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Drug Drug Interactions

A drug-drug interaction occurs when one drug interacts with or interferes with the action of another drug. For example, taking an antacid with oral tetracycline causes a decrease in the effectiveness of the tetracycline. The antacid chemically interacts with the tetracycline and impairs its absorption into the bloodstream, thus reducing the effectiveness of the tetracycline. Drugs known to cause interactions include oral anticoagulants, oral hypoglycemics, anti-infectives, antiarrhyth-mics, cardiac glycosides, and alcohol. Drug-drug interactions can produce effects that are additive, synergistic, or antagonistic.

Drug Drug Interactions General

The potential of aldesleukin to participate in drug interactions has been investigated in 18 patients who underwent surgical resection of hepatic metastases (123). Compared with seven control patients who did not receive aldesleukin before surgery, six patients who received 9 or 12 MU m2 from days 7-3 before hepatect-omy had a significant fall in the activities of total cytochromes and several mono-oxygenases. No such effect was found in five patients treated with 3 or 6 MU m2 before hepatectomy. This suggests that high-dose aldesleukin might cause drug interactions by inhibiting hepatic drug metabolism.

Fooddrug Interactions

Food-drug interactions may be pharmacokinetic or pharmacodynamic in nature. Certain foods alter activity of drug metabolic enzymes, and especially CYP3A4 appears to be the key enzyme in food-drug interaction (94). It has also long been recognized that intake of food and fluid can alter the extent of drug absorption. This alteration may be related to alteration of physiological factors in the gut such as gastric pH, gastric emptying time, intestinal motility, hepatic portal blood flow or bile flow rate. Moreover, direct interaction of food with drug may also alter bioavailability such as adsorption of a drug in insoluble dietary component, complex formation of a drug with a metal ion or partitioning of a drug in dietary fat. Food may be able to alter performance of modified released oral formulation (95). It has been recognized that smoking, intake of charcoal-broiled food or cruciferous vegetables induce the metabolism of multiple drugs, whereas grapefruit juice increases...

Grapefruit Juice and Drug Interactions

Concentrations of such compounds also vary significantly between different sources of grapefruit juice. De Casto et al. (105) reported that concentrations of naringin may vary from 174 to 1492 mol L among various grapefruit juices whereas concentrations of bergamottin varied from 1.0 to 36.6 mol L. Therefore, the magnitude of grapefruit juice-drug interactions may also be variable. Paine et al. (106) reported that furanocoumarin-free grapefruit juice showed no interaction with felodipine, thus establishing that furanocoumarins are responsible for interactions between felodipine and grapefruit juice.

Drug Drug Interactions General interactions with NSAIDs

Widespread use of NSAIDs, particularly in the elderly, who often take other drugs at the same time, leads to a high risk of clinically significant drug interactions, both pharma-cokinetic and pharmacodynamic. The inhibitory effects of azapropazone, oxyphenbutazone, and phenylbutazone on the metabolism of other drugs, such as oral anticoagulants, oral hypoglycemic drugs, and phenytoin, is an example of a pharmacokinetic mechanism. Other NSAIDs inhibit the renal excretion of lithium (although toxicity is less likely with aspirin, ibuprofen, and sulindac) and methotrexate. Pharmacodynamic mechanisms are exemplified by the interactions between indometacin and other NSAIDs (except perhaps sulindac) and with antihypertensive agents (including beta-blockers, diuretics, and ACE inhibitors). Interactions of NSAIDs with other drugs (230) are summarized in Tables 2 and 3.

Contamination of Herbal Drugs and Herb Drug Interactions

Many people, especially those living with HIV AIDS, use both herbal medicines and prescription drugs. A number of clinically significant interactions between prescribed and herbal medicines have been identified. When these medications are used together, they can interact in the body, causing changes in the way the herbs and or the drug works. Such changes are called herb-drug interactions. Concurrent use of herbal or homeopathic remedies alongside prescribed or over-the-counter medicines are frequent, and may mimic, magnify, or oppose the effect of the drug 100 . Herb-drug interactions are not chemical interactions between a drug and a herbal component to produce something toxic. Instead, the interactions generally cause either an increase or decrease in the amount of drug in the bloodstream. As with conventional medicines, herbal medicines interact with drugs in two general ways pharmacokinetically and pharmacodynamically. Pharmacokinetic interactions result in alterations in the...

Drug Interactions And Special Precautions

Drug interactions with benzodiazepines are common. When mixed with other sedating compounds the effects are additive. Narcotic medications, alcohol, and antihistamines are examples where the additive sedation can lead to significant confusion. Alcohol ingestion slows hepatic metabolism and causes transiently higher concentrations of oxidatively metabolized benzodiazepines leading to further sedation. Antacids that slow gastric emptying may decrease the rate of absorption of a hypnotic agent from its primary site, the small intestine. This could alter both peak concentration and onset of effects. Benzodiazepines all undergo some form of hepatic metabolism, although some agents are much more extensively metabolized than others. Medications that inhibit hepatic microsomal oxidative metabolism may cause clinically meaningful drug interactions when combined with benzodiazepines. All currently available triazolobenzodiazepines (e.g., alpra-zolam, estazolam, midazolam, triazolam) and...

Drug Interactions

Studies are needed to confirm this potential drug interaction. Steroids such as dexam-ethasone lower MPA concentrations by augmenting the activity of the enzyme responsible for MPA metabolism. Several non-steroidal inflammatory drugs such as niflumic acid, diflunisal, flufenamic acid, mefenamic acid, and salicylic acid increase MPA concentrations by inhibiting MPA glucuronidation (194). Antacids (aluminum and magnesium hydroxide) lower total MPA exposure by reducing drug absorption in the gastrointestinal tract. Other drugs such as calcium polycarbophil and iron ion preparations also result in decreased MPA concentrations by the same mechanism (195). Lastly, salicylic acid and furosemide increase the free fraction of MPA by altering albumin binding.

Factors affecting serum drug concentrations

The serum concentration of a particular drug is determined by absorption, distribution, metabolism, and excretion of a drug. Major characteristics that affect serum drug concentrations include genetic make up of a patient as well as age, gender, weight, habits (such as smoking), and diet. Elderly and newborns may metabolize a particular drug more slowly than others. Some drugs, for example theophylline, distributes to lean weight only where other drugs, such as phenytoin, distributes to total weight. Diseases may alter serum drug concentrations dramatically. Hepatic disease may alter metabolism of a drug where a patient with renal failure may clear a drug in urine more slowly than a patient with normal renal function. Pregnancy alters metabolism of several drugs while drug-drug interactions may also significantly alter serum drug concentrations.

Genetic Factors Affecting Serum Drug Concentrations

There are wide variations in a patient's response to drug therapy. One patient may demonstrate desirable pharmacological effect after administration of a particular dose of a drug whereas another patient may show only subtle effects. Although such variability may be related to renal disease or liver disease or due to drug-drug interactions, alteration of drug-metabolizing capacity caused by hereditary enzymatic deficiency or over-expression may also lead to an altered response of a patient to a drug. As early as in 1964, Kurt et al. (36) reported that phenytoin toxicity in a patient receiving the usual dose of phenytoin was probably related to a rare genetic deficiency in phenytoin hydroxylation. Although over 15 different enzymes have been identified in the liver, in practice the cytochrome P450 isoenzymes that mediate the oxidative metabolism of many drugs include CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. These enzymes show marked variations in different people. Some of these...

Therapeutic Drug Monitoring of Anticonvulsants

In the past decade, 10 new antiepileptic drugs have been approved for use. These drugs include felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, prega-balin, tiagabine, topiramate, vigabatrin, and zonisamide. In general, these antiepileptic drugs (except felbamate) have better pharmacokinetic profiles, improved tolerability in patients, and are less involved in drug interactions compared with traditional anticon-vulsants phenytoin, carbamazepine, phenobarbital, and valproic acid. Gabapentin, levetiracetam, and vigabatrin are mainly eliminated by the renal route with a fraction of unchanged drug in the urine of 65, 66, and 100 , respectively. These anticonvul-sants are not involved in drug interactions. Other new anticonvulsants are metabolized by cytochrome P450 and uridine glucuronosyltransferase enzyme and may be involved in pharmacokinetic drug interactions with conventional anticonvulsants or other drugs (118). Clinical utility of therapeutic drug monitoring as...

General Information

Anorectic drugs, which are structurally related to the amphetamines, act mainly on the satiety centre in the hypothalamus and also increase general physical activity (1). All of them, except fenfluramine, stimulate the central nervous system and can cause restlessness, nervousness, irritability, and insomnia. Adverse effects also occur through sympathetic stimulation and gastrointestinal irritation. Drug interactions can occur with monoamine oxidase inhibitors. Dexamfetamine, phenmetrazine, and benzfetamine can cause dependence. Some of them have been associated with cardiac valvulopathy and primary pulmonary hypertension (2).

Amitava Dasgupta PhD

Drug-Drug Interactions and Elevated Free Anticonvulsant Concentrations Measurement of serum drug concentration may be misleading for a strongly protein-bound drug because a drug bound to protein is inactive and only unbound or free drug is pharmacologically active. Although free drug concentration can be estimated from total concentration in most cases, under certain pathophysiological conditions such as uremia, liver disease, and hypoalbuminemia free drug concentration may be significantly elevated even if the concentration of the total drug is within therapeutic range. Drug-drug interactions may also lead to a disproportionate increase in free drug concentrations. Elderly patients usually show increased free drug concentrations because of hypoalbuminemia. Elevated free phenytoin concentrations have also been reported in patients with AIDS and pregnancy. Currently, free drug concentrations of anticonvulsants such as phenytoin, carbamazepine, and valproic acid are widely measured in...

Organs and Systems Cardiovascular

There are no good predictors of the occurrence of dysrhyth-mias, but there are several susceptibility factors (26,27), including a history of sustained tachydysrhythmias, poor left ventricular function, and myocardial ischemia. Potassium depletion and prolongation of the QT interval are particularly important, and these particularly predispose to polymorphous ventricular dysrhythmias (for example torsade de pointes). Altered metabolism of antidysrhythmic drugs (for example liver disease, polymorphic acetylation or hydroxylation, and drug interactions) can also contribute. Avoiding drug interactions or changing the dosage of the antidysrhythmic drug in anticipation of a change in its disposition secondary to an interaction. Table 5 Some important drug-drug interactions with antidysrhythmic drugs

Profile of Proton Pump Inhibition

Comparative studies with lansoprazole and pantoprazole suggest that they have a potency similar to that of omeprazole (143). Rabepra-zole is readily converted to the active drug form and has a more rapid onset of effect than that of omeprazole in both in vitro and in vivo studies. In the rat, there is evidence to suggest that rabeprazole may have a slightly shorter duration of action than that of other PPIs. Compared with lansoprazole, the onset of action of rabeprazole was faster and its duration of action was shorter, as determined by measuring acid output and microsomal enzyme activity (144). However, in another study in dogs, the rate of recovery of acid output was similar when rabeprazole was compared with omeprazole (145). The rate of activation of PPIs is pH dependent, with rabeprazole being fully activated at pH 5.0, whereas omeprazole and lansoprazole are only partially activated. These different pH selectivities may have an impact on drug interactions and safety (146)....

Free Valproic Acid Concentrations and Clinical Outcome

Significant inter-individual variations can be observed in the Fu of phenytoin, carba-mazepine, and valproic acid, especially in the presence of uremia and liver disease. Drug-drug interactions can also lead to elevated free drug concentration. When binding is changed, the total concentration no longer reflects the pharmacologically active free drug in the plasma. Measuring free drug concentrations for antiepileptic drugs eliminates a potential source of interpretative errors in therapeutic drug monitoring using traditional total drug concentrations (37). Usually, total drug concentrations (free + protein bound) are measured in the laboratory because it is technically easier than free drug monitoring, but changes in the extent of protein binding for highly protein-bound drugs are clinically significant (38). For example, if the binding of a drug changes from 98 to 96 , the total drug concentration is unaltered, but the concentration of Fu is doubled (39).

Free Phenytoin Concentrations and Clinical Outcome

Monitoring free phenytoin concentration is very important in patients with hypoal-buminemia to avoid toxicity. Lindow et al. (61) described severe phenytoin toxicity associated with hypoalbuminemia in critically ill patients that was confirmed by direct measurement of free phenytoin. Zielmann et al. reported that in 76 of 38 trauma patients, the free phenytoin fraction was increased to as high as 24 compared with 10 Fu in otherwise healthy subjects. The major causes of elevated free phenytoin were hypoalbuminemia, uremia, and hepatic disease (62). The authors recommended monitoring of free phenytoin in such patients. Thakral et al. reported a case where a 19-year-old man who developed blurred vision and xanthopsia after administration of phenytoin for status epilepticus. The free phenytoin level was found to be toxic. Phenytoin was withheld, and the patient experienced partial recovery. The authors concluded that phenytoin toxicity as revealed by an elevated free phenytoin...

Contraindications Precautions And Interactions

Clofazimine is used cautiously in patients with gastrointestinal disorders, diarrhea, and during pregnancy (Pregnancy Category C) and lactation. If clofazimine is used during pregnancy, the infant may be born with pig-mented skin. No significant drug-drug interactions are associated with the use of clofazimine.

Free Anticonvulsant Concentrations in Patients with AIDS

Seizures are a common manifestation of central nervous system disease in patients with HIV infection. The incidence is approximately 10 in a population of hospitalized patients with an advanced stage of disease (83). Phenytoin is widely prescribed in the treatment of tonic-clonic seizures and other forms of epilepsy. Burger et al. investigated serum concentrations of phenytoin in 21 patients with AIDS. The total phenytoin concentrations were significantly lower in patients with AIDS than in the control population, although phenytoin doses were significantly higher in patients with AIDS. Calculation of Michaelis-Menten parameters demonstrated that Vmax values were similar in patients with AIDS and the control group, but a non-significant trend of lower Km values was observed in patients with HIV. The authors demonstrated that unbound phenytoin concentrations were significantly higher in patients with HIV and concluded that the lower protein binding of phenytoin in patients with AIDS...

Pharmacokinetic interactions

Beta-adrenoceptor antagonists that are cleared predominantly by the liver (for example metoprolol, oxprenolol, propranolol, and timolol) are more likely to participate in drug interactions involving changes in liver blood flow, hepatic drug metabolism, or both. Thus, enzyme-inducing drugs, such as phenobarbital and rifampicin, increase the clearance of drugs such as propranolol and metoprolol and reduce their systemic availability (386,387). Similarly, the histamine H2 receptor antagonist cimeti-dine increases the systemic availability of labetalol, meto-prolol, and propranolol by inhibiting hepatic oxidation (388-391). The disposition of drugs with high extraction ratios, such as propranolol and metoprolol, is also affected by changes in liver blood flow, and this may be the mechanism by which hydralazine reduces the firstpass clearance of oral propranolol and metoprolol (392).

Aerosolized Antifungal Prophylaxis

A major concern with prophylaxis is exposure of a large group of patients, many of whom will not develop an invasive fungal infection even without prophylaxis, to the associated systemic toxicities and drug interactions that occur with currently available antifungal agents. Recently, attention has been focused on the pulmonary delivery of antifungal agents for the prevention of invasive aspergillosis (64). This strategy is gaining favor for the prevention of invasive mycoses that primarily affect the upper and lower respiratory tract. Aerosolized delivery results in high concentrations of antifungal agents localized at the site of infection, and systemic toxicities and drug interactions may be minimized due to low systemic exposures. However, to date wide spread use of this strategy has not been well studied in clinical trials.

Policies and Regulations

It is a widely held myth that modern drugs are dangerous foreign chemicals with side effects, while herbals are natural, gentle and safe. The truth is that some herbs can be dangerous and can bring about serious diseases and even lead to death. Unlike conventional drugs, herbal products are not regulated for purity and potency and this could cause adverse effects and can even lead to drug interactions 138, 139 . There are fewer studies on herbal medicines than on conventional drugs, mainly because, unlike synthetic chemicals, herbs cannot be patented, so there is little money to be made by funding such research.

Epidemiology of digitalis toxicity

In a study of serum digoxin concentrations in 1433 patients admitted to hospital, 115 had a raised concentration (17). Of the 82 in whom the blood sample had been taken at an appropriate time, 59 had electrocardiographic or clinical features of digoxin toxicity. The patients whose serum digoxin concentrations were over 3.2 nmol l (2.5 ng ml) were slightly older (78 versus 73 years) and had higher serum creatinine concentrations (273 versus 123 mmol l) than those whose plasma concentrations were below 3.1 nmol l. Of 47 patients with raised digoxin concentrations on admission, 21 were admitted because of digoxin toxicity, and impaired or worsening renal function contributed to high concentrations in 37 patients. A drug interaction was a contributory factor in 10 cases. These results suggest that digoxin toxicity is still very common and confirms the increased risk in elderly patients, patients with renal impairment, and patients taking drugs that may interact with digoxin. Serum...

Other features of the patient

The effects of renal insufficiency on the pharmacokinetics of cardiac glycosides have been reviewed (146). The most important effect of renal failure is a reduced rate of elimination of digoxin, leading to increased accumulation during steady-state treatment. The same applies to some other glycosides, including beta-methyldigoxin, beta-acetyldigoxin, ouabain, and k-strophanthin, but not to glycosides that are mostly metabolized, such as digitoxin, the proscillaridins, and peruvoside (4). Drug interactions can also lead to reduced digoxin renal elimination. Altered non-renal elimination See Drug-Drug Interactions.

Macrolide antibiotics

Macrolides have also been suggested to interact with digoxin by inhibiting P glycoprotein (SEDA-26, 200). However, in a study of this mechanism in nine healthy Japanese men, clarithromycin 200 mg bd and erythromy-cin 200 mg qds did not alter the plasma concentration versus time curve of a single intravenous dose of digoxin 0.5 mg, but increased its renal clearance (268). This contrasts with an observation of reduced renal clearance of digoxin in two patients taking clarithromycin (SEDA-23, 194). That inhibition of renal P glycoprotein may not reduce the renal clearance of digoxin has also been suggested by studies with talinolol (SEDA-25, 172) and ator-vastatin (269). Other transport mechanisms for digoxin, including the organic anion-transporting polypeptides, have not been well studied and may play a role in digoxin disposition and hence drug interactions.

Pregnancy Category C

Actions of anti-blood clotting medicines may be temporarily boosted by chloral hydrate, but the amount of change and its medical significance are disputed. The drug may reduce blood levels of the epilepsy medicine phenytoin, thereby impeding phenytoin's therapeutic actions. In mice experimentation chloral hydrate had inconsistent impact on alcohol blood level (sometimes raising it, sometimes reducing it) but extended the time that intoxication lasted. In humans the combination produces changes in heart rate and blood pressure that might harm cardiac patients (the face and neck of one volunteer turned reddish purple from the combination). Alcohol and chloral hydrate are both depressants, and taking them together is like taking an extra dose of one or the other. Injecting marijuana's main active ingredient THC (tetrahydrocannabinol) into animals increases chloral hydrate's potency.

Susceptibility Factors Age

Drug-Drug Interactions General The many drug interactions described with cimetidine are largely attributable to inhibition of CYP isozymes or renal clearance of other drugs. Cimetidine also reduces hepatic blood flow and so can, for example, reduce the clearance of lidocaine. In the kidneys cimetidine interferes with the tubular excretion of procainamide and quinidine. Both effects are small, and the long list of drugs for which interference is demonstrable (Table 1) is out of all proportion to the number for which interference is of clinical significance.

Monoamine Oxidase Inhibitors

DRUG INTERACTIONS The most common drug interaction with antidepressants is their influence on the metabolism of other drugs. Antide-pressants are metabolized through catabolic enzymes located in a variety of places, but primarily in the smooth endo-plasmic reticulum of hepatocytes the cytochrome P450 (CYP) enzymes. Many other drugs are also metabolized through similar pathways it is estimated that about half of all drugs prescribed depend on CYP for their metabolism.

Theophylline and other xanthines

Drug interactions with dirithromycin have rarely been reported, since it does not interact with cytochrome P450. Nevertheless, in 13 healthy volunteers 500mg day for 10 days caused a significant 18 fall in the average steady-state plasma theophylline concentration and a 26 fall in peak concentration, with a 14-15 increase in clearance (4). In contrast, the steady-state pharmacokinetics of theo-phylline did not change in 14 patients with chronic obstructive airways disease who took dirithromycin for 10 days (5).

Toxicological Considerations

No systematic toxicological testing of Hp has been reported. However, it is to be expected that some preparation-specific toxicological data, such as genotoxicity and potential for drug-drug interaction data, have been submitted to the authorities by manufacturers. Unger and Frank 63 reported significant inhibition by Hp of the liver drug metabolising cytochrome P450 (CYP) isoenzymes 2C9,2D6 and 3A4 and measured IC50 values, respectively, of 121, 1044 and 335 g ml. The implication of these data is that the tested Hp extract may exert clinically important interactions with co-medications. There are a number of shortcomings in the report from Unger and Frank 63 . They aimed to validate a novel high-throughput procedure, and the drug interaction potential of the Devil's Claw extract was not the primary aim. The study contains no details of the nature of the Devil's Claw extract. The assays were not performed under GLP conditions and employed commercial preparations of the CYP isoenzymes....

Antihistamines H1 receptor antagonists

Concerns about the potential for cardiotoxic-ity and the impact of drug-drug interactions associated with some second-generation H1 receptor antagonists. Furthermore, the potential for sedation by some of the newer antihista-mines still remains an issue for many. This is important, as many patients using antihis-tamines want to remain alert and active and may also use other medications. Consequently, progress with this class of drugs should involve not only increased efficacy but also improved safety and specificity.

Rationale for immunosuppressive drug monitoring

A prerequisite for optimizing and individualizing immunosuppressive therapy is a reliable and precise method for monitoring drug concentrations. However, not all immunosuppressive drugs require routine monitoring of blood concentrations. For instance, corticosteroids are dosed based on empirical guidelines and are not routinely monitored. Although methods have been developed to measure blood concentrations of azathioprine (14-16), this antiproliferative agent is seldom monitored by transplant centers. Blood concentrations of CsA, tacrolimus, sirolimus, and MPA are routinely monitored at transplant centers for the following reasons (a) there is a clear relationship between drug concentration and clinical response (b) these drugs have a narrow therapeutic index (c) these drugs exhibit a high degree of inter- and intrapatient variability (d) the pharmacological response can be difficult to distinguish from unwanted side effects (e) there is a risk of poor or non-compliance because the...

Calcineurin inhibitors

Drug Interactions Numerous drugs influence the absorption and metabolism of CsA. Any drug that inhibits the cytochrome P-450 system or the P-glycoprotein efflux pump increases blood CsA concentrations because of increased absorption and decreased metabolism. Drugs having the opposite effect (P-450 and or P-glycoprotein inducers) produce decreased CsA concentrations. Drugs causing increased CsA blood concentrations include calcium channel blockers, several antifungal agents, and the antibiotic erythromycin. Several anticonvulsants and antibiotics, including antituberculosis agents, reduce blood CsA concentrations. In addition, there are many other drugs that synergize with CsA and potentiate nephrotoxicity. There are several excellent reviews that discuss specific drug interactions with CsA (53,54). Not all of the interactions are caused by pharmaceuticals as various foods and herbal remedies can influence CsA concentrations. For instance, grapefruit juice increases CsA blood...

Pregnancy Category X

A catalepsy effect from marijuana may become stronger in mice if they also receive flurazepam, but the reason is unclear. Alcohol and flurazepam boost some of each other's effects. Experimenters find that caffeine can lessen flurazepam's adverse next-day effects on performance. The heartburn medicine cimetidine lengthens the time that flurazepam's metabolite de-salkylflurazepam stays in the body. In a monkey experiment, that metabolite

Pregnancy Category None

Not enough scientific information to report about tolerance, dependence, withdrawal, or addiction. Drug interactions. Not enough scientific information to report. Cancer. Not enough scientific information to report. Pregnancy. Not enough scientific information to report. Additional scientific information may be found in

Herbal Alert Warfarin Interaction

Much of the information on drug-herb interactions is speculative. Herb-drug interactions are sporadically reported and difficult to determine. Because herbal supplements are not regulated by the Food and Drug Administration (FDA), products lack standardization, purity, and potency. In addition, multiple ingredients in products and batch-to-batch variation make it difficult to determine if reactions occur as the result of the herb. To assist with the identification of herb-drug interactions, nurses should report any potential interactions to the FDA through its MedWatch program (see Appendix A). Because the absorption, metabolism, distribution, and elimination characteristics of most herbal products are poorly understood, many herb-drug interactions are speculative. It is especially important to take special care when patients are taking any drugs with a narrow therapeutic index (the difference between the minimum therapeutic and minimum toxic drug concentrations is small-such as...

Reasons for TDM in AIDS

This finding is all the more impressive, considering < 20 of the physicians responded to the dosing recommendations of the intervention group (13). One of the main reasons for TDM of antiretrovirals is the well-known lack of compliance of patients on long-term therapy for chronic illnesses. For HIV AIDS patients, this lack of adherence to their drug regimens commonly occurs in 33-60 of patients (1-3). When failure of antiretroviral therapy occurs, assessment of compliance (adherence) by TDM, prior to resistance testing is very important. Documentation of ongoing antiretroviral drug presence makes the results of both genotypic and pheno-typic HIV resistance tests more meaningful. Drug-drug interactions and interpatient variability in drug handling are other major reasons for TDM in this population.

General adverse effects

The toxicity and drug interactions of flucytosine have been reviewed (13). Nausea, vomiting, and diarrhea are common. Enterocolitis is infrequent. Hepatic dysfunction, hepatitis, and even hepatic necrosis and blood disorders, including fatal aplastic anemia, can occur (14). Severe reactions mainly occurred at a time when the importance of high serum concentrations (in excess of 100 mg ml) of flucytosine in causing these adverse effects was not recognized. The importance of parenteral versus intravenous administration in the development of enterocolitis is unclear. Patients have been described who suffered adverse effects, such as hepatotoxicity or eosinophilia, that were idiosyncratic and not related to flucytosine concentrations. Hypersensitivity reactions can occur. Neither teratogenic nor tumor-inducing effects have been recorded.

Clinical Applications

Directed to these references for detail. Other important and emerging areas include cancer, cardiovascular disorders, and hematology. It would be important to recognize the role of therapeutic drug monitoring (TDM) as a global phenotypic index including contributing pharmacokinetic, pharmacodynamic, drug-drug interaction, and other environmental factors. Thus, pharmacogenomic biomarkers might be readily characterized as an adjunct to enable the practice of personalized medicine. In order to update on these applications, a summary of recent examples would include pharmacogenomics for warfarin therapy and the treatment of colorectal cancer by irinotecan.

Anesthetic combinations

The use of combinations and repeated administration of a single agent can lead to cumulative effects. Drug interactions in anesthesia are therefore potentially common and have been reviewed, both systematically (1) and as uncritical listings (2,3). Many of the interactions are beneficial, the concurrent use of two or more different agents improving the quality of anesthesia. Several reviews of this have appeared (4-6). Disadvantages of combinations include unpredictability of synergistic actions or toxicity, mutual alterations in pharmacokinetics, increased likelihood of errors in drug administration, and difficulties in planning drug therapy when adverse effects occur and are not attributable to a particular drug.

Health Supplement Alert Cranberry

Cranberry juice has long been recommended for use in treating and preventing urinary tract infections (UTIs). Clinical studies have confirmed that cranberry juice is beneficial to individuals with frequent UTIs. Cranberries inhibit bacteria from attaching to the walls of the urinary tract and prevent certain bacteria from forming dental plaque in the mouth. Cranberry juice is safe for use as a food and for urinary tract health. Cranberry juice and capsules have no contraindications, no known adverse reactions, and no drug interactions. The recommended dosage is 9 to 15 capsules a day (400-500 mg d) or 4 to 8 ounces of juice per day. (See Chap. 6 for more information.)

TABLE 311 Management of Serious Lithium Toxicity

Taking further lithium and contact their psychiatrist promptly. A lithium level should be obtained as soon as possible that same day and the symptoms followed closely for the next several days. The psychiatrist should also be contacted if the patient develops new gastrointestinal symptoms, especially vomiting or diarrhea. These symptoms may reflect an elevated lithium level or may, even if caused by an unrelated factor (such as gastrointestinal infection), trigger an elevation in the lithium level as a consequence of fluid and electrolyte changes. Other causes of fluid loss with insufficient replacement, such as excessive sweating due to heat exposure or fever, should also prompt a temporary discontinuation of lithium treatment until fluid balance is restored. Concomitant use of other medications may also increase levels of lithium and lead to lithium intoxication (See 'Drug Interactions').

Interaction Of Kava With Drugs

Recently, it has been demonstrated that several kava lactones are potent inhibitor of several enzymes of cytochrome P 450 system (CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4 and CYP4A9 11). Therefore, there is a potential of drug interaction with kava-kava especially for drugs metabolized by cytochrome P 450 system, but actual systemic studies with human subjects to demonstrate such drug interactions are very limited (89). A recent study involving six healthy human volunteers who consumed traditional aqueous extract of kava indicated that caffeine metabolic ratio increased twofold from 0.3 with consumption of kava to 0.6 at 30 days after the subjects stopped using kava. The later value corresponds to metabolic ratios in healthy subjects. The authors concluded that kava drinking inhibits CYP1A2 (90).

Drugs Active Against Human Immunodeficiency Virus Protease Inhibitors

Drug interactions Amprenavir is extensively metabolized by and induces CYP3A4. Plasma methadone concentrations fell by 35 when amprenavir was used (44A ). Drug interactions Venlafaxine 50 mg 8-hourly reduced the AUC of a single dose of indinavir 800 mg by 28 in nine healthy subjects (52a). Drug interactions Since HMG CoA reduc-tase inhibitors (statins) are partially or completely metabolized by CYP3A4, protease drug interactions can be expected. When nelfinavir was combined with atorvastatin and simvasta-tin, their AUCs increased by 74 and 505 respectively (58c). As myopathy and rhabdomy-olysis are concentration-related, simvastatin is contraindicated with any protease inhibitor, not just nelfinavir. Based on the data, the starting dose of atorvastatin should be reduced by about 50 .

Use of methadone in opioid withdrawal

The major adverse effects during treatment occur during the initial stabilization phase. In addition to constipation and sweating, the most frequently reported adverse effects are transient skin rash, weight gain, and fluid retention. Since the main metabolic pathway of methadone is CYP3A4, numerous drug interactions can be expected. Drugs that interact with methadone are listed in the table in the monograph on opioids.

Prescription Medications

Benzodiazepines (BZDs) (triazolam, temazepam, estazolam, flurazepam, quazepam), and more recently, a series of non-BZD type hypnotics, or Z-drugs (zolpidem, zaleplon, es zopiclone), have replaced most older hypnotics such as barbiturates, glutethimide, methaqualone, methyprylone, meproba-mate, and tybamate. The replaced hypnotics were highly addicting and, due to their low therapeutic index, were also dangerous in overdose. In contrast, BZDs, and particularly the Z-drugs, are characterized by decreased abuse potential, fewer drug-drug interactions, broader therapeutic index, and lower risk in overdose. Daytime sedation and the risk for abuse and physiological dependence are the least likely complications of Z-drug use. BZDs and the Z-drugs are currently the most frequently prescribed hypnotics, but the off-label use (FDA-approved drug use for not FDA-approved indication)

Blood blood components plasma and plasma products

Drug interactions In children with the ne-phrotic syndrome, albumin in combination with furosemide carries a risk of thrombotic complications. In 12 children although antithrom-bin and alpha2 macroglobulin fell, which is in accordance with a thrombotic tendency, there were no thrombotic complications (3c). Furthermore, there was a fall in fibrinogen concentration, which is not consistent with a throm-botic tendency.

Pregnancy Category D

In some circumstances midazolam can lower blood pressure drastically and cause seizures administering the drug with fentanyl or other opiates can increase the likelihood of such severe actions. Rat experiments unexpectedly found that the stimulant caffeine boosts difficulties in movement caused by midazolam, and cocaine also worsened that performance. Opiates or alcohol can deepen some midazolam effects in humans,

Other Prescription Hypnotics

These agents have not been approved by the FDA for insomnia, but due to their sedating properties, they are considered useful alternative hypnotics in cases of treatment resistance, intolerable side effects, drug-drug interactions, certain comorbid conditions, current or past history of drug use etc.

Selective Serotonin Reuptake Inhibitors

A review on the metabolism of SSRIs by Preskorn revealed a substantial inhibitory effect on the P450 isoenzyme system CYP2D6, with Prozac also inhibiting CYP3A4 (Preskorn 1994). Furthermore, as discussed previously, functionally significant genetic polymorphisms exist in most of the CYPs, especially CYP2D6, that metabolize most of the SSRIs including fluoxetine, paroxetine, and sertraline. CYP2D6*4 (CYP2D6B) leads to the production of defective proteins and is found in 25 of Caucasians but is rarely identified in other ethnic groups. This mutation is mainly responsible for the high percentage of poor metabolizers among Caucasians (5 -9 ) who are sensitive to drugs metabolized by CYP2D6 (Ruiz 2000). A high frequency of CYP2D6*17 in African Americans and of CYP2D6*10 in Asian Americans was found to be associated with lower enzyme activities and slower metabolism of CYP2D6 substrates and may be responsible in part for the slower pharmacokinetic profiles and lower dose ranges observed in...

What causes an overdose

Overdose can occur by accident or design. An accidental overdose occurs most frequently among children and the elderly. Young children put almost anything they find in their mouths, including drugs or chemicals. The elderly, on the other hand, typically take a whole battery of drugs on a regular schedule. Many consult a variety of specialists and receive different medications from each of them. Sometimes the combination of certain drugs will cause a reaction different from the one intended. At other times, an elderly person may unintentionally take larger doses of the drugs than prescribed, thus causing an overdose. Drug-tracking systems in pharmacies have helped reduce the problem of drug interactions caused by taking medicines prescribed by different physicians. New devices for assisting visually impaired seniors are also being used to prevent overmedicating.

Plasma concentrations and adverse effects

Plasma concentrations of antidepressants are influenced by pharmacogenetic factors, age, and drug interactions. Several studies have attempted to define the relation between plasma concentrations of tricyclic antidepres-sants and their therapeutic or adverse effects. However, the results are conflicting (SEDA-3, 12) (SEDA-5, 15) (3). Sometimes there is a clear relation between cardiac toxicity and high plasma concentrations (4-6), but in some individuals cardiotoxic effects occur at presumed therapeutic concentrations. Sporadic reports of severe adverse effects, mostly of the anticholinergic type, have often been associated with high plasma concentrations of amitriptyline or nortriptyline (7,8), although these vary with each drug and from patient to patient. The risk of central nervous system toxicity in patients treated with tricyclic antidepressants may be correlated with plasma concentrations, age, and sex (SEDA-16, 8) (SEDA-17, 17). It can be concluded that routine plasma...

Trends and Developments

Herbs are still marketed without sufficient research but evidence must always be shown to consumers to support claims of products 24, 36, 54, 137, 143, 144 . More clinical studies are needed and doctors, along with other professionals, should work towards on untangling this herbal maze. Standards should be developed for each natural health product and the same regulatory standards that apply to manufactured pharmaceuticals should apply equally to herbal products as well. Unlike conventional drugs, herbal products are not regulated for purity and potency and this could cause adverse effects and drug interactions 108 . Herbal manufacturing processes should be refined in order to improve the purity, safety and quality of products and the herbal industry needs to follow strict guidelines, for herbal products are now classified as medicines. Manufacturers and producers tend to resist these laws because such laws will increase cost, which will have to be passed on to consumers, and thus the...

Screening of Herbal Drugs

The technology of plant medicinal screening processes has even advanced to enzyme isolation. The enzymes that cause the disease are first isolated and the plant extracts are tested to determine if they block enzyme action 131 . An enzyme immunoassay for the quantification of femtomole quantities of therapeutically important alkaloids has been established 132 . Ethanolic extracts, tinctures, and pure plant compounds from commercially available herbs have been analyzed for their in vitro cytochrome P450 3A4 (CYP3A4) inhibitory capability via a fluorometric mi-crotiter plate assay. These studies indicate that high-throughput screening methods for assessing CYP3A4 inhibition by natural products have important implications for predicting the likelihood of potential herb-drug interactions 133 .

Formulation of pMDI Systems

Modified Release Medication

The monitoring of particle surface energy is another possibility that has been explored in order to improve the suspension stability in pMDIs. For example, the atomic force microscope colloidal probe technique (as described previously) may be used to measure the forces between individual micron sized particulates in model propellants, similar to those used in pMDIs, namely, pressurized HFAs (95,96). Furthermore, these techniques can be expanded to investigate the relationship between drug-drug interactions, surface free energy, and in vitro performance (97,98). Figure 14 Influence of PEG molecular weight and concentration on drug-drug interactions in a model pMDI system. Abbreviations PEG, polyethelene glycol pMDI, pressurized metered dose inhaler. Figure 14 Influence of PEG molecular weight and concentration on drug-drug interactions in a model pMDI system. Abbreviations PEG, polyethelene glycol pMDI, pressurized metered dose inhaler.

Simulating Effects of Drugs through Cenomics

Drug-target interactions have also been explored by Marton et al. (29) using expression profiling and yeast mutants. Cells with mutations in putative drug target proteins were used to confirm drug interactions and downstream effects on gene expression. The gene expression fingerprints found in target-less cells pointed to other pathway interactions for the drugs tested. The ability to define target-specific effects of drugs and their cross-reactions with other cellular components and pathways paves the way for future drug design with improved targeting and specificity. employed gene expression profiling to identify both the specific and non-specific interactions of antisense oligonucleotides. A reference library of human gene expression profiles for antisense oligonucleotides specific to potential targets could conceivably be used in the same way as the yeast mutants for identifying relevant pathways and drug interactions in the cell.

Antihistamines blocker

Second- and third-generation antihistamines such as acrivastin, astemizole, azelastirte, cetirizine, desloratadine, ebastin, fexofenadin, levocabastine, levocetirizine, loratadine, mequitazine, mizolastine, oxatomide, terfenadine, and tritoqualin are less sedating than the firstgeneration agents. The half-lives for astemizole and for terfenadine are very long (20-26 hours, astemizole metabolites 9 days ). Serious cardiovascular events and potentially serious drug interactions have been reported with respect to terfenadine and astemizol. In many countries, astemizole and terfenadine have been removed from the market. Some of the above-mentioned drugs are only available for local use. For azelastine and oxatomide, see also Chapter 2.3.

Itraconazole Prophylaxis

Itraconazole Fungal Infections

Prospective, open-label multi-center trial of antifungal prophylaxis in allogeneic hematopoietic stem cell transplants recipients itraconazole did reduce the number of invasive fungal infections compared to fluconazole (9 vs. 25 , respectively Fig. 2B) (60). A second open-label study conducted at a single-center reported significantly more proven and probable invasive fungal infections in patients randomized to fluconazole versus itraconazole (61). This difference was due to increases in the number of invasive mould infections (primarily aspergillosis). Interestingly, this study was amended after 197 patients were enrolled due to concerns with the safety of itraconazole when administered with cyclophosphamide during the conditioning regimen. Increases in serum bilirubin and a doubling of serum creatinine were observed in patients due a previously unrecognized drug interaction between these two agents when administered concurrently (62). Following this interim analysis, the protocol...

Cumulative index of special reviews Annuals 1625

Drug interactions (azoles), 24.318 Pneumocystis carinii pneumonia, 18.289 Antihistamines Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 insulin resistance, 24.504 malignancy, 23.468 Mibefradil, drug interactions, 23.210 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387 Crohn's disease, 23.350, 25.387 Muscle relaxants Salmeterol, tolerance, 24.187 Sex hormones, tumors, 22.465 Specific serotonin reuptake inhibitors, drug interactions, 22.13 Statins, see HMG co-A reductase inhibitors Steroids, see corticosteroids Sumatriptan, 17.171 comparative toxicity, 22.268 in pregnancy, 25.280 in rheumatology, 23.255 therapeutic effects, 24.278 Theophylline, asthma, 17.2, 18.1, 18.2 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 Total parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Drug interactions

OTC Classification After OTC Drug

Clear and understandable labeling to average consumers, including those individuals with low literacy, is crucial to the safe and effective use of an OTC product without professional supervision. The label should contain information such as active ingredient, indications, warnings, directions for use, and proper storage condition. An average consumer of the target population of users should be able to understand the product label to self-recognize the signs and symptoms, select the right OTC product, understand the warnings, and self-treat appropriately as directed (30). Warnings may include contraindications, precautions, situations to avoid, what to do in the case of overdose, and drug-drug interactions (42). However, not all warnings are included in the label, only those that are clinically significant and important to the safe

Pharmacotherapy for Specific Psychiatric Disorders

Substance abuse and bipolar disorder (particularly in the manic phase) are frequently comorbid disorders but there is little information about the effects of treatments for bipolar disorder on substance abuse. Research in the treatment of alcohol and cocaine dependence suggests that concurrent use of lithium is relatively safe with regard to drug interactions but


Small Molecule Drugs

Log TOP-53, a promising agent effective against non-small cell lung cancer in animal tumor models 63 . Although TOP-53 has top2 as its primary cytotoxic target and kills cells by acting as a top2 poison, it displays nearly wild-type activity against a mutant yeast type II enzyme that is highly resistant to etoposide. This shows that substituents on the etoposide C-ring can subtly modulate top2-drug interactions.

Future Trends For Otc And Lifestyle Drugs

The advance of communication technology will also significantly alter the landscape of the OTC industries. There are already companies that provide data-logging devices that allow transfer of diagnostic data between patients at home and the physician's office (327). Right now, the technology is limited to immobile patients. The advance of handheld wireless devices and cellular phones will make transfer of medical information much easier for mobile OTC consumers. With the advance of better internet security, personal data may be readily portable (328). It is not hard to image that consumers can carry a credit card-like device that has all his her medical history and possible drug-drug interactions stored on the device.

Pharmacokinetics and Serum Drug Concentrations

Renal excretion is a major pathway for the elimination of drugs and their metabolites. Therefore, impaired renal function may cause accumulation of drugs and metabolites in serum, thus increasing the risk of adverse drug effect. This may be particularly important for drugs that have active metabolites, such as procainamide and carba-mazepine. Moreover, other pathological conditions such as liver disease, congestive heart failure, and hypothyroidism may also decrease clearance of drugs. Drugs may also be excreted through other routes, such as biliary excretion. The factors that determine elimination of a drug through the biliary track include chemical structure, polarity, and molecular weight as well as active transport sites within the liver cell membranes for that particular drug. A drug excreted in bile may be reabsorbed from the gastrointestinal track or a drug conjugate may be hydrolyzed by the bacteria of the gut, liberating the original drug, which can return into the blood...

Safety and Efficacy of Phytomedicines in Cancer Prevention and Treatment

Abstract In this review we discuss some aspects of herbal use either to prevent cancer or to treat the disease or the side effects of chemotherapy. The most powerful reasons, for cancer patients, to use phytomedicines are related to the wish to leave no option untried and to the dissatisfaction with mainstream oncology treatments. In the review, herbs commonly used in cancer and their mechanism of action are referred. Moreover, clinical trials about the use of some herbs for treating the side effects of chemotherapy and radiation are cited. As regards the safety data of phytomedicines in cancer patients, considering the narrow therapeutic window of chemotherapic drugs, the risk of clinically relevant herb-drug interactions can increase in the USA more than 100,000 deaths per year can be attributed to drug interactions, most of them connected to the use of herbs. Some experts believe that the potential risk of herb drug interactions is enough to recommend patients on chemotherapy not...

Mesalazine 5aminosalicylic acid mesalamine

Drug interactions In a prospective, parallel-group study in 34 patients with Crohn's disease taking azathioprine or mercaptopurine, co-administration of mesalazine 4 g day, sul-fasalazine 4 g day, or balsalazide 6.75 g day for 8 weeks resulted in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leukopenia (62c). Thiop-urines are metabolized by thiopurine methyl-transferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosuppression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors and pro-drugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine...

Toxicity of Herbal Drugs

The definition of toxic is ultimately a matter of viewpoint. Traditionally, herbs and herbal products have been considered to be nontoxic and have been used by the general public and traditional medicinal doctors worldwide to treat a range of ailments. The fact that something is natural does not necessarily make it safe or effective. The active ingredients of plant extracts are chemicals that are similar to those in purified medications, and they have the same potential to cause serious adverse effects. Whilst the literature documents severe toxicity resulting from the use of herbs, on many occasions the potential toxicity of herbs and herbal products has not been recognized 108 . In certain countries, such as Taiwan, herbs can be obtained from temples, night markets, street vendors, herbal stores, neighborhoods, or relatives, and from traditional medicine practitioners. Ordinary people recommend the medicines to others without safety considerations. The general public and many...

Helicobacter Pylori Eradication Regimens

Drug interactions In an open, randomized, crossover study of the effects of oral omepra-zole 20 mg day for 7 days on the distribution of co-administered clarithromycin in the gastric juice in 18 male volunteers with Helicobac-ter pylori, short-term omeprazole increased the amount of clarithromycin transferred to the gastric juice, confirming synergy between these two drugs (44c).

Smoking and Serum Drug Concentrations

Cigarette smoke is responsible for pharmacokinetic drug interactions, not nicotine. Therefore, nicotine replacement therapy does not cause hepatic enzyme induction (66). Theophylline is metabolized by CYP1A2. In one study, the half-life of theophylline was reduced by almost twofolds in smokers compared with that in non-smokers (65). Lee et al. (67) reported that theophylline clearance was increased by 51.1 and that steady state serum concentrations were reduced by 24.5 in children who were exposed to passive smoking. Clinically significant drug interactions with smoking have also been reported for caffeine, chlorpromazine, clozapine, flecainide, fluvoxamine, haloperidol, mexiletine, olanzapine, proprandol, and tacrine. With all medications, serum concentrations of drugs are significantly reduced in smokers because of increased metabolism of drugs. Smokers may therefore require higher doses than non-smokers to achieve pharmacological responses (66)....

See also Antiepileptic drugs General Information

Oxcarbazepine is the 10-keto analogue of carbamazepine and a prodrug for monohydroxycarbazepine, to which it is rapidly reduced. Its efficacy and tolerability profiles are similar to those of carbamazepine, from which oxcarba-zepine differs in kinetic profile (lack of autoinduction, linear kinetics, half-life of 10-20 hours, elimination by glucuronidation), lower allergenicity, greater antidiuretic activity, possibly slightly better central nervous system tolerability, and less potential for drug interactions (1). Like carbamazepine, oxcarbazepine can exacerbate absence and myoclonic seizures (SEDA-21, 73).

Third Generation Antidepressants

Venlafaxine does not substantially inhibit the CYP enzyme, and is not highly protein-bound, thus it tends to have few clinically significant drug-drug interactions. Duloxetine is metabolized by 1A2 and 2D6 P450 isoenzymes, and may increase plasma levels of other antidepressants, antipsychotics, and Type 1C antiarrhythmics, such as flecainide (Tambocor). Nefa-zodone is highly protein-bound, and has several active metabolites. It is also a strong inhibitor of CYP3A4, and affects other drugs also metabolized by that pathway however, it has little affinity for the CYP2D6 enzyme. Mirtazapine is highly protein-bound as well, but appears to only weakly affect the cytochrome enzymes.

Treatment should have the shortest possible duration

Numerous drug interactions, as noted above, dictate that drugs should be prescribed only after the data from the history, physical examination and laboratory results have been reviewed and a diagnosis established, and the costs and benefits of a particular therapy assessed. The attitude that addiction is to be avoided at all costs, cannot be justified. When such an attitude does determine clinical decisions, it frequently causes much unnecessary suffering.

Nontricyclic antidepressants

The other class of antidepressants called SSRIs has become the most widely prescribed group of antidepressants in the USA. In addition to inhibiting serotonin uptake, these drugs interact with serotonin receptors to cause pharmacological response. Advantages of SSRIs over TCAs include their lack of adrenergic, antihis-taminic and anticholinergic effects, better tolerability, and superior safety profile. SSRIs are also used in the treatment of obsessive-compulsive disorder, panic disorder, bulimia, and many other conditions. Drug interactions include any drug that increases serotonin concentrations including monoamine oxidase inhibitors, tramadol, sibutramine, meperidine, sumatriptan, lithium, St. John's wort, ginkgo biloba, and atypical antipsychotic agents. Overdose situations or drug-drug interactions leading to an increase in serotonin may cause serotonin syndrome. The syndrome is associated with changes in mental status, agitation, myoclonus, diaphoresis, shivering, tremor,...

Federal Schedule Listing Schedule Iv Dea no 1680 USA Availability Prescription Pregnancy Category C

Modafinil can make birth control pills and implants less effective. A laboratory test indicated that the drug may reduce blood levels of cyclosporine, an immunosuppressant used to help organ transplant patients. Modafinil may raise blood levels of diazepam, tricyclic antidepressants, the anti-blood clot medicine warfarin, and the epilepsy medicine phenytoin.

The Cytochrome P450 Gene Family

Specific dose recommendation based on CYP2D6 genotypes have already been put forward (Kirchheiner et al. 2001) with doses of TCA halved for PM. The proposed doses adjustments for SSRIs were significantly smaller than otherwise recommended, and some authors even question the relevance of genotype-adjusted dosing for SSRIs, given their flat dose-response curve (Brosen and Naranjo 2001). Nonetheless, an identification of PM may prevent overdosing and the occurrence of specific side effects with SSRIs or SNRIs. In addition, knowledge of the metabolizer status of a patient may also be helpful in predicting problems with drug interactions. Brosen et al. (1993) report that pharmacokinetic interactions of paroxetine (an inhibitor of CYP2D6) and the TCA desipramine (extensively metabolized by CYP2D6) are dependent on the metabolizer status. Co-administration of the two drugs in EM who have at least two functional copies of the CYP2D6 gene leads to a fivefold decrease in desipramine clearance....

Secondgeneration antihistamines

There are several novel antihistamines that are either metabolites or enantiomers of existing drugs. The aim has been to develop antihistamines with improved potency, onset and duration of action, and greater predictability and safety. Drugs of this kind that have received regulatory approval and are effective in several allergic conditions include desloratadine, fexofenadine, levocabastine, and levocetirizine. These have been developed in response to widespread concerns about the potential for cardiotoxicity and the impact of drug-drug interactions associated with some earlier second-generation H1 receptor antagonists. Furthermore, the potential for sedation by some of the newer antihistamines still remains an issue for many. This

Quality Efficacy and Safety Considerations

For example, flavonoids exhibit a range of biological activities and have the ability to modulate several enzymes or cell receptors, mainly as a result of their antioxidant properties. By comparison, synthetic drugs usually contain single chemical entities so that drug-drug interactions are less likely 61 . This highlights the need to identify and purify active components from medicinal plant preparations as the potential for adverse interactions with purified compounds is less likely. Various phytochemicals, including piperine, flavonoids, triterpenoids, anthra-quinones, polyphenols, and alkaloids, some of which are present in antidiarrheal preparations, interact with and inhibit cytochrome P450 systems and can impact on the pharmacokinetics of any co-administered drugs metabolized by these systems 31 . For example, piperine (Fig. 12.2) has been shown to inhibit arylhydrocar-bon hydroxylase and 7-ethoxycourmarin deethylase (CYP2A) by a noncompetitive mechanism....

Computerized Drugstores

The DEA is encouraging llie adoption of computer systems by pharmacies throughout the country, but has received mixed reactions from stale pharmacy boards. Six competing computer systems were displayed last June at the annual convention of the National Association of Boards of Pharmacy at Lake Buena Vista, Florida. These systems lypically respond lo a refill order with a read-out of the patients and physician's names, llie I patientls previous prescriptions, allergy J and drug interaction warnings and llie jj prescription label in triplicate. Ken Dur- j rin, director of the DEA's Compliance i Investigation Division, said that any sys- 5 tem he approved would also have to 1 prevent unauthorized prescriptions from j being entered under the forged initials of j the pharmacist


Fig.4a-c Molecular modelling of the FP-quinoline drug interaction. Thefigure depicts a low-energy complex of haem Fe(III)FPIX (in vacuo) with a synthetic quinoline F2TB and clearly shows the n-n-stacking interaction between the porphyrin ring of FP and the quinoline ring and an electrostatic interaction between the carboxylic acid group and the protonated amino side chain of the drug. The space-filling model for the complex is shown on the right. c Carbon atoms are represented in grey. Hydrogens are white, nitrogens are blue, oxygens light red, chlorine green and iron dark red Fig.4a-c Molecular modelling of the FP-quinoline drug interaction. Thefigure depicts a low-energy complex of haem Fe(III)FPIX (in vacuo) with a synthetic quinoline F2TB and clearly shows the n-n-stacking interaction between the porphyrin ring of FP and the quinoline ring and an electrostatic interaction between the carboxylic acid group and the protonated amino side chain of the drug. The space-filling model for...

Opiate Class

Classic unwanted actions from opiates are constipation, urinary difficulty, low blood pressure, and breathing trouble. MAOI drugs, described earlier, may interact dangerously with opiates. In contrast to such problems, a desirable drug interaction is that opiates may boost pain relief from aspirin.


While voriconazole has been a significant advancement in the treatment of invasive aspergillosis, the use of this agent is associated with a number of clinically significant drug interactions as well as the potential for hepatotoxicity. In addition, recent attention has focused on the variable bioavailability of orally administered voriconazole. A potential cause for this variability may be genetic polymorphisms in the cytochrome P450 enzyme 2C19, an influential covariant for exposure and clearance of this drug (37,38). This variability may influence response to therapy as a recent study has suggested that voriconazole trough plasma concentrations below 1 mcg mL may be associated with poor outcomes in patients with invasive fungal infections (39).


Itraconazole is contraindicated in patients with a known hypersensitivity to the drug. The drug is used cautiously in patients with hepatitis, those with human immunodeficiency virus, impaired liver function, and in pregnant women (Pregnancy Category C). In patients with hypochlorhydria, the absorption of itraconazole is decreased. Multiple drug interactions occur with itra-conazole. Itraconazole elevates blood concentrations of digoxin and cyclosporine. Phenytoin decreases blood levels of itraconazole and alters the metabolism of phenytoin. Histamine antagonists, isoniazid, and rifampin decrease plasma levels of itraconazole. There is an increased anticoagulant effect when warfarin is administered concurrently with itraconazole.


Drug interactions A San Francisco woman with a history of diabetes and high blood pressure was hospitalized in January 2001 with a life-threatening low blood sugar concentration after she consumed Anso Comfort capsules (7a). The hospitalization may have been necessitated by a drug interaction of chlordiazepox-ide and the prescribed medications for her other medical conditions.


One of the most important advances in the treatment of invasive fungal infections has been the development and availability of the echinocandin class of antifungal agents. Currently, three agents are available for use in the United States anidulafungin, caspofugnin, and micafungin. By inhibiting the fungal specific target beta-1,3-glucan synthase, resulting in the reduction of beta-1,3-glucan in the cell walls of Candida and Aspergillus species, these agents avoid toxicities to mammalian cells associated with amphotericin B as well as the drug interactions commonly caused by triazoles due to inhibiton of cytochrome P450 enzymes (45-47). While the excellent safety profile and therapeutic efficacy for the treatment of invasive candidiasis have been well documented in clinical trials (48-50), the efficacy of the echinocandins for the treatment of infections caused by Aspergillus species is less established. The majority of clinical data for the treatment of invasive aspergillosis come...


Drug interactions The safety of the thrombolytic drug alteplase (tPA) plus clomethiazole in patients with acute ischemic stroke has been assessed in a randomized, double-blind study (22C). All received alteplase 0.9 mg kg beginning within 3 hours of stroke onset and then either intravenous clomethiazole 68 mg kg


Therapeutic drug monitoring of strongly protein-bound antiepileptic drugs such as phenytoin, valproic acid, and carbamazepine is useful for patients with uremia, liver disease, and hypoalbuminemia. Drug-drug interactions may also increase Fu of antiepileptic drugs without significantly altering total drug concentrations. Monitoring


Alcohol lengthens the duration of effects from chlordi-azepoxide, diazepam, and lorazepam. Cocaine worsens liver damage caused by alcohol. When rats receiving morphine or methadone drink alcohol, the alcohol blood level takes longer to increase but then lasts longer, a result suggesting that a human opiate user might have to drink more in order to get an alcohol effect and would then stay intoxicated longer than someone who does not use opiates. Rat studies indicate that steady opiate consumption may intensify alcohol dependence. In rats, alcohol, chlordiazepoxide, and pen-tobarbital all have cross-tolerance with one another, meaning that one will substitute for the other to some extent. So many drugs interact dangerously with alcohol that a person should always check information labels on drug containers before using the substances simultaneously with alcohol.


Drug interactions The effects of alcohol combined with either zaleplon or triazolam have been studied in 18 healthy volunteers (25c ). Triazolam, with and without ethanol, impaired digit symbol substitution, symbol copying, simple and complex reaction times, and divided attention performance compared with placebo. Zaleplon without ethanol impaired only digit symbol substitution and divided attention tracking, but when it was combined with ethanol all measures were impaired. However, zaleplon without ethanol was consistently better than triazolam alone. Zaleplon produced less performance impairment and a shorter period of ethanol potentiation than triazolam.


Drug interactions An 86-year-old white woman taking nefazodone for depression started to take zopiclone for insomnia, but subsequently had morning drowsiness (36A). The concentration of plasma zopiclone was measured 8 hours after administration on two occasions, during and after nefazodone therapy. After withdrawal of nefazodone, the plasma concentration of the S-enantiomer of zopiclone fell from 107 to 17 ng ml, while the plasma concentration of the R-enantiomer fell from 21 to 1.5 ng ml. The substantial fall in plasma zopiclone concentrations after withdrawal of nefazodone probably reflects a drug interaction. Despite the normally short half-life of zopi-clone, the residual sedation initially observed in this case suggests that the interaction had clinical significance.

Other Side Effects

DRUG INTERACTIONS AND ANTIPSYCHOTIC AGENTS Most antipsychotics are metabolized by hepatic microsomal oxidases (cytochrome P450 system) the major isoenzyme systems involved are CYP1A2, CYP2C19, CYP2D6, and CYP3A4. Induction or inhibition of these enzymes by other drugs may occasionally produce clinically important drug interactions. Table 1-5 summarizes clinically significant phar-macokinetic drug interactions involving second-generation antipsychotic drugs. SSRI's, particularly fluoxetine and parox-etine, can increase plasma concentrations of antipsychotic medications by inhibiting CYP2D6 and decreasing the clearance of antipsychotics, possibly leading to toxicity. Conventional antipsychotic drug clearance can be decreased by 50 with concurrent administration of certain heterocyclic antide-pressants, beta-blockers, some antibiotic antifungal agents, and cimetidine. Clozapine toxicity has occurred following co-administration with the CYP1A2 inhibitors cimetidine, erythromycin, and...


The main varieties of adverse effects attributed to cime-tidine relate to its antiandrogenic properties and its actions in sufficient concentrations on the central nervous system. There is also a spectrum of drug interactions, mainly attributable to inhibition of hepatic CYP isoforms, but they only have clinical consequences under special circumstances. Occasional adverse effects, which are generally minor, include bradycardia and conduction defects, thrombocytopenia, neutropenia, interstitial nephritis, mild hepatic dysfunction, and headache. Intestinal infection due to loss of the gastric acid barrier also occurs, and myalgia, fever, monoamine oxidase-like interactions, and neuropathies have been well documented occasionally. Allergic reactions, such as bronchospasm, have rarely been described. Anaphylaxis with recurrence on rechallenge is on record, as are asthma and skin effects.


The most important metabolite of carbamazepine is carbamazepine 10, 11-epoxide (Fig. 4), which possesses similar pharmacodynamic activity to its parent drug. Carbamazepine is extensively metabolized by the cytochrome P450 enzyme system (CYP3A4 and CYP2C8) to form the epoxide metabolite (22). At steady state, pre-dose concentrations of carbamazepine epoxide should be approximately 20-25 of the parent drug concentration. However, when other drugs are coadministered, the concentration of carbamazepine epoxide can reach much higher levels at steady state because of drug-drug interactions. Quetiapine increases concentrations of epoxide (epoxide to carba-mazepine ratio may increase three- to fourfold) and levels of epoxide returned to normal after discontinuation of quetiapine. Quetiapine may inhibit epoxide hydrolase that


The echinocandins are currently available only for intravenous administration. They have dose-proportional plasma pharmacokinetics, with half-lives of 10-15 hours, which allows once-daily dosing. All echinocan-dins are highly protein-bound (over 95 ) and distribute into all major tissues, including the brain concentrations in non-inflammatory CSF are low. The echinocandins are eliminated by degradation and or hepatic metabolism, and are slowly excreted as inactive metabolites in the urine and feces only small fractions are excreted unchanged in the urine. As a class they are generally well tolerated and lack significant potential for drug interactions mediated by CYP450 isozymes (1-4). In vitro biotransformation studies of caspofungin have shown that it is not a substrate of P-glycoprotein and is a poor substrate and a weak inhibitor of cytochrome P450 enzymes (5). However, other in vitro studies have shown that it may inhibit CYP3A4 (6).


Normally people should avoid fentanyl if they have taken monamine oxidase inhibitors (MAOIs found in some antidepressants and other medicine) in the past two weeks, as MAOIs can greatly increase opioid actions. For the same reason, using fentanyl with other depressants (including alcohol) can be risky. Midazolam hydrochloride and fentanyl appear to boost each other's actions. The HIV AIDS medicine ritonavir makes a fentanyl dose last longer.


Drug Interactions CYP3A inhibitors such as antifungal agents (itraconazole, ketoconazole), clarithromycin, erythromycin, and verapamil increase blood levels of sirolimus. CYP3A inducers such as carbamazepine, phenobarbital, phenytoin, and rapamycin may decrease sirolimus blood levels. Grapefruit juice can increase sirolimus by decreasing drug clearance. St John's wort can decrease sirolimus levels. As previously noted, the concomitant use of CsA can result in increased sirolimus concentrations (140). Although tacrolimus and sirolimus compete for sites on the same binding protein, the two drugs do not appear to have significant drug-drug interactions in clinical practice (104).

Methods of Analysis

When MPA was originally approved for use (as mycophenolate mofetil), therapeutic drug monitoring was considered unnecessary. However, recent studies have found wide variations in total drug exposure (as high as 10-fold) following a fixed dose, suggesting that individualized dosing may be of considerable benefit (206,207). A roundtable meeting recently recommended therapeutic drug monitoring based on the interpatient variability and the significant drug interactions associated with combination immunosuppressive therapy (208).


DRUG INTERACTIONS Use with extra caution and notify your physician if you take Anticonvulsants, antidepressants, antihistamines, antipsychotics, barbiturates, or any drug that causes sedation or central nervous system depression, because the combination can cause pronounced sedation. Use extra


DRUG INTERACTIONS Do not use if you take MAOIantidepressants, as their use with amitriptyline can cause pronounced hypertension and the potential for strokes. Use with extra caution if you take Phenothiazines, as the combination may cause irregular heart rhythms that are potentially fatal antihypertensives as they may combine to lower blood pressure excessively antihistamines, phenothiazines, and antiparkinsonian agents as they may combine to produce pronounced dry mouth, blurry vision, constipation, low blood pressure, rapid heart rate, and even mental confusion guanethadine to lower blood pressure, as amitriptyline may block its effects.


The drug reduces effectiveness of warfarin, a medicine that fights heart attack and stroke by reducing blood clotting. Glutethimide is also supposed to be avoided if someone is taking the anti-blood-clotting substance coumarin. A U.S. Army aerospace test found that using alcohol with glutethimide did not harm breathing. That finding has rather narrow significance for most persons, but a more generally relevant finding came from an experiment showing that glutethimide raised blood alcohol levels of persons who had been drinking. Alcohol and glutethimide may be a mix to avoid. Antihistamines should be used cautiously with glutethimide. Animal experimentation shows that injection of marijuana's main active component THC (tetrahydrocannabinol) increases the potency of glutethimide, thereby increasing risk of overdose.


Normally hydromorphone should not be taken along with antihistamines or various tranquilizers and antidepressants, including monoamine oxidase inhibitors (MAOIs, found in some antidepressants and in other medicine). Taking hydromorphone and cocaine together can increase each drug's effects.