Pharmacotherapy for Weight Management Lecture Notes

Vocabulary flashcards covering long-term and short-term pharmacological therapies for obesity, including mechanism of action, dosing, monitoring, and specific drug characteristics based on lecture notes.

Orlistat (Xenical, Alli)

A peripheral lipase inhibitor that reduces intestinal fat absorption in the GI tract. It is available OTC at half-strength and prescription at full-strength, taken as a capsule TID with meals. Expectation: weight loss of $4.8\,kg$ in the first month.

Phentermine IR / Topiramate ER (Qsymia)

A CNS-acting sympathomimetic and anti-epileptic combination capsule taken Qday, best for percentage of weight loss with an expected $10\%$ loss after 1 year. Discontinued if $< 5\%$ baseline weight loss occurs at max dose after 3 months.

Topiramate ER (Mechanism of Action)

Blocks $\text{Na}^+$ channels, enhances $\text{GABA}_A$ activity, antagonizes glutamate receptors, and weakly inhibits carbonic anhydrase to suppress appetite and promote fullness.

GLP-1 RAs (Mechanism of Action)

Agents that agonize GLP-1 receptors in the peripheral system and brain regions (including marcuated dorsomedial nuclei of hypothalamic, parabrachial nuclei, nucleus accumbens (NAc), NTS, and area postrema) to decrease food intake, slow gastric emptying, and decrease body weight.

Liraglutide (Saxenda)

A daily sub-Q injectable multi-dose pen GLP-1 RA titrated from $0.6\,mg$ to $3.0\,mg$ over 2 months. Features a 16-carbon fatty acid side chain with moderate binding to blood proteins, and is discontinued if $< 4\%$ baseline weight loss occurs.

Semaglutide (Wegovy, Ozempic, Rybelsus)

A GLP-1 RA formulated as a weekly sub-Q injection (Wegovy for obesity, Ozempic for diabetes) or daily tablet (Rybelsus for diabetes). Features an 18-carbon di-acid chain, highly potent binding to blood proteins, a position-8 amino acid substitute to prevent DPP-4 degradation, and SNAC technology for stomach absorption in tablet form.

Orforglipron (Foundayo)

An oral synthetic non-peptide GLP-1 with a lower molecular weight and simplified chemical structure. Taken as 1 tablet a day without regard to food, utilizing a tablet coating that allows it to pass through the stomach into the intestinal lining.

Trizepetide (Mounjaro, Zepbound)

A GIP/GLP-1 RA administered once weekly by auto-injector, vials, or kwikpen, producing up to $15.7\%$ weight loss. It improves fat metabolism, reduces appetite, and can be used to treat obstructive sleep apnea in adults with obesity.

Bupropion ER / Naltrexone ER (Contrave)

A combination tablet taken once to twice daily that works in the CNS on POMC and opioid receptors to increase energy expenditure, reduce hunger, and decrease food cravings, with an expected weight loss of $5\%$.

Naltoxene (MOA in Contrave)

An opioid antagonist that acts to decrease food cravings.

Bupropion (MOA in Contrave)

Enhances POMC cell production and the release of alpha-MSH and beta-endorphin to suppress appetite.

Short Term Therapy (Anti-Obesity)

Nonadrenergic sympathomimetic amine agents that stimulate CNS activity, suppress appetite, and enhance CNS release of NE, serotonin, and dopamine; treatment duration should not exceed $12\text{ weeks}$.

Phendimetrazine

A short-term anti-obesity agent contraindicated in patients with HTN, coronary disease, hyperthyroidism, glaucoma, anxiety, insomnia, previous sensitivity to stimulants, pregnancy, or a history of drug abuse.

Orlistat (Xenical, Alli) - Class, MOA & Dosing

Peripheral GI lipase inhibitor that reversibly binds pancreatic and gastric lipases, decreasing dietary fat absorption by approximately $30\%$. Available OTC ($60\,mg$) and prescription ($120\,mg$); taken as 1 capsule TID with fat-containing meals.

Orlistat (Xenical, Alli) - ADRs & Contraindications

ADRs: GI distress, oily rectal leakage, abdominal pain, bowel urgency, flatulence with discharge, steatorrhea, fecal incontinence, and increased risk of cholelithiasis. Contraindicated in pregnancy, chronic malabsorption syndromes, and cholestasis (gallstones).

Orlistat (Xenical, Alli) - Monitoring & Expectations

Monitor BMI, diet, BG, thyroid, liver, and renal function, plus levels of fat-soluble vitamins (A, D, E, K). Expected weight loss is $4.8\,kg$ in the first month.

Phentermine IR / Topiramate ER (Qsymia) - MOA

Phentermine IR is a sympathomimetic adrenergic agonist that increases norepinephrine release to suppress appetite and increase energy expenditure. Topiramate ER blocks voltage-dependent $Na^+$ channels, enhances $\text{GABA}_A$ activity, antagonizes glutamate receptors, and weakly inhibits carbonic anhydrase to promote satiety.

Phentermine IR / Topiramate ER (Qsymia) - Dosing & Efficacy

Taken orally Qday in the morning. Follow up monthly for 3 months then every 3 months. Discontinue if <$5\%$ baseline weight loss at maximum dose after 12 weeks. Yields highest average weight loss among oral agents, with an expected $10\%$ weight loss at 1 year.

Phentermine IR / Topiramate ER (Qsymia) - ADRs & Contraindications

ADRs: Tachycardia, paresthesias, headache, insomnia, dizziness, depression, anxiety, decreased serum bicarbonate, hypokalemia, URTI, dry mouth. Contraindications: Pregnancy, hyperthyroidism, glaucoma, acute myopia/angle closure, severe renal disease, and active depression.

GLP-1 Receptor Agonists - General MOA

Agonize GLP-1 receptors in peripheral systems and CNS hypothalamic regions (arcuate and dorsomedial nuclei, parabrachial nuclei, NAc, NTS, area postrema) to decrease food intake, delay gastric emptying, and reduce total body weight.

Liraglutide (Saxenda) - Administration & Structural Features

Daily subcutaneous injection titrated from $0.6\,mg$ to $3.0\,mg$ daily over 2 months. Features a 16-carbon fatty acid side chain providing moderate protein binding. Discontinue if <$4\%$ baseline weight loss after 16 weeks.

Liraglutide (Saxenda) - ADRs & Contraindications

ADRs: Nausea, diarrhea, constipation, vomiting, abdominal pain, dyspepsia, hypoglycemia, headache, tachycardia. Contraindications: Pregnancy, personal/family history of medullary thyroid carcinoma (MTC), MENS type 2, pancreatitis, gastroparesis, and gallbladder disease.

Semaglutide (Wegovy, Ozempic, Rybelsus) - Features & Technology

Features an 18-carbon di-acid chain (potent albumin binding) and position-8 substitution protecting against DPP-4 degradation. Oral tablet (Rybelsus) uses SNAC technology for stomach absorption. Wegovy is injected subcutaneously once weekly for obesity.

Semaglutide - Monitoring & ADRs

ADRs: Nausea, diarrhea, constipation, vomiting, abdominal pain, hypoglycemia, headache, fatigue, tachycardia, injection site discomfort. Monitor weight, HbA1c, HR, pancreatitis, diabetic retinopathy, and gallbladder disease.

Orforglipron (Foundayo) - Chemistry & Administration

Oral synthetic non-peptide GLP-1 RA with low molecular weight. Uses a tablet coating to pass through the stomach and absorb directly through the intestinal lining. Taken as 1 tablet daily without regard to food.

Tirzepatide (Mounjaro, Zepbound) - Class & Efficacy

Dual GIP and GLP-1 receptor agonist administered once weekly subcutaneously. Achieves up to $15.7\%$ weight loss. Improves fat metabolism, reduces appetite, and treats obstructive sleep apnea in adults with obesity.

Bupropion ER / Naltrexone ER (Contrave) - Central MOA

Naltrexone is an opioid antagonist that blocks autoinhibitory feedback on POMC neurons to decrease cravings. Bupropion enhances POMC cell firing and release of $\alpha\text{-MSH}$ and $\beta\text{-endorphin}$ to suppress appetite.

Bupropion ER / Naltrexone ER (Contrave) - Dosing & Contraindications

Administered as 1-2 daily tablets. Discontinue if <$5\%$ baseline weight loss after 12 weeks. Contraindicated in pregnancy, uncontrolled HTN, seizure disorders, anorexia/bulimia, and abrupt withdrawal of alcohol/sedatives.

Short-Term Sympathomimetic Therapy - Overview & Duration

Nonadrenergic agents (Phentermine, Diethylpropion, Phendimetrazine) that stimulate CNS release of norepinephrine, serotonin, and dopamine to suppress appetite. Treatment duration must not exceed $12\text{ weeks}$.

Phentermine Monotherapy - Class, ADRs & Contraindications

Schedule IV sympathomimetic amine. ADRs: HTN, tachycardia, headache, insomnia, irritability, xerostomia, constipation, diarrhea. Contraindicated in pregnancy, hyperthyroidism, glaucoma, cardiovascular disease, and history of drug abuse.

Short-Term Sympathomimetics - Class ADRs & Contraindications

ADRs: Xerostomia, insomnia, dizziness, fatigue, flushing, constipation, tremor, HTN, tachycardia, palpitations. Contraindicated in HTN, coronary disease, hyperthyroidism, glaucoma, anxiety, insomnia, stimulant sensitivity, pregnancy, and drug abuse history.