dispense mEq, meq milliequivalent qh, q1h rept, repet tbsp, T (do not use) Tr, tinct i, ii, iii, iv, etc by mouth one, two, three, four, etc dram (in fluid measure 3.7 mL) ounce (in fluid measure 29.6 mL) cap capsule q2h, q3h, etc every 2 hours, every 3 hours, etc gtt drops SC, SQ subcutaneous hs at bedtime Sig, S label IM intramuscular ss, ss one-half IVPB IV piggyback sup, supp suppository mcg, μg (do not use) microgram (always write out “microgram”) tab tablet OS, OL left eye vag vaginal


Pharmacology_Katzung

Pharmacology_Katzung. IM intramuscular ss, ss one-half IVPB IV piggyback sup, supp suppository mcg, μg (do not use) microgram (always write out “microgram”) tab tablet OS, OL left eye vag vaginal All prescription orders should be legible, unambiguous, dated (and timed in the case of a chart order), and signed clearly for optimal communication between prescriber, pharmacist, and nurse. Furthermore, a good prescription or chart order should contain sufficient information to permit the pharmacist or nurse to discover possible errors before the drug is dispensed or administered. Certain types of prescribing errors are particularly common. These include errors involving omission of needed information; poor writing perhaps leading to errors of drug dose or timing; and prescription of drugs that are inappropriate for the specific situation.


Pharmacology_Katzung

Pharmacology_Katzung. Errors of omission are common in hospital orders and may include instructions to “resume pre-op meds,” which assumes that a full and accurate record of the “pre-op meds” is available; “continue present IV fluids,” which fails to state exactly what fluids are to be given, in what volume, and over what time period; or “continue eye drops,” which omits mention of which eye is to be treated as well as the drug, concentration, and frequency of administration. Chart orders may also fail to discontinue a prior medication when a new one is begun; may fail to state whether a regular or long-acting form is to be used; may fail to specify a strength or notation for long-acting forms; or may authorize “as needed” (prn) use that fails to state what conditions will justify the need.


Pharmacology_Katzung

Pharmacology_Katzung. Poor prescription writing is traditionally exemplified by illegible handwriting. However, other types of poor writing are common and often more dangerous. One of the most important is the misplaced or ambiguous decimal point. Thus “.1” is easily misread as “1,” a tenfold overdose, if the decimal point is not unmistakably clear. This danger is easily avoided by always preceding the decimal point with a zero. On the other hand, appending an unnecessary zero after a decimal point increases the risk of a tenfold overdose, because “1.0 mg” is easily misread as “10 mg,” whereas “1 mg” is not. The slash or virgule (“/”) was traditionally used as a substitute for a decimal point. This should be abandoned because it is too easily misread as the numeral “1.” Similarly, the abbreviation “U” for units should never be used because “10 U” is easily misread as “100”; the word “units” should always be written out. Doses in micrograms should always have this unit written out because the abbreviated


Pharmacology_Katzung

Pharmacology_Katzung. should never be used because “10 U” is easily misread as “100”; the word “units” should always be written out. Doses in micrograms should always have this unit written out because the abbreviated form (“μg”) is very easily misread as “mg,” a 1000-fold overdose! Orders for drugs specifying only the number of dosage units and not the total dose required should not be filled if more than one size dosage unit exists for that drug. For example, ordering “one ampule of furosemide” is unacceptable because furosemide is available in ampules that contain 20, 40, or 100 mg of the drug. The abbreviation “OD” should be used (if at all) only to mean “the right eye”; it has been used for “every day” and has caused inappropriate administration of drugs into the eye. Similarly, “Q.D.” or “QD” should not be used because it is often read as “QID,” resulting in four daily doses instead of one. Acronyms and abbreviations such as “ASA” (aspirin), “5-ASA” (5-aminosalicylic acid), “6MP” (6-mercaptopurine),


Pharmacology_Katzung

Pharmacology_Katzung. be used because it is often read as “QID,” resulting in four daily doses instead of one. Acronyms and abbreviations such as “ASA” (aspirin), “5-ASA” (5-aminosalicylic acid), “6MP” (6-mercaptopurine), etc, should not be used; drug names should be written out. Unclear handwriting can be lethal when drugs with similar names but very different effects are available, eg, acetazolamide and acetohexamide, methotrexate and metolazone. In this situation, errors are best avoided by noting the indication for the drug in the body of the prescription, eg, “acetazolamide, for glaucoma.” Pharmacy and Therapeutics committees have developed some additional principles to lessen errors, such as a High-Alert Medication list and using a comma (in the USA) when the dose exceeds 999.


Pharmacology_Katzung

Pharmacology_Katzung. Prescribing an inappropriate drug for a particular patient often results from failure to recognize contraindications imposed by other diseases the patient may have, failure to obtain information about other drugs the patient is taking (including over-thecounter drugs), or failure to recognize possible physicochemical incompatibilities between drugs that may react with each other. Contraindications to drugs in the presence of other diseases or pharmacokinetic characteristics are listed in the discussions of the drugs described in this book. The manufacturer’s package insert usually contains similar information. Many of the important drug interactions are listed in Chapter 66 of this book as well as in package inserts.


Pharmacology_Katzung

Pharmacology_Katzung. Physicochemical incompatibilities are of particular concern when parenteral administration is planned. For example, certain insulin preparations should not be mixed. Similarly, the simultaneous administration of antacids or products high in metal content may compromise the absorption of many drugs in the intestine, eg, tetracyclines. The package insert and the Handbook on Injectable Drugs (see References) are good sources for this information.


Pharmacology_Katzung

Pharmacology_Katzung. Seventy percent of prescriptions in the USA are now E-prescribed. Congress has passed legislation related to E-prescribing, including Medicare Improvement for Patients and Providers Act (MIPPA) and the Medicare and Medicaid Electronic Health Record Incentive Program or the “meaningful use program.” E-prescribing provides an electronic flow of information between the prescriber, intermediary, pharmacy, and health plan. The health plan can provide information on patient eligibility, formulary, benefits, costs, and sometimes, a medication history. The prescriber selects the medication, strength, dosage form, quantity, and directions for use and the prescription is transmitted to the pharmacy where the appropriate data fields are populated. The pharmacist reviews the order and, if appropriate, dispenses the prescription. The electronic system must be Health Insurance Portability and Accountability Act (HIPAA)-compliant, and there is often a business association agreement between the


Pharmacology_Katzung

Pharmacology_Katzung. dispenses the prescription. The electronic system must be Health Insurance Portability and Accountability Act (HIPAA)-compliant, and there is often a business association agreement between the parties involved.


Pharmacology_Katzung

Pharmacology_Katzung. Prescribers can obtain decision support information such as disease-drug and drug-drug interaction information or cost information prior to prescribing as part of the health plan information. Prescriptions can be clear in their writing, but pull-down drug lists can create new errors. Prescription renewals can be processed electronically and drug misuse or abuse may be identifiable. Theoretically, time to process prescription orders should be reduced and patients would have their medication ready when they arrive at the pharmacy.


Pharmacology_Katzung

Pharmacology_Katzung. The DEA has issued rules for e-prescribing of controlled substances. Currently, only registered prescribers can e-prescribe, and there will be several independent identification proofing sources required: a unique pin number, or retinal scan, or a finger print. The objective is to prevent drug diversion. DEA registrants, including pharmacies and physicians, can order controlled drugs via computer using a specific form once they are certified (Controlled Substances Ordering System, CSOS).


Pharmacology_Katzung

Pharmacology_Katzung. Compliance (also called adherence) is the extent to which patients follow treatment instructions. There are four types of noncompliance leading to medication errors and increased health care costs as given below: 1. The patient fails to obtain the medication. Some studies suggest that one third of patients never have their prescriptions filled. Patients usually leave the hospital without obtaining their discharge medications because the hospital is not reimbursed for them by the insurer; others leave the hospital without having their prehospitalization medications resumed. In many cases, patients cannot afford the medications prescribed. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. The patient fails to take the medication as prescribed. Examples include wrong dosage, wrong frequency of administration, improper timing or sequencing of administration, wrong route or technique of administration, or taking medication for the wrong purpose. This usually results from inadequate communication between the patient, the prescriber, and the pharmacist. 3. The patient prematurely discontinues the medication. This can occur, for instance, if the patient incorrectly assumes that the medication is no longer needed because the bottle is empty or symptomatic improvement has occurred. 4. The patient (or another person) takes medication inappropriately. For example, the patient may share a medication with others for any of several reasons.


Pharmacology_Katzung

Pharmacology_Katzung. Several factors encourage noncompliance. Some diseases cause no symptoms (eg, hypertension); patients with these diseases therefore have no symptoms to remind them to take their medications. Patients with painful conditions such as arthritis may continually change medications in the hope of finding a better one. Characteristics of the therapy itself can limit the degree of compliance; patients taking a drug once a day are much more likely to be compliant than those taking a drug four times a day. Various patient factors also play a role in compliance. Patients living alone are much less likely to be compliant than married patients of the same age. Packaging may also be a deterrent to compliance—elderly arthritic patients often have difficulty opening their medication containers. Lack of transportation as well as various cultural or personal beliefs about medications are likewise barriers to compliance. For example, some parents refuse to allow their children to be vaccinated because


Pharmacology_Katzung

Pharmacology_Katzung. transportation as well as various cultural or personal beliefs about medications are likewise barriers to compliance. For example, some parents refuse to allow their children to be vaccinated because of a misguided fear of autism.


Pharmacology_Katzung

Pharmacology_Katzung. Strategies for improving compliance include enhanced communication between the patient and health care team members; assessment of personal, social, and economic conditions (often reflected in the patient’s lifestyle); development of a routine for taking medications (eg, at mealtimes if the patient has regular meals); provision of systems to assist taking medications (ie, containers that separate drug doses by day of the week, or medication alarm clocks that remind patients to take their medications); and mailing of refill reminders by the pharmacist to patients taking drugs chronically. The patient who is likely to discontinue a medication because of a perceived drug-related problem should receive instruction about how to monitor and understand the effects of the medication. Compliance can often be improved by enlisting the patient’s active participation in the treatment.


Pharmacology_Katzung

Pharmacology_Katzung. The United States government recognizes two classes of drugs: (1) over-the-counter (OTC) drugs and (2) those that require a prescription from a licensed prescriber (Rx Only). OTC drugs are those that can be safely self-administered by the layman for self-limiting conditions and for which appropriate labels can be written for lay comprehension (see Chapter 63). Half of all drug doses consumed by the American public are OTC drugs. In 2014 in the USA, $373.9 billion was spent on prescription drugs and $30.7 billion was spent on OTC drugs, more than any other country.


Pharmacology_Katzung

Pharmacology_Katzung. Physicians, dentists, podiatrists, and veterinarians—and, in many states, specialized pharmacists, nurses, physician’s assistants, and optometrists—are granted authority to prescribe certain drugs (those bearing the federal legend statement, “Rx Only”) on the basis of their training in diagnosis and treatment (see Box: Who May Prescribe?). Depending on the state, mid-level practitioners may prescribe/furnish prescriptions. Pharmacists are authorized to dispense prescriptions pursuant to a prescriber’s order provided that the medication order is appropriate and rational for the patient. Nurses are authorized to administer medications to patients subject to a prescriber’s order.


Pharmacology_Katzung

Pharmacology_Katzung. Because of the multiplicity of third-party payers (health insurers) and Medicare and Medicaid claimants, the concept of electronic processing of prescriptions (“e-prescribing”) has become urgent. (Further information about e-prescribing may be found at http:// www.cms.gov/Medicare/E-Health/Eprescribing/.) To further standardize electronic prescription transmission and billing, the Centers for Medicare and Medicaid (CMS) issued regulations effective in 2008 requiring all US health care providers to obtain a National Provider Identification (NPI) number. This 10-digit identifier is issued by the National Plan and Provider Enumeration System (NPPES) at https://NPPES.cms.hhs.gov. The purpose of the NPI is to identify all health care transactions (and associated costs) incurred by a particular practitioner with a single number.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to a health care provider’s unique identification number, some states require that prescriptions for controlled substances be written on tamper-resistant security prescription forms. The purpose of this legislation is to prevent forgeries and to tighten the control of prescription order forms.


Pharmacology_Katzung

Pharmacology_Katzung. The concept of a “secure” prescription form was expanded by the federal government in 2008 to all prescriptions written for Medicaid patients. Any prescription for a Medicaid patient must be written on a security form if the pharmacist is to be compensated for the prescription service. In turn, the use of “triplicate” prescription forms was eliminated and replaced with an online electronic transmission system whereby orders for Schedule II, Schedule III, and Schedule IV prescriptions are transmitted to a company that acts as a repository for these transactions. In California, it is called the CURES program (Controlled Substances Utilization Review and Evaluation System). Prescribers are provided with a record of who prescribed which controlled drug to which patient. Additional information about CURES may be found at http://oag.ca.gov/cures-pdmp.


Pharmacology_Katzung

Pharmacology_Katzung. In the USA, prescription drugs are controlled by the US Food and Drug Administration (FDA) as described in Chapter 1. The federal legend statement as well as the package insert are part of the packaging requirements for all prescription drugs. The package insert is the official brochure setting forth the indications, contraindications, warnings, and dosing for the drug. The prescriber, by writing and signing a prescription order, controls who may obtain prescription drugs. The pharmacist may purchase these drugs, but they may be dispensed only on the order of a legally qualified prescriber. Thus, a prescription is actually three things: the prescriber’s order in the patient’s chart, the written order to which the pharmacist refers when dispensing, and the patient’s medication container with a label affixed. Who May Prescribe?


Pharmacology_Katzung

Pharmacology_Katzung. The right to prescribe drugs has traditionally been the respon-sibility of the physician, dentist, podiatrist, or veterinarian. Prescribing now includes—in a number of states and in varying degrees—pharmacists, nurse practitioners, nurse midwives, phy-sician’s assistants, and optometrists (see below; Table 65–2). In the future, physical therapists may be licensed to prescribe drugs relevant to their practice. The development of large health main-tenance organizations has greatly strengthened this expansion of prescribing rights because it offers these extremely powerful economic bodies a way to reduce their expenses. The primary organizations controlling the privilege of prescribing in the USA are the state boards, under the pow-ers delegated to them by the state legislatures. Many state boards have attempted to reserve some measure of the primary responsibility for prescribing to physicians by requiring that the ancillary professional work with or under a physician according to a


Pharmacology_Katzung

Pharmacology_Katzung. boards have attempted to reserve some measure of the primary responsibility for prescribing to physicians by requiring that the ancillary professional work with or under a physician according to a specific protocol. In the state of California, this protocol must include a statement of the training, supervision, and docu-mentation requirements of the arrangement and must specify referral requirements, limitations to the list of drugs that may be prescribed (ie, a formulary), and a method of evaluation by the supervising physician. The protocol must be in writing and must be periodically updated. The following rules govern prescribing by nonphysicians in the various states at the time of this writing. In almost all states, nurse practitioners (NPs) and physician assistants (PAs) may prescribe with or without physician supervi-sion depending on the state. Likewise, optometrists may prescribe selected formulary drugs for ophthalmologic indications. Pharmacists can initiate prescriptions


Pharmacology_Katzung

Pharmacology_Katzung. with or without physician supervi-sion depending on the state. Likewise, optometrists may prescribe selected formulary drugs for ophthalmologic indications. Pharmacists can initiate prescriptions in three states: Montana, New Mexico, and North Carolina. They may practice with physicians in collaborative drug therapy management (CDTM) programs in 47 states—all except New York, Maine, Oklahoma, and Alabama. Pharmacists may prescribe controlled substances under physician supervision in California, Massachusetts, Montana, New Mexico, North Carolina, Ohio, and Washington. New Mexico grants prescribing authority to medical psychologists with advanced training.


Pharmacology_Katzung

Pharmacology_Katzung. Whereas the US FDA controls the drugs and their labeling and distribution, the state legislatures control who may prescribe drugs through their licensing boards, eg, the Board of Medical Examiners. Prescribers must pass examinations, pay fees, and—in the case of some states and some professions—meet other requirements for TABLE 65–2 Prescribing authority of certain allied health professionals in selected states. 1Under protocol; see Box: Who May Prescribe? 2In collaboration with or under the supervision of a physician. TABLE 65–3 Classification of controlled substances. (See Inside Front Cover for examples.) relicensure such as continuing education. If these requirements are met, the prescriber is licensed to order dispensing of drugs.


Pharmacology_Katzung

Pharmacology_Katzung. The FDA Amendments Act of 2007 gave the FDA authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks. The goal of this strategy is to inform physicians of the emphasized risks and benefits. Furthermore, some drugs have “boxed warnings” to elucidate their risks as part of FDA-mandated labeling.


Pharmacology_Katzung

Pharmacology_Katzung. The federal government and the states further impose special restrictions on drugs according to their perceived potential for abuse (Table 65–3). Such drugs include opioids, hallucinogens, stimulants, depressants, and anabolic steroids. Special requirements must be met when these drugs are to be prescribed. The Controlled Drug Act requires prescribers and dispensers to register with the Drug Enforcement Agency (DEA), pay a fee, receive a personal registration number, and keep records of all controlled drugs prescribed or dispensed. Every time a controlled drug is prescribed, a valid DEA number must appear on the prescription. In the USA, there is an opioid epidemic with an increase in overdoses. To combat this public health trend, prescriber education, tracking of prescribing patterns, limitations on amounts prescribed, and target education are being instituted.


Pharmacology_Katzung

Pharmacology_Katzung. Prescriptions for substances with a high potential for abuse (Schedule II drugs) cannot be refilled without a new prescription. However, multiple prescriptions for the same drug may be written with instructions not to dispense before a certain date and up to a total of 90 days. Prescriptions for Schedules III, IV, and V can be refilled if ordered, but there is a five-refill maximum, and in no case may the prescription be refilled after 6 months from the date of writing. Schedule II drug orders may not be transmitted over the telephone, and some states require a tamper-resistant security prescription blank to reduce the chances for drug diversion. These restrictive prescribing laws are intended to limit the amount of drugs of abuse that are made available to the public.


Pharmacology_Katzung

Pharmacology_Katzung. Unfortunately, the inconvenience occasioned by these laws— and an unwarranted fear by medical professionals themselves regarding the risk of patient tolerance and addiction—continues to hamper adequate treatment of patients with terminal conditions. This has been shown to be particularly true in children and elderly patients with cancer. There is no excuse for inadequate treatment of pain in a terminal patient; not only is addiction irrelevant in such a patient, it is actually uncommon in patients who are being treated for pain (see Chapter 31). Unfortunately, the initiative begun several years ago to manage pain more actively has led to the overuse of opioids in patients with chronic pain, a condition that does not respond well to these drugs. Chronic use of oxycodone, hydrocodone, and methadone has resulted in a marked increase in habituation, overdoses, and deaths. As a result, most professional authorities now advise limiting the use of any opioid to acute pain only and the use of


Pharmacology_Katzung

Pharmacology_Katzung. has resulted in a marked increase in habituation, overdoses, and deaths. As a result, most professional authorities now advise limiting the use of any opioid to acute pain only and the use of NSAIDs and other nonaddicting therapies in chronic conditions.


Pharmacology_Katzung

Pharmacology_Katzung. Some states have recognized the underutilization of pain medications in the treatment of pain associated with chronic and terminal conditions. In California, upon receipt of a copy of the order from the prescriber, eg, by fax, a pharmacist may write a prescription for a Schedule II substance for a patient under hospice care or living in a skilled nursing facility or in cases in which the patient is expected to live less than 6 months, provided that the prescriber countersigns the order (by fax); the word “exemption” with regulatory code number is written on a typical prescription, thus providing easier access for the terminally ill. Labeled & Off-Label Uses of Drugs


Pharmacology_Katzung

Pharmacology_Katzung. Labeled & Off-Label Uses of Drugs In the USA, the FDA approves a drug only for the specific uses proposed and documented by the manufacturer in its New Drug Application (see Chapter 1). These approved (labeled) uses or indications are set forth in the package insert that accompanies the drug. For a variety of reasons, these labeled indications may not include all the conditions in which the drug might be useful. Therefore, a clinician may wish to prescribe the agent for some other, unapproved (off-label), clinical condition, often on the basis of adequate or even compelling scientific evidence. Federal laws governing FDA regulations and drug use place no restrictions on such unapproved use. *


Pharmacology_Katzung

Pharmacology_Katzung. Even if the patient suffers injury from the drug, its use for an unlabeled purpose does not in itself constitute “malpractice.” However, the courts may consider the package insert labeling as a complete listing of the indications for which the drug is considered safe unless the clinician can show that other use is considered safe by competent expert testimony. Governmental drug-regulating agencies have responsibility for monitoring drug safety. In the USA, the FDA-sponsored Med Watch program collects data on safety and adverse drug effects (ADEs) * “Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in the approved labeling. Such ‘unapproved’ or, more precisely, ‘unlabeled’ uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.”–FDA Drug Bull 1982;12:4.


Pharmacology_Katzung

Pharmacology_Katzung. through mandatory reporting by drug manufacturers and voluntary reporting by health care practitioners. Practitioners may submit reports on any suspected adverse drug (or medical device) effect using a simple form obtainable from http://www.fda.gov/ medwatch/index.html. The FDA is expected to use these data to establish an adverse effect rate. It is not clear that the FDA has sufficient resources at present to carry out this mandate, but they are empowered to take further regulatory actions if deemed necessary. A similar vaccine-reporting program is in place to monitor vaccine safety (VAERS, vaccine adverse event reporting system). The FDA homepage can be found at https://vaers.hhs.gov.


Pharmacology_Katzung

Pharmacology_Katzung. The FDA has also increased requirements for labeling on drugs that carry special risks. Dispensers of medications are required to distribute “Med Guides” to patients when these medications are dispensed. These guides are generated by the manufacturers of the medications. In addition, pharmacists often provide patient educational materials that describe the drug, its use, adverse effects, storage requirements, methods of administration, what to do when a dose is missed, and the potential need for ongoing therapy. The Cost of Prescriptions


Pharmacology_Katzung

Pharmacology_Katzung. Multiple factors are involved in the pricing of pharmaceuticals. Research costs, marketing costs, production costs, shipping costs, regulatory costs, and profit all contribute to a drug’s price. Insurance companies pay for the drug because an extensive formulary is mandated by regulations. Federal law and regulations require Medicare Part D pharmacy and therapeutics committees to make prescription drug coverage decisions based on scientific evidence and standards of practice, and also to prevent discrimination in a patient’s drug therapy. Because these companies are publicly owned, the shareholders exert a strong influence to maximize profits. While the cost to make the drug may be 20% (or less) of the wholesale price, the aforementioned costs contribute to the cost of the drug to the pharmacist or physician. Greed and the excessive influence of shareholder funds (as opposed to the interests of consumers) add another component of cost and have sometimes resulted in startling increases


Pharmacology_Katzung

Pharmacology_Katzung. or physician. Greed and the excessive influence of shareholder funds (as opposed to the interests of consumers) add another component of cost and have sometimes resulted in startling increases in the price of long-established drugs (which have no current development costs) as well as newer ones. In the case of pyrimethamine, a simple and long-established drug used for toxoplasmosis, the US price increased from approximately $13/tablet to $750/tablet in 2015 when a new company acquired the rights to this drug. In 2016, the price of the formulation of epinephrine most commonly used for anaphylaxis (Epi-Pen) increased from $50 to $300 per single dose, even though no changes were made in the drug, the vehicle, or the injection unit.


Pharmacology_Katzung

Pharmacology_Katzung. A more complex situation applies to the pricing of new, complex molecules that, unlike the above examples, required massive research, development, and manufacturing investment, eg, the new agents used for hepatitis B and C. These agents are extremely expensive in the USA ($75,000–$120,000 for one course of treatment), but the manufacturers justify the cost as being less than the alternative (which is often a liver transplant). In fact, these “specialty drugs” represent one third of the drug spending in the USA. Because the US Congress currently prohibits price negotiations by the largest purchaser of drugs (Medicare), the public has no protection from excessive pricing by manufacturers. Currently, only the Veteran’s Administration and the largest private pharmacy benefits manager (PBM) agencies are able to negotiate prices, and as a result, drug expenses constitute a large and growing burden to patients, Medicare, and private health insurers.


Pharmacology_Katzung

Pharmacology_Katzung. Generic drug dispensing represents 10% of the total US drug expense but 90% of the drugs dispensed. Prescribing by generic name offers the pharmacist flexibility in selecting the particular drug product to fill the order and offers the patient a potential savings when there is price competition. For example, the brand name of a popular sedative is Valium. The generic (public non-proprietary) name of the same chemical substance adopted by United States Adopted Names (USAN) and approved by the FDA is diazepam. All diazepam drug products in the USA meet the pharmaceutical standards expressed in the United States Pharmacopeia (USP). However, there are several manufacturers, and prices vary. For drugs in common use, the difference in cost between the trade-named product and generic products varies from less than twofold to more than 100-fold. For drugs with a limited market (eg, pyrimethamine, Epi-Pen), the incentive for generic manufacturing and marketing is very low, so only one or two


Pharmacology_Katzung

Pharmacology_Katzung. from less than twofold to more than 100-fold. For drugs with a limited market (eg, pyrimethamine, Epi-Pen), the incentive for generic manufacturing and marketing is very low, so only one or two generics (or none) may be available, and price competition is low or absent.


Pharmacology_Katzung

Pharmacology_Katzung. In most states and in most hospitals, pharmacists have the option of supplying a generically equivalent drug product even if a proprietary name has been specified in the order. If the prescriber wants a particular brand of drug product dispensed, handwritten instructions to “dispense as written” or words of similar meaning are required. Some government-subsidized health care programs and many third-party insurance payers require that pharmacists dispense the cheapest generically equivalent product in the inventory (generic substitution). However, the principles of drug product selection by private pharmacists do not permit substituting one therapeutic agent for another (therapeutic substitution); that is, dispensing trichlormethiazide for hydrochlorothiazide would not be permitted without the prescriber’s permission even though these two diuretics may be considered pharmacodynamically equivalent. Pharmacists within managed care organizations may follow different policies; see below.


Pharmacology_Katzung

Pharmacology_Katzung. It cannot be assumed that every generic drug product is as satisfactory as the trade-named product, although examples of unsatisfactory generics are rare. Bioavailability—the effective absorption of the drug product—varies between manufacturers and sometimes between different lots of a drug produced by the same manufacturer. Despite the evidence, many practitioners avoid generic prescribing, thereby increasing medical costs. In the case of a very small number of drugs, which usually have a low therapeutic index, poor solubility, or a high ratio of inert ingredients to active drug content, a specific manufacturer’s product may give more consistent results. In the case of life-threatening diseases, the advantages of generic substitution may be outweighed by the clinical urgency so that the prescription should be filled as written.


Pharmacology_Katzung

Pharmacology_Katzung. In an effort to codify bioequivalence information, the FDA publishes Approved Drug Products with Therapeutic Equivalence Evaluations, with monthly supplements, commonly called “the Orange Book.” The book contains listings of multisource products in one of two categories: Products given a code beginning with the letter “A” are considered bioequivalent to a reference standard formulation of the same drug and to all other versions of that product with a similar “A” coding. Products not considered bioequivalent are coded “B.” Of the approximately 8000 products currently listed, 90% are coded “A.” Additional code letters and numerals are appended to the initial “A” or “B” and indicate the approved route of administration and other variables.


Pharmacology_Katzung

Pharmacology_Katzung. Mandatory drug product selection on the basis of price is common practice in the USA because third-party payers (insurance companies, health maintenance organizations, etc) enforce money-saving regulations. If outside a managed care organization, the prescriber can sometimes override these controls by writing “dispense as written” on a prescription that calls for a brand-named product. However, in such cases, the patient may have to pay the difference between the dispensed product and the cheaper one. Within most managed care organizations, formulary controls have been put in place that force the selection of less expensive medications whenever they are available. In a managed care environment, the prescriber often selects the drug group rather than a specific agent, and the pharmacist dispenses the formulary drug


Pharmacology_Katzung

Pharmacology_Katzung. Aiken M, IMS Institute for Health Care Informatics: Medicines use and spending shifts: A review of the use of medicines in the U.S. in 2014. http:// www.imshealth.com/en/thought-leadership/quintilesims-institute/reports/ medicines-use-in-the-us-2014. Allen L Jr: Remington’s The Science and Practice of Pharmacy, 22nd ed. Pharmaceutical Press, 2012. American Pharmacists Association and The National Association of Chain Drug Stores: MTM in Pharmacy Practice, Core Elements v. 2, 2008. Bell D: A toolset for e-prescribing implementation. Rand Health, US AHRQ, 2011. California Business and Professions Code, Chapter 9, Division 2, Pharmacy Law. Department of Consumer Affairs, Sacramento, California, 2016. Consumer Healthcare Products Association: OTC Retail Sales 1964-2015. http:// chpa.org/OTCRetailSales.aspx. de Oliveira, DJ, Brummel AR, Miller DR: Medication therapy management: 10 years of experience in a large integrated health system. J Managed Care Pharm 2010;3:185.


Pharmacology_Katzung

Pharmacology_Katzung. de Oliveira, DJ, Brummel AR, Miller DR: Medication therapy management: 10 years of experience in a large integrated health system. J Managed Care Pharm 2010;3:185. Department of Health and Human Services: About the (opioid) epidemic. https:// www.hhs.gov/opioids/about-the-epidemic/. from that group. For example, if a prescriber in such an organization decides that a patient needs a thiazide diuretic, the pharmacist automatically dispenses the single thiazide diuretic carried on the organization’s formulary. As noted below, the choice of drugs for the organization’s formulary may change from time to time, depending on negotiation of prices and rebates with different manufacturers.


Pharmacology_Katzung

Pharmacology_Katzung. The private pharmacy bases its charges on the cost of the drug plus a fee for providing a professional service. Each time a prescription is dispensed, there is a fee. The prescriber controls the frequency of filling prescriptions by authorizing refills and specifying the quantity to be dispensed. However, for medications used for chronic illnesses, the quantity covered by insurance may be limited to the amount used in 1 month or 30 days. Thus, the prescriber can save the patient money by prescribing standard sizes (so that drugs do not have to be repackaged) and, when chronic treatment is involved, by ordering the largest quantity consistent with safety, expense, and third-party plan. Optimal prescribing for cost savings often involves consultation between the prescriber and the pharmacist. Because of continuing increases in the wholesale prices of drugs in the USA, prescription costs have risen dramatically over the past three decades, and with the passage of the Affordable Care Act


Pharmacology_Katzung

Pharmacology_Katzung. Because of continuing increases in the wholesale prices of drugs in the USA, prescription costs have risen dramatically over the past three decades, and with the passage of the Affordable Care Act (ACA), prescription volume increased while hospital services decreased.


Pharmacology_Katzung

Pharmacology_Katzung. Drug Enforcement Administration: Mid-Level Practitioners Authorized by State, Title 21, Code of Federal Regulations, Section 1300.01 (b28), 5-24-16. Gabriel MH: E-Prescribing Trends in the US, ONC Data Brief, 18, July, 2014. Graber MA, Easton-Carr R: Poverty and pain: Ethics and the lack of opioid pain medications in fixed-price, low-cost prescription plans. Ann Pharmacother 2008;42:1913. Institute for Safe Medication Practices. http://www.ismp.org. Jerome JB, Sagan P: The USAN nomenclature system. JAMA 1975;232:294. Kesselheim AS, Avorn J, Sarpatwari JD: The high cost of prescription drugs in the United States. Origins and prospects for reform. JAMA 2016;316:858. Kesselheim AS et al: Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: A systematic review and meta-analysis. JAMA 2008;300:2514.


Pharmacology_Katzung

Pharmacology_Katzung. Kesselheim AS et al: Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: A systematic review and meta-analysis. JAMA 2008;300:2514. Levinson DR. Gaps in Oversight of Conflicts of Interest in Medicare Prescription Drug Decisions, DHHS, Office of Inspector General, March, 2013. https:// oig.hhs.gov/oei/reports/oei-05-10-00450.pdf. Schnipper JL et al: Role of pharmacist counseling in preventing adverse drug events after hospitalization. Arch Intern Med 2006;166:565. Trissel LA: Handbook on Injectable Drugs, 19th ed. American Society of Hospital Pharmacists, 2016. John R. Horn, PharmD, FCCP


Pharmacology_Katzung

Pharmacology_Katzung. Trissel LA: Handbook on Injectable Drugs, 19th ed. American Society of Hospital Pharmacists, 2016. John R. Horn, PharmD, FCCP One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic (additive, synergistic, or antagonistic effects), or combined interactions. The general principles of pharmacokinetics are discussed in Chapters 3 and 4; the general principles of pharmacodynamics are discussed in Chapter 2.


Pharmacology_Katzung

Pharmacology_Katzung. Botanical medications (“herbals”) may interact with each other or with conventional drugs. Unfortunately, botanicals are much less well studied than other drugs, so information about their interactions is scanty. Pharmacodynamic herbal interactions are described in Chapter 64. Pharmacokinetic interactions that have been documented (eg, St. John’s wort) are listed in Table 66–1. Knowledge of the mechanism by which a given drug interaction occurs is often clinically useful, since the mechanism may influence both the time course and the methods of circumventing the interaction. Some important drug interactions occur as a result of two or more mechanisms.


Pharmacology_Katzung

Pharmacology_Katzung. The designations listed in Table 66–1 are used here to estimate the predictability of the drug interactions. These estimates are intended to indicate simply whether or not the interaction will occur, and they do not always mean that the interaction is likely to produce an adverse effect. Whether or not the interaction occurs (precipitant drug produces a measurable change in the object drug action) and produces an adverse effect depends on both patientand drug-specific factors. Patient factors can include intrinsic drug clearance, genetics, gender, concurrent diseases, and diet. Drug-specific factors include dose, route of administration, drug formulation, and the sequence of drug administration. The most important factor that can mitigate the risk of patient harm is recognition by the prescriber of a potential interaction followed by appropriate action.


Pharmacology_Katzung

Pharmacology_Katzung. The gastrointestinal absorption of drugs may be affected by concurrent use of other agents that (1) have a large surface area upon which the drug can be adsorbed, (2) bind or chelate, alter gastric pH, (4) alter gastrointestinal motility, or affect transport proteins such as P-glycoprotein and organic anion transporters. One must distinguish between effects on absorption rate and effects on extent of absorption. A reduction in only the absorption rate of a drug is seldom clinically important, whereas a reduction in the extent of absorption is clinically important if it results in subtherapeutic serum concentrations. Similarly, an increase in the extent of absorption can lead to adverse patient outcomes.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanisms by which drug interactions alter drug distribution include (1) competition for plasma protein binding, displacement from tissue binding sites, and (3) alterations in local tissue barriers, eg, P-glycoprotein inhibition in the blood-brain barrier. Although competition for plasma protein binding can increase the free concentration (and thus the effect) of the displaced drug in plasma, the increase will be transient owing to a compensatory increase in drug disposition. The clinical importance of protein binding displacement has been overemphasized; current evidence suggests that such interactions are unlikely to result in adverse effects. Displacement from tissue binding sites would tend to transiently increase the blood concentration of the displaced drug. (Text continues on page 1171.) TABLE 66–1 Important drug interactions.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. agents gastrointestinal tract, thus reducing absorption. Some antacids (eg, magnesium hydroxide with aluminum hydroxide) alkalinize the urine somewhat, thus altering excretion of drugs sensitive to urinary pH. H2-antagonists and proton-pump inhibitors can alter the absorption of drugs requiring gastric acidity for dissolution. Alcohol Chronic alcoholism results in enzyme induction. Acute alcoholic intoxication tends to inhibit drug metabolism (whether person is alcoholic or not). Severe alcohol-induced hepatic dysfunction may inhibit ability to metabolize drugs. Disulfiram-like reaction in the presence of certain drugs. Additive central nervous system depression with other central nervous system depressants. Allopurinol Inhibits hepatic drug-metabolizing enzymes. Febuxostat will also inhibit the metabolism of azathioprine and mercaptopurine.


Pharmacology_Katzung

Pharmacology_Katzung. Allopurinol Inhibits hepatic drug-metabolizing enzymes. Febuxostat will also inhibit the metabolism of azathioprine and mercaptopurine. Antivirals: [P] Decreased absorption of antivirals that require acid for dissolution including atazanavir, fosamprenavir, indinavir, nelfinavir, rilpivirine. Azole antifungals: [P] Reduced gastrointestinal absorption of itraconazole, ketoconazole, and posaconazole due to increased gastric pH. Digoxin: [NP] Decreased gastrointestinal absorption of digoxin. Iron: [P] Decreased gastrointestinal absorption of iron with calcium-containing antacids. Kinase inhibitors: [P] Reduced gastrointestinal absorption of bosutinib, dabrafenib, dasatinib, erlotinib, idelalisib, and lapatinib due to increased gastric pH.


Pharmacology_Katzung

Pharmacology_Katzung. Quinolones: [HP] Decreased gastrointestinal absorption of ciprofloxacin, norfloxacin, and enoxacin (and probably other quinolones). Rosuvastatin: [P] Decreased absorption of rosuvastatin. Salicylates: [P] Increased renal clearance of salicylates due to increased urine pH; occurs only with large doses of salicylates. Tetracyclines: [HP] Decreased gastrointestinal absorption of tetracyclines. Thyroxine: [NP] Reduced gastrointestinal absorption of thyroxine. Acetaminophen: [NE] Increased formation of hepatotoxic acetaminophen metabolites (in chronic alcoholics). Acitretin: [P] Increased conversion of acitretin to etretinate (teratogenic). Anticoagulants, oral: [NE] Increased hypoprothrombinemic effect with acute alcohol intoxication. Central nervous system depressants: [HP] Additive or synergistic central nervous system depression. Insulin: [NE] Acute alcohol intake may increase hypoglycemic effect of insulin (especially in fasting patients).


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that may produce a disulfiram-like reaction: Cephalosporins: [NP] Disulfiram-like reactions are noted with cefamandole, cefoperazone, cefotetan, and moxalactam. Chloral hydrate: [NP] Mechanism not established. Disulfiram: [HP] Inhibited aldehyde dehydrogenase. Metronidazole: [NP] Mechanism not established. Sulfonylureas: [NE] Chlorpropamide is most likely to produce a disulfiram-like reaction; acute alcohol intake may increase hypoglycemic effect (especially in fasting patients). Anticoagulants, oral: [NP] Increased hypoprothrombinemic effect. Azathioprine: [P] Decreased azathioprine detoxification resulting in increased azathioprine toxicity. Mercaptopurine: [P] Decreased mercaptopurine metabolism resulting in increased mercaptopurine toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. (Continued) E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Antidepressants, tricyclic and heterocyclic


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Antidepressants, tricyclic and heterocyclic Inhibition of transmitter uptake into 5-HT and NE neurons. Antimuscarinic effects may be additive with other antimuscarinic drugs. Susceptible to induction and inhibition of metabolism via CYP2D6, CYP3A4, and other CYP450 enzymes. Inhibition of CYP3A4 (itraconazole = ketoconazole > posaconazole > voriconazole > fluconazole). Inhibition of CYP2C9 (fluconazole, voriconazole). Inhibition of P-glycoprotein (itraconazole, ketoconazole, posaconazole). Susceptible to enzyme inducers (itraconazole, ketoconazole, voriconazole).


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone: [P] Decreased antidepressant metabolism. Expect similar interactions with dronedarone. Barbiturates: [P] Increased antidepressant metabolism. Bupropion: [NE] Decreased antidepressant metabolism. Carbamazepine: [NP] Enhanced metabolism of antidepressants. Cimetidine: [P] Decreased antidepressant metabolism. Clonidine: [P] Decreased clonidine antihypertensive effect. Diphenhydramine: [P] Decreased metabolism of antidepressants metabolized by CYP2D6. Guanadrel: [P] Decreased uptake of guanadrel into sites of action. Haloperidol: [P] Decreased metabolism of antidepressants metabolized by CYP2D6. Monoamine oxidase inhibitors (MAOIs): [NP] Some cases of excitation, hyperpyrexia, mania, and convulsions, especially with serotonergic antidepressants such as clomipramine and imipramine, but many patients have received combination without ill effects.


Pharmacology_Katzung

Pharmacology_Katzung. Quinidine: [NP] Decreased metabolism of antidepressants metabolized by CYP2D6. Rifampin: [P] Increased antidepressant metabolism. Selective serotonin reuptake inhibitors (SSRIs): [P] Fluoxetine and paroxetine inhibit CYP2D6 and decrease metabolism of antidepressants metabolized by this enzyme (eg, desipramine). Citalopram, sertraline, and fluvoxamine are only weak inhibitors of CYP2D6, but fluvoxamine inhibits CYP1A2 and CYP3A4 and thus can inhibit the metabolism of antidepressants metabolized by these enzymes. Sympathomimetics: [P] Increased pressor response to norepinephrine, epinephrine, and phenylephrine. Terbinafine: [P] Decreased antidepressant metabolism. Antivirals: [P] Decreased metabolism of amprenavir, atazanavir, boceprevir, daclatasvir, darunavir, delavirdine, etravirine, fosamprenavir, indinavir, lopinavir, maraviroc, nelfinavir, rilpivirine, ritonavir, saquinavir, and tipranavir.


Pharmacology_Katzung

Pharmacology_Katzung. Barbiturates: [P] Increased metabolism of itraconazole, ketoconazole, voriconazole. Benzodiazepines: [P] Decreased metabolism of alprazolam, midazolam, triazolam. Calcium channel blockers: [P] Decreased calcium channel blocker metabolism. Carbamazepine: [P] Decreased carbamazepine metabolism. Potential increased metabolism of itraconazole, ketoconazole, and voriconazole. Cisapride: [NP] Decreased metabolism of cisapride. Colchicine: [P] Decreased metabolism and transport of colchicine. Cyclosporine: [P] Decreased elimination of cyclosporine. Digoxin: [NE] Increased plasma concentrations of digoxin with itraconazole, posaconazole, and ketoconazole.


Pharmacology_Katzung

Pharmacology_Katzung. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Barbiturates Induction of hepatic microsomal drug metabolizing enzymes and P-glycoprotein. Additive central nervous system depression with other central nervous system depressants. Antivirals: Increased metabolism of antivirals amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir with barbiturates.


Pharmacology_Katzung

Pharmacology_Katzung. Beta-adrenoceptor blockers: [P] Increased β-blocker metabolism. Calcium channel blockers: [P] Increased calcium channel blocker metabolism. Central nervous system depressants: [HP] Additive central nervous system depression. Corticosteroids: [P] Increased corticosteroid metabolism. Cyclosporine: [NE] Increased cyclosporine metabolism. Doxycycline: [P] Increased doxycycline metabolism. Estrogens: [P] Increased estrogen metabolism. Kinase inhibitors: [P] Increased metabolism of axitinib, bosutinib, ceritinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, ibrutinib, idelalisib, imatinib, ixazomib, lapatinib, nilotinib, nintedanib, olaparib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ruxolitinib, sunitinib, tofacitinib, vandetanib, vemurafenib. Methadone: [NE] Increased methadone metabolism.


Pharmacology_Katzung

Pharmacology_Katzung. Methadone: [NE] Increased methadone metabolism. Opioid analgesics: [P] Increased elimination of alfentanil, fentanyl, methadone, oxycodone, and sufentanil. Phenothiazine: [P] Increased phenothiazine metabolism. Phenytoin: [P] Increased phenytoin metabolism. Quinidine: [P] Increased quinidine metabolism. Sirolimus: [NE] Increased sirolimus metabolism. Tacrolimus: [NE] Increased tacrolimus metabolism. Theophylline: [NE] Increased theophylline metabolism. Valproic acid: [P] Decreased phenobarbital metabolism. See also Anticoagulants, oral; Antidepressants, tricyclic. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Acetaminophen: [NE] Decreased gastrointestinal absorption of acetaminophen. Digitalis glycosides: [NE] Decreased gastrointestinal absorption of digitoxin (possibly also digoxin). Furosemide: [P] Decreased gastrointestinal absorption of furosemide. Methotrexate: [NE] Reduced gastrointestinal absorption of methotrexate. Mycophenolate: [P] Reduced gastrointestinal absorption of mycophenolate. Thiazide diuretics: [P] Reduced gastrointestinal absorption of thiazides. Thyroid hormones: [P] Reduced thyroid absorption. See also Anticoagulants, oral. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Carbamazepine Induction of hepatic microsomal drug-metabolizing enzymes and P-glycoprotein. Susceptible to induction and inhibition of metabolism, primarily by CYP3A4. Amiodarone: [P] Decreased metabolism of carbamazepine; increased metabolism of amiodarone. Expect similar interactions with dronedarone. Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of carbamazepine. Increased metabolism of antivirals by carbamazepine.


Pharmacology_Katzung

Pharmacology_Katzung. Cimetidine: [P] Decreased carbamazepine metabolism. Corticosteroids: [P] Increased corticosteroid metabolism. Cyclosporine: [P] Increased cyclosporine metabolism and possible decreased carbamazepine metabolism. Danazol: [P] Decreased carbamazepine metabolism. Digitalis glycosides: [P] Increased digoxin elimination. Fluvoxamine: [NE] Decreased carbamazepine metabolism. Estrogens: [P] Increased estrogen metabolism. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Carbamazepine (cont.)


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Carbamazepine (cont.) Cimetidine Inhibits hepatic microsomal drug-metabolizing enzymes. (Ranitidine, famotidine, and nizatidine do not.) May inhibit the renal tubular secretion of weak bases. Cisapride Susceptible to induction and inhibition of metabolism by CYP3A4 inhibitors. High cisapride serum concentrations can result in ventricular arrhythmias. Haloperidol: [P] Increased haloperidol metabolism. Isoniazid: [P] Decreased carbamazepine metabolism. Kinase inhibitors: [P] Decreased metabolism of carbamazepine with ceritinib, dasatinib, imatinib, idelalisib, and lapatinib. Increased metabolism of kinase inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the metabolism of carbamazepine. Nefazodone: [NE] Decreased carbamazepine metabolism. Opioid analgesics: [P] Increased elimination of alfentanil, fentanyl, methadone, oxycodone, and sufentanil. Rifampin: [P] Increased carbamazepine metabolism. Selective serotonin reuptake inhibitors (SSRIs): [NE] Fluoxetine and fluvoxamine decrease carbamazepine metabolism. Sirolimus: [P] Increased sirolimus metabolism. St. John’s wort: [P] Increased carbamazepine metabolism. Tacrolimus: [P] Increased tacrolimus metabolism. Theophylline: [NE] Increased theophylline metabolism. See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals; Calcium channel blockers. Antivirals: [P] Decreased metabolism of amprenavir, atazanavir, boceprevir, daclatasvir, darunavir, delavirdine, etravirine, fosamprenavir, indinavir, lopinavir, maraviroc, nelfinavir, rilpivirine, ritonavir, saquinavir, and tipranavir. Benzodiazepines: [P]


Pharmacology_Katzung

Pharmacology_Katzung. boceprevir, daclatasvir, darunavir, delavirdine, etravirine, fosamprenavir, indinavir, lopinavir, maraviroc, nelfinavir, rilpivirine, ritonavir, saquinavir, and tipranavir. Benzodiazepines: [P] Decreased metabolism of alprazolam, chlordiazepoxide, diazepam, halazepam, prazepam, and clorazepate but not oxazepam, lorazepam, or temazepam. Carmustine: [NE] Increased bone marrow suppression. Dofetilide: [NP] Decreased renal excretion of dofetilide. Lidocaine: [P] Decreased metabolism of lidocaine. Opioid analgesics: [P] Decreased elimination of alfentanil, fentanyl, methadone, oxycodone, and sufentanil. Phenytoin: [NE] Decreased phenytoin metabolism. Procainamide: [P] Decreased renal excretion of procainamide. Quinidine: [P] Decreased metabolism of quinidine. Theophylline: [P] Decreased theophylline metabolism.


Pharmacology_Katzung

Pharmacology_Katzung. See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals; β-Adrenoceptor blockers; Calcium channel blockers; Carbamazepine. Amiodarone: [NP] Decreased cisapride metabolism. Expect similar interaction with dronedarone. Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of cisapride. Cobicistat: [P] Decreased metabolism of cisapride. Conivaptan: [P] Decreased metabolism of cisapride. Cyclosporine: [NE] Decreased metabolism of cisapride. Kinase inhibitors: [P] Decreased metabolism of cisapride with ceritinib, dasatinib, imatinib, idelalisib, and lapatinib.


Pharmacology_Katzung

Pharmacology_Katzung. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Cyclosporine (cont.)


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Cyclosporine (cont.) Statins: [NP] Decreased metabolism of atorvastatin, lovastatin, and simvastatin. Myopathy and rhabdomyolysis noted in patients taking statins and cyclosporine. Drugs that may decrease cyclosporine effect: Bosentan: [P] Increased cyclosporine elimination. Dexamethasone: [NP] Increased cyclosporine metabolism. Efavirenz: [P] Increased cyclosporine metabolism. Etravirine: [NP] Increased cyclosporine metabolism. Nevirapine: [NP] Increased cyclosporine metabolism. Phenytoin: [P] Increased cyclosporine metabolism. Rifabutin: [NP] Increased cyclosporine metabolism. Rifampin: [P] Increased cyclosporine elimination. St. John’s wort: [NP] Increased cyclosporine elimination. See also Azole antifungals; Barbiturates; Calcium channel blockers; Carbamazepine. Drugs that may increase digitalis effect:


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that may increase digitalis effect: Amiodarone: [P] Increased digoxin plasma concentrations. Expect similar interaction with dronedarone. Antivirals: [P] Daclatasvir, indinavir, nelfinavir, paritaprevir, ritonavir, saquinavir, and telaprevir reduce the elimination of digoxin. Conivaptan: [P] Increased digoxin plasma concentrations. Cyclosporine: [P] Increased digoxin plasma concentrations. Macrolide antibiotics: [P] Azithromycin, clarithromycin, and erythromycin inhibit the elimination of digoxin. Potassium-depleting drugs: [P] Increases likelihood of digitalis toxicity. Propafenone: [P] Increases digoxin plasma concentrations. Quinidine: [HP] Increased digoxin plasma concentrations; displaces digoxin from tissue binding sites. Spironolactone: [NE] Increased digoxin plasma concentrations. Tacrolimus: [P] Increased digoxin plasma concentrations. Ticagrelor: [P] Increased digoxin plasma concentrations. See also Azole antifungals; Calcium channel blockers.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that may decrease digitalis effect: Kaolin-pectin: [P] Decreased gastrointestinal digoxin absorption. Rifampin: [NE] Increased metabolism of digitoxin and elimination of digoxin. St. John’s wort: [NP] Increased digoxin elimination. Sulfasalazine: [NE] Decreased gastrointestinal digoxin absorption. See also Acid reducing agents; Bile acid-binding resins; Carbamazepine. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Disulfiram Inhibits CYP2C9. Inhibits aldehyde dehydrogenase.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Disulfiram Inhibits CYP2C9. Inhibits aldehyde dehydrogenase. Estrogens Estrogen metabolism (CYP3A4) susceptible to induction and inhibition. Enterohepatic circulation of estrogen may be interrupted by alteration in bowel flora (eg, due to antibiotics). Benzodiazepines: [P] Decreased metabolism of chlordiazepoxide and diazepam but not lorazepam and oxazepam. Metronidazole: [NE] Confusion and psychoses reported in patients receiving this combination; mechanisms unknown. Phenytoin: [P] Decreased phenytoin metabolism. See also Alcohol; Anticoagulants, oral.


Pharmacology_Katzung

Pharmacology_Katzung. Phenytoin: [P] Decreased phenytoin metabolism. See also Alcohol; Anticoagulants, oral. Ampicillin: [NP] Interruption of enterohepatic circulation of estrogen; possible reduction in oral contraceptive efficacy. Some other oral antibiotics may have a similar effect. Bexarotene: [P] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy. Bosentan: [NP] Enzyme induction leading to reduced estrogen effect. Corticosteroids: [P] Decreased metabolism of corticosteroids leading to increased corticosteroid effect. Dexamethasone may increase estrogen metabolism. Efavirenz: [P] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy. Griseofulvin: [NP] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy. Nelfinavir: [P] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy. Nevirapine: [NP] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy.


Pharmacology_Katzung

Pharmacology_Katzung. Nelfinavir: [P] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy. Nevirapine: [NP] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy. Phenytoin: [P] Increased estrogen metabolism; possible reduction in oral contraceptive efficacy. Primidone: [P] Increased estrogen metabolism; possible reduction in oral contraceptive efficacy. Rifabutin: [P] Increased estrogen metabolism; possible reduction in oral contraceptive efficacy. Rifampin: [P] Increased estrogen metabolism; possible reduction in oral contraceptive efficacy. St. John’s wort: [P] Increased estrogen metabolism; possible reduction in oral contraceptive efficacy. See also Barbiturates; Carbamazepine. Amiodarone: [NP] Decreased atorvastatin, lovastatin, and simvastatin metabolism.


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone: [NP] Decreased atorvastatin, lovastatin, and simvastatin metabolism. Expect similar interactions with dronedarone. Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of atorvastatin, lovastatin, and simvastatin. Bosentan: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. Carbamazepine: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. Clofibrate: [NP] Increased risk of myopathy. Cobicistat: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin. Conivaptan: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin. Cyclosporine: [P] Decreased atorvastatin, lovastatin, rosuvastatin, pitavastatin, and simvastatin elimination.


Pharmacology_Katzung

Pharmacology_Katzung. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. HMG-CoA reductase inhibitors (statins) (cont.) Iron Binds with drugs in gastrointestinal tract, reducing absorption. Levodopa Levodopa degraded in gut prior to reaching sites of absorption. Agents that alter gastrointestinal motility may alter degree of intraluminal degradation. Antiparkinsonism effect of levodopa susceptible to inhibition by other drugs. Lithium Renal lithium excretion sensitive to changes in sodium balance. (Sodium depletion tends to cause lithium retention.) Susceptible to drugs enhancing central nervous system lithium toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Lithium Renal lithium excretion sensitive to changes in sodium balance. (Sodium depletion tends to cause lithium retention.) Susceptible to drugs enhancing central nervous system lithium toxicity. Gemfibrozil: [NP] Increased plasma lovastatin and simvastatin and increased risk of myopathy. Kinase inhibitors: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin by ceritinib, dasatinib, imatinib, idelalisib, and lapatinib.


Pharmacology_Katzung

Pharmacology_Katzung. Macrolide antibiotics: [P] Clarithromycin and erythromycin inhibit the elimination of statins. Nefazodone: [NP] Decreased atorvastatin, lovastatin, and simvastatin metabolism. Phenytoin: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. Rifampin: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. St. John’s wort: [NP] Increased atorvastatin, lovastatin, and simvastatin metabolism. See also Azole antifungals; Calcium channel blockers; Cyclosporine. Methyldopa: [NE] Decreased methyldopa absorption. Mycophenolate: [P] Decreased mycophenolate absorption. Quinolones: [P] Decreased absorption of ciprofloxacin and other quinolones. Tetracyclines: [P] Decreased absorption of tetracyclines; decreased efficacy of iron. Thyroid hormones: [P] Decreased thyroxine absorption. See also Antacids. Clonidine: [NE] Inhibited antiparkinsonism effect. Haloperidol: [NP] Inhibited antiparkinsonism effect.


Pharmacology_Katzung

Pharmacology_Katzung. Metoclopramide: [NP] Inhibited antiparkinsonism effect. Monoamine oxidase inhibitors (MAOIs): [P] Hypertensive reaction (carbidopa prevents the interaction).


Pharmacology_Katzung

Pharmacology_Katzung. Papaverine: [NE] Inhibited antiparkinsonism effect. Phenothiazines: [P] Inhibited antiparkinsonism effect. Phenytoin: [NE] Inhibited antiparkinsonism effect. Pyridoxine: [P] Inhibited antiparkinsonism effect (carbidopa prevents the interaction). ACE inhibitors (ACEIs): [NE] Reduce renal clearance of lithium; increase lithium effect. Angiotensin II receptor blockers (ARBs): [NE] Reduce renal clearance of lithium; increase lithium effect. Diuretics (especially thiazides): [P] Decreased excretion of lithium; furosemide may be less likely to produce this effect than thiazide diuretics. Haloperidol: [NP] Occasional cases of neurotoxicity in manic patients, especially with large doses of one or both drugs. Methyldopa: [NE] Increased likelihood of central nervous system lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): [NE] Reduced renal lithium excretion (except sulindac and salicylates). Theophylline: [P] Increased renal excretion of lithium; reduced lithium effect.


Pharmacology_Katzung

Pharmacology_Katzung. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Macrolides The macrolides clarithromycin and erythromycin are known to inhibit CYP3A4 and P-glycoprotein. Azithromycin does not appear to inhibit CYP3A4 but is a modest inhibitor of P-glycoprotein. Monoamine Increased norepinephrine stored in oxidase adrenergic neuron. Displacement inhibitors of these stores by other drugs (MAOIs) may produce acute hypertensive response. MAOIs have intrinsic hypoglycemic activity.


Pharmacology_Katzung

Pharmacology_Katzung. Benzodiazepines: [P] Decreased metabolism of alprazolam, midazolam, triazolam. Eplerenone: [P] Decreased metabolism of eplerenone. Ergot alkaloids: [P] Decreased elimination of ergot alkaloids. Kinase inhibitors: [P] Decreased metabolism of axitinib, bosutinib, ceritinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, ibrutinib, idelalisib, imatinib, ixazomib, lapatinib, nilotinib, nintedanib, olaparib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ruxolitinib, sunitinib, tofacitinib, vandetanib, and vemurafenib by clarithromycin and erythromycin. Opioid analgesics: [P] Decreased elimination of alfentanil, fentanyl, methadone, oxycodone, and sufentanil. Phosphodiesterase inhibitors: [P] Decreased metabolism of phosphodiesterase inhibitor.


Pharmacology_Katzung

Pharmacology_Katzung. Opioid analgesics: [P] Decreased elimination of alfentanil, fentanyl, methadone, oxycodone, and sufentanil. Phosphodiesterase inhibitors: [P] Decreased metabolism of phosphodiesterase inhibitor. Pimozide: [P] Increased pimozide concentrations. Quinidine: [P] Increased serum quinidine concentrations. Theophylline: [P] Decreased metabolism of theophylline. See also Anticoagulants, oral; Calcium channel blockers; Carbamazepine; Cisapride;


Pharmacology_Katzung

Pharmacology_Katzung. Colchicine; Cyclosporine; Digitalis glycosides; HMG-CoA reductase inhibitors. Anorexiants: [P] Hypertensive episodes due to release of stored norepinephrine (benzphetamine, diethylpropion, mazindol, phendimetrazine, phentermine). Antidiabetic agents: [P] Additive hypoglycemic effect. Buspirone: [NE] Possible serotonin syndrome; avoid concurrent use. Dextromethorphan: [NP] Severe reactions (hyperpyrexia, coma, death) have been reported. Guanethidine: [P] Reversal of the hypotensive action of guanethidine. Mirtazapine: [NE] Possible serotonin syndrome; avoid concurrent use. Nefazodone: [NP] Possible serotonin syndrome; avoid concurrent use. Opioid analgesics: [NP] Some patients develop hypertension, rigidity, excitation; meperidine more likely to interact than morphine; avoid concurrent use. Phenylephrine: [P] Hypertensive episode, since phenylephrine is metabolized by monoamine oxidase. Selective serotonin reuptake inhibitors (SSRIs): [P] Fatalities have occurred due to serotonin


Pharmacology_Katzung

Pharmacology_Katzung. use. Phenylephrine: [P] Hypertensive episode, since phenylephrine is metabolized by monoamine oxidase. Selective serotonin reuptake inhibitors (SSRIs): [P] Fatalities have occurred due to serotonin syndrome; contraindicated in patients taking MAOIs; avoid concurrent use. Sibutramine: [NE] Possible serotonin syndrome; avoid concurrent use. Sympathomimetics (indirect-acting): [HP] Hypertensive episode due to release of stored norepinephrine (amphetamines, ephedrine, isometheptene, phenylpropanolamine, pseudoephedrine). Tramadol: [NP] Possible serotonin syndrome; avoid concurrent use. Venlafaxine: [NP] Possible serotonin syndrome; avoid concurrent use. See also Antidepressants, tricyclic and heterocyclic; Levodopa.


Pharmacology_Katzung

Pharmacology_Katzung. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Prostaglandin inhibition may result in reduced renal sodium excretion, impaired resistance to hypertensive stimuli, and reduced renal lithium excretion. Most NSAIDs inhibit platelet function; may increase likelihood of bleeding due to other drugs that impair hemostasis.


Pharmacology_Katzung

Pharmacology_Katzung. Opioid analgesics that are substrates of CYP3A4 (alfentanil, fentanyl, oxycodone, sufentanil, and to a lesser extent methadone) are susceptible to inhibitors and inducers. Methadone is primarily metabolized by CYP2B6. Additive central nervous system depression with other central nervous system depressants. Induces hepatic microsomal drug metabolism. Susceptible to inhibition of metabolism by CYP2C9 and, to a lesser extent, CYP2C19. ACE inhibitors (ACEIs): [P] Decreased antihypertensive response. Angiotensin II receptor blockers (ARBs): [P] Decreased antihypertensive response. Furosemide: [P] Decreased diuretic, natriuretic, and antihypertensive response to furosemide. Hydralazine: [NE] Decreased antihypertensive response to hydralazine. Methotrexate: [NP] Possibly increased methotrexate toxicity (especially with anticancer doses of methotrexate).


Pharmacology_Katzung

Pharmacology_Katzung. Selective serotonin reuptake inhibitors (SSRIs): [P] Increased risk of bleeding due to platelet inhibition. Thiazide diuretics: [P] Decreased diuretic, natriuretic, and antihypertensive response. Triamterene: [NE] Decreased renal function noted with triamterene plus indomethacin in both healthy subjects and patients. See also Anticoagulants, oral; β-Adrenoceptor blockers; Lithium. Amiodarone: [NP] Decreased CYP3A4-dependent opioid metabolism. Expect similar interactions with dronedarone. Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of CYP3A4-dependent opioids. Boceprevir: [P] Decreased metabolism of CYP3A4-dependent opioids. Bosentan: [P] Increased CYP3A4-dependent opioid metabolism. Cobicistat: [P] Decreased metabolism of CYP3A4-dependent opioids. Conivaptan: [P] Decreased metabolism of CYP3A4-dependent opioids.


Pharmacology_Katzung

Pharmacology_Katzung. Efavirenz: [P] Increased metabolism of CYP3A4-dependent opioids. Kinase inhibitors: [P] Decreased metabolism of CYP3A4-dependent opioid by ceritinib, dasatinib, imatinib, idelalisib, and lapatinib. Nefazodone: [NP] Decreased CYP3A4-dependent opioid metabolism. Nevirapine: [P] Increased metabolism of CYP3A4-dependent opioids. Phenytoin: [P] Increased CYP3A4-dependent opioid metabolism. Rifampin: [P] Increased CYP3A4-dependent opioid metabolism. St. John’s wort: [NP] Increased CYP3A4-dependent opioid metabolism. See also Azole antifungal agents; Barbiturates; Carbamazepine; Cimetidine; Macrolides; Monoamine oxidase inhibitors. Drugs whose metabolism is stimulated by phenytoin:


Pharmacology_Katzung

Pharmacology_Katzung. Monoamine oxidase inhibitors. Drugs whose metabolism is stimulated by phenytoin: Corticosteroids: [P] Decreased serum corticosteroid levels. Doxycycline: [P] Decreased serum doxycycline levels. Mexiletine: [NE] Decreased serum mexiletine levels. Quinidine: [P] Decreased serum quinidine levels. Theophylline: [NP] Decreased serum theophylline levels. See also Calcium channel blockers; Cyclosporine; Estrogens; Opioid analgesics. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Phenytoin (cont.) Pimozide Susceptible to CYP3A4 inhibitors; may exhibit additive effects with other agents that prolong QTc interval.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Phenytoin (cont.) Pimozide Susceptible to CYP3A4 inhibitors; may exhibit additive effects with other agents that prolong QTc interval. Drugs that inhibit phenytoin metabolism: Amiodarone: [P] Increased serum phenytoin concentration; possible reduction in serum amiodarone concentration. Capecitabine: [NE] Increased phenytoin plasma concentrations. Chloramphenicol: [P] Increased phenytoin plasma concentrations. Felbamate: [P] Increased phenytoin plasma concentrations. Fluorouracil: [NE] Increased phenytoin plasma concentrations. Fluvoxamine: [NP] Increased phenytoin plasma concentrations. Isoniazid: [NP] Increased serum phenytoin; problem primarily with slow acetylators of isoniazid. Metronidazole: [NP] Increased phenytoin plasma concentrations. Sulfamethoxazole: [P] Increased phenytoin plasma concentrations. Ticlopidine: [NP] Increased phenytoin plasma concentrations. See also Azole antifungals; Cimetidine; Disulfiram.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that enhance phenytoin metabolism: Bosentan: [P] Decreased phenytoin plasma concentrations. Carbamazepine: [P] Decreased phenytoin plasma concentrations. Rifampin: [P] Decreased phenytoin plasma concentrations. St. John’s wort: [P] Decreased phenytoin plasma concentrations. See also Barbiturates. Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of pimozide. Boceprevir: [P] Decreased metabolism of pimozide. Cobicistat: [P] Decreased metabolism of pimozide. Conivaptan: [P] Decreased metabolism of pimozide. Kinase inhibitors: [P] Decreased metabolism of pimozide with ceritinib, dasatinib, imatinib, idelalisib, and lapatinib. Nefazodone: [NP] Decreased pimozide metabolism. See also Azole antifungals; Cyclosporine; Macrolides.


Pharmacology_Katzung

Pharmacology_Katzung. ACE inhibitors (ACEIs): [NP] Additive hyperkalemic effect. Angiotensin II receptor blockers (ARBs): [NP] Additive hyperkalemic effect. Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of eplerenone. Boceprevir: [P] Decreased metabolism of eplerenone. Cobicistat: [P] Decreased metabolism of eplerenone. Conivaptan: [P] Decreased metabolism of eplerenone. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 66–1 Important drug interactions. Potassium-sparing diuretics (amiloride, eplerenone, spironolactone, triamterene) (cont.) Probenecid Interference with renal excretion of drugs that undergo active tubular secretion, especially weak acids. Inhibition of glucuronide conjugation of other drugs. Quinidine Substrate of CYP3A4. Inhibits CYP2D6. Renal excretion susceptible to changes in urine pH. Additive effects with other agents that prolong the QTc interval. Kinase inhibitors: [P] Decreased metabolism of eplerenone with ceritinib, dasatinib, imatinib, idelalisib, and lapatinib. Potassium-sparing diuretics: [P] Additive hyperkalemic effect. Potassium supplements: [P] Additive hyperkalemic effect; especially a problem in presence of renal impairment. See also Azole antifungals; Digitalis glycosides; Macrolides; Nonsteroidal anti-inflammatory drugs.


Pharmacology_Katzung

Pharmacology_Katzung. See also Azole antifungals; Digitalis glycosides; Macrolides; Nonsteroidal anti-inflammatory drugs. Clofibrate: [P] Reduced glucuronide conjugation of clofibric acid. Methotrexate: [P] Decreased renal methotrexate excretion; possible methotrexate toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Pralatrexate: [P] Decreased renal pralatrexate excretion; possible pralatrexate toxicity. Penicillin: [P] Decreased renal penicillin excretion. Salicylates: [P] Decreased uricosuric effect of probenecid (interaction unlikely with less than 1.5 g of salicylate daily). Acetazolamide: [P] Decreased renal quinidine excretion due to increased urinary pH; elevated serum quinidine. Amiodarone: [NP] Increased serum quinidine levels; additive prolongation of QTc interval. Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of quinidine. Boceprevir: [P] Decreased metabolism of quinidine. Cobicistat: [P] Decreased metabolism of quinidine. Conivaptan: [P] Decreased metabolism of quinidine. Kaolin-pectin: [NE] Decreased gastrointestinal absorption of quinidine. Kinase inhibitors: [P] Decreased metabolism of quinidine with ceritinib, dasatinib, imatinib, idelalisib,


Pharmacology_Katzung

Pharmacology_Katzung. of quinidine. Kaolin-pectin: [NE] Decreased gastrointestinal absorption of quinidine. Kinase inhibitors: [P] Decreased metabolism of quinidine with ceritinib, dasatinib, imatinib, idelalisib, and lapatinib. Rifampin: [P] Increased quinidine metabolism. Thioridazine: [NE] Decreased thioridazine metabolism; additive prolongation of QTc interval.


Pharmacology_Katzung

Pharmacology_Katzung. See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals; Barbiturates; Cimetidine; Digitalis glycosides; Macrolides; Phenytoin. Caffeine: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit caffeine metabolism. Frovatriptan: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit frovatriptan metabolism. Ropinirole: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit ropinirole metabolism. Sucralfate: [HP] Reduced gastrointestinal absorption of ciprofloxacin, norfloxacin, and probably other quinolones. Theophylline: [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit theophylline metabolism.


Pharmacology_Katzung

Pharmacology_Katzung. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. Rifampin Inducer (strong) of hepatic microsomal drug-metabolizing enzymes and P-glycoprotein. Salicylates Interference with renal excretion of drugs that undergo active tubular secretion. Salicylate renal excretion dependent on urinary pH when large doses of salicylate used. Aspirin (but not other salicylates) interferes with platelet function. Large doses of salicylates have intrinsic hypoglycemic activity. Corticosteroids: [P] Increased corticosteroid hepatic metabolism; reduced corticosteroid effect.


Pharmacology_Katzung

Pharmacology_Katzung. Corticosteroids: [P] Increased corticosteroid hepatic metabolism; reduced corticosteroid effect. Mexiletine: [NE] Increased mexiletine metabolism; reduced mexiletine effect. Sulfonylurea hypoglycemics: [P] Increased hepatic metabolism of tolbutamide and probably other sulfonylureas metabolized by the liver (including chlorpropamide). Theophylline: [P] Increased theophylline metabolism. See also Anticoagulants, oral; Antidepressants, tricyclic and heterocyclic; Azole antifungals; Beta-adrenoceptor blockers; Calcium channel blockers; Cyclosporine; Digitalis glycosides; Estrogens; HMG-CoA reductase inhibitors; Opioid analgesics; Phenytoin; Quinidine. Carbonic anhydrase inhibitors: [NE] Increased acetazolamide serum concentrations; increase salicylate toxicity due to decreased blood pH. Corticosteroids: [P] Increased salicylate elimination; possible additive toxic effect on gastric mucosa.


Pharmacology_Katzung

Pharmacology_Katzung. Corticosteroids: [P] Increased salicylate elimination; possible additive toxic effect on gastric mucosa. Heparin: [NP] Increased bleeding tendency with aspirin, but probably not with other salicylates. Methotrexate: [P] Decreased renal methotrexate clearance; increases methotrexate toxicity (primarily at anticancer doses). Selective serotonin reuptake inhibitors (SSRIs): [P] Increased risk of bleeding due to platelet inhibition. Sulfinpyrazone: [HP] Decreased uricosuric effect of sulfinpyrazone (interaction unlikely with less than 1.5 g of salicylate daily). See also Acid-reducing agents; Anticoagulants, oral; Probenecid. Codeine: [HP] Reduced analgesic effect due to inhibition of codeine metabolism to morphine by fluoxetine and paroxetine. Theophylline: [P] Decreased metabolism of theophylline by fluvoxamine-induced inhibition of CYP1A2.


Pharmacology_Katzung

Pharmacology_Katzung. Theophylline: [P] Decreased metabolism of theophylline by fluvoxamine-induced inhibition of CYP1A2. See also Anticoagulants, oral; Antidepressants, tricyclic and heterocyclic; β-Adrenoceptor blockers; Carbamazepine; Cisapride; Colchicine; Cyclosporine; HMG-CoA reductase inhibitors; Monoamine oxidase inhibitors; Nonsteroidal anti-inflammatory drugs; Phenytoin; Pimozide; Salicylates. Beta-adrenoceptor blockers: [NP] Decreased theophylline bronchodilation especially with noncardioselective β blockers. Smoking: [HP] Increased theophylline metabolism. Tacrine: [NP] Decreased theophylline metabolism. Ticlopidine: [NP] Decreased theophylline metabolism. Zileuton: [NP] Decreased theophylline metabolism. See also Barbiturates; Calcium channel blockers; Carbamazepine; Cimetidine; Lithium; Macrolides; Phenytoin; Quinolones; Rifampin; Selective serotonin reuptake inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. See also Barbiturates; Calcium channel blockers; Carbamazepine; Cimetidine; Lithium; Macrolides; Phenytoin; Quinolones; Rifampin; Selective serotonin reuptake inhibitors. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability.


Pharmacology_Katzung

Pharmacology_Katzung. The metabolism of drugs can be induced or inhibited by concurrent therapy, and the importance of the effect varies from negligible to dramatic. Drug metabolism primarily occurs in the liver and the wall of the small intestine, but other sites include plasma, lung, and kidney. Induction of cytochrome P450 isozymes in the liver and small intestine can be caused by drugs such as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine, phenytoin, primidone, rifampin, rifabutin, and St. John’s wort. Enzyme inducers can also increase the activity of phase II metabolism such as glucuronidation. Enzyme induction does not take place quickly; maximal effects usually occur after 7–14 days and require an equal or longer time to dissipate after the enzyme inducer is stopped. Inhibition of metabolism generally takes place more quickly than enzyme induction and may begin as soon as the tissue concentration of the inhibitor is sufficient to cause reduced enzyme activity. However, if the


Pharmacology_Katzung

Pharmacology_Katzung. metabolism generally takes place more quickly than enzyme induction and may begin as soon as the tissue concentration of the inhibitor is sufficient to cause reduced enzyme activity. However, if the half-life of the affected (object) drug is long, it may take a week or more (3–4 half-lives) to reach a new steady-state serum concentration. Drugs that may inhibit the cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexiletine, miconazole, omeprazole, paroxetine, quinidine, ritonavir, sulfamethizole, sulfamethoxazole, verapamil, voriconazole, zafirlukast, and zileuton.


Pharmacology_Katzung

Pharmacology_Katzung. The renal excretion of active drug can also be affected by concurrent drug therapy. The renal excretion of drugs that are weak acids or weak bases may be influenced by other drugs that affect urinary pH. This is due to changes in ionization of the object drug, as described in Chapter 1 under Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation. For some drugs, active secretion into the renal tubules is an important elimination pathway. P-glycoprotein, organic anion transporters, and organic cation transporters are involved in active tubular secretion of some drugs, and inhibition of these transporters can inhibit renal elimination with attendant increase in serum drug concentrations. Many drugs are partially eliminated by P-glycoprotein, including digoxin, cyclosporine, dabigatran, colchicine, daunorubicin, and tacrolimus. The plasma concentration of these drugs can be increased by inhibitors of P-glycoprotein including amiodarone, clarithromycin, erythromycin,


Pharmacology_Katzung

Pharmacology_Katzung. dabigatran, colchicine, daunorubicin, and tacrolimus. The plasma concentration of these drugs can be increased by inhibitors of P-glycoprotein including amiodarone, clarithromycin, erythromycin, ketoconazole, ritonavir, and quinidine. To access over 200 brief reviews of specific drug interactions visit http://www.hanstenandhorn.com/news.htm.


Pharmacology_Katzung

Pharmacology_Katzung. When drugs with similar pharmacologic effects are administered concurrently, an additive or synergistic response is usually seen. The two drugs may or may not act on the same receptor to produce such effects. In theory, drugs acting on the same receptor or process are usually additive, eg, benzodiazepines plus barbiturates, until the receptor is saturated or the effect is maximal. However, two drugs competing for the same binding site may result in less than an additive effect. Drugs acting on different receptors or sequential processes may be synergistic, eg, nitrates plus sildenafil or sulfonamides plus trimethoprim. Conversely, drugs with opposing pharmacologic effects may reduce the response to one or both drugs. Pharmacodynamic drug interactions are relatively common in clinical practice, but adverse effects can usually be minimized if one understands the pharmacology of the drugs involved. In this way, the interactions can be anticipated and appropriate counter-measures taken.


Pharmacology_Katzung

Pharmacology_Katzung. The combined use of two or more drugs, each of which has toxic effects on the same organ, can greatly increase the likelihood of organ damage. For example, concurrent administration of two nephrotoxic drugs can produce kidney damage, even though the dose of either drug alone may be insufficient to produce toxicity. Furthermore, some drugs can enhance the organ toxicity of another drug, even though the enhancing drug has no intrinsic toxic effect on that organ. Boobis A et al: Drug interactions. Drug Metab Rev 2009;41:486. DeGorter MK et al: Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol 2012;52:249. DuBuske LM: The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. Drug Saf 2005;28:789. Hansten PD, Horn JR: The Top 100 Drug Interactions. A Guide to Patient Management. H&H Publications, 2016, www.hanstenandhorn.com.


Pharmacology_Katzung

Pharmacology_Katzung. Hansten PD, Horn JR: The Top 100 Drug Interactions. A Guide to Patient Management. H&H Publications, 2016, www.hanstenandhorn.com. Hillgren KM et al: Emerging transporters of clinical importance: An update from the international transporter consortium. Clin Pharmacol Ther 2013;94:52. Horn JR et al: Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41:674. Hukkanen J: Induction of cytochrome P450 enzymes: A view on human in vivo findings. Expert Rev Clin Pharmacol 2012;5:569. Juurlink DN et al: Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;289:1652. Leucuta SE, Vlase L: Pharmacokinetics and metabolic drug interactions. Curr Clin Pharmacol 2006;1:5. Meng Q, Lin K: Pharmacokinetic interactions between herbal medicines and prescribed drugs: Focus on drug metabolic enzymes and transporters. Curr Drug Metab 2014;15:791.


Pharmacology_Katzung

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