Unit 5: obesity - ILE 1

common complications of obesity

pulmonary diseases, liver diseases, cancer, osteoarthritis, heart disease, strike, diabetes, gout

etiology of obesity

Genetic factors, environmental factors, medical conditions (ex: cushing syndrome, growth hormone deficiency, insulinoma, psychiatric disorders), medications (anticonvulsants, antidepressants, antipsychotics, hormones)

What influences appetite?

neural network involving hypothalamus, limbic system, brainstem, hippocampus, elements of the cortex, & pituitary gland

Leptin

hormone released by adipocytes (fat calls) that goes to blood-brain targets and peripheral targets (β-cell, immune cells), to let the body know it is satiated

there is an increase in leptin when…

we feel fed

hypothalamus

brain region composed of several distinct nuclei; involved in coordinating the GI and nervous systems to the endocrine system

What brain region plays a key role in appetite?

hypothalamus

Anorexigenic

causing appetite suppression

Orexigenic

causing increased appetite

satiation

pertaining to the cessation of hunger

satiety

sensation of being full

enteroendocrine cells

specialized endocrine cells of GI tract and pancreas

incretin

any gut hormone associated with food intake-stimulation of insulin secretion from the pancreas

oxyntic cells

parietal cells of gastric glands responsible for gastric acid secretion

hypocretins are also known as

orexins

Which of the following hormones play the most important roles in regulating appetite and food intake?

leptin, insulin, cortisol

A pharmacist is counseling a patient about the physiologic regulation of appetite and food intake. Which of the following gut peptides primarily influence appetite and satiety?

Ghrelin, peptide YY (PYY), and Cholecystokinin (CCK)

Ghrelin

hormone released by the stomach that stimulated the orexigenic neurons to induce hunger

The adipose tissue releases Leptin to ____ orexigenic neurons & ____ anorexigenic neurons to induce satiety

suppress, stimulate

the pancreas releases insulin to stimulate ____ neurons to induce satiety

anorexigenic

What are orexigenic neuropeptides?

NPY & AgRP

What are Anorexigenic neuropeptides?

CART & alpha-MSH

Which hormones are utilized in the gut-brain cross talk?

GLP-1 & ghrelin

A 45-year-old patient is diagnosed with irritable bowel syndrome and asks how the gastrointestinal tract communicates with the central nervous system. The pharmacist explains that the gut-brain axis involves bidirectional communication between the gastrointestinal tract and the brain through multiple neural pathways.

Which neural components are primarily utilized in gut-brain cross-talk?

vagal afferent pathways

A 38-year-old patient with obesity is discussing appetite regulation with a pharmacist. The pharmacist explains that leptin is a hormone produced primarily by adipose tissue that signals the hypothalamus to decrease food intake and increase energy expenditure.

Which of the following best describes the effect of obesity on leptin?

Obesity increases leptin production, but leptin resistance reduces its ability to suppress appetite

How much of a % decrease in body weight must a drug cause to be FDA approved for weight loss?

5

how to calculate BMI

body weight (kg) / height (m²)

What is an underweight BMI

<18.5

What is the normal BMI range?

18.5 - 24.9

What is an Overweight BMI

25 - 29.9

What is an obesity class I BMI?

30.0 - 34.9

What is an Obesity class II BMI?

35.0 - 39.9

What BMI is considered extreme obesity (class III)?

>40.0

Why does inflammation often result from obesity?

due to enlargement of adipose tissue cells, and thus overproduction of immune cells

obesity causes an increase in

low density lipids (LDL)

Obesity induced insulin resistance

• prevents glucose uptake

• increased liver and kidney mediated gluconeogenesis

• increased inflammatory markers in circulation

Non-Alcoholic Fatty liver disease (NAFLD)/ Metabolic dysfunction associated fatty liver disease (MAFLD)

found in 80-90% obese adults, 30-50% diabetics, 90% hyperlipidemia

occurs due to fatty acid accumulation in hepatocytes of liver → mitochondrial dysfunction

common influenced of MAFLD

prediabetes/T2D, obesity, insulin resistance, HDL cholesterol triglycerides, changes in gut microbiota, BP, inflammation

Resmetriron (Rezdiffra)

Used for MAFLD associated steatohepatitis and moderate-to-advanced liver fibrosis; can prevent disease from progressing, but cannot undo damage

Resmetrirom MOA

selectively binds to thyroid hormone receptor, THR-beta (*beta is ONLY in the Liver) → upregulated mitochondrial biogenesis and beta-oxidation → reduced triglyceride accumulation and improved cholesterol metabolism (clearance)

how does obesity influence your cardiovascular health?

heart progresses from compensated to decompensated cardiac hypertrophy or diabetic cardiomyopathy

often leading to contractile dysfunction due to energy dysregulation and lipid accumulation, progresses to heart failure from left ventricular enlargement

When should you use pharmacologic therapy for obesity?

BMI ≥30 OR BMI ≥27 with 1 or more associated comorbid medical conditions

what are some comorbid medical conditions associated with obesity

HTN, DLD, T2D, OSA, CVD, prediabetes, elevated waist circumference)

What is the 1st line therapy for obesity?

non-pharmocologic: reduced caloric intake, increased physical activity, behavioral modification

Where does phentermine/topiramate work?

brain

Is Orlistat (xenical, alli) long term or short term?

long term

Orlistat (xenical, alli) category

lipase inhibitor

Orlistat (xenical, alli) MOA

binds to lipase activity → inhibits pancreatic intestinal lipase activity → decreases intestinal fat absorption

Orlistat (xenical, alli) ADRs

GU, oily rectal leakage, abdominal distress and pain, flatulence with discharge, bowel urgency, steatorrhea, oily evacuation, frequent bowel movements, nausea, URTI, back/leg pain, risk of hepatotoxicity

Orlistat (xenical, alli) contraindications

pregnancy, chronic malabsorption syndromes, cholestasis (gallstones)

What should you monitor when a patient is taking Orlistat (xenical, alli)?

BMI, Diet, BG, Thyroid function, liver function/hepatotoxicity, renal function, growth rate, levels of fat-soluble vitamins A, D, E, K

Where does Orlistat (Xenical, Alli) work in the body?

peripheral systems at GI

How to take Orlistat (Xenical, Alli)

take one capsule TID with meals & is available OTC (½ strength) and prescription (full strength)

Orlistat (Xenical, Alli) follow up and expectations

Follow up monthly for 3 months then every 3 months and expected to lose 4.8 kg in first month

is Phentermine IR / Topiramate ER (Qsymia) a long or short term therapy

long

Phentermine IR / Topiramate ER (Qsymia) classification

sympathomimetic/ anti-epileptic

Phentermine IR / Topiramate ER (Qsymia) works in the

CNS, GABA RA

Phentermine IR MOA

sympathomimetic amine / adrenergic agonist → sympathomimetic causes appetite suppression and increased energy expenditure

topiramate ER MOA

block Na⁺ channels, enhance GABA(A) activity, antagonizers glutamate receptors, weakly inhibits carbonic anhydrase; suppresses appetite and makes you feel full

ADRs of Phentermine IR / Topiramate ER (Qsymia)

tachycardia, paresthesia, headache, insomnia, dizziness, depression, anxiety, decreased serum bicarbonate, hypokalemia

Phentermine IR / Topiramate ER (Qsymia) contraindications

pregnancy, hyperthyroidism, glaucoma, acute myopia and secondary angle closure glaucoma, renal and kidney disease, depression

What should you monitor when a patient is taking Phentermine IR / Topiramate ER (Qsymia)

weight, HR, serum bicarbonate, K⁺, Gluconate, renal function (Scr), BP, glaucoma, acidosis, mood and sleep disorders

How much weight loss should you expect when taking Phentermine IR / Topiramate ER (Qsymia)

10% after 1 year

Phentermine IR / Topiramate ER (Qsymia) follow up

monthly for 3 months then every 3 months & discontinue when <5% baseline weight loss at max dose

How does GLP-1 RA use differ when used for obesity vs T2D

it is dosed higher for obesity vs T2D

GLP-1 RA MOA

work in peripheral system with gut hormones to agonize GLP-1 receptors → decreased food intake, slowing of gastric emptying, and decreased body weight

Liraglutide (saxenda) information

daily sub-Q from multidose pen GLP-1 RA that is titrated from 0.6 → 3.0mg over the course of 2 months

has a 16-carbon fatty acid side chain and moderate binding to blood proteins

Liraglutide (saxenda) follow up

monthly for 3 months then every 3 months & discontinue if <4% baseline weight loss

Liraglutide (saxenda) ADRs

nausea, diarrhea, constipation, vomiting, abdominal pain, dyspepsia, hypoglycemia, headache, tachycardia 

Liraglutide (saxenda) Contraindications

personal or family history of medullary thyroid carcinoma, pregnancy, history of pancreatitis, gastroparesis, gallbladder disease, thyroid tumors, Multiple endocrine neoplasia syndrome type 2 (MENS)

Liraglutide (saxenda) monitoring

weight, A1c, pancreatitis, gallbladder disease, HR

Semaglutide (Wegovy for obesity) (Ozempic subq + Rybelsus tab for diabetes) info

Weekly sub-Q inj. or Daily tablet; gradually increase dose each week

18-carbon di-acid chain and highly potent binding to blood proteins + has a position-8 amino acid substitute to prevent DPP-4 from degrading drug

Tablet form utilizes SNAC so it can be absorbed through the stomach

Semaglutide (Wegovy for obesity) (Ozempic subq + Rybelsus tab for diabetes) follow up

monthly for 3 months then every 3 months & discontinue if patient cannot tolerate

Semaglutide (Wegovy for obesity) (Ozempic subq + Rybelsus tab for diabetes) ADRs

nausea, diarrhea, constipation, vomiting, abdominal pain, hypoglycemia, headache, fatigue, tachycardia, injection site discomfort  

Semaglutide (Wegovy for obesity) (Ozempic subq + Rybelsus tab for diabetes) Contraindications

pregnancy, medullary thyroid carcinoma, pancreatitis, Multiple endocrine neoplasia syndrome type 2 (MENS)

Semaglutide (Wegovy for obesity) (Ozempic subq + Rybelsus tab for diabetes) Monitoring

Weight, A1c, HR, pancreatitis, diabetic retinopathy, gallbladder disease

Orforglipron (Foundayo) info

daily oral tablet GLP-1 that is synthetic (*not a peptide, but a small molecule with lower molecular weight) and has a simplified chemical structure

encoated in a special tablet coating that allows it to pass through the stomach and be absorbed by intestinal lining

(take without regard to food)

Orforglipron (Foundayo) follow up

monthly for 3 months then every 3 months

Orforglipron (Foundayo) ADRs

nausea, diarrhea, constipation, vomiting, abdominal pain, abdominal distension, dyspepsia, headache, tachycardia, dizziness, fatigue 

Orforglipron (Foundayo) Contraindications

pregnancy, medullary thyroid carcinoma, Multiple endocrine neoplasia syndrome type 2 (MENS)

Orforglipron (Foundayo) monitoring

A1c, weight, pancreatitis, gallbladder disease, diabetic retinopathy, kidney function

Tripeptide (monjaro, zepbound) info

weekly injection by auto-injector GIP/GLP-1 RA that can achieve up to 15.7% weight loss by improving fat metabolism and reducing appetite

can also be used to treat obstructive sleep apnea in adults with obesity 

Tripeptide (monjaro, zepbound) follow up

monthly for 6 months

Tripeptide (monjaro, zepbound) ADRs

GI, nausea, diarrhea, constipation, vomiting, abdominal pain, dyspepsia, gastroesophageal reflux disease, eructation, injection site reactions, fatigue, hair loss

Tripeptide (monjaro, zepbound) contraindications

pregnancy, medullary thyroid cancer, Multiple endocrine neoplasia syndrome type 2 (MENS)

Tripeptide (monjaro, zepbound) monitoring

weight, A1c, pancreatitis, gallbladder, HR, diabetic retinopathy, renal function, kidney injury

bupropion ER/ naltrexone ER (Contrave) Drug Class

opioid antagonist/ dopamine and norepinephrine reuptake inhibitor

Where does bupropion ER/ naltrexone ER (Contrave) work

CNS in POMC and opioid

naltrexone

opioid antagonist that decreases cravings

bupropion

dopamine and norepinephrine reuptake inhibitor that enhances POMC cell production and release of alpha-MSH and beta-endorphin to suppress appetite

bupropion ER/ naltrexone ER (Contrave) ADRs

Headache, sleep disorder, N/V, constipation, dry mouth, dizziness, HTN, palpitations, depression, hyperhidrosis, UTI, hot flashes, diarrhea

positive outcomes of bupropion ER/ naltrexone ER (Contrave)

daily tablet that improves cardiometabolic risk factors and improves A1C, reduces hunger, reduced food cravings, increased satiety

expected to lose 12 lbs or 5%

bupropion ER/ naltrexone ER (Contrave) monitoring parameters

BMI, BP, HR, renal and hepatic function, mental status

bupropion ER/ naltrexone ER (Contrave) contraindications

pregnancy, uncontrolled HTN, seizure disorder, anorexia, alcohol

bupropion ER/ naltrexone ER (Contrave) follow up

monthly for 3 months then every 3 months & discontinue if <5% baseline weight loss

When should you discontinue pharmacologic therapy for obesity

<5% baseline weight loss or if safety/tolerability issue arises

When treating obesity, short term pharmacologic therapies should not exceed

12 weeks

Short term therapies for obesity

noradrenergic agents like phentermine, diethylpropion, and phendimetrazine

non-adrenergic agents MOA

sympathomimetic amines, stimulate CNS activity and suppress appetite; enhance NE, serotonin, and dopamine release in CNS

ADRs of non-adrenergic agents

xerostomia (dry mouth), insomnia, dizziness, fatigue, constipation, insomnia, tremor, HTN, tachycardia, palpitations