According to Studies Medication Occurs Most Frequently in What Patient Population
This learning module was developed based on a needs survey sent to all third year medicine clerkship directors and all medicine residency programme directors in the United States. This module was developed by the Eye for Education and Research on Therapeutics (CERT) while at Georgetown University (CERT at present located at the University of Arizona Wellness Sciences Center) in collaboration with the Center for Drug Evaluation and Inquiry at the Food and Drug Assistants. The work was sponsored by the Agency for Healthcare Research and Quality (AHRQ). Nosotros encourage you to complete the Module Evaluation Form, as it will provide feedback for the development of future learning modules.
- Sample Case
- ADRs: Prevalence and Incidence
- Types of Drug Interactions
- Drug Metabolism
- ADR Reporting
- Preventing Drug Interactions
- Acknowledgements
Welcome to the Agin Drug Reaction (ADR) learning module. The module will begin with a presentation of a instance that was published in 1990. This case demonstrates why it is important that health care practitioners report ADRs to the Food and Drug Administration (FDA). It was also a pivotal case resulting in recognition and definition of one type of preventable adverse drug reaction— drug interactions mediated past the cytochrome P450 pathway of drug metabolism.
Afterward discussing this case, nosotros will discuss the prevalence and incidence of adverse drug reactions. We will so examine several well-recognized types of drug interactions that are the causes of preventable adverse reactions. This section volition focus primarily on cytochrome P450-mediated drug interactions, although other types of interactions will too be included, also as examples of drug-drug, drug-nutrition, and drug-herbal interactions. The emphasis volition exist on current noesis that tin assistance healthcare providers predict possible drug interactions. This will be followed by a discussion of ADR reporting via the FDA'south MedWatch program. Finally, a stepwise systems arroyo to preventing ADRs due to drug interactions volition be outlined.
Sample Example
The starting time case nosotros will consider is that of the potentially lethal arrhythmia, torsades de pointes, occurring in association with terfenadine (Seldane) employ in a young woman.one
This ECG is a classic example of torsades de pointes, which is French for "twisting of the points." Torsades is a form of ventricular tachycardia that can most oft exist due to medications. The QRS complexes during this rhythm tend to bear witness a series of "points up" followed past "points down" often with a narrow waist betwixt. Recognition and reporting of this arrhythmia in association with terfenadine, astemizole (Hismanal), cisapride (Propulsid), grepafloxacin (Raxar), and mibefradil (Posicor) ultimately led to the removal of these medications from the market.
1Monahan BP, Ferguson CL, Carve ES, Lloyd BK, Troy J, Cantilena LR. Torsade de pointes occurring in association with terfenadineuse. JAMA 1990;264:2788–2790.
A 39-year-old female was evaluated for episodes of syncope and lite-headedness that began two days prior to her hospital admission.ane The history was consistent with possible cardiovascular causes, and the patient was admitted and placed on telemetry where the preceding rhythm strip was observed.
Ten days prior to admission she had been prescribed terfenadine (Seldane—an antihistamine) 60 mg twice-a-day and cefaclor (Ceclor—a cephalosporin antibody) 250 mg three-times-a-day. On the eighth mean solar day of terfenadine therapy the patient began a cocky-medicated course of ketoconazole (Nizoral—an azole antifungal) at 200 mg twice-a-day for vaginal candidiasis. She was also taking medroxyprogesterone acetate at a dosage of 2.five mg a-twenty-four hours. Upon admission to the hospital the patient was noted to have a QTc interval of 655 milliseconds (normal is less than 440 milliseconds). During the hospitalization the patient experienced almost syncopal episodes associated with torsades de pointes noted on telemetry.
After discontinuing the medications, the QTc interval normalized. She had no farther episodes of torsades de pointes, and she was discharged with no recurrence of syncope.
1Monahan BP, Ferguson CL, Cleave ES, Lloyd BK, Troy J, Cantilena LR. Torsade de pointes occurring in association with terfenadineuse. JAMA 1990;264:2788–2790.
This figure illustrates the time form of the medications that the patient took.ane In relation to when the symptoms started, the most recently prescribed drug was ketoconazole. Ketoconazole has non been associated with development of torsades de pointes when used by itself. How did ketoconazole interact with terfenadine to cause QT prolongation and torsades de pointes in this patient? That question will exist answered during the course of this module.
1Monahan BP, Ferguson CL, Cleave ES, Lloyd BK, Troy J, Cantilena LR. Torsade de pointes occurring in association with terfenadineuse. JAMA 1990;264:2788–2790.
ADRs: Prevalence and Incidence
The commencement question healthcare providers should ask themselves is "why is it important to learn well-nigh ADRs?" The respond is because ADRs are i of the leading causes of morbidity and mortality in health care. The Institute of Medicine reported in January of 2000 that from 44,000 to 98,000 deaths occur annually from medical errors.1 Of this full, an estimated 7,000 deaths occur due to ADRs. To put this in perspective, consider that half-dozen,000 Americans die each yr from workplace injuries.
However, other studies conducted on hospitalized patient populations take placed much higher estimates on the overall incidence of serious ADRs. These studies estimate that six.7% of hospitalized patients take a serious adverse drug reaction with a fatality rate of 0.32%.2 If these estimates are correct, then there are more than two,216,000 serious ADRs in hospitalized patients, causing over 106,000 deaths annually. If true, then ADRs are the quaternary leading cause of decease—ahead of pulmonary affliction, diabetes, AIDS, pneumonia, accidents, and car deaths.
These statistics do not include the number of ADRs that occur in ambulatory settings. Also, information technology is estimated that over 350,000 ADRs occur in U.S. nursing homes each year.3 The exact number of ADRs is non sure and is express by methodological considerations. However, whatever the true number is, ADRs represent a meaning public health problem that is, for the most office, preventable.
oneCommittee on Quality of Health Intendance in America: Institute of Medicine. To err is man: building a safer health system. Washington, D.C.: National Academy Press; 2000. twoLazarou J, Pomeranz B, Corey PN. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 1998;279:1200–1205. iiiGurwitz JH, Field TS, Avorn J, McCormick D, Jain Due south, Eckler Thou, et al. Incidence and preventability of adverse drug events in nursing homes. Am J Med 2000;109(two):87–94.
We can next ask ourselves, what are the health care costs associated with adverse drug reactions? Again, methodological constraints limit making completely accurate estimates, only one estimate of the cost of drug-related morbidity and mortality is $136 billion annually,1 which is more than the total cost of cardiovascular or diabetic care in the United states. In addition, one out of 5 injuries or deaths per year to hospitalized patients may be equally a result of ADRs.ii Finally, a 2-fold greater hateful length of stay, cost and mortality has been reported for hospitalized patients experiencing an ADR compared to a control group of patients without an adverse drug reaction.3
1Johnson JA, Bootman JL. Drug-related morbidity and bloodshed. A cost-of-illness model. Arch Intern Med 1995;155(xviii):1949–1956. 2Leape LL, Brennan TA Laird N, Lawthers AG ,Localio AR, Barnes BA et al. The nature of agin events in hospitalized patients. Results of the Harvard Medical Practice Written report Ii. N Engl J Med 1991;324(6):377–384. iiiClassen DC , Pestotnik SL, Evans RS, Lloyd JF, Shush JP. Agin drug events in hospitalized patients. Backlog length of stay, extra costs, and attributable mortality. JAMA 1997;277(four):301–306.
Why are there and then many ADRs? There are many reasons. Here are just a few.
Showtime, more drugs—and many more combinations of drugs—are being used to treat patients than ever before. To exemplify this point, 64% of all patient visits to physicians event in prescriptions.1
Secondly, 2.8 billion prescriptions were filled in the year 2000. two That is about 10 prescriptions for every person in the Usa.
Finally, the rate of ADRs increases exponentially after a patient is on 4 or more medications.iii
Efforts to reduce polypharmacy are of import but for many patients, the number of medications cannot always exist reduced without doing damage. That is why it is of import to understand the basis for drug interactions. This volition permit the states to make the nearly appropriate choices in prescribing and avoiding preventable ADRs.
1Schappert SM. Ambulatory intendance visits to medico offices, hospital outpatient departments, and emergency departments: United states of america,1997. National Centre for Health Statistics. Vital Health Stat. 1999;xiii(143).
iiNational Clan of Concatenation Drug Stores. 2000 community pharmacy results. 2001. Alexandria, VA. 3Jacubeit T, Drisch D, Weber E. Risk factors every bit reflected by an intensive drug monitoring organisation. Agents Actions 1990;29:117–125.
It is worth because how well a drug's prophylactic is defined prior to its approving and marketing. This will indicate how confident practitioners tin can be that a new drug'southward safety contour has been fully defined.
Most new drugs are approved with an boilerplate of 1,500 patient exposures and usually for only relatively curt periods of fourth dimension. However, some drugs cause serious ADRs at very low frequencies and would crave many more exposures to observe the reaction. For example, bromfenac (Duract) was a not-steroidal anti-inflammatory agent (NSAID) that was removed from the market in 1998, less than 1 twelvemonth later on it was introduced. Bromfenac acquired serious hepatotoxicity in only 1 in 20,000 patients taking the drug for longer than 10 days.1 To reliably find the toxic effects of a drug with a i in twenty,000 adverse drug reaction frequency, the new drug application database would have to include 100,000 patient exposures. A drug that is tested in a few thousand people xi may accept an fantabulous safety profile in those few k patients. However, within a brusk time after entering the market, the drug may be administered to several million patients. That means that for drugs that cause rare toxicity, their toxicity tin can only be detected later, non before, marketing.
If one instance of hepatotoxicity is seen during pre-marketing testing, information technology tin be difficult, if non incommunicable, to ascertain whether information technology was secondary to the drug or just the groundwork rate of disease that is seen in the population.
So, the safety profile for new drugs that come on the market place is never totally defined because new drugs are studied simply in relatively small-scale and homogenous patient populations. The complete prophylactic contour of a new drug will be divers only after it has been approved and is in use on the market.
1Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ. The prophylactic of newly approved medicines: practice recent market removals hateful there is a problem? JAMA 1999; 281(18):1728–1734.
Health care providers have misconceptions most reporting ADRs.1–3 These misconceptions include the ideas that: 1) All serious ADRs are documented by the time a drug is marketed; 2) It is hard to determine if a drug is responsible for the ADR; 3) ADRs should but be reported if absolute certainty exists that the ADR is related to a detail drug; and, finally, 4) One case reported by an private physician does not contribute to medical noesis. Let's expect at each one of these points.
1) Equally we accept seen, rare ADRs are unremarkably NOT documented past the time a drug is marketed.
2) It can be hard to determine if an individual drug caused a reaction in a complicated patient receiving multiple medications. However, the temporal relationship of a reaction with regard to the administration of a new medication can be helpful. Also, biological plausibility (asking if the drug'southward mechanism of action makes this possible or likely) tin besides be helpful. The lesser line is, even when in doubt about whether a drug acquired the reaction, report it.
3) A suspicion of an adverse drug reaction should be reported. A health care provider does not have to be admittedly certain that a drug caused a reaction. All reports contribute to the heightening of the awareness of FDA rubber scientists as they monitor all of the bear witness to evaluate the potential for drug-related toxicity.
four) One individual report Tin brand a deviation. Many drug withdrawals began with one clinical report that initiated further investigation. In the example example in this module, a unmarried study ultimately led to the removal of terfenadine from the marketplace. This report potentially saved many lives and led to a better agreement of the mechanism involved in causing torsades de pointes. Almost all drugs are at present evaluated prior to being released on the market for their potential to induce cardiac arrhythmias, also as a result of this unmarried case report.
1Figueiras A, Tato F, Fontainas J, Gestal-Otero JJ. Influence of physicians' attitudes on reporting adverse drug events: a case-control report. Med Intendance 1999;37(8):809-814. 2Eland IA, Belton KJ, van Grootheest Air-conditioning, Meiners AP, Rawlins Doctor, Stricker BH. Attitudinal survey of voluntary reporting of adverse drug reactions. Br J Clin Pharmacol 1999;48(4):623–627. 3Chyka PA, McCommon SW. Reporting of adverse drug reactions by poisonous substance control centres in the The states. Drug Saf 2000;23(1):87–93.
The disability of the FDA to effectively warn wellness care providers and patients well-nigh drug interactions and our inability to interpret existing knowledge into changes in prescribing have resulted in huge economic consequences for the pharmaceutical industry and the loss from the marketplace of effective drugs, including terfenadine, mibefradil, astemizole, and cisapride.
These 4 drugs were removed from the marketplace or restricted in their utilize considering it became clear that they continued to be prescribed in an unsafe manner, even after multiple alert letters were disseminated by the manufacturer and the FDA to health care professionals concerning their proper use. Each of these drugs has value in the pharmaceutical marketplace, and each has value to patients. Notwithstanding, because the manufacturer and the FDA could non preclude co-prescription of these drugs with interacting drugs resulting in fatal interactions, the risk associated with continued widespread availability could not be justified.
This effigy shows data from a national survey conducted in 1999 by the American Society of Health Systems Pharmacists (ASHP)1 that evaluated patient concerns about health systems. This was a random telephone survey of 1,008 adults. Although the respondents were very concerned about suffering from pain and the cost of filling prescriptions, they were most concerned about being given the incorrect drug or that a drug interaction would occur. The public in full general has a much greater level of business organisation nearly ADRs than almost health care providers would suspect. These data demonstrate that drug interactions and reactions are not only a concern to health care providers but to patients too.
1American Guild of Health Systems Pharmacists. ASHP Patient Concerns National Survey Research Report. 1999. Bethesda, MD.
Types of Drug Interactions
The previous slides take reviewed information about the magnitude of agin drug reactions and the brunt they place on the health care system. How much do drug interactions contribute to the total number of preventable ADRs?
Again, estimates of the numbers of patients injured due to drug interactions vary widely. However, some reasonable estimates come from the piece of work of Dr. Lucien Leape and colleagues.ane In a systems assay of ADRs, they estimated that drug-drug interactions represent from iii–5% of all in-hospital medication errors. Drug interactions are also an of import crusade of patient visits to emergency departments.2
aneLeape LL, Bates DW, Cullen DJ, Cooper J, Demonaco HJ, Gallivan T, et al. Systems analysis of adverse drug events. ADE Prevention Study Grouping. JAMA 1995;274(1):35–43. iiRaschetti R, Morgutti M, Menniti-Ippolito F, Belisari A, Rossignoli A, Longhini P, et al. Suspected agin drug events requiring emergency department visits or hospital admissions. Eur J Clin Pharmacol 1999;54(12):959–963.
Recent publications take shown that many agin drug reactions can be prevented and detected through the employ of systems interventions. For example, many wellness systems have instituted new technologies to minimize patient injury due to medication errors and drug-drug interactions.ane–three Tools like computerized dr. order and prescription entry 1 and bar coding systems 3 take demonstrated tangible benefits. The potential for reducing medication errors by using computerized medical records equally well every bit drug-interaction screening software that detects and alerts the physician and/or pharmacist to potentially serious drug interactions has been recognized.4
These technological solutions practise accept limitations, notwithstanding. The fragmentation of healthcare commitment may consequence in incomplete records. More pregnant is the fact that, although this information is avail-able, information technology is not uniformly or optimally incorporated into decision making. This is exemplified in the observation by Cavuto et al. that pharmacists filled prescriptions for drug combinations that were known to interact even though computerized drug interaction software was in identify.5 This trouble persists as shown in the 2000 newspaper by Smalley et al. on prescription errors with cisapride.6
These findings should reinforce the demand for the wellness care practitioner to develop their own systems arroyo to prescribing without creating undesirable drug interactions. A primal understanding of the clinical pharmacology of drug interactions and a framework for fugitive preventable drug interactions remains critically important. Thus we need to overlay technologic solutions on a base that is strong in basic principles of clinical pharmacology and drug interactions. Incorporation of upward-to-date computerized databases is valuable, and frequent consultation with other members of the healthcare team, such as nurses and pharmacists, is essential.
1Bates DW, Leape LL, Cullen DJ ,Laird N, Petersen LA, Teich JM et al. Issue of computerized medico club entry and a team intervention on prevention of serious medication errors. JAMA 1998;280(15):1311–1316. 2Evans RS, Pestotnik SL, Classen DC, Horn SD, Bass SB, Burke JP. Preventing adverse drug events in hospitalized patients. Ann Pharmacother 1994;28(4):523–527. 3Gebhart F. VA facility slashes drug errors via bar-coding. Drug Topics 1999;1:44. 4Committee on Quality of Health Care in America: Constitute of Medicine. To err is human: building a safer health system. Washington, D.C.: National Academy Printing,2000. vCavuto NJ, Woosley RL, Sale G. Pharmacies and prevention of potentially fatal drug interactions. JAMA 1996;275: 1086–1087. 6Smalley West, Shatin D, Wysowski DK, Gurwitz J Andrade SE, Goodman Thou, et al. Contraindicated utilise of cisapride: impact of food and drug administration regulatory action. JAMA 2000;284(23):3036–3039.
Nosotros will discuss an approach to prescribing drugs in ways that avert agin drug interactions every bit a cause for preventable medication errors.
Drug interactions tin occur via several mechanisms:
• Drugs interactions tin can occur fifty-fifty earlier drugs enter the body due to formulation incompatibility, or at any signal in the process of absorption, distribution metabolism, and emptying.
• Drugs can bind to each other in the GI tract, preventing absorption, and reducing systemic availability.
• In theory, drugs could interact in the plasma via protein-bumping reactions just, despite the emphasis placed on these in many texts and pharmacology courses, there are no known clinically relevant examples in which this mechanism is responsible.
• A large number of important interactions do occur in the liver and GI tract due to changes in the rates of drug metabolism brought about by other medicines that are inducers or inhibitors of drug metabolism. We will be looking at this topic in depth.
• A few interactions occur through competition at drug transporters.
• Finally, interactions can occur at the level of drug action, such as the combination of verapamil, a calcium channel blocker, and a beta-blocker. Both slow the centre rate by different mechanisms, and the combination is relatively contraindicated because heart block tin can result. Because of this interaction many textbooks and computer pro-grams warn against concomitant utilise of whatever beta-blocker and any calcium aqueduct blocker. This creates a dandy deal of confusion and distrust of drug interaction warnings, considering most health care providers know that drugs in these two classes are often employed successfully and safely in patients with hypertension.
The next few slides will review some of the mechanisms for drug interactions in more detail. Several examples of drug interactions that occur prior to drug administration are listed here. When phenytoin is added to solutions of dextrose, a precipitate forms and the phenytoin falls to the bottom of the IV bag as an insoluble table salt. When this happens, it is no longer bachelor to control seizures. Amphotericin is even so used widely as a urinary bladder perfusion to treat aggressive fungal infections. If it is administered in saline, the drug precipitates and can erode through the bladder wall if not removed. The clinical presentation of such cases is an acute belly due to perforation of the bladder.ane Lastly, it is recommended that aminoglycosides not exist co-mixed in 4 fluids with betalactam antibiotics. This can markedly reduce antibiotic efficacy.
onePersonal Advice, David Flockhart, Doctor, PhD, University of Indiana, July 2001.
A number of interactions occur in the GI tract and reduce the entry of drugs into the systemic circulation.
Particularly notable among these is the ability of aluminum-containing medicines such as sucralfate (Carafate) and antacids to reduce the absorption of expensive and potentially life-saving antibiotics like ciprofloxacin (Cipro) and azithromycin (Zithromax). Women taking iron supplements frequently do non consider them as a medicines, and should be specifically questioned near whether they are taking iron if they are to be prescribed a quinolone or azithromycin. Drugs such equally ketoconazole (Nizoral) and delavirdine (Rescriptor) require an acidic environment to exist in the not-charged class that is preferentially absorbed. Solubility is drastically reduced in neutral or basic medications such as omeprazole (Prilosec), lansoprazole (Prevacid), or H2-antagonists that raise the breadbasket'south pH.
Some drugs can "crash-land" other drugs off proteins in the plasma and result in an increased amount of gratuitous drug, but this is just transient because the usual elimination mechanisms respond by increasing the rate of elimination. There is no clinically relevant poly peptide-bumping interaction that has been reported. The previously cited examples accept later been shown to be due to inhibition of elimination, not plasma protein displacement.
Drug Metabolism
The adjacent few slides will focus on drug metabolism. Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either inhibition (reduced activity) of the enzyme or induction (increased activity) of the enzyme. There are many potential consequences of changes in drug metabolism for a given drug. It is fabricated more circuitous past the fact that there are multiple pathways of metabolism for many drugs.
The majority of drugs that are metabolized are converted to inactive metabolites. This is the most mutual fate for most drugs. Of the remaining drugs, some are converted to metabolites that retain the same action as the parent. An example of this is fexofenadine (Allegra), the active metabolite of terfenadine that has equal potency at the histamine receptor and now is on the market and used clinically for allergic rhinitis. However, fexofenadine is more fifty times less active in blocking potassium channels in the heart and therefore, dissimilar terfenadine, does not cause torsades de pointes.1
In some cases the metabolites are actually more than strong than the parent. For case, a pro-drug such as enalapril must exist hydrolyzed to enalaprilat to get active.
In some cases, the metabolites have entirely new pharmacologic actions not seen with the parent drug. Metabolites tin can also be toxic, such as the metabolites of acetaminophen, which can cause liver failure, or the metabolite of meperidine, which tin cause seizures.
Inhibition of metabolism could result in potentially toxic concentrations of the parent chemical compound. On the other mitt, if the parent drug needs to be metabolized to the active chemical compound and metabolism is inhibited, and then a therapeutic failure could outcome. This happens, for example, if codeine, a prodrug, is non metabolized to morphine. Induction of drug metabolizing enzymes could similarly outcome in a subtherapeutic result by reducing drug levels beneath that required for efficacy.
1Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269(12):1532–1536.
The major group of enzymes in the liver that metabolize drugs can exist isolated in a subcellular fraction termed the microsomes. The largest and most important of these enzymes are the cytochrome P450 family of enzymes. The origin of the term "cytochrome P450" will be explained later. In add-on to cytochrome P450, in that location are other enzymes in microsomes such equally flavin monooxygenase (termed FMO3). These are as well responsible for metabolism of some drugs, only have not been besides characterized as the cytochrome P450 arrangement, and will not be discussed farther in this presentation.
Drug metabolism is generally classified in two phases, termed Phase I and Phase II.
Phase I reactions include oxidation or reduction reactions, usually through the actions of cytochrome P450 oxidative enzymes or reductases. These enzymes prepare very lipophilic molecules for Stage II reactions past creating a conjugation site, often a reactive group such as an hydroxyl grouping.
Phase II reactions "conjugate" a water soluble entity such every bit acetate or glucuronate onto the drug at the newly created or pre-existing sites, forming a more polar and water soluble metabolite that can exist more easily excreted in the urine and/or bile.
There are some characteristics of drug metabolism that tin aid predict important interactions due to inhibition of metabolism. Since Stage Ii reactions more often than not result in conjugation of a drug to a water-soluble group like a sugar, peptide (glutathione) or sulfur grouping, and, considering there is a large excess of these groups in well nourished cells, these reactions are rarely rate-limiting. Thus, they are rarely involved in drug interactions. In contrast, the Phase I reactions carried out by cytochrome P450 enzymes, flavin monooxygenases, and reductases are more frequently charge per unit-limiting. These are the target of clinically significant drug interactions, such every bit the inhibition of cyclosporine metabolism by erythromycin.
Six cytochrome P450 isoforms have been well characterized in terms of drug metabolism in humans. These will exist reviewed in the next few slides. Of annotation, iii of these isoforms—CYP2C9,CYP2C19, and CYP2D6—can be genetically absent.
Phase I oxidative enzymes are mostly institute in the endoplasmic reticulum, a subcellular organelle in the liver. The predominant enzymes responsible for Phase I reactions are those involving the microsomal mixed function oxidation system. This system requires the presence of NADPH and NADPH-cytochrome P450 reductase. "Cytochrome P450" is a superfamily of enzymes that is the concluding oxidase of this oxidation arrangement. These enzymes are companions and part of a cascade that shuttles electrons from molecular oxygen to oxidize drugs. "Cytochrome" means colored cells, and the enzymes incorporate iron, which gives the liver its red colour. "P450" comes from the ascertainment that the enzyme absorbs a very characteristic wavelength (450 nm) of UV light when it is exposed to carbon monoxide.
At that place are many different isoforms of cytochrome P450, but half-dozen have been particularly well characterized in terms of clinically relevant drug metabolism and will be discussed here.
As shown in the slide, the enzymes part in a cascade of oxidation-reduction reactions that ultimately effect in one cantlet of oxygen beingness incorporated into an oxidized metabolite, such every bit the hydroxylated form of drug shown in the slide.
This slide lists the major cytochrome P450 isozymes that are responsible for metabolism of drugs in humans. These enzymes will be reviewed in item. Considering many drugs are metabolized principally by these enzymes, important interactions between drugs can be predicted by using a listing of drugs that are inhibitors or inducers of that enzyme. This simplifies the search for interacting drugs and provides a framework for prediction of interactions. Next we volition review how these enzymes are named.
Cytochrome P450s were named by molecular biologists and protein chemists. The enzymes are named co-ordinate to families that are defined past the similarity of their amino acid sequence.
A very important principle in pharmacology applies in this instance: A pocket-sized alter in the structure of a drug or a protein that interacts with it can result in major changes in the deportment of the drug. Because of this nifty sensitivity, small changes in amino acrid sequence can consequence in huge changes in substrate specificity for the cytochrome P450 enzymes. For example, 2C19 is the principal metabolic enzyme for omeprazole (Prilosec) metabolism, simply a closely related enzyme, 2C9, has no catabolic effect on omeprazole. Thus, fiddling functional similarity is imparted by the similarity in amino acid sequence on which this nomenclature is based. All the same, as will exist seen afterward, at that place is some concordance between classes of drugs and the P450 family that metabolizes them. The focus of the subsequent slides will be to outline the part of the cytochrome P450 isozymes in metabolism of normally used drugs and to identify tools that can be used in clinical practice to avoid cytochrome P450-mediated drug interactions.
The graph on the left lists the major isoforms of CYP450 and their relative roles in drug metabolism (not relative amounts found in the liver) based upon the number of drugs that are known to be metabolized by that particular isozyme. CYP3A is responsible for the metabolism of the largest number of drugs followed past CYP2D6.
The graph on the correct summarizes the relative quantity of specific P450 families plant in the liver.1 The CYP3A family unit is present in the largest amounts. CYP2D6 accounts for less than 2% of the total content of P450 in the liver, but equally shown on the left, is responsible for the metabolism of a big fraction of drugs. A large corporeality of cytochrome P450 has not yet been characterized.
There is tremendous variability betwixt individuals in terms of expression of cytochrome P450 isozymes. For example, CYP2D6 is not nowadays at all in some livers.
Notation: 2C on the graph on the correct refers to both CYP2C9 and CYP2C19.
1Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994;270(i):414–423.
The cytochrome P450 enzymes take iii interesting properties that often make information technology possible to predict drug interactions.
First, some people have mutations in ane or more than of the nucleic acids in the Dna sequence expressing a given cytochrome P450 isozyme. As a consequence, the enzyme may exist absent-minded or have low, or no, metabolizing activeness for drugs that are normally metabolized by that enzyme. If the mutation is relatively common (more than 1%) it creates a polymorphism—this is a trait that has genetic variation that results in more than than a single population being represented in greater than i% of the total population. It literally means that the distribution of the trait has "multiple" "forms," i.e. "poly" "morphic." At to the lowest degree three of the cytochrome P450s that we will be discussing (2D6, 2C19, 2C9) are polymorphic in their distribution. People expressing a polymorphism will therefore metabolize drugs at a different rate than the residue of the population.
This graph demonstrates a population drug metabolism distribution for CYP2D6. On the graph, PM means poor metabolizer, EM means extensive metabolizer, which is the normal or usual phenotype, and URM means ultra-rapid metabolizer. Approximately 7% of the U.S. population has a genetic defect in CYP2D6 that results in a poor metabolizer phenotype. Ultra-rapid metabolizers usually do not appear equally a separate distribution in most phenotypic data but are important because a usual dose of drug in these people will be cleared more than chop-chop than in the rest of the population and will result in lower blood levels of the drug and, perhaps, less therapeutic effect. For CYP2D6, it is known that these individuals have very loftier activity because they have multiple copies of the CYP2D6 factor (up to13 copies have been reported).
Second, people that have usual drug metabolizing ability (EM) can become phenotypic poor metabolizers if they are given a substance (drug or food as we volition see later) that inhibits the enzyme. Then if two drugs are given that are metabolized by the same enzyme, and one inhibits the enzyme, the second drug can accumulate to college and potentially toxic levels.
Third, several of the cytochrome P450 isozymes can be "induced" to have increased activity. If this occurs, metabolism of any drug that is a substrate for that isozyme will be metabolized more chop-chop resulting in lower plasma concentrations of the drug. This may as well reduce the efficacy of the drug. Also, if the drug is metabolized to a toxic chemical compound, the toxic metabolite may accumulate to higher levels.
The P450 isozymes volition now be reviewed in more detail. The laminated card in the pocket of the module can be used equally a reference for the side by side few slides.
CYP3A is responsible for metabolizing the greatest number of marketed drugs. These include a broad range of of import medications including cyclosporine and HIV protease inhibitors, besides every bit cisapride (Propulsid) and the no longer marketed not-sedating antihistamines terfenadine (Seldane) and astemizole (Hismanal). Although CYP3A is not polymorphic in its distribution (information technology doesn't have a distinctly separate population as seen on the previous graph), its action varies over fifty-fold in the general population. CYP3A has been recently reviewed.1
CYP3A is the drug metabolizing pathway involved in the case of torsades de pointes described at the showtime of the module. Terfenadine, one of the beginning non-sedating antihistamines, is metabolized by CYP3A to fexofenadine. When the CYP3A-mediated metabolism of terfenadine is inhibited by ketoconazole, as in the case described, terfenadine accumulates to loftier levels. At these high levels, terfenadine is a blocker of potassium channels in the heart.two Potassium channels are of import for repolarization of the heart. Once these channels are blocked, QT interval on the electrocardiogram can exist prolonged and torsades de pointes tin develop, as was seen in this case. Many commonly used drugs can inhibit this enzyme as we volition see in the next slide. This of import enzyme has been the basis for almost of the fatal drug interactions that take gained so much publicity in recent years. For terfenadine, as well as astemizole and cisapride, recognition and reporting of torsades de pointes in association with the drug and its interactions ultimately led to withdrawal of these drugs from the marketplace.
The vast majority of drugs that may cause cardiac arrhythmias past prolonging the QT interval are metabolized by cytochrome P450 3A. While the biological ground for this remains unclear, information technology does make it easier to retrieve!
Also note that CYP3A is plant in the liver and also in the GI tract. Drugs that are substrates of CYP3A can exist extensively metabolized in the GI tract, and ,in fact, the GI tract is responsible for a large part of the metabolism that was formerly attributed totally to the liver! Inhibition of GI tract CYP3A also results in college plasma levels of substrate drugs.
iThummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998;38:389–430. 2Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269(12):1532–1536.
These are the important inhibitors of CYP3A that will make patients announced phenotypically to resemble poor metabolizers. Azole antifungal drugs, in general, are stiff inhibitors of CYP3A, although fluconazole is a weak inhibitor and inhibits CYP3A only at loftier doses. All the macrolide antibiotics, except azithromycin, are also potent inhibitors of this cytochrome P450 isoform. Cimetidine is a broad, just relatively weak, inhibitor of many cytochrome P450 enzymes. Also, observe that a food, grapefruit juice, is listed equally an inhibitor. The role of grapefruit juice in drug interactions will be discussed subsequently.
Several commonly used drugs have been characterized every bit inducers of CYP3A. Use of these drugs could potentially result in lack of therapeutic efficacy of a CYP3A substrate. Drug interactions with the herbal remedy St. John's wort will be discussed later in the presentation.
CYP2D6 metabolizes many of the cardiovascular and neurologic drugs in use today. Written report of CYP2D6 has led to understanding the failure of codeine to relieve hurting in some patients. Codeine is really a pro-drug that is converted to morphine. Codeine itself is much less active as an analgesic, but causes nausea and other adverse effects. The absence of cytochrome P450 2D6 in 7% of Caucasians means that these individuals cannot metabolize codeine to the agile metabolite, morphine, and therefore will become little, if whatsoever, pain relief from codeine.1 Even so, they will experience codeine's adverse effects, particularly if the dose is increased in the futile attempt to obtain pain relief.
30 percent of Ethiopians studied had multiple copies of the 2D6 gene (upward to13) and increased eynzyme action resulting in ultrarapid metabolism.2 Ultra-rapid metabolism results in lower blood levels following a standard dose of any drug metabolized by this enzyme. Therefore these patients may have an inadequate response to standard dosages of ß-blockers, narcotic analgesics, or antidepressants and may require higher dosages for clinical effectiveness.
Several commonly used medications inhibit CYP2D6. These include quinidine3 equally well as haloperidol and another antipsychotics.4,5 The well-described pharmacokinetic interaction between selective serotonin reputake inhibitor (SSRI) antidepressants and tricyclic antidepressants appears to be due to the fact that fluoxetine and paroxetine are both potent inhibitors of CYP2D66,7 and render patients metabolically equivalent to people who exercise not take the enzyme. This increases the plasma levels of tricyclic antidepressants and increases the potential for side effects. In dissimilarity, patients co-prescribed fluoxetine or paroxetine with codeine may feel no analgesic benefit, since codeine requires CYP2D6 for metabolism to morphine.
1Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996; 278(3):1165–1174. 2Aklillu Eastward, Persson I, Bertilsson Fifty, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996;278(1):441–446. 3Branch RA, Adedoyin A, Frye RF, Wilson JW, Romkes Chiliad. In vivo modulation of CYP enzymes by quinidine and rifampin. Clin Pharmacol Ther 2000; 68(four):401–411. fourShin JG, Kane Grand, Flockhart DA. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition past reduced halo-peridol. Br J Clin Pharmacol 2001;51(i):45–52. 5Shin JG, Soukhova N, Flockhart DA. Upshot of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6. Drug Metab Dispos 1999;27(9):1078–1084. 6Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 1992;51(3):239–248. 7Leucht Southward, Hackl HJ, Steimer W, Angersbach D, Zimmer R. Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Psychopharmacology (Berl) 2000;147(4):378–383.
CYP2C9 has a polymorphic distribution in the population and is missing in ane% of Caucasians. It is the major enzyme responsible for metabolism of many of the not-steroidal anti-inflammatory drugs (NSAIDs), including the 2d generation cyclooxygenase-two (COX-2) specific inhibitors. A number of other of import medications have their metabolism primarily catalyzed by CYP2C9. An important drug metabolized by this enzyme is warfarin (Coumadin), and nearly all inter-patient variability in warfarin levels and anticoagulant effects can be explained on the basis of CYP2C9 action (non the differences in protein binding every bit originally thought).
The azole antifungal amanuensis fluconazole (Diflucan) is a potent inhibitor of CYP2C9. Fluconazole, at conventional doses, abolishes CYP2C9 activity.
An interaction between fluconazole and warfarin results in at least a two-fold increment in warfarin claret level, a reduction in warfarin clearance, and increased anticoagulation.1 Clinical studies have identified a significant interaction between fluconazole and celecoxib (Celebrex), leading to a twofold increment in celecoxib plasma concentrations.2 A clinical pharmacokinetic written report demonstrated an increase in phenytoin area under the plasma concentration curve (AUC) following fluconazole administration,three and symptomatic phenytoin toxicity has been reported with concomitant administration of fluconazole and phenytoin.four
iBlack DJ, Kunze KL , Wienkers LC, Gidal Be, Seaton TL, McDonnell ND, et al. Warfarin-fluconazole. 2. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 1996;24(4):422–428. iiCelebrex. Physicians'Desk Reference. Montvale, NJ: Medical Economic science Visitor, Inc., 2001:2482–2485. threeTouchette MA, Chandrasekar PH, Milad MA, Edwards DJ. Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man. Br J Clin Pharmacol 1992;34(ane):75–78. 4Cadle RM, Zenon GJ,Three, Rodriguez-Barradas MC, Hamill RJ. Fluconazole-induced symptomatic phenytoin toxicity. Ann Pharmacother 1994;28(2):191–195.
Cytochrome P450 2C19 is notable considering of its genetic absence in such a high pct of Asians (approximately 20–thirty%). This enzyme metabolizes many anticonvulsants, diazepam (Valium), omeprazole (Prilosec) and several of the tricyclic antidepressants. Asians accept reduced clearance of diazepam compared to Caucasians,1 and, in fact, a survey of Asian and Western physicians demonstrated the use of lower doses of diazepam in Asians.two Asian patients may have a lower omeprazole dosage requirement for effective handling of Helicobacter pylori. According to the omeprazole package insert, Asians have about a iv-fold increase in the AUC of omeprazole compared to Caucasians, and the labeling recommends that one should consider dosage adjustment.iii In addition, the poor metabolizer genotype for CYP2C19 resulted in a higher cure rate for H. pylori (100%) than the rapid metabolizer genotype (28.6%) in an Asian population treated with omeprazole as office of dual therapy.iv Similar results take been shown more recently with proton pump inhibitors in a triple therapy regimen.5
Ketoconazole6 and omeprazole7 are inhibitors of CYP2C19 and have the potential for clinically significant interactions with substrates of CYP2C19 such equally diazepam8 or phenytoin.9 Isoniazid, used to care for tuberculosis, is an inhibitor of CYP2C1910 and should be prescribed cautiously to patients taking phenytoin and other drugs metabolized by CYP2C19.
1Ghoneim MM, Korttila M, Chiang CK ,Jacobs 50 ,Schoenwald RD, Mewaldt SP, et al. Diazepam effects and kinetics in Caucasians and Orientals. Clin Pharmacol Ther 1981;29(6):749–756. 2Rosenblat R, Tang SW. Do Oriental psychiatric patients receive dissimilar dosages of psychotropic medication when compared with occidentals. Tin J Psychiatry 1987;32(iv):270–274. 3Prilosec. Physicians' Desk Reference. Montvale, NJ: Medical Economic science Company, Inc.;2001:587–591. 4Furuta T, Ohashi M, Kamata T, Takashima M ,Kosuge K, Kawasaki T, et al. Upshot of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med 1998; 129(12):1027–1030. 5Furuta T, Shirai Northward, Takashima M, Xiao F, Hanai H, Sugimura H, et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 2001;69(three):158–168. 6Atiba JO, Blaschke TF, Wilkinson GR. Furnishings of ketoconazole on the polymorphic iv-hydroxylations of South-mephenytoin and debrisoquine. Br J Clin Pharmacol 1989;28(2):161–165. 7Ko JW, Sukhova N, Thacker D, Chen P, Flockhart DA. Evaluation of omeprazole and lansoprazole every bit inhibitors of cytochrome P450 isoforms. Drug Metab Dispos 1997;25(vii): 853–862. 8Ishizaki T, Chiba M, Manabe 1000, Koyama East, Hayashi M, Yasuda South, et al. Comparing of the interaction potential of a new proton pump inhibitor, E3810,versus omeprazole with diazepam in extensive and poor metabolizers of South-mephenytoin 4'-hydroxylation. Clin Pharmacol Ther 1995;58(2):155–164. ixPrichard PJ, Walt RP, Kitchingman GK, Somerville KW ,Langman MJ, Williams J,et al. Oral phenytoin pharmacokinetics during omeprazole therapy. Br J Clin Pharmacol 1987;24(iv):543–545. 10Desta Z, Soukhova NV, Flockhart DA. Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: stiff inhibition of CYP2C19 and CYP3A. Antimicrob Agents Chemother 2001;45(2):382–392.
Cytochrome P450 1A2 is an of import drug metabolizing enzyme in the liver that metabolizes many commonly used drugs including theophylline, imipramine, propranolol, and clozapine. CYP1A2 is induced in a clinically relevant manner past tobacco smoking. The clearance of theophylline, imipramine, propranolol and clozapine are all increased by smoking. Thus, people who smoke may crave higher doses of some of the medications that are substrates of CYP1A2. In contrast, a smoker would crave a decrease in theophylline dosage if, for case, smoking were discontinued and the enzyme no longer induced. This topic has been recently reviewed by Zevin and Benowitz.i
Inhibitors of CYP1A2, including some fluoroquinolone antibiotics, can increase the plasma concentrations of drugs that are metabolized by CYP1A2,with a potential for increased toxicity.ii,3
1Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 1999;36(6):425–438. 2Raaska M, Neuvonen PJ. Ciprofloxacin increases serum clozapine and Due north-desmethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol 2000;56(viii):585–589. 3Grasela Thursday, Jr., Dreis MW. An evaluation of the quinolone-theophylline interaction using the Food and Drug Assistants spontaneous reporting organization. Arch Intern Med 1992;152(iii):617–621.
It would be impossible to memorize all of the drug interactions that have been presented here. Fortunately there are aids to help health care providers to anticipate and prevent drug interactions, such every bit the tool shown here. This is a pocket version of a much larger CYP P450 drug interaction table. A more complete version of this menu is at Indiana University'south P450 Drug Interactions Table. This table includes a listing of the 6 major cytochrome P450 isozymes involved in drug metabolism and the drugs that are metabolized by them. Nosotros recommend using this or some other tabular array as a quick reference for detection of potential drug interactions.
If 2 drugs are metabolized by the same cytochrome P450 isozyme, it is very possible that competitive inhibition could lead to college than usual levels of either or both of the drugs. If a drug is metabolized past a specific cytochrome P450 and is taken with an inhibitor or inducer of that isozyme, an interaction is also likely.
The following are examples of how to apply this card. Suppose your patient is taking amiodarone and you lot want to add a statin amanuensis to decrease the patient'due south cholesterol (follow red circles and arrows above). The card shows that amiodarone is an inhibitor of CYP2D6 and CYP3A. We also notation that lovastatin and simvastatin are metabolized by CYP3A and that if given with amiodarone (which is inhibiting the enzyme) a toxic level of the statin may occur. The issue may be an adverse reaction (rhabdomyolysis or liver toxicity). The best pick would be pravastatin, which is not metabolized past CYP3A. Another example would be if your patient were taking an HIV protease inhibitor and wants to have St. John's wort (follow dark-green squares and arrows above). According to the carte, St. John's wort induces CYP3A4, which metabolizes most protease inhibitors. The concomitant administration of St. John'southward wort with protease inhibitors could outcome in the induction of CYP3A4, increased metabolism, and subtherapeutic levels of the protease inhibitor.
Laminated versions of this card can be ordered from the website listed above. At the website, it is possible to easily obtain the reference for a given drug by clicking on the drug. The website hyperlinks to PubMed and searches for a list of the relevant publications.
In improver to the drug-drug interactions just reviewed, drug-disease interactions can occur. These include interactions between certain drugs and specific disease states. Severe liver disease can be associated with reduced metabolic clearance and higher plasma levels of drugs extensively metabolized by the liver.1 Although liver affliction reduces drug clearance on boilerplate, the change is relatively small and ordinarily not clinically relevant except in patients with near terminal liver illness. The effects of renal disease on elimination of drugs that are primarily cleared renally are more predictable, and well-established guidelines exist for dosage of many drugs in renal disease.two Eye failure reduces liver blood menses and causes a reduction in clearance for drugs such as lidocaine or propranolol that are ordinarily extensively cleared by the liver,3 and astute myocardial infarction reduces clearance of some drugs, such as lidocaine, as well.4 Astute viral infection and changes in thyroid part have been associated with altered clearance for some drugs, such equally theophylline and warfarin.v–vii Still, the results are then variable between individuals that it is difficult to predict who is at take a chance, and these changes are usually but clinically of import in cases of extremely impaired organ function.
1Brouwer KLR, Dukes GE, Powell JR. Influence of liver function on drug disposition. In: Evans We, Schentag JJ, Jusko WJ, editors. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics, Inc.; 1992:vi-i-6-59. 2Lam YW, Banerji S, Hatfield C, Talbert RL. Principles of drug administration in renal insufficiency. Clin Pharmacokinet 1997;32(1):xxx-57. threeShammas FV, Dickstein One thousand. Clinical pharmacokinetics in centre failure. An updated review. Clin Pharmacokinet 1988;fifteen(2):94-113. 4Pieper JA, Johnson KE. Lidocaine. In: Evans We, Schentag JJ, Jusko WJ, editors. Applied Pharmacokinetics:Principles of Therapeutic Drug Monitoring. Vancouver, WA: Practical Therapeutics Inc.; 1992:21-1-21-37. fivePokrajac M, Simic D,Varagic VM. Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease. Eur J Clin Pharmacol 1987;33(5):483–486. half-dozenStephens MA, Self TH, Lancaster D, Nash T. Hypothyroidism: effect on warfarin anticoagulation. South Med J 1989;82(12):1585–1586. sevenYamaguchi A, Tateishi T, Okano Y, Matuda T, Akimoto Y, Miyoshi T, et al. Higher incidence of elevated body temperature or increased C-reactive protein level in asthmatic children showing transient reduction of theophylline metabolism. J Clin Pharmacol 2000;40(3):284–289.
Several drugs are known to collaborate with foods,i some of which are listed here. Ane of the early on observations was the reduced absorption of tetracycline when taken with milk products. The chelation of tetracycline by calcium prevents it from being absorbed from the intestines. Dietary sources of vitamin K, such every bit spinach or broccoli, may increase the dosage requirement for warfarin past a pharmacodynamic animosity of its result. Patients should be counseled to maintain a consequent nutrition during warfarin therapy. Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolism of many drugs. This was outset described for felodipine (Plendil)two but has now been observed with several drugs.3 This interaction can pb to reduced clearance and higher blood levels when the drugs are taken simultaneously with grapefruit juice. With regular consumption, grapefruit juice as well reduces the expression of CYP3A in the GI tract.4
oneWilliams Fifty, Davis JA, Lowenthal DT. The influence of food on the absorption and metabolism of drugs. Med Clin N Am 1993;77(4):815–829. 2Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991;337(8736):268–269. 3Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000;75(nine):933–942. fourLown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA et al. Grapefruit juice increases felodipine oral availability in humans by decreasing abdominal CYP3A protein expression. J Clin Invest 1997;99(10):2545–2553.
This slide demonstrates the furnishings of grapefruit juice on felodipine pharmacokinetics and pharma-codynamics.1 The left graph shows felodipine plasma concentrations at specific time points, up to 24 hours, following administration of a unmarried dose of felodipine with 250 cc of grapefruit juice or h2o. The right graph shows systolic and diastolic blood pressure from the same time points. Compared with water, there is an increase in felodipine plasma concentrations, likewise as a decrease in systolic and diastolic claret pressure. This demonstrates a potentially clinically significant outcome of the grapefruit juice-felodipine interaction.
iDresser GK, Bailey DG, Carruthers SG. Grapefruit juice-felodipine interaction in the elderly. Clin Pharmacol Ther 2000;68:28–34.
It has been suspected that herbal remedies could interact with other herbals or even prescription drugs. Ingestion of St. John'southward wort has resulted in several clinically significant interactions with drugs that are metabolized by CYP1A2 or CYP3A, including indinavir (Crixivan)1 and cyclosporin (Sandimmuneand Neoral).2,3 An interaction with digoxin (Lanoxin) has too been reported that may be mediated past interference with P-glycoprotein (P-GP), a transport organization that pumps drugs across membranes.4 These interactions are most likely due to induction of the cytochrome P450 isozyme or the drug transporter and have caused decreased plasma concentrations of prescription drugs. In the instance of cyclosporin, subtherapeutic levels resulted in transplant organ rejection. Warnings about St. John's wort drug interactions have been extended to oral contraceptives, with labeling suggesting the possibility of breakthrough bleeding and potential for loss of contraceptive outcome.
It is likely that many drug-herbal interactions exist but accept not nonetheless been detected. It is therefore important that health care providers obtain a complete drug history that includes herbal remedies and other natural products and dietary supplements and that they be alert to potential interactions.
1Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John'south wort. Lancet 2000;355(9203):547–548. 2Breidenbach T, Hoffmann MW, Becker T, Schlitt H, Klempnauer J. Drug interaction of St John's wort with cyclosporin. Lancet 2000;355(9218):1912. threeRuschitzka F, Meier PJ, Turina Yard, Luscher TF, Noll G. Astute heart transplant rejection due to Saint John's wort. Lancet 2000;355(9203):548–549. fourJohne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66(iv):338–345.
This slide shows the mean plasma concentration time grade of indinavir in 8 good for you volunteers with indinavir alone or subsequently taking indinavir with St. John's wort.1 After administration of St. John's wort, a 57% reduction was observed in the indinavir surface area under the plasma concentration-fourth dimension curve (AUC), indicative of reduced exposure to indinavir. This study prompted a public health informational released past the FDA on February10, 2000 (https://web.archive.org/web/20090117050826/http://www.fda.gov/cder/drug/advisory/stjwort.htm) about the gamble of drug interactions between St. John's wort and other medications. The potential for loss of therapeutic efficacy due to this interaction suggests the importance of taking a complete medication history. This history should include questions about herbal therapy and other natural products as well every bit over-the-counter medications.
iPiscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John'due south wort. Lancet 2000;355(9203):547–548.
ADR Reporting
Given the vital importance of postmarketing surveillance of new drugs, MedWatch, the FDA Medical Products Reporting Programme, was established in 1993. The programme has 4 general goals. The first goal is to increase sensation of drug, device and other medical product induced disease and the importance of reporting.
The second goal of MedWatch is to analyze what should (and should not) exist reported. Health professionals are asked to limit reporting to serious agin reactions. This is important both in improving the quality of individual reports and enabling the FDA and the manufacturer to focus on the most significant reactions. Causality is not a prerequisite for reporting; suspicion that a medical production may exist related to a serious reaction is sufficient reason to written report.
The third goal is to brand it as easy as possible to report to the FDA. Merely one reporting form is necessary. The postage stamp-paid class for voluntary reporting is available in the back of the Physicians' Desk Reference or from the FDA via the toll free number (1-800-FDA-1088) or from the FDA/MedWatch website (www.fda.gov/medwatch).
The fourth and final goal of the program is to provide feedback to health professionals almost new rubber problems with pharmaceuticals and medical devices. Prophylactic-related labeling changes, "Love Health Care Professional person" correspondence, condom alerts and FDA public health advisories are posted on the FDA/MedWatch website.
1Kessler DA. Introducing MedWatch: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993;269:2765–8.
Preventing Drug Interactions
In closing, it is impossible to remember all of the drug interactions that can occur. It is therefore important to develop a stepwise approach to preventing adverse reactions due to drug interactions.
First, taking a proficient medication history is essential. The "AVOID Mistakes" mnemonic presented on the next slide tin help wellness care practitioners to develop good habits when performing this task.
Second, it is essential that physicians develop an agreement of which patients are at risk for drug interactions. Of course any patient taking ii medications is at some risk. Studies prove that the rate of adverse drug reactions increases exponentially in patients taking 4 or more medications.1 Chiefly, some categories of drugs are especially at loftier risk for interactions. These categories include anticonvulsants, antibiotics, and certain cardiac drugs such as digoxin, warfarin, and amiodarone.
Third, any time a patient is taking multiple drugs, nosotros recommend that the outset step be to check a readily available pocket reference, recognizing that the interaction may non be listed and a more complete search may exist required.
Fourth, consult other members of the health care team. Depending upon the practice setting, this may be a clinical pharmacologist, a hospital pharmacist, a particularly trained office staff nurse, or the nearby chemist in community practice.
Fifth, use 1 of the computerized databases available. Up-to-date databases are maintained by gsm.com and epocrates.com, and others.* The latter can exist placed on a manus-held computer (e.g. Palm Pilot) and tin can exist configured to automatically update each fourth dimension yous synchronize with the desktop computer. The Medical Letter Drug Interaction Plan is inexpensive and updated quarterly.*
*These programs are non endorsed by the FDA.
1Jacubeit T, Drisch D, Weber E. Hazard factors equally reflected by an intensive drug monitoring organisation. Agents Actions 1990;29:117–125.
Finally, use of the "AVOID Mistakes" mnemonic tin assist to develop good practice habits and offers a useful style of remembering the components of a practiced drug history.
A history of allergies or previous history of agin reactions to whatsoever drugs should be elicited in a style that will yield the virtually useful information. For example, rather than asking about a history of drug allergy, the patient should be asked whether at that place is whatever drug that should not be prescribed for whatsoever reason. A specific question should be asked nearly the use of vitamins and herbal or other natural products. Old drugs (prescription and over the counter) should be considered as well as new drugs, since some of the effects (either toxicity or potential for drug interactions) could be relatively long-lasting. The potential for adverse drug interactions should exist evaluated. The need for a behavioral contract between the medico and the patient should be considered in an attempt to help the patient reach the therapeutic goal, either in the instance of drug dependence or adherence to a therapeutic regimen, with a clear program. Finally, a family unit history of benefits or issues with whatever medications will help determine whether pharmacogenetics should be considered in tailoring drug therapy.
These web sites are not endorsed by the FDA.
Post-doctoral preparation for physicians and pharmacologists interested in clinical pharmacology every bit a career is available at NIH-sponsored sites also as other sites throughout the country. For a listing of available preparation programs and contact information, encounter the website of the American Order for Clinical Pharmacology and Therapeutics (ASCPT).
Acknowledgements
Source: https://www.fda.gov/drugs/drug-interactions-labeling/preventable-adverse-drug-reactions-focus-drug-interactions
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