Marloes Emous

Influence of Bariatric Surgery on the Use and Pharmacokinetics of Some Major Drug Classes

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.

Dumping syndrome after esophageal, gastric or bariatric surgery : pathophysiology, diagnosis, and management

Dumping syndrome, a common complication of esophageal, gastric or bariatric surgery, includes early and late dumping symptoms. Early dumping occurs within 1 h after eating, when rapid emptying of food into the small intestine triggers rapid fluid shifts into the intestinal lumen and release of gastrointestinal hormones, resulting in gastrointestinal and vasomotor symptoms. Late dumping occurs 1–3 h after carbohydrate ingestion, caused by an incretin‐driven hyperinsulinemic response resulting in hypoglycemia. Clinical recommendations are needed for the diagnosis and management of dumping syndrome.

Diagnostic tools for post-gastric bypass hypoglycaemia

In spite of its evident success, several late complications can occur after gastric bypass surgery. One of these is post‐gastric bypass hypoglycaemia. No evidence‐based guidelines exist in the literature on how to confirm the presence of this syndrome. This study aims to describe and compare the tests aimed at making a diagnosis of post‐gastric bypass hypoglycaemia and to provide a diagnostic approach based upon the available evidence. A search was conducted in PubMed, Cochrane and Embase. A few questionnaires have been developed to measure the severity of symptoms in post‐gastric bypass hypoglycaemia but none has been validated. The gold standard for provocation of a hypoglycaemic event is the oral glucose tolerance test or the liquid mixed meal tolerance test. Both show a high prevalence of hypoglycaemia in post‐gastric bypass patients with and without hypoglycaemic complaints as well as in healthy volunteers. No uniformly established cut‐off values for glucose concentrations are defined in the literature for the diagnosis of post‐gastric bypass hypoglycaemia. For establishing an accurate diagnosis of post‐gastric bypass hypoglycaemia, a validated questionnaire, in connection with the diagnostic performance of provocation tests, is the most important thing missing. Given these shortcomings, we provide recommendations based upon the current literature.

The short- to mid-term symptom prevalence of dumping syndrome after primary gastric-bypass surgery and its impact on health-related quality of life

BACKGROUND Early and late dumping are complications of gastric bypass surgery. Early dumping occurs within an hour after eating, when the emptying of food into the small intestine triggers rapid fluid shifts into the intestinal lumen and the release of gastrointestinal hormones, resulting in gastrointestinal and vasomotor symptoms. Late dumping occurs between 1 and 3 hours after carbohydrate ingestion and is caused by an exaggerated insulin release, resulting in hypoglycemia. Almost no data are currently available on the prevalence of early and late dumping or their impact on health-related quality of life (QoL). OBJECTIVES To study the prevalence of early and late dumping in a large population of patients having undergone a primary Roux-en-Y gastric bypass (RYGB) and its effect on QoL. SETTING Cross-sectional study at a single bariatric department in the Medical Center Leeuwarden, The Netherlands between 2008 and 2011. METHODS In 2013, this descriptive cohort study approached by email or post all patients who underwent a primary RYGB in the setting between 2008 and 2011 in one hospital. These patients were asked to fill in standardized questionnaires measuring their QoL (RAND-36), anxiety and depression (HADS), fatigue (MFI-20) and any disease specific indicators of early and late dumping syndrome. RESULTS The questionnaire was completed and returned by 351 of 613 patients (57.1%) and 121 nonobese volunteers. Participants were mostly female (80%), aged 42 (40-54 years), with an excess weight loss of 76.8% [IQR 61-95] after RYGB surgery 2.3 [ IQR 1.6-3.4] years earlier. Self-reported complaints of moderate to severe intensity suggestive of early and late dumping were present in 18.8% and 11.7% of patients, respectively. Patients with early and late dumping demonstrated significantly lower scores on the RAND-36 and HADS compared with patients without dumping. No differences were seen in the MFI-20 scores between patients with or without early and late dumping. CONCLUSION In this descriptive cohort, self-reported complaints suggestive of early and late dumping of moderate-to-severe intensity were, respectively, 18.8% and 11.7% in a cohort after primary gastric bypass surgery. These complaints were associated with markedly reduced health-related QoL.

Satiety and gastrointestinal hormones during a Mixed Meal Tolerance Test after gastric bypass surgery: association with plasma amino acid concentrations,

BACKGROUND Circulating amino acids have been associated with both appetite and the secretion of anorexigenic hormones in healthy and obese populations. This effect has not been investigated in subjects having undergone Roux-en-Y gastric bypass surgery (RYGB). OBJECTIVE To investigate the association between postprandial plasma concentrations of amino acids and the anorexigenic hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY), the orexigenic hormone ghrelin, and satiety and hunger in post-RYGB subjects. SETTING A Dutch surgical department. METHODS Participants after primary RYGB were studied during a Mixed Meal Tolerance Test (MMTT). Satiety and hunger were assessed every 30 minutes on visual analogue scales. Blood samples were collected at baseline, every 10 minutes during the first half hour and every 30 minutes until 210 minutes after the start. The samples were assessed for 24 amino acids and 3 gastrointestinal hormones. Incremental areas under the curve (iAUCs) were calculated. Exploratory analyses were performed in which subjects were divided into high and low responders depending on the median iAUC. RESULTS 42 subjects, aged 48 ± 11 (mean ± SD) years, 31 to 76 months post-RYGB and with total weight loss of 30 ± 9% completed the MMTT. Subjects with high satiety scores had more than a 25% higher net iAUC of PYY and GLP-1 and at least a 10% higher net iAUC of 10 amino acids compared to subjects with low scores (P < 0.05). The net iAUC of five of these amino acids (i.e. arginine, asparagine, histidine, serine and threonine) was more than 10% higher in subjects with high responses on GLP-1 and/or PYY (P < 0.05). CONCLUSIONS Certain postprandial amino acids were associated with satiety and anorexigenic hormones and could therefore play a role in appetite regulation after RYGB; either by a direct effect on satiety, indirectly through gastrointestinal hormones, or both.

Prevalence and pathophysiology of early dumping in patients after primary Roux-en-Y gastric bypass during a Mixed Meal Tolerance Test.

BACKGROUND Early dumping is a poorly defined and incompletely understood complication after Roux-en-Y gastric (RYGB). OBJECTIVE We performed a mixed-meal tolerance test in patients after RYGB to address the prevalence of early dumping and to gain further insight into its pathophysiology. SETTING The study was conducted in a regional hospital in the northern part of the Netherlands. METHODS From a random sample of patients who underwent primary RYGB between 2008 and 2011, 46 patients completed the mixed-meal tolerance test. The dumping severity score for early dumping was assessed every 30 minutes. A sum score at 30 or 60 minutes of ≥5 and an incremental score of ≥3 points were defined as indicating a high suspicion of early dumping. Blood samples were collected at baseline, every 10 minutes during the first half hour, and at 60 minutes after the start. RESULTS The prevalence of a high suspicion of early dumping was 26%. No differences were seen for absolute hematocrit value, inactive glucagon-like peptide-1, and vasoactive intestinal peptide between patients with or without early dumping. Patients at high suspicion of early dumping had higher levels of active glucagon-like peptide-1 and peptide YY. CONCLUSION The prevalence of complaints at high suspicion of early dumping in a random population of patients after RYGB is 26% in response to a mixed-meal tolerance test. Postprandial increases in both glucagon-like peptide-1 and peptide YY are associated with symptoms of early dumping, suggesting gut L-cell overactivity in this syndrome.

Long-term self-reported symptom prevalence of early and late dumping in a patient population after sleeve gastrectomy, primary, and revisional gastric bypass surgery

BACKGROUND Early and late dumping are side effects of bariatric surgery. Almost no data are available on the prevalence of dumping after different surgical procedures. OBJECTIVES Comparison of the relative risks of dumping in a large population of patients having undergone primary Roux-en-Y gastric bypass (pRYGB), sleeve gastrectomy (SG), or revisional RYGB (rRYGB; after removal of band). SETTING Bariatric center of a teaching hospital. METHODS In this descriptive cohort study, all patients who underwent a pRYGB (n = 615), SG (n = 157), or rRYGB (n = 274) between 2008 and 2011 were approached by mail and asked to complete and return a questionnaire of general and disease-specific questions related to dumping syndrome. Relative risks (RR) were calculated (mean with 95% confidence intervals) by comparing the prevalence of high suspicion for early and late dumping between different surgical procedure groups and primary gastric bypass surgery. RESULTS The questionnaire was completed and returned by 593 (57%) of 1046 patients. Fewer patients with SG were at high suspicion of early dumping than after pRYGB (RR [95% confidence interval] .46 [.22-.99], P = .049). No differences for early dumping were seen between rRYGB and pRYGB (RR 1.21 [.77-1.91], P = .40). More patients were at high suspicion for late dumping after rRYGB compared with after pRYGB (RR 1.78 [1.09-2.90] P = .021). No differences for late dumping were seen between SG and pRYGB (RR .59 [.22-1.61], P =.30). CONCLUSION Fewer complaints of early dumping are reported after SG, while patients report more complaints of late dumping after rRYGB compared with pRYGB.

Therapeutic potential of deep brain stimulation of the nucleus accumbens in morbid obesity

OBJECTIVE Morbid obesity is a growing problem worldwide. The current treatment options have limitations regarding effectiveness and complication rates. New treatment modalities are therefore warranted. One of the options is deep brain stimulation (DBS) of the nucleus accumbens (NAC). This review aims to summarize the current knowledge on NAC-DBS for the treatment of morbid obesity. METHODS Studies were obtained from multiple electronic bibliographic databases, supplemented with searches of reference lists. All animal and human studies reporting on the effects of NAC-DBS on body weight in morbidly obese patients were included. Articles found during the search were screened by 2 reviewers, and when deemed applicable, the relevant data were extracted. RESULTS Five relevant animal experimental papers were identified, pointing toward a beneficial effect of high-frequency stimulation of the lateral shell of the NAC. Three human case reports show a beneficial effect of NAC-DBS on body weight in morbidly obese patients. CONCLUSIONS The available literature supports NAC-DBS to treat morbid obesity. The number of well-conducted animal studies, however, is very limited. Also, the optimal anatomical position of the DBS electrode within the NAC, as well as the optimal stimulation parameters, has not yet been established. These matters need to be addressed before this strategy can be considered for human clinical trials.

Pharmacokinetics of glucocorticoid replacement before and after bariatric surgery in patients with adrenal insufficiency

Abstract Adequate glucocorticoid replacement in patients with primary or secondary adrenal insufficiency is essential to maintain general well-being. Little is known about the effects of bariatric surgery on glucocorticoid absorption. This study evaluates glucocorticoid absorption before and after bariatric surgery, with assessment of plasma cortisol profiles in five patients receiving glucocorticoid replacement therapy for primary (n = 1) or secondary (n = 4) adrenal insufficiency. One patient underwent sleeve gastrectomy (SG), one a one-anastomosis gastric bypass (mini-GB), and three a Roux-en-Y gastric bypass (RYGB). Pharmacokinetic calculations were based on plasma cortisol measurements performed during the first 6 hours after ingestion of the morning dose. Plasma cortisol profiles were very similar before and after surgery; only minor differences were observed. After SG, plasma peak cortisol concentration and cortisol area under the curve (AUC) were higher by 23% and 24%, respectively, and time to peak cortisol was 10 minutes shorter. The mini-GB had no marked effect on pharmacokinetic parameters. In the three patients who underwent RYGB, AUC changes ranged from −12% to 20%. In conclusion, in this small number of patients with adrenal insufficiency, plasma cortisol profiles were similar before and after bariatric surgery. However, in view of individual differences in response to different types of surgery, we recommend postoperative cortisol profiling to guide appropriate glucocorticoid dose adjustment.

A gastrointestinal simulation system for dissolution of oral solid dosage forms before and after Roux-en-Y gastric bypass

Background The Roux-en-Y gastric bypass (RYGB) is a bariatric procedure, greatly reducing the stomach size and bypassing the duodenum and proximal jejunum. Hence, RYGB may reduce the absorption and bioavailability of oral medication. For clinical decisions on the use of medication, knowledge of altered modifications in drug disposition is a prerequisite. An in vitro dissolution method for solid oral medications, simulating conditions before and after RYGB, might be a valuable tool to predict the pharmaceutical availability of medicines frequently used by patients after RYGB. Objectives To develop a gastrointestinal simulation system (GISS), mimicking conditions before and after RYGB for investigating dissolution characteristics of solid oral medications, and to assess the pharmaceutical availability of metoprolol from immediate-release (IR) and controlled-release (CR) tablets under these conditions. Methods With an adjusted, pharmacopoeial paddle dissolution apparatus, the GISS enables variation in parameters which are relevant to drug release in vivo: pH, volume, residence time, osmolality and agitation. Metoprolol tartrate 100 mg IR tablets and metoprolol CR tablets were tested. Release profiles were determined by measuring the concentrations of metoprolol spectrophotometrically. Results From IR tablets, under all conditions applied, >85% of metoprolol was released within 25 min. From all tested CR tablets >90% of metoprolol was released after 22 hours. Conclusions This GISS is a suitable dissolution system to assess pharmaceutical availability before and after RYGB. In patients who have undergone RYGB, no problems in pharmaceutical availability of metoprolol IR and CR tablets are to be expected. Any changes in response to metoprolol in patients after RYGB should therefore be ascribed to changes in bioavailability.