John R. Horn

The proton-pump inhibitors: Similarities and differences

OBJECTIVE This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.

Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know.

Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H+/K+-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H+/K+-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property.Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them — even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk.Thus, whereas all PPIs have been shown to be generally effective and safely used for the treatment of acid-mediated disorders, there are chemical, pharmacodynamic and pharmacokinetic differences among these drugs that may make certain ones more, or less, suitable for treating different patient subgroups. Of course, the absolute magnitude of risk from any PPI in terms of drug-drug interactions is probably low — excepting interactions occurring as class effects related to acid suppression (e.g. increased digoxin absorption or inability to absorb ketoconazole).

Performance of community pharmacy drug interaction software.

OBJECTIVE To evaluate the performance of computerized drug-drug interaction (DDI) software in identifying clinically important drug-drug interactions. DESIGN One-time performance test of computer systems using a standard set of prescriptions. SETTING Community pharmacies or central corporate locations with pharmacy terminals identical to those used in actual pharmacies. PARTICIPANTS Chain and health maintenance organization (HMO) pharmacies with seven or more practice sites in Washington State. A total of nine different DDI software programs were installed in 516 community pharmacies represented by these chains and HMOs. MAIN OUTCOME MEASURES Sensitivity, specificity, and positive and negative predictive values of software in detecting 16 well-established DDIs contained within six fictitious patient profiles. RESULTS The software systems failed to detect clinically relevant DDIs one-third of the time. Sensitivity of the software programs ranged from 0.44 to 0.88, with 1.00 being perfect; specificity ranged from 0.71 to 1.00; positive predictive value ranged from 0.67 to 1.00; and negative predictive value ranged from 0.69 to 0.90. For software packages that were installed at different locations, between-installation differences were observed. CONCLUSION The performance of most DDI-detecting software programs tested in this study was suboptimal. Improvement is needed to advance their contribution to detection of DDIs.

Changes in antipyrine and indocyanine green kinetics during nifedipine, verapamil, and diltiazem therapy

Ten healthy subjects received oral antipyrine and intravenous indocyanine green (ICG) alone and after 5 days of oral nifedipine, diltiazem, and verapamil. Antipyrine clearance decreased during verapamil (range 4% to 26%) and diltiazem (6% to 24%) therapy (P < 0.001) but did not change during nifedipine treatment. Antipyrine t1/2 also increased during verapamil and diltiazem treatment (P < 0.001). ICG clearance did not change during diltiazem therapy but increased during dosing with nifedipine and verapamil (P < 0.05). Estimated liver blood flow (derived from ICG clearance and hematocrit) also increased during verapamil (mean 33%) and nifedipine (mean 27%) treatment (P < 0.05). Drug interactions with other liver‐metabolized drugs may occur during therapy with these calcium antagonists. Nifedipine appears to increase liver blood flow whereas diltiazem inhibits oxidative drug metabolism. Drug interactions with verapamil could involve both mechanisms.

Accuracy of duplex scanning for measurement of arterial volume flow

This study examined the accuracy of duplex ultrasound measurements of volume flow in a baboon model. Volume flow (Vf) through the external iliac artery was calculated from measurements of blood velocity averaged over several cardiac cycles (time-averaged velocity [TAV]) and vessel cross-sectional area (A) measured from the B-mode image: Vf = TAV x A. Fourteen anesthetized baboons were studied with a duplex scanner with a 7 MHz imaging transducer and 5 MHz pulsed Doppler. B-mode ultrasound measurements of external iliac artery diameters (2.5 +/- 0.2 mm) were used for calculation of cross-sectional area. Timed blood collections obtained through a cannula inserted into the common femoral artery and TAV measurements were obtained simultaneously during 6 to 15-second intervals. These measurements were repeated three to five times per animal with different flow rates each time. Flow rates ranged from 56 to 280 ml/min (170 +/- 54 ml/min). Average velocity was 55 +/- 17 cm/sec. There was no significant difference between the two methods of volume flow measurement (Student t test). Linear regression analysis revealed a high degree of correlation (r = 0.90, slope 0.95, and p = 0.0001). The absolute percentage error was 13% +/- 8%. Volume flow measured by duplex scanning correlates highly with timed blood collections. This method has potential application for the evaluation of diseased arteries and bypass grafts whose rates of flow and waveform patterns are similar to those of this experiment.

The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers

Background The macrolide antibiotics clarithromycin and erythromycin may potentiate calcium-channel blockers by inhibiting cytochrome P450 isoenzyme 3A4. However, this potential drug interaction is widely underappreciated and its clinical consequences have not been well characterized. We explored the risk of hypotension or shock requiring hospital admission following the simultaneous use of calcium-channel blockers and macrolide antibiotics. Methods We conducted a population-based, nested, case-crossover study involving people aged 66 years and older who had been prescribed a calcium-channel blocker between Apr. 1, 1994, and Mar. 31, 2009. Of these patients, we included those who had been admitted to hospital for the treatment of hypotension or shock. For each antibiotic, we estimated the risk of hypotension or shock associated with the use of a calcium blocker using a pair-matched analytic approach to contrast each patient’s exposure to each macrolide antibiotic (erythromycin, clarithromycin or azithromycin) in a seven-day risk interval immediately before admission to hospital and in a seven-day control interval one month earlier. Results Of the 7100 patients admitted to hospital because of hypotension while receiving a calcium-channel blocker, 176 had been prescribed a macrolide antibiotic during either the risk or control intervals. Erythromycin (the strongest inhibitor of cytochrome P450 3A4) was most strongly associated with hypotension (odds ratio [OR] 5.8, 95% confidence interval [CI] 2.3–15.0), followed by clarithromycin (OR 3.7, 95% CI 2.3–6.1). Azithromycin, which does not inhibit cytochrome P450 3A4, was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8–2.8). We found similar results in a stratified analysis of patients who received only dihydropyridine calcium-channel blockers. Interpretation In older patients receiving a calcium-channel blocker, use of erythromycin or clarithromycin was associated with an increased risk of hypotension or shock requiring admission to hospital. Preferential use of azithromycin should be considered when a macrolide antibiotic is required for patients already receiving a calcium-channel blocker.

Toward a complete dataset of drug-drug interaction information from publicly available sources

Although potential drug-drug interactions (PDDIs) are a significant source of preventable drug-related harm, there is currently no single complete source of PDDI information. In the current study, all publically available sources of PDDI information that could be identified using a comprehensive and broad search were combined into a single dataset. The combined dataset merged fourteen different sources including 5 clinically-oriented information sources, 4 Natural Language Processing (NLP) Corpora, and 5 Bioinformatics/Pharmacovigilance information sources. As a comprehensive PDDI source, the merged dataset might benefit the pharmacovigilance text mining community by making it possible to compare the representativeness of NLP corpora for PDDI text extraction tasks, and specifying elements that can be useful for future PDDI extraction purposes. An analysis of the overlap between and across the data sources showed that there was little overlap. Even comprehensive PDDI lists such as DrugBank, KEGG, and the NDF-RT had less than 50% overlap with each other. Moreover, all of the comprehensive lists had incomplete coverage of two data sources that focus on PDDIs of interest in most clinical settings. Based on this information, we think that systems that provide access to the comprehensive lists, such as APIs into RxNorm, should be careful to inform users that the lists may be incomplete with respect to PDDIs that drug experts suggest clinicians be aware of. In spite of the low degree of overlap, several dozen cases were identified where PDDI information provided in drug product labeling might be augmented by the merged dataset. Moreover, the combined dataset was also shown to improve the performance of an existing PDDI NLP pipeline and a recently published PDDI pharmacovigilance protocol. Future work will focus on improvement of the methods for mapping between PDDI information sources, identifying methods to improve the use of the merged dataset in PDDI NLP algorithms, integrating high-quality PDDI information from the merged dataset into Wikidata, and making the combined dataset accessible as Semantic Web Linked Data.

Therapeutic drug monitoring reduces toxic drug reactions: A meta-analysis

Therapeutic drug monitoring (TDM) is commonly employed to optimize the dosing of certain drugs, including digoxin, aminoglycosides, theophylline, and phenytoin. Studies were reviewed in order to (a) evaluate the effect of TDM on the occurrence of toxic drug reactions (TDRs) and (b) identify factors that may modify or invalidate the relationship. In 14 studies, monitored patients suffered fewer toxic drug reactions than nonmonitored patients (odds ratio = 0.35, 95% confidence interval, 0.13 to 0.89). The average effect size was larger in studies that utilized a control group for comparisons rather than a before-and-after study design. TDM appeared to be most beneficial for patients taking theophylline or digoxin. Issues that must be addressed in future TDM service evaluations include (a) study design, (b) adverse patient selection, (c) insufficient sample size, (d) incomplete or inconsistent description of the TDM service, and (e) incomplete, inconsistent, or absent description of criteria for reporting TDRs.

Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support.

BackgroundHealthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug–drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations.ObjectiveThe aim of this study was to provide recommendations for systematic evaluation of evidence for DDIs from the scientific literature, drug product labeling, and regulatory documents.MethodsA conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 18 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar 12 times from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations.ResultsWe developed expert consensus answers to the following three key questions. (i) What is the best approach to evaluate DDI evidence? (ii) What evidence is required for a DDI to be applicable to an entire class of drugs? (iii) How should a structured evaluation process be vetted and validated?ConclusionEvidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug compendia and clinical decision support systems in which these recommendations are implemented should be able to provide higher-quality information about DDIs.

Estimation of Hepatic Blood Flow in Branches of Hepatic Vessels Utilizing a Noninvasive, Duplex Doppler Method

The measurement of hepatic blood flow by indirect methods such as indocyanine green clearance has several limitations. The duplex Doppler offers the potential for noninvasive, real‐time measurement of blood flow and has been employed in the evaluation of arterial disease in a variety of vascular beds. We evaluated Doppler ultrasound estimation of blood flow in branches of the hepatic artery, hepatic vein, and portal vein in 12 healthy subjects on two separate days. In vitro accuracy of the scanner was assessed using phantom targets of known diameter and velocity. Blood velocity and vessel diameter measurements were obtained five times over a period of 2 hours. No significant differences were seen in velocity or blood flow measurements within or between days. The interday coefficients of variation, which include intrasubject variability, were 10–15% and 14–20% for velocity and blood flow measurements, respectively. This study demonstrates the potential utility of Doppler ultrasound to detect intrinsic, drug, or disease‐induced changes in hepatic blood flow.