Bariatric surgery and the effects on drug pharmacokinetics

The worldwide prevalence of obesity has continued to dramatically increase over the past few decades ^[1],[2],[3]
. More than 2 billion people are considered as being overweight globally, of whom 600 million are considered obese, defined as a body mass index (BMI) of ≥30 kg/m^2[1],[2]
. Obesity is a complex chronic multisystem condition with physiological, psychological and social implications. It is described as abnormal, excessive fat accumulation and contributes to a significant increase in mortality ^[1],[4],[5]
. In the UK, rates doubled between 1993 and 2011^[6]
and the estimated prevalence of being overweight or obese is 62.1%^[7]
. In comparison, the United States has an estimated prevalence of up to 75%, with 6.3% being morbidly obese (BMI of ≥50kg/m²)^[1],[2],[8]
(see ‘Graph 1: Prevalence of obesity worldwide’).

The UK societal cost of treating obesity and associated comorbidities is estimated to reach £7bn per year, with £1bn per year attributed to health service costs^[9]
. Further calculations have predicted that by 2050, obesity will add £5.5bn to the total annual cost of the NHS^[9],[10]
. In response, there have been efforts to educate and promote lifestyle and medical therapies, including exercise regimens, dietary advice and lipase inhibitors such as Orlistat (tetrahydrolipstatin)^[1]
. However, results are modest and sustained weight loss is rarely achieved^{[3],[11],[12],[13]}
.

Consequently, bariatric surgery is increasingly popular and techniques have advanced since the first operations were described in the 1950s. Complication rates in the UK are approximately 2.9%^[14]
, while global mortality rates are around 0.07% and surgery is often associated with a short length of stay in hospital (mean 2.7 days)^[12],[15]
. The National Institute for Health and Care Excellence (NICE) guidelines currently offer bariatric surgery to people with a BMI of ≥40kg/m² or 35–40kg/m², plus one medical condition that may be improved with weight loss^[16]
(see ‘Box 1: The National Institute for Health and Care Excellence criteria for consideration of bariatric surgery’). However, there is a significant mismatch between eligible patients (approximately 260,000 in the UK) and uptake of surgery, which may be on account of a lack of adequate resources and a lack of understanding of the criteria for bariatric surgery^[16],[17]
.

In the UK, 16,956 bariatric surgical procedures were carried out between 2011 and 2013, on patients with an average BMI of 48.8kg/m³. In contrast, 179,000 operations were carried out in the United States in 2013 alone^[12]
. The majority of patients having bariatric surgery in the UK are aged 45–54 years. Worldwide, more adolescents are now undergoing surgery on account of an increasing prevalence of significant comorbidities and an increased prevalence of adolescents who are “super-obese” (i.e. BMI of ≥45)^[3],[12]
. There is also a global trend towards operating on higher risk individuals with established disease or end-organ damage^[3]
. This is because surgical management can increase lifespan^[18]
and lead to improvement in a number of conditions, such as diabetes and hyperlipidaemia^{[3],[12],[13],[19]}
(see ‘Graph 2: Improvement or resolution of associated conditions following bariatric surgery’) as well as significant weight loss (see ‘Graph 3: Loss of excess body weight (EBW) after bariatric surgery’)^[3]
. Consequently, bariatric surgery is cost-effective in the developed world on account of reductions in obesity-related conditions and an increase in quality of life^[11],[12]
.

Bariatric surgery, in its various forms, affects specific sites involved in drug absorption and metabolism, potentially affecting pharmacological management in individuals who have undergone surgery.

This article will discuss types of bariatric surgery, the impact on drug pharmacokinetics and specific recommendations for drug regimens following bariatric surgery.

Types of bariatric surgery

Bariatric surgery was traditionally categorised into restrictive, malabsorptive and combined types. More recent understanding that these surgical procedures alter hormonal regulation of metabolism has superseded this categorisation (see ‘Table 1: Proposed mechanism of bariatric surgery’)^{[20]
,[21],[22],[23],[24],[25]}
.

Surgical procedures comprise those that decrease stomach volume or that utilise a bypass of part of the gastrointestinal tract. These include adjustable gastric banding (AGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), the bilio-pancreatic bypass/duodenal switch procedure and vertical banded gastroplasty (see ‘Figure 1: Types of bariatric surgical procedures’).

AGB involves application of a synthetic band just distal to the gastro-oesophageal junction, creating a gastric pouch with a small outlet (≈ 1cm diameter). The band can be inflated or deflated via an external port.

In SG, the stomach is stapled vertically, essentially removing the greater curvature and preserving the pylorus and antrum.

In RYGB, the stomach is reduced to approximately the size of a golf ball and the outlet measures around 1cm in diameter. A section of small intestine between the jejunum and ileum is divided and the proximal end of the shortened distal ileum (‘Roux’ limb) is attached to the new gastric pouch, bypassing the duodenum and jejunum, a primary site for absorption of nutrients and medications. The bilio-pancreatic limb of the jejunum, carrying biliary and gastric secretions, is then reconnected to the small intestine distal to the gastro-jejunal anastomosis (80–120cm) creating a ‘common limb,’ where food contents and digestive enzymes mix.

The bilio-pancreatic bypass/duodenal switch is a variation of RYGB where a longer length of the small intestine is bypassed. This leads to profound weight loss but has an increased operative time (usually performed as a two-part procedure), post-operative risks and higher malnutrition rate. Therefore, it is usually reserved for the severely obese with a BMI of ≥50-60.

The now virtually unused vertical banded gastroplasty involves partitioning of the stomach with staples and then use of a band to create a small gastric pouch. Although not routinely performed, patients who have had this procedure will continue to present to health services.

In the United States and the UK, RYGB and SG represent the majority of bariatric procedures and more than 90% are performed laparoscopically^[3],[12]
.

Bariatric surgery is cost-effective and safe^{[3],[10],[11]
[12
]
,[17]}
but it introduces concern about nutrient delivery and altered drug pharmacokinetics. There have been no prospective, randomised studies to date looking at drug pharmacokinetics in the post-bariatric surgery population,^[26],[27]
however, in vitro studies and case series have provided some suggestion of drug-specific alterations in drug pharmacokinetics.

Absorption and bioavailability

Nearly all nutrient and oral absorption occurs in the small intestine, which normally has an absorptive surface area of 250m². Important considerations here include drug specific factors (i.e. ionisation, lipophilicity, stability, dissolution properties) and patient factors (i.e. gastric pH, gastric emptying, area of mucosal exposure and contact with transporter systems). The type of surgery has an impact, with bypass procedures theoretically more likely to affect overall absorption, on account of loss of mucosal exposure and reduced bile-salt mixing^[26],[27]
.

It is important to remember drug dosage and regimens are developed in trials involving participants with ‘normal’ gastrointestinal anatomy. Therefore, bariatric patients may exhibit altered responses to standard medications and doses^{[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49]}
(see ‘Table 2: Medications with specific advice following bariatric surgery’).

Gastric pH

In the first instance, drug breakdown and solubility is affected by gastric pH. Drugs more soluble at an acidic pH are absorbed in the stomach, whereas those soluble in an alkaline environment are absorbed in the small intestine. In bariatric procedures such as RYGB or SG, the acid-producing cells in the fundus are excised or partitioned off, leading to decreased production of hydrochloric acid and an increase in gastric pH. Gastric pH is also increased with the use of proton pump inhibitors (PPI’s), such as lansoprazole or omeprazole, which is common after bariatric procedures.

This may affect the dissolution rate of specific drugs^[26],[28]
and, theoretically, could increase solubility of certain medications (e.g. allopurinol, i.e. basic drugs), and decrease solubility and absorption of medications dependent on an acidic environment (e.g. acetylsalicylic acid)^[26],[27]
. Where possible, switching to a liquid formulation would eliminate the need for drug dissolution and therefore increase absorption. Effects on nutrient absorption may also be observed^[26]
. This can be overcome with a different preparation, such as calcium citrate, which does not depend on an acidic environment unlike other forms and has demonstrated an increased bioavailability compared with calcium carbonate^[50]
. Additionally, iron is dependent on hydrochloric acid to reduce it to a ferrous form. In order to overcome this, iron supplements can be combined with ascorbic acid^[51]
, which have been demonstrated to improve ferritin levels and anaemia. 

It is important to consider that the majority of drug absorption occurs in the small intestine as the stomach exhibits a much lower surface area to volume ratio. This makes the significance of reduced gastric pH and absorption unclear^[26],[27]
.

Gastric emptying

Following surgery, gastric emptying, which is reliant partially on the pylorus but also affected by peptide YY (see ‘Table 1: Proposed mechanism of bariatric surgery’), is delayed^[52]
. This is especially relevant with SG and gastric banding, where the pylorus is preserved and leads to a prolonged and earlier feeling of satiety. This may have implications when administering medications, although the significance is uncertain^[27],[37]
. It is suggested the rate of absorption may be reduced but the degree of absorption should remain unchanged^[27]
. Commonly, patients who undergo bariatric surgery can usually only tolerate a liquid diet for the first six weeks post-operatively^[53]
. Although no guidelines exist, standard practice is to switch to liquid formulations, where possible, until a solid diet is resumed^[53]
.

Mucosal exposure

Bypass procedures markedly reduce the surface area available for drugs to be absorbed along the gastrointestinal tract^[27],[37]
as a result of loss of villi and microvilli that would normally increase the absorptive area. Through bypassing the proximal small intestine, the largest surface area per unit length of the tract is removed and this leads to lower nutrient and fat absorption, and therefore greater weight loss. However, the distal small intestine, which has a smaller surface area in comparison, has a slower transit time that may aid in increasing drug absorption^[26],[27]
.

Drugs with slow dissolution properties (e.g. extended release) are likely to exhibit reduced bioavailability and absorption as a result of a significant portion of the gastric tract being bypassed. This can be important in critical drugs such as antiepileptics (see ‘Table 2: Medications with specific advice following bariatric surgery’). Current recommendations are that these preparations should be avoided, as they may have exited the gastrointestinal tract before absorption is complete^{[27],[37],[53]}
. Overcoming this issue can be achieved by replacing it with immediate release formulations of the same drug. However, a potential disadvantage of this is increased frequency of administration, which could affect patient compliance and adherence.

Lipophylicity

On account of bypass of the biliary system and the restriction of bile-salt mixing with nutrients and drugs to the common channel, drugs that are highly lipophilic may be affected. These are dependent on the presence of bile salts for absorption and usually undergo entero-hepatic recirculation. Lipophilic medications include tacrolimus and levothyroxine, which will need monitoring in this subset of patients (see ‘Table 2: Medications with specific advice following bariatric surgery’).

Transporter systems

Located in numerous sites, including the intestine, liver and kidneys, transporter systems are important in drug absorption and distribution and have complex interactions with drugs. For example, some medications, such as atorvastatin, are substrates for P-glycoprotein, a transporter that has increasing activity in the distal intestine, and through bypassing the main site for absorption this may lead to increased efflux of the drug through the transporter and reduced drug levels. In addition, antibiotics such as the fluoroquinolones depend on the organic anion transporting polypeptide (OATP) influx transporter, and therefore bioavailability may be reduced in bypass procedures because of reduced exposure^[54]
.

There is suggestion that compensatory mechanisms may take place leading to unaltered drug absorption, however current evidence is inconclusive^[27],[55]
.

Distribution

Drugs with high lipid solubility or low plasma binding have a higher volume of distribution (Vd) and the physical volume of the individual affects this. The other factors that influence drug distribution (e.g. cardiac output and vascular permeability) are not usually affected. Following bariatric surgery, there is profound weight loss and this appears to include both fat mass and lean mass^[56]
. There is no evidence that distribution is affected and current recommendations are that doses are calculated according to total body weight for lipophilic drugs and with ideal body weight for those drugs where distribution is mostly to lean body mass^[57]
. Accurate monitoring of weight and drug levels where appropriate is advised (see ‘Table 2: Medications with specific advice following bariatric surgery’). Clearance rates should also be regularly monitored, as many patients in this population have pre-existing renal impairment that may improve with weight loss^[58]
.

Metabolism

Most drug metabolism occurs in the presence of liver enzymes (e.g Cytochrome P450 oxidases), while some occurs in the small intestine and to a lesser degree (e.g.CYP3A) in the proximal small intestine. However, in the absence of pre-existing liver disease or interacting medications, there is no clear effect of bariatric surgery on drug metabolism^[31],[34]
.

Another consideration is the effect on entero-hepatic recirculation. On account of the diminished surface area, there will be reduced initial absorption and subsequent reabsorption also. The overall effect may be reduced drug levels (e.g. lithium), and close monitoring of narrow therapeutic index drug levels is advised (see ‘Table 2: Medications with specific advice following bariatric surgery’).

Other considerations

On account of the reduced gastric capacity following bariatric surgery, there is an observed risk of gastric ulceration in relation to non-steroidal anti-inflammatory drugs^[59]
. Marginal ulcers have been reported in up to 16% of patients[59], therefore, standard practice in bariatric centres is avoidance of these agents^[53]
. Alternative analgesics include paracetamol, tramadol or oramorph, which are available as liquid preparations.

Studies show a prevalence of nutrient and vitamin deficiency in 50–69% of post-operative patients^[60]
, likely caused by reduced mucosal exposure and bile-salt mixing. Therefore, international (American Association of Clinical Endocrinologists, The Obesity Society and American Society for Metabolic and Bariatric Surgery) and UK (British Obesity and Metabolic Surgery Society) guidelines^[61],[62]
suggest close monitoring of folate, B12, ferritin, calcium, vitamin D, zinc and copper as routine. Multivitamins are recommended following all bariatric procedures but RYGB and SG have higher requirements. Specifically, it is recommended patients take 2mg copper, 45–50mg iron (100mg if menstruating), 800–1200mg calcium and 20µg vitamin D daily. Thiamine should be considered with prolonged vomiting post-operatively and a three-monthly vitamin B12 injection is advised^[61]
. This is because the bypass of gastric parietal cells causes a lack of intrinsic factor, leading to malabsorption of oral vitamin B12. In addition, bisphosphonates present a risk of gastric ulceration because of the reduced gastric size, and therefore alternatives such as raloxifene or calcitonin nasal spray are advised^[37]
.

Contraception is an important consideration in the pre-operative and post-operative population. International guidelines advise against oral hormonal contraception because of concerns about absorption. Alternative options are recommended, specifically barrier methods, intrauterine devices, the implant or the contraceptive ring^[63]
.

For those wishing to become pregnant, women who are obese or who have undergone bariatric surgery should have pre-conception planning and follow-up in a specialist clinic because of an increased risk of complications. Management includes high-dose folic acid (5mg), vitamins that do not contain vitamin A in the retinol form because of its teratogenic effect, and nutritional screening every trimester^[61],[62]
.