MEDICATIONS AFTER BARIATRIC SURGERY Jess Bates Pharm D

MEDICATIONS AFTER BARIATRIC SURGERY Jess Bates, Pharm. D, BCACP Clinical Pharmacist Assistant Clinical Faculty Penobscot Community Health Care University of New England April 26, 2018

ACKNOWLEDGEMENTS This presentation was adapted with permission from slides originally prepared by Tyson Thornton, Pharm. D

OBJECTIVES Describe the epidemiology of obesity in the United States, risks of obesity, and surgical methods for weight reduction. Review the pharmacology and pharmacokinetics of specific drug classes to implement safe prescribing practices following bariatric surgery. Discuss recognize common nutritional deficiencies following and how to properly replace them using nutritional supplements.

EPIDEMIOLOGY: OBESITY IN THE U. S. >70% of our adult population is considered overweight, obese, or morbidly obese 37. 9% of adults considered obese Marked increase from 1960 Women > men Middle age + older adults > younger adults Black > Hispanic > White > Asian 1995 • $99. 2 billion impact 2008 • $147 billion impact NCHS Health E-Stats. July 2016, https: //www. cdc. gov/nchs/data/hestat/obesity_adult_13_14. pdf 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults. Circulation 2013.

THE RISKS OF OBESITY Strongest risk factor associated with sleep apnea Risk of chronic pain 2 -4 x higher Every 10 kg 3 mm. Hg BP increase Lipid levels impacted when BMI >25 Risk of DM and CHD increase at BMI >22 Increased risk of heart structure changes in CHF Morbidity increases when BMI >20 Mortality increases when BMI >25 Female BMI >27 increases stroke risk 75% Increased risk of gallstones Cancer risk (colon, breast, endometrial, gallbladder) Increased mental health risk 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults. Circulation 2013.

CLASSIFICATION OF OBESITY BMI Classification <18. 5 Underweight 18. 5 -24. 9 Normal weight 25 -29. 9 Overweight ≥ 30 Obese 30 -34. 9 Obesity Class I 35 -39. 9 Obesity Class II ≥ 40 Obesity Class III (severe/extreme/morbid obesity)

VARIOUS LEVELS OF BMI (BASED OF 5’ 4” FEMALE) Normal Weight (BMI 19 to 24. 9) 130# BMI 22 Overweight (BMI 25 to 29. 9) Obese (Class I) (BMI 30 to 34. 9) Obese (Class II) (BMI 35 to 39. 9 ) Morbidly Obese (BMI 40 or more) 152# BMI 26 175# BMI 30 205# BMI 35 234# BMI 40 Agency for Healthcare Research and Qulaity. Screening for obesity in adults. Dugdale DC. Obesity. Medline. Plus.

DECIDING ON BARIATRIC SURGERY NIH Consensus Statement 1991: “Gastric bypass and gastroplasty are the ONLY effective treatment for those with morbid obesity”

SURGICAL CANDIDATES* BMI 35 -39. 9 with serious comorbidities Willing to change lifestyle drastically ≥ 40 without comorbidities Usually 18 -65 years of age Unsuccessful with conservative efforts Willing to participate in long-term follow-up Highly motivated Determined by insurance companies Non-smoker *Highly variable depending on surgeon and/or surgical center protocol

National Institute of Diabetes and Digestive and Kidney Diseases. Types of Bariatric Surgery, July 2016.

SURGICAL COMPLICATIONS Early Risks Long-Term Risks Leak Visceral injury Anesthetic complications Respiratory Cardiovascular DVT, PE Wound Diabetic issues Slip or obstruction with band N, V, dehydration Death Hardware failure, slippage, erosion Vitamin/mineral deficiencies (Ca, vit D, B 12, Fe) Medication intolerances/malabsorption Strictures Gallstones, kidney stones Hernias Anastomotic ulcers, GI bleeding, perforation Dumping Hypoglycemia

NIH DEFINITION OF SUCCESS Greater than or equal to 50% excess body weight loss at 5 years post-op

KEYS TO DRUG ABSORPTION Drug dissolution (solubility/p. Ka) p. H of stomach increased to around 5 after surgery Diffusion Transport, surface area, metabolism (OATP/PEPT 1) Primary site of drug absorption Amount of blood flow supplied to the GI tract for distribution (endohepatic cycling) Protein binding Lingtak-Neander C. Drug Therapy-Related Issues in Patients who Received Bariatric Surgery (Part I). Practical Gastroenterology; 2010. Smith A. Pharmacokinetic Considerations in Roux-en-Y gastric bypass patients. ASHP, 2011.

LACKING DATA Almost no randomized controlled trials observing medication use Few consensus statements Data we do have is based on outdate procedures Mostly case-reports and small cohorts

HOW PHARMACISTS CAN HELP! Avoid contraindicated medications Optimize dosage form Help monitor the disease state Get drug levels when appropriate Educate the patient Be creative

EXTENDED RELEASE MEDICATIONS XR, SR, XL, DR, ER, XT, CR, CD medications all have some type of timed release mechanism These MUST be switched to immediate release formulations Mun E. Medical Management of patients after bariatric surgery. Up. To. Date, 2009.

CAPSULES Not all are created equal Examples of some that are ok to open: Nexium, Prilosec, Prevacid Flomax Depakote Sprinkles Gabapentin Effexor XR Adderall XR Tiazac or Taztia XT Verelan PM Aggrenox Cymbalta (apple sauce/juice) Strattera Institute of Safe Medicine Practices 2017 do not crush or chew list: http: //www. ismp. org/tools/donotcrush. pdf Clinical Pharmacology. Mosby CP, 2011.

PAIN NSAIDs MUST be avoided in the gastric bypass patient Including topical patches and creams Weak acids (p. Ka 3 -5) decreased absorption Preferred: APAP Tramadol, and opioids Lidocaine patches Padwal R. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obesity Reviews; 2009. Smith A. Pharmacokinetic considerations in Roux-en-Y gastric bypass patients. ASHP; 2011.

THE ACID-BASE RELATIONSHIP 1. Determine if the drug is a week acid or a weak base 2. Determine the drug’s p. Ka (tells us how likely the drug is to ionize) Weak acids and weak bases can have p. Ka’s in the same range, which is what gets confusing p. H < p. Ka p. H > p. Ka Weak acids Weak bases Unionized Ionized Unionized

DRUG EXAMPLES

CARDIO-PROTECTIVE ASPIRIN, CLOPIDOGREL, PRASUGREL All aspirin (including 81 mg) will be held post-op Risk of post-operative marginal ulcer outweighs cardio risk of stopping aspirin Decision to continue clopidogrel/prasugrel post-op should be made on a case -by-case basis Consult cardiology

OSTEOPOROSIS Avoid oral bisphonates Alternatives: calcitonin nasal spray, teriperatide, raloxifene All patients should receive a minimum of: Calcium 600 mg bid Vitamin D 400 iu bid Zoledronic acid 5 mg IV qyear or ibandronate 3 mg IV q 3 months are alternatives Lingtak-Neander C. Management of patients receiving bariatric surgery. Pharmacotherapy Self-Assessment Program.

WARFARIN Only case reports Can require very large daily doses (10 -20 mg/day) Frequent INRs p. Ka around 5 = more ionized drug for passive diffusion = lower absorption EMMC surgical group does not perform RYGB on warfarin patients Sobieraj DM. Warfarin resistance after total gastrectomy and roux-en-y esophagojejunostomy. Pharmacotherapy 2008.

DOACS (DIRECT ORAL ANTICOAGULANTS) Small case reports, mostly unpublished data Pradaxa biggest concern because it is only active after it is metabolized Eliquis and Xarellto more favorable Eliquis is a weak base (p. Ka 6. 8) Likely unaffected by p. H changes Lipophillic Extensive P-gp and CYP metabolism may be problematic Xarelto is non-ionizable at any p. H Lipophillic No P-gp, some CYP Fastest time to peak

ORAL CONTRACEPTIVES Varied, unreliable absorption Possibly less effective due to eneterohepatic recycling requirements Two case control studies: Single oral doses of D-norgestrel, oestradiol, oestrone produced no significant difference Single oral doses of norethisterone or L-norgestrel produced lower AUC post-op Alternatives: Nuvaring, IUD, barrier methods, Depo-Provera Anderson, et al. Inj J Obes, 1982. Victor, et al. Gastroenterol Clin North Am, 1987. Lingtak-Neander C. Management of patients receiving bariatric surgery. Pharmacotherapy Self-Assessment Program.

ORAL ANTIBIOTICS Penicillins and cephalosporins have vastly varied absorption based on acidity and presence of food Penicillin case report of 1 g dose significantly increased AUC (p. Ka 2. 75) Ampicillin report of bioavailability reduced by 109 -41% post-op Nitrofurantoin ok Must avoid Macrobid Bactrim has low BA post-RYGB Quinolones maintain good absorption (OATP transporter) Macrolides variable absorption Clarithromycin best Rifampin levels reduced in 6 case reports Consider IM injections when possible Magee S. Malabsorption of oral antibiotics in pregnancy after gastric bypass surgery. JABFM 2007. Terry SI. Eur J Clin Pharmacol 1982. Kampmann JP. Clin Pharmacokinet 1984.

THYROID Propylthiouracil One case report demonstrated no difference in bioavailability Thyroxine Two case reports showed patients requiring a 3 -fold dose increase Titrated to TSH Padwal R. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obesity Reviews; 2009.

STATINS Atorvastatin: low bioavailability, lipophilic, protein-bound, CYP substrate, Pgp activity Mixed study results Simvastatin: lipophilic, prodrug, results unknown Pravastatin: hydrophilic, moderate binding, no substantial metabolism Yska. Obes Surg 2013.

BETA-BLOCKERS Propranolol Reduction of AUC 32% and Cmax 20% in single-dose trial Lipophilic, basic, p. H change big consideration Atenolol No difference in single-dose studies Basic, hydrophilic 2014 study showed many patients required dose adjustments for up to 12 months following surgery Yska. Obes Surg 2013. Obes Surg 2014.

PSYCHIATRIC MEDICATIONS Medication Pre-op absorption Post-op absorption Amitriptyline* 28% 21% Fluoxetine* 30% 11% Paroxetine* 9% 3% Sertraline* 116% 10% Bupropion* 52% 73% Venlafaxine 59% Citalopram 27% 31% Clonazepam* 57% 52% Buspirone 59% Diazepam 6% 6% Lorazepam 8% 0% Trazodone 59% Seaman J. Dissolution of common psychiatric medication in a roux-en-y gastric bypass model. Psychosomatics 2005.

PSYCHIATRIC MEDICATIONS (CONT’D) Medication Pre-op absorption Post-op absorption Zolpidem 82% 74% Clozapine* 54% 43% Olanzapine* 45% 38% Quetiapine* 53% 23% Risperidone* 64% 49% Ziprasidone* 77% 27% Lithium carbonate* 35% 75% Haloperidol 7% 7% Methylphenidate 48% 54% Oxcarbazepine 5% 2% Seaman J. Dissolution of common psychiatric medication in a roux-en-y gastric bypass model. Psychosomatics 2005.

ANTIDEPRESSANT FOLLOWUP 23% of patients required antidepressant dose increase following surgery 40% continued same dose 18% required change in therapy 16% discontinued or changed therapy Another study showed a positive impact on depressive features at 1 year Waned in following years Cunningham. Oves Surg 2012. Obesity (Silver Spring) 2014.

ACID-REDUCING MEDICATIONS Michigan Collaborative showed reduction in acid-reducing medications following surgery Reduction of 37. 7% to 29. 6% in year one in 35, 000 patients Sleeve gastrectomy showed biggest reduction Surg Obes Relat Dis 2014.

PATIENT CASE QUESTION JS is a 37 yo male with a BMI of 45. He takes the following medications and is scheduled for a gastric bypass. What changes would you make? Cardizem CD 120 mg po qd Ibuprofen 400 mg q 6 h prn pain Citalopram 40 mg po qd

ANSWER Convert Cardizem to IR and monitor HR post-op Switch ibuprofen to acetaminophen Crush citalopram and monitor for symptoms

NUTRITIONAL SUPPLEMENTS Increased risk of macronutrient deficiencies (carbs, fats, proteins) Increased risk of micronutrient deficiencies (trace elements) More common: ADEK, calcium 2014 Study: “The high prevalence of nutrient deficiencies after obesity surgery makes lifelong 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. ” Lingtak-Neander C. Management of Patients Receiving Bariatric Surgery. Pharmacotherapy Self-Assessment Program. Aliment Pharmacol Ther 2014.

A, E, K, B 12, FOLIC ACID A: 52% incidence xerosis, changes in night vision E: 50% incidence K: 51% incidence affects clotting factors and fetal development B 12: 26 -70% incidence decrease in intrinsic factor Failure of separation of foodstuff-bound cobalamin due to p. H 350 mcg po qd recommended 1000 mcg IM qmonth or 3000 mcg IM q 6 months Folic acid (B 9): 30% incidence due to primary intake reduction Prevented with 1 -2 mg po qd Sawaya. Curr Drug Metab 2013. Scheitzer DH. Prevention of vitamin D and mineral deficiencies after bariatric surgery. Obes Surg 2008. Lingtak-Neander C. Management of patients receiving bariatric surgery. Pharmacotherapy Self-Assessment Program.

IRON Symptomatic deficiency in 40% within 4 years Decreased: Intake Conversion Sites of absorption Need at least 65 mg elemental iron May consider iron infusion service Lingtak-Neander C. Management of patients receiving bariatric surgery. Pharmacotherapy Self-Assessment Program.

CALCIUM 90% show increases in parathyroid hormone function 1 year post-op Surgery reduces surface area for passive and active calcium absorption At least 1200 mg elemental calcium/day recommended Carbonate delivers most elemental calcium Available as chewable Cheaper Avoid administering with iron supplement Lingtak-Neander C. Management of patients receiving bariatric surgery. Pharmacotherapy Self-Assessment Program. Miller A. Medication and nutrient administration considerations after bariatric surgery. Am J Health-Syst Pharm 2006.

VITAMIN D Large volume of literature showing vitamin D deficiency in bariatric patients Most require 400 -1000 IU per day Levels should be measured pre-operatively and at least yearly afterward Target level >30 Treated with 50, 000 IU qweek x 8 weeks Severe: 50, 000 IU twice weekly x 8 weeks Toxicity at levels >150 Lingtak-Neander C. Management of patients receiving bariatric surgery. Pharmacotherapy Self-Assessment Program. Miller A. Medication and nutrient administration considerations after bariatric surgery. Am J Health-Syst Pharm 2006.

QUESTIONS? jbates@pchc. com