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JPrP 2019 1 9 bariatric
Abstract
Obesity is an increasing problem in the UK, with over half the population being overweight or obese. The use of gastric surgery is increasing, with a 5% increase in 2016/17 compared to 2015/16. However, little is known about ideal drug formulations after bariatric surgery. An exploratory literature search of research databases was carried out to address this. We found that there was a dearth
of high-quality primary studies available, with many studies using low numbers of participants. The major finding was of the need for increased vigilance and monitoring of patients after surgery.
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Background
Bariatric surgery leads to several anatomo-physiological modifications that may affect pharmacokinetic parameters and consequently alter the therapeutic effect of drugs, such as antibiotics. The pharmacokinetics of oral amoxicillin after Roux-en-Y gastric bypass (RYGB) surgery is unknown.
Objectives
The objective of this study was to evaluate the impact of bariatric surgery on the pharmacokinetics of amoxicillin.
Methods
This study was performed as a randomized, open-label, single-dose clinical trial, with two periods of treatment, in which obese subjects (n = 8) received an amoxicillin 500 mg capsule orally before and 2 months after the RYGB surgery. The amoxicillin plasma concentration was determined by liquid chromatography coupled to mass spectrometry (LC-MS/MS).
Results
After the surgery, the mean weight loss was 17.03 ± 5.51 kg, and mean body mass index (BMI) decreased from 46.21 ± 2.82 to 38.82 ± 3.32 kg/m². The mean amoxicillin area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration (AUC0–tlast) increased significantly (3.5-fold); the maximum plasma concentration (Cmax) increased 2.8-fold after the bariatric surgery. No correlation was found between amoxicillin absorption, BMI, and weight loss percentage.
Conclusion
The alterations observed in the amoxicillin pharmacokinetics suggest that obese subjects included in this trial had a substantially increase in amoxicillin systemic exposure after RYGB surgery. However, despite this increase, its exposure was lower than the values reported for non-obese volunteers.
Trial Registration
Identifiers: NCT03588273
Iron deficiency (ID) is usually treated with oral iron salts, but up to 50% of patients complain of gastrointestinal side effects, leading to reduced treatment compliance. Intravenous (IV) iron formulations are increasingly safer, but there is still a risk of infusion and hypersensitivity reactions and the need for a venous access and infusion monitoring. Sucrosomial® iron (SI) is an innovative oral iron formulation in which ferric pyrophosphate is protected by a phospholipid bilayer plus a sucrester matrix (sucrosome), which is absorbed through para-cellular and trans-cellular routes (M cells). This confers SI unique structural, physicochemical and pharmacokinetic characteristics, together with high iron bioavailability and excellent gastrointestinal tolerance. The analysis of available evidence supports oral SI iron as a valid option for ID treatment, which is more efficacious and better tolerated than oral iron salts. SI has also demonstrated similar effectiveness, with lower risks, in patients usually receiving IV iron (e.g., chronic kidney disease, cancer, bariatric surgery). Thus, oral SI emerges as a most valuable first option for treating ID, even more for subjects with intolerance to or inefficacy of iron salts. Moreover, SI should be also considered as an alternative to IV iron for initial and/or maintenance treatment in different patient populations.
Objective
Following Roux‐en‐Y gastric bypass (RYGB), elevated parathyroid hormone (PTH) levels potentially harmful to bone health are commonly observed. Owing to assumed superior absorption, calcium citrate is often recommended over calcium carbonate following RYGB for the treatment of elevated PTH. We aimed to investigate the impact of either calcium carbonate or calcium citrate (1200 mg elementary calcium) in patients with elevated PTH levels following RYGB.
Design
Clinical, double‐blinded, randomized controlled trial of a 12‐week‐duration at a Danish University Hospital.
Patients and measurements
Thirty‐nine (no drop out) RYGB operated patients with elevated PTH levels (PTH>6.9 pmol/l) and normal plasma levels of calcium and 25‐hydroxyvitamin D were randomized to either calcium carbonate or calcium citrate (1200 mg elementary calcium/daily). We assessed change in PTH as the primary outcome.
Results
The effect of the two calcium formulations on change in PTH was comparable and neutral: ‐1.9% (calcium citrate) vs +0.9% (calcium carbonate), p=0.680. Compared to the carbonate‐treated group, the following bone turnover markers decreased significantly in the citrate‐treated group: procollagen I N‐terminal propeptide (‐16.6% vs ‐3.2%, p=0.021), osteocalcin (‐17.2% vs ‐4.3%, p= 0.007), and bone‐specific alkaline phosphatase (‐5.9% vs 3.7%, p=0.027) and remained significantly decreased after multivariable adjustment.
Conclusion
Increasing the dose of calcium supplementation in RYGB operated patients with slightly elevated PTH levels does not normalize PTH levels, regardless of the type of supplement. Our results do not support recommending supplementation with calcium citrate over calcium carbonate in RYGB patients.
This article is protected by copyright. All rights reserved.
Background:
The evidence behind recommendations for treatment of iron deficiency (ID) following roux-en-y gastric bypass surgery (RYGB) lacks high quality studies.
Setting:
Academic, United States OBJECTIVE: The objective of the study is to compare the effectiveness of oral iron supplementation using non-heme versus heme iron for treatment of iron deficiency in RYGB patients.
Methods:
In a randomized, single-blind study, women post-RYGB and iron deficient received non-heme iron (FeSO4, 195 mg/day) or heme iron (heme-iron-polypeptide, HIP, 31.5 to 94.5 mg/day) for 8 weeks. Measures of iron status, including blood concentrations of ferritin, soluble transferrin receptor (sTfR), and hemoglobin, were assessed.
Results:
At baseline, the mean ± standard deviation for age, BMI, and years since surgery of the sample was 41.5 ± 6.8 years, 34.4 ± 5.9 kg/m(2), and 6.9 ± 3.1 years, respectively; and there were no differences between FeSO4 (N = 6) or HIP (N = 8) groups. Compliance was greater than 94%. The study was stopped early due to statistical and clinical differences between groups. Values before and after FeSO4 supplementation, expressed as least square means (95% CI) were hemoglobin, 10.8 (9.8, 11.9) to 13.0 (11.9, 14.0) g/dL; sTfR, 2111 (1556, 2864) to 1270 (934, 1737) μg/L; ferritin, 4.9 (3.4, 7.2) to 15.5 (10.6, 22.6) μg/L; and sTfR:ferritin ratio, 542 (273, 1086) to 103 (51, 204); all p < 0.0001. With HIP supplementation, no change was observed in any of the iron status biomarkers (all p > 0.05).
Conclusions:
In accordance with recommendations, oral supplementation using FeSO4, but not HIP, was efficacious for treatment of iron deficiency after RYGB.
Objective:
Bariatric surgery offers a highly effective mode of treatment for obese patients. Some procedures such as bypass cause an alteration in normal gastrointestinal tract with possible consequences for the uptake of orally administered drugs.
Methods:
We assessed the literature to ascertain whether the use of oral drugs and especially oral contraceptives is effective and adequate after bariatric surgery.
Results:
The bioavailability of drugs could be affected by the solubility and pH of the modified medium after bariatric surgery and by the loss of gastrointestinal transporters. Bariatric surgery could potentially result in a transient change in the absorption of drugs such as analgesics, antibiotics, antiarrhythmics, anticoagulants, psychotropic, and oral contraceptive drugs. Effective contraception is especially critical in the postoperative period, and implants might be representing a safe contraceptive method in women undergoing bariatric surgery.
Conclusion:
Each drug will have to be evaluated with respect to its site of absorption and its mechanism of absorption, with special attention on parameters influencing the effectiveness of the absorption processes.
Bariatric surgery is the most effective solution for severe obesity and obesity with comorbidities, and the number of patients going through bariatric surgery is rapidly and constantly growing. The modified gastrointestinal anatomy of the patient may lead to significant pharmacokinetic alterations in the oral absorption of drugs after the surgery; however, because of insufficient available literature and inadequate awareness of the medical team, bariatric surgery patients may be discharged from the hospital with insufficient instructions regarding their medication therapy. In this article, we aim to present the various mechanisms by which bariatric surgery may influence oral drug absorption, to provide an overview of the currently available literature on the subject, and to draw guidelines for the recommendations bariatric surgery patients should be instructed before leaving the hospital. To date, and until more robust data are published, it is essential to follow and monitor patients closely for safety and efficacy of their medication therapies, both in the immediate and distant time post-surgery. © 2016 World Obesity.
Objective
Drug malabsorption is one of the potential troubles after bariatric surgery. Evidence for diminished levothyroxine (L-T4) absorption has been reported in patients after bariatric surgery.
Methods
This study reports 17 cases of hypothyroid patients [who were well replaced with thyroxine tablets (for >1 year) to euthyroid thyrotropin (TSH) levels before surgery (13 Roux-en-Y gastric bypasses (RYGB); 4 biliary pancreatic diversions (BPD))]. From 3 to 8 months after surgery, these patients had elevated TSH levels. Patients were then switched from oral tablets to a liquid L-T4 formulation (with the same dosage, 30 min before breakfast).
Results
Two–three months after the switch, TSH was significantly reduced both in patients treated with RYGB, as in those treated with BPD, while FT4 and FT3 levels were not significantly changed (RYGB group, TSH μIU/mL: 7.58 ± 3.07 vs 3.808 ± 1.83, P < 0.001; BPD group, TSH μIU/mL: 8.82 ± 2.76 vs 3.12 ± 1.33, P < 0.01).
Conclusions
These results first show that liquid L-T4 could prevent the problem of malabsorption in patients with BPD and confirm those of previous studies in patients submitted to RYGB, suggesting that the L-T4 oral liquid formulation could circumvent malabsorption after bariatric surgery.
Background
Use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in bariatric surgery patients. If use of an NSAID is inevitable, a proton pump inhibitor (PPI) should also be used.
Aim
To determine the effect of an, compared to care-as-usual, additional intervention to reduce NSAID use in patients who underwent bariatric surgery, and to determine the use of PPIs in patients who use NSAIDs after bariatric surgery.
Methods
A randomized controlled intervention study in patients after bariatric surgery. Patients were randomized to an intervention or a control group. The intervention consisted of sending a letter to patients and their general practitioners on the risks of use of NSAIDs after bariatric surgery and the importance of avoiding NSAID use. The control group received care-as-usual. Dispensing data of NSAIDs and PPIs were collected from patients’ pharmacies: from a period of 6 months before and from 3 until 9 months after the intervention.
Results
Two hundred forty-eight patients were included (intervention group: 124; control group: 124). The number of users of NSAIDs decreased from 22 to 18 % in the intervention group and increased from 20 to 21 % in the control group (NS). The use of a PPI with an NSAID rose from 52 to 55 % in the intervention group, and from 52 to 69 % in the control group (NS).
Conclusions
Informing patients and their general practitioners by letter, in addition to care-as-usual, is not an effective intervention to reduce the use of NSAIDs after bariatric surgery (trial number NTR3665).
Purpose:
Bariatric surgery can influence the prevalence and incidence of comorbidities, as well as the pharmacokinetics of drugs. This might lead to changes in the use of drugs. This study aimed to assess the influence of bariatric surgery on the use of medication in patients before and after surgery, focusing on type, number of medications, and daily dosage.
Methods:
In a retrospective and prospective observational study, drug dispensing data from pharmacies of patients undergoing their first bariatric surgery between January 2008 and September 2011 was collected. Dispensing data from 1 month before until 12 months after surgery was analyzed. Drugs were classified according to the WHO-ATC classification system. Dosages of drugs were compared using defined daily dose (DDD).
Results:
Among 450 patients, 12 months after surgery, the mean number of drugs per patient for antidiabetics, drugs acting on the cardiovascular system, anti-inflammatory and antirheumatic drugs, and drugs for obstructed airway diseases decreased by, respectively, 71.3 % (95 % CI 57.2 to 85.4), 34.5 % (95 % CI 28.2 to 43.0), 45.5 % (95 % CI 13.3 to 72.6), and 33.1 % (95 % CI 15.3 to 53.2). Patients used lower median DDD of oral antidiabetics, beta-blocking agents, and lipid-modifying drugs.
Conclusions:
For some major drug classes 12 months after bariatric surgery, the use of drugs decreases in terms of mean number per patient. A reduction in dose intensity was observed for oral antidiabetics, beta-blocking agents, and lipid-modifying drugs. Dispensing data from pharmacies may provide detailed information on the use of medications by patients after bariatric surgery.
Literature search was performed for bariatric surgery from inception to September 2013, in which the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) on body mass index (BMI), percentage of excess weight loss (EWL%), and diabetes mellitus (DM) were compared 2 years post-surgery. A total of 9,756 cases of bariatric surgery from 16 studies were analyzed. Patients receiving LRYGB had significantly lower BMI and higher EWL% compared with those receiving LSG (BMI mean difference (MD) = -1.38, 95 % confidence interval (CI) = -1.72 to -1.03; EWL% MD = 5.06, 95 % CI = 0.24 to 9.89). Improvement rate of DM was of no difference between the two types of bariatric surgeries (RR = 1.05, 95 % CI = 0.90 to 1.23). LRYGB had better long-term effect on body weight, while both LRYGB and LSG showed similar effects on DM.
Drug malabsorption is a potential concern after bariatric surgery. We present four case reports of hypothyroid patients who were well replaced with thyroxine tablets to euthyroid thyrotropin (TSH) levels prior to Roux-en-Y gastric bypass surgery. These patients developed elevated TSH levels after the surgery, the TSH responded reversibly to switching from treatment with oral tablets to a liquid formulation.
The purpose of this review is to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. A PubMed literature search was conducted. Literature was included on influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. Drug classes to be searched for were antidepressants, antidiabetics, statins, antihypertensive agents, corticosteroids, oral contraceptives, and thyroid drugs. A reduction in the use of medication by patients after bariatric surgery has been reported for various drug classes. Very few studies have been published on the influence of bariatric surgery on the pharmacokinetics of drugs. After bariatric surgery, theoretically, reduced drug absorption may occur. Correct dosing and choosing the right dosage form for drugs used by patients after bariatric surgery are necessary for optimal pharmacotherapy. Therefore, more clinical studies are needed on the influence of bariatric surgery on the pharmacokinetics of major drugs.
Azithromycin is used widely for community-acquired infections. The timely administration of azithromycin in adequate doses minimizes treatment failure. Gastric bypass, a procedure that circumvents the upper gut, may compromise azithromycin plasma levels. We hypothesized that azithromycin concentrations would be reduced following gastric bypass.
A single-dose pharmacokinetic study in 14 female post-gastric bypass patients and 14 sex- and body mass index (BMI)-matched controls (mean age 44 years and BMI 36.4 kg/m(2)) was performed. Subjects were administered two 250 mg azithromycin tablets at time 0 and plasma azithromycin levels were sampled at 0.5, 1, 1.5, 2, 3, 5, 7 and 24 h. The AUC of the plasma azithromycin concentrations from time 0 to 24 h (AUC(0-24)) was the primary outcome.
Azithromycin concentrations were lower in gastric bypass patients compared with controls throughout the entire duration of sampling. Compared with controls, the AUC(0-24) was reduced in gastric bypass subjects by 32% [1.41 (SD 0.51) versus 2.07 (0.75) mg · h/L; P = 0.008], and dose-normalized AUC(0-24) was reduced by 33% [0.27 (0.12) versus 0.40 (0.13) kg · h/L; P = 0.009]. Peak azithromycin concentrations were 0.260 (0.115) in bypass subjects versus 0.363 (0.200) mg/L in controls (P = 0.08), and were reached at 2.14 (0.99) h in gastric bypass subjects and 2.36 (1.17) h in controls (P = 0.75).
Azithromycin AUC was reduced by one-third in gastric bypass subjects compared with controls. The potential for early treatment failure exists, and dose modification and/or closer clinical monitoring of gastric bypass patients receiving azithromycin should be considered.
The use of bariatric surgery in the management of morbid obesity is rapidly increasing. The two most frequently performed procedures are laparoscopic Roux-en-Y bypass and laparoscopic gastric banding. The objective of this short overview is to provide a critical appraisal of the most relevant scientific evidence comparing laparoscopic gastric banding versus laparoscopic Roux-en-Y bypass in the treatment of morbidly obese patients.
There is mounting and convincing evidence that laparoscopic gastric banding is suboptimal at best in the management of morbid obesity. Although short-term morbidity is low and hospital length of stay is short, the rates of long-term complications and band removals are high, and failure to lose weight after laparoscopic gastric banding is prevalent.
The placement of a gastric band appears to be a disservice to many morbidly obese patients and therefore, in the current culture of evidence based medicine, the prevalent use of laparoscopic gastric banding can no longer be justified. Based on the current scientific literature, the laparoscopic gastric bypass should be considered the treatment of choice in the management of morbidly obese patients.
Background:
Bariatric surgery can lead to changes in the oral absorption of many drugs. Levothyroxine is a narrow therapeutic drug for hypothyroidism, a common condition among patients with obesity.
Objective:
The purpose of this work was to provide a mechanistic overview of levothyroxine absorption, and to thoroughly analyze the expected effects of bariatric surgery on oral levothyroxine therapy.
Methods:
We performed a systematic review of the relevant literature reporting the effects of bariatric surgery on oral levothyroxine absorption and postoperative thyroid function. A PubMed search for relevant keywords resulted in a total of 14 articles reporting levothyroxine status before versus after bariatric surgery.
Results:
Different mechanisms may support opposing trends as to levothyroxine dose adjustment postsurgery. On the one hand, based on impaired drug solubility/dissolution attributable to higher gastric pH as well as reduced gastric volume, compromised levothyroxine absorption is expected. On the other hand, the great weight loss, and altered set-point of thyroid hormone homeostasis with decreased thyroid-stimulating hormone after the surgery, may result in a decreased dose requirement.
Conclusions:
For patients after bariatric surgery, close monitoring of both the clinical presentation and plasma thyroid-stimulating hormone and T4 levels is strongly advised. Better understanding and awareness of the science presented in this article may help to avoid preventable complications and provide optimal patient care.
Study objective:
The extended-release (ER) form of venlafaxine is preferred because of improved patient adherence, but the immediate-release form is frequently used after Roux-en-Y gastric bypass surgery (RYGB) because of concerns for malabsorption. The objective of this study was to determine whether a statistically significant and predictable change in the bioavailability of venlafaxine ER capsules occurs after RYGB.
Design:
Prospective, nonblinded, single-dose pharmacokinetic study.
Setting:
Clinical research unit at a large, tertiary care medical practice.
Patients:
Ten adult pre-bariatric surgery patients who met the criteria for noncomplicated RYGB were enrolled and served as their own controls.
Interventions:
Patients were administered one venlafaxine ER 75-mg capsule at two visits-the first visit at least 1 week before undergoing RYGB and the second visit 3-4 months after RYGB. Blood samples were collected at predetermined intervals over 48 hours after each dose, and the pharmacokinetics of venlafaxine were measured.
Measurements and main results:
Plasma levels of venlafaxine and its primary metabolite, O-desmethylvenlafaxine (ODV), were compared at baseline and 3-4 months after RYGB. The areas under the serum concentration-time curves from 0-24 hours (AUC0-24 ) for venlafaxine (mean ± SD 734 ± 602 vs 630 ± 553 ng•hr/mL, P=0.22) and ODV (mean ± SD 894 ± 899 vs 1083 ± 972 ng•hr/mL, P =0.07) were similar before and after RYGB. Using a bioequivalence approach, differences in pre-RYGB and post-RYGB values of AUC0-24 , peak serum concentration, and time to peak serum concentration were not statistically significant for either venlafaxine or ODV.
Conclusion:
This study suggests that RYGB does not significantly alter the amount of venlafaxine or its active metabolite, ODV, absorbed from a venlafaxine ER capsule or the time over which it is absorbed. This article is protected by copyright. All rights reserved.
The anatomical and physiological changes in the gastrointestinal (GI) tract following bariatric surgery may significantly affect the pharmacokinetics of medications taken by the patients, from various reasons. Unfortunately, there is little information regarding changes in drug absorption after bariatric surgeries, limiting the ability of medical professionals to produce clear recommendations on what changes should be made to the formulations and dosing regimens of drugs following bariatric surgery.
Bariatric surgery may alter the absorption, distribution, metabolism and/or elimination (disposition) of orally administered drugs via changes to the gastrointestinal tract anatomy, body weight, and adipose tissue composition. As some patients who have undergone bariatric surgery will need therapeutic anticoagulation for various indications, appropriate knowledge is needed regarding anticoagulant drug disposition and resulting efficacy and safety in this population. We review general considerations about oral drug disposition in patients after bariatric surgery, as well as existing literature on oral anticoagulation after bariatric surgery. Overall, available evidence on therapeutic anticoagulation is very limited and individual drug studies are necessary to learn how to safely and effectively use the direct oral anticoagulants. Given the sparsity of presently available data, it appears most prudent to use warfarin with INR monitoring, and not direct oral anticoagulants, when full-dose anticoagulation is needed after bariatric surgery.
Aims:
Roux-en-Y gastric bypass (RYGB) alters the anatomical structure of the GI-tract, which can result in alterations in drug disposition. The aim of this study was to evaluate the oral disposition of two compounds belonging to the Biopharmaceutical Classification System Class II, fenofibrate (bile salt dependent solubility) and posaconazole (gastric pH dependent dissolution), before and after RYGB in the same individuals.
Methods:
A single-dose pharmacokinetic study with two model compounds, namely 67 mg of fenofibrate (Lipanthyl®) and 400 mg of posaconazole (Noxafil®) was performed in 12 volunteers pre- and post-RYGB, In the posaconazole study one patient dropped out. After oral administration, blood samples were collected at different time-points up to 48 h after administration. Plasma concentrations were determined by HPLC in order to calculate AUC0-48h , Cmax and Tmax .
Results:
After administration of fenofibrate, no relevant differences in AUC0-48h , Cmax and Tmax between pre- and post-operative setting were observed. The geometric mean of the ratio of AUC0-48h pre/post-RYGB for fenofibrate was 0.91 (95% CI 0.72; 1.15)(P = 0.40). For posaconazole, an important decrease in AUC0-48h and Cmax following RYGB was shown; the geometric mean of the AUC0-48h pre/post-RYGB ratio was 1.48 (95% CI 1.04; 2.10) (P = 0.03) and the geometric mean of the Cmax pre/post-RYGB ratio was 1.66 (95% CI 1.07; 2.58)(P = 0.03). The decreased exposure of posaconazole could be explained by the increased gastric pH and accelerated gastric emptying of fluids post-RYGB. No difference for Tmax was observed.
Conclusions:
The disposition of fenofibrate was not altered after RYGB, whereas the oral disposition of posaconazole was significantly decreased following RYGB.
Purpose:
Pharmacists' role in optimizing long-term pharmacotherapy for bariatric surgery patients is detailed.
Summary:
Bariatric surgery patients provide a difficult challenge in terms of many pharmacotherapy issues, especially in the chronic care setting, where data on long-term effects of bariatric surgery are limited. The most common procedures are Roux-en-Y gastric bypass (RYGB), adjustable gastric banding, and sleeve gastrectomy. Sleeve gastrectomy has become the most common procedure in the United States, primarily because it has less overall chronic malabsorption effects than RYGB. Pharmacotherapy management is complicated by rapid weight loss combined with a number of pharmacokinetic changes, such as decreased absorption of some medications due to altered gastrointestinal tract anatomy and potentially increased concentrations of some medications due to a decreased volume of distribution resulting from weight loss. Nutritional and metabolic supplementation are of the utmost importance in order to limit deficiencies that can lead to a number of conditions. Many chronic diseases, including hypertension, diabetes, gastroesophageal reflux disease, and urinary incontinence, are improved by bariatric surgery but require close monitoring to ensure the effectiveness of maintenance pharmacotherapy and avoidance of adverse effects. Psychotropic medication management is also an important pharmacotherapy concern, as evidenced by antidepressants being the most commonly used medication class among preoperative bariatric surgery patients.
Conclusion:
Pharmacists have an increasing role in the chronic management of the bariatric surgery patient due to their knowledge of medication dosage forms and expertise in disease states affected by bariatric surgery.
There are many unsolved questions about safety of bariatric surgery in the context of severely obese patients living with human immunodeficiency virus (HIV) and notably on antiretroviral therapy (ART) absorption. Here, we provide the first case series of tenofovir disoproxil fumarate (TDF) pharmacokinetic in four HIV-infected patients before and after sleeve-gastrectomy. Our case-series showed a transient and reversible decrease of TDF bioavailability one month after sleeve-gastrectomy without any consequences on CD4 cells and HIV viral load. More studies are needed since the impact of bariatric surgery on drug absorptions in the field of infectious diseases remains poorly investigated.
We report the case of a 49-year-old female patient with hypothyroidism who underwent bariatric surgery and developed severe hypothyroidism despite high doses of oral levothyroxine (L-T4) tablets. Initially, a high-dose L-T4 tablets absorption test was performed to exclude pseudo-malabsorption. In view of a modest increase in serum T4 levels, L-T4 liquid formulation absorption test was performed, and showed faster and more efficient absorption of thyroid hormones. We discuss the issue of distinguishing malabsorption from pseudo-malabsorption, review the literature concerning the benefits of liquid L-T4 in cases of impaired absorption such as bariatric surgery and consider the socio-economic implications of different liquid formulations.
Bariatric surgery constitutes an approach to the management of obesity in which the anatomy of the gastrointestinal tract is altered to reduce access of nutrients to absorptive surfaces, to restrict the absolute volume of material that can be ingested at once, or a combination of the two. Roux-en-Y gastric bypass (RYGB), currently the most common bariatric surgical procedure worldwide, has both malabsorptive and restrictive features. RYGB can be associated with alterations in absorption and disposition of medications. However documenting and predicting the specific pharmacokinetic changes associated with RYGB is a difficult research challenge. Because obesity and weight loss themselves can alter drug disposition, it may be difficult or impossible to resolve whether pharmacokinetic alterations in post-RYGB patients are due to the surgery itself as opposed to the subsequent weight loss. Changes in disposition of medications may be drug-specific as opposed to generalized. Further, statistically significant modifications in drug disposition are not necessarily of clinical importance. Clinical decisions on medication use in post-bariatric surgical patients should be based on a review of the original literature dealing with the particular drug in question.
Study Objectives
To evaluate the effect of Roux-en-Y gastric bypass surgery (RYGB) on the pharmacokinetics of midazolam (a CYP3A4 substrate) and digoxin (a P-glycoprotein substrate).DesignProspective, nonblinded, longitudinal, single-dose pharmacokinetic study in three phases: presurgery baseline and postoperative assessments at 3 and 12 months.PatientsTwelve obese patients meeting current standards for bariatric surgery.Measurements and Main ResultsAt each study visit, patients received a single dose of oral digoxin and midazolam at 8 a.m. Blood samples were collected at regular intervals for 24 hours after dosing. Continuous 12-lead electrocardiogram (EKG), heart rate, blood pressure, and respiratory rate were monitored, and pharmacokinetic parameters from the three visits were compared. The peak plasma concentration (Cmax) of midazolam increased by 66% and 71% at 3- and 12-month post-RYGB (p=0.017 and p=0.001, respectively), whereas the median time to peak concentration (Tmax) was reduced by 50%. The mean Cmax for 1′-hydroxymidazolam increased by 87% and 80% at 3 and 12 months (p=0.001 and p<0.001, respectively). However, neither the area under the concentration-time curve (AUC) for midazolam nor the metabolite-to-parent AUC ratio changed significantly over time. For digoxin, the median Tmax decreased from 40 minutes at baseline to 30 and 20 minutes at 3 and 12 months, respectively. The mean AUC for digoxin, heart rate, and EKG patterns were similar across the three study phases.Conclusion
Contemporary proximal RYGB increases the rate of drug absorption without significantly changing the overall exposure to midazolam and digoxin. The Cmax of a CYP3A4 substrate with a high extraction ratio was substantially increased after RYGB.
Background:
Obesity surgery is acknowledged as a highly effective therapy for morbidly obese patients. Beneficial short-term effects on common comorbidities are practically undisputed, but a growing data pool from long-term follow-up reveals increasing evidence of potentially severe nutritional and pharmacological consequences.
Aims:
To assess the prevalence, causes and symptoms of complications after obesity surgery, to elucidate and compare therapy recommendations for macro- and micronutrient deficiencies, and to explore surgically-induced effects on drug absorption and bioavailability, discussing ramifications for long-term therapy and prophylaxis.
Methods:
PubMed, Embase and MEDLINE were searched using terms including, but not limited to, bariatric surgery, gastric bypass, obesity surgery and Roux-en-Y, coupled with secondary search terms, e.g. anaemia, micronutrients, vitamin deficiency, bacterial overgrowth, drug absorption, pharmacokinetics, undernutrition. All studies in English, French or German published January 1980 through March 2014 were included.
Results:
Macro- and micronutrient deficiencies are common after obesity surgery. The most critical, depending on surgical technique, are hypoalbuminemia (3-18%) and deficiencies of vitamins B1 (≤49%), B12 (19-35%) and D (25-73%), iron (17-45%) and zinc (12-91%). Many drugs commonly administered to obese patients (e.g. anti-depressants, anti-microbials, metformin) are subject to post-operative and/or PPI-associated changes affecting bioavailability and absorption.
Conclusions:
Complications are associated with pre-operative and/or post-operative malnutrition or procedure-related changes in intake, absorption and drug bioavailability. The high prevalence of nutrient deficiencies after obesity surgery makes life-long nutritional monitoring and supplementation essential. Post-operative changes to drug absorption and bioavailability in bariatric patients cast doubt on the validity of standard drug dosage and administration recommendations.
Gastrointestinal (GI) surgery associated with resection or bypass can affect the absorption and kinetics of certain drugs. The goal of this article is 3-fold: (1) highlight the physiologic changes associated with selected GI surgeries (specifically gastric, small intestine, and colon), (2) review the implications for drug and nutrient absorption, and (3) suggest modifications of the pharmacologic agents, dosing regimens, and routes of delivery. Few large trials are available to use as references, but there is a wealth of individual reports and small series. Understanding the predictable challenges of drug administration in these patients will improve care.
There is a growing research literature suggesting that there may be elevated risk of suicide following bariatric surgery. Most of the data reported thus far has been cross-sectional and observational, and very little is known about the possible specific causal variables involved.
The purpose of this report is to review this literature and to review possible risk factors for increased suicidal risk following bariatric surgery, to delineate future research directions.
First a variety of medical, biological, and genetic factors, including the persistence or recurrence of medical comorbidities after bariatric surgery, the disinhibition and impulsivity secondary to changes in the absorption of alcohol, hypoglycemia, as well as pharmacokinetic changes that may affect the absorption of various medications including antidepressant medications are reviewed. Also reviewed are possible mediating factors involving changes in various peptidergic systems such as GLP-1 and Ghrelin. A number of psychosocial issues that might be involved are discussed, including lack of improvement in quality of life after surgery, continued or recurrent physical mobility restrictions, persistence or recurrence of sexual dysfunction and relationship problems, low self-esteem, and a history of child maltreatment. Inadequate weight loss or weight regain are also discussed.
A number of possible contributing factors have been identified. Possible theoretical models involved and directions for research are suggested.
Unlabelled:
The prevalence of obesity continues to rise throughout the world. Increasingly, bariatric surgery is used for those with morbid obesity as a pivotal approach to achieve weight loss. Along with substantial weight loss, malabsorption of essential vitamins, minerals, and drugs also occurs. Therefore, more than ever, a better understanding of the physiology and mechanisms by which these deficiencies occur is essential. We review the normal physiology of vitamin, mineral, and drug absorption. This is followed by a description of currently performed bariatric surgeries in the United States. A detailed review of specific nutrient and mineral deficiency states is presented, based on the most significant studies published in the last two decades. Of note, screening and supplementation recommendations have been included. Drug absorption data after these procedures is presented and discussed. Studies were identified by searching the Cochrane Registry and MEDLINE using relevant search terms, as well as through review of the reference section of included manuscripts.
Conclusions:
Bariatric surgery can be effectively used to achieve sustainable weight-loss in morbidly obese patients. It simultaneously brings forth important functional consequences on nutrient deficiencies and drug absorption that clinician's must be aware of. Further prospective, randomized research on specific procedures and deficiencies is required.
Due to the multi-factorial physiological implications of bariatric surgery, attempts to explain trends in oral bioavailability following bariatric surgery using singular attributes of drugs or simplified categorisations such as the biopharmaceutics classification system have been unsuccessful. So we have attempted to use mechanistic models to assess changes to bioavailability of model drugs.
Pharmacokinetic post bariatric surgery models were created for Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, sleeve gastrectomy and jejunoileal bypass, through altering the 'Advanced Dissolution Absorption and Metabolism' (ADAM) model incorporated into the Simcyp® Simulator. Post to pre surgical simulations were carried out for five drugs with varying characteristics regarding their gut wall metabolism, dissolution and permeability (simvastatin, omeprazole, diclofenac, fluconazole and ciprofloxacin).
The trends in oral bioavailability pre to post surgery were found to be dependent on a combination of drug parameters, including solubility, permeability and gastrointestinal metabolism as well as the surgical procedure carried out.
In the absence of clinical studies, the ability to project the direction and the magnitude of changes in bioavailability of drug therapy, using evidence-based mechanistic pharmacokinetic in silico models would be of significant value in guiding prescribers to make the necessary adjustments to dosage regimens for an increasing population of patients who are undergoing bariatric surgery.
Demand for bariatric surgery has risen exponentially and bariatric patients often have multiple indications for post‐operative pharmacotherapy. The purpose of this study was to systematically review the published literature examining the effect of bariatric surgery on drug absorption.
Studies were sought through searches of MEDLINE, EMBASE, the Cochrane Controlled Trials Registry and hand searches of reference lists. Two reviewers independently assessed studies for inclusion.
Twenty‐six studies (15 case reports/case series evaluating 12 different agents and 11 non‐randomized controlled studies examining 15 different agents) were found. Evidence for diminished drug absorption was found in 15/22 studies involving jejunoileal bypass, 1/3 studies of gastric bypass/gastroplasty and 0/1 studies examining biliopancreatic diversion. The effect of bariatric surgery on drug absorption appears drug‐specific. Drugs that are intrinsically poorly absorbed, highly lipophilic and/or undergo enterohepatic recirculation exhibited the greatest potential for malabsorption. The most consistent evidence for diminished absorption was found for cyclosporine, thyroxine, phenytoin and rifampin.
Reduced drug absorption may occur post‐bariatric surgery and this effect appears drug‐specific. Individual dose‐adjustment and therapeutic monitoring may be required. Rigorously conducted controlled studies are needed to evaluate the effect of modern bariatric procedures on drug absorption.
BACKGROUND: The pharmacokinetic variables of drug clearance and volume of distribution are usually corrected for body weight or surface area. Only recently have the relationships which exist between body size, physiologic function and pharmacokinetic variables been evaluated in the obese population. These effects are not widely known, and data on this and the effects of bariatric surgical procedures are scantily documented in the surgical literature. METHODS: Literature review. RESULTS: Drugs with a low or moderate affinity for adipose tissue have a moderate increase in the volume of distribution (Vd), and this correlates with the increase in lean body mass (LBM). Highly lipophilic drugs, with some exceptions, show the expected increase in Vd and prolongation of elimination half-life, indicating a marked distribution into adipose tissue. Drug absorption, in general, is slowed by delayed gastric emptying and is normal when gastric emptying is normal or increased. Most drug absorption occurs in the small intestine where duration of drug/mucosal contact is the most important factor. CONCLUSIONS: Drugs whose distribution is restricted to LBM should utilize a loading dose based on ideal body weight (IBW). For those drugs which distribute freely into adipose tissue, the loading dose should be based on total body weight (TBW). Adjustment of the maintenance dose depends on clearance rates. In a few cases dosage adjustment depends on pharmacodynamic data, since drug clearance does not conform to these recommendations, for reasons which remain to be defined. Following bariatric surgery, in the absence of delayed gastric emptying or uncontrolled diarrhea, drug absorption rates are usually comparable to the non-operated patient.
Large numbers of Roux-en-Y gastric bypass (RYGB) surgery patients have psychiatric illnesses that are in part treated with medication preoperatively, but there are no objective data to guide psychiatric drug dosing postoperatively. An in vitro drug dissolution model was developed to approximate the gastrointestinal environment of the preoperative (control) and post-RYGB states. Medication tablets were placed in the two environments, and the median calculated weights of the dissolved portions were compared. Ten of 22 psychiatric medication preparations had significantly less dissolution and two had significantly greater dissolution in the post-RYGB environment, compared with the control environment. The results suggest a need for an in vivo study of serum drug levels after RYGB surgery in patients taking psychiatric medications. Differences in the pharmacokinetics of the postoperative RYGB patient may necessitate adjustments in dosing.
Roux-en-Y gastric bypass versus sleeve gastrectomy: risks and benefits
- M D Ettleson
- C J Lager
- A T Kraftson
Ettleson MD, Lager CJ, Kraftson AT, et al. Roux-en-Y gastric
bypass versus sleeve gastrectomy: risks and benefits.
Minerva Chir. 2017;72(6):505-19.
BOMSS guidelines on perioperative and postoperative biochemical monitoring and micronutrient replacement for patients undergoing bariatric surgery
- M O'kane
- J Pinkney
- E T Aasheim
O'Kane M, Pinkney J, Aasheim ET, et al. BOMSS guidelines
on perioperative and postoperative biochemical
monitoring and micronutrient replacement for patients
undergoing bariatric surgery. London: British Obesity &
Metabolic Surgery Society; 2014