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KIN 334 > Pharmacotherapy & Surgery for Weight Loss in Obesity > Flashcards

Pharmacotherapy & Surgery for Weight Loss in Obesity Flashcards

1
Q

Obesity is defined clinically as having a BMI:

A

> 30 (kg/m^2)

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2
Q

BMI for healthy range:

A

18.5-24.9

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3
Q

BMI for overweight:

A

25-30

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4
Q

BMI for obese:

A

30-40

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5
Q

BMI for severe obese:

A

> 40

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6
Q

You will gain weight if your _____ _____ (energy ___) is greater than the _____ _____ _____ (energy ____).

A
  • calorie intake (energy in)

- calories you burn (energy out)

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7
Q

Weight gain comes from _____ caloric balance, where energy ____ > energy ____.

A
  • positive

- energy in > energy out

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8
Q

Obesity is a significant risk factor for numerous disorders:

A
  • insulin resistance
  • T2D
  • dyslipidemia
  • hypertension
  • heart diseases
  • cancer
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9
Q

In order to lose weight, you need to….

A

burn more calories than you consume

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10
Q

Non-pharmacological approaches to weight loss:

A
  • exercise
  • supplements
  • dietary
  • surgical
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11
Q

Dietary approaches to weight loss includes:

A
  • calorie restriction

- ketogenic diet

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12
Q

Surgical approaches to weight loss includes:

A

gastric bypass

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13
Q

DNP:

A
  • dinitrophenol
  • classic uncoupler of energy metabolism
  • used in the 1930s as a weight loss agent
  • increases in hyperthermia led to fatalities and banning of the substance in the USA
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14
Q

Calorie restriction:

A
  • a dietary approach to weight loss and health benefit that doesn’t induce malnutrition
  • ~40% reduction in caloric intake
  • burn more calories than you consume
  • difficult to maintain
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15
Q

Beneficial effects of caloric restriction may also be mediated via….

A

activation of 5’AMP activated protein kinase or sirtuins

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16
Q

Ketogenic diet:

A

diet enriched in calories from fat with minimal calories from carbs and protein that promotes ketogenesis

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17
Q

Describe a classic (standard) ketogenic diet:

A
  • 90% of calories derived from fat
  • remaining 10% of calories from carbs and proteins
  • 4:1 ratio by weight (fat:carbs/protein)
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18
Q

Why do our bodies undergo adaptive ketogenesis physiologically?

A
  • our body has small reserves of carbs (glycogen)
  • our body has limited protein stores
  • our body has plentiful fat stores as triacylglycerol in adipose tissue
  • our brains are unable to oxidize fatty acids for energy
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19
Q

A ketone body is a ______ ____ _____ that can be _____ by the brain.

A
  • pre-catabolized fatty acid

- metabolized/oxidized

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20
Q

Normal circulating ketone levels:

A

0.2 mM

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21
Q

Fasting circulating ketone levels:

A

1-3 mM

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22
Q

Circulating ketone levels for diabetic ketoacidosis:

A

levels can be > 25 mM

  • blood pH: 7.25-7.3 (mild)
  • pH: 7-7.25 (moderate)
  • pH: < 7 (severe)
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23
Q

You are considered at risk of diabetic ketoacidosis if blood glucose > ____ and blood ketones > _____.

A
  • 16.7 mM

- 1.5 mM

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24
Q

What is the leading cause of death in people under 24 years old who have diabetes?

A

diabetic ketoacidosis

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25
Q

The ketogenic diet makes the body behave like it’s ____ and ….

A
  • fasting
  • continually produces ketones (liver)
  • adipose tissue fatty acids constantly mobilized from triacylglycerol depots for delivery to the liver
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26
Q

The low carb content of the ketogenic diet keeps ____ levels low. This is good because….

A
  • insulin

- insulin inhibits hepatic ketogenesis and fatty acid mobilization from adipose tissue

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27
Q

5 adverse effects of ketogenic diet:

A
  • metabolic abnormalities
  • dehydration
  • GI symptoms
  • kidney stones
  • “fruity” breath
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28
Q

Metabolic abnormalities from ketogenic diet:

A
  • hypoglycemia
  • excessive ketosis (metabolic acidosis)
  • electrolyte imbalances
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29
Q

Dehydration is more common in ketogenic diet protocols that include _____.

A

fasting

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30
Q

GI symptoms from the ketogenic diet includes:

A
  • abdominal pain
  • vomiting
  • constipation
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31
Q

Ketogenic diet-associated risk of kidney stones ranges from __ - __ %

A

2-6%

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32
Q

Why can we get “fruity” breath with the ketogenic diet?

A

we eliminate acetone mainly via respiration in the lungs

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33
Q

Pharmacotherapy should be considered for what people?

A
  • people with BMI > 30 or > 27 with associated weight related comorbidities (eg. T2D)
  • people who historically have not responded well to lifestyle based interventions for weight loss
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34
Q

The goal of pharmacotherapy should be to aim for weight loss of ____% within the first 6 months.

A

5-10%

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35
Q

If > 5% weight loss is not observed after 3-4 months treatment, recommendations are to….

A

discontinue the current pharmacotherapy unless significant improvements in comorbidities is observed (eg. glucose control in people with T2D)

36
Q

Leptin:

A
  • an adipokine (adipose tissue-derived peptide hormone) that induces satiety
  • recently approved for the treatment of lipodystrophy (Myalept)
37
Q

Leptin mechanism of action:

A

agonism of leptin receptors present in the hypothalamus of the brain leads to potent suppression of appetite (reduced AMPK signaling) and subsequent body weight gain

38
Q

Leptin only demonstrates real clinical utility in who?

A

leptin or leptin receptor deficient humans

39
Q

Liraglutide:

A
  • a GLP-1R agonist
  • normally used in the treatment of T2D
  • 1.8 mg for T2D
  • 3.0 mg for obesity
40
Q

Liraglutide mechanism of action:

A
  • activate GLP-1Rs that are expressed in the hypothalamus of the brain
  • reduce food intake/appetite
41
Q

Pharmacokinetics of liraglutide:

A
  • half-life prolonged via acylation, which allows it to bind to albumin in the circulation
  • also protects it from cleavage vis dipeptidyl peptidase 4)
42
Q

Adverse effects of liraglutide:

A
  • generally well tolerated
  • GI upset (nausea, vomiting, diarrhea)
  • increase in HR
  • pancreatitis?
43
Q

Lorcaserin mechanism of action:

A
  • a selective 5-HT (2C) receptor agonist

- will increase proopiomelanocortin (POMC) expression in the hypothalamus which induces satiety

44
Q

Adverse effects of lorcaserin:

A
  • GI (nausea, constipation)
  • headache
  • dizziness
  • fatigue
  • dry mouth
  • hypoglycemia
  • hallucinogenic actions
  • valvular heart disease?
45
Q

What is the first combination therapy approved for obesity in the USA?

A
  • phentermine/topiramate
  • provided as an adjunct to reduced caloric consumption and/or exercise
  • most potent pharmacotherapy for 1 year weight loss
46
Q

Phentermine/topiramate mechanism of action:

A
  • phentermine is a sympathomimetic amine that acts as agonist for the trace amine-associated receptor (similar to amphetamine)
  • topiramate is an anticonvulsant agent
  • mechanism of action for how combination reduces body weight is unknown
47
Q

Adverse effects of phentermine/topiramate:

A
  • paresthesia
  • dizziness
  • insomnia
  • constipation
  • dry mouth
  • mood changes
  • HR elevation
48
Q

Phentermin/topiramate is contraindicated for:

A
  • pregnancy (teratogenic)
  • glaucoma
  • hyperthyroidism
49
Q

Bupropion/naltrexone (contrave):

A

a combination of low dose bupropion and naltrexone used in conjunction to exercise/dietary changes for weight loss

50
Q

Bupropion/naltrexone (contrave) mechanism of action:

A
  • bupropion is noradrenaline-dopamine reuptake inhibitor (normally used for treating depression)
  • active metabolites can also antagonize the nicotinic acetylcholine receptor
  • naltrexone is a competitive opioid receptor antagonist
  • in combination, they modify the reward pathway to reduce appetite
51
Q

Adverse effects of bupropion/naltrexone (contrave):

A
  • may affect mood and increase suicide risk
  • GI upset (nausea, vomiting, diarrhea)
  • headache
  • dry mouth
  • increased HR and BP
52
Q

Bupropion/naltrexone (contrave) is contraindicated for those with:

A
  • history of seizures
  • eating disorders
  • taking other opioid medicines (eg. for pain management)
  • pregnancy
  • during withdrawal from barbiturates, benzodiazepines, and antiepileptic drugs)
53
Q

Orlistat:

A
  • a lipase inhibitor
54
Q

What is the only approved medication that acts by a purely peripheral mechanism?

A

orlistat

55
Q

Orlistat mechanism of action:

A
  • reacts with serine residues at the active sites for gastric and pancreatic lipases to irreversibly inhibit their enzymatic activity
  • prevents breakdown of dietary fat (triglycerides) into free fatty acids and glycerol (decreases absorption of dietary fat)
56
Q

Pharmacokinetics of orlistat:

A
  • primarily excreted in the feces (~97%) with minimal metabolism (~87% unchanged)
  • 1-2 hours
57
Q

Adverse effects of orlistat:

A
  • abdominal cramps
  • flatulence
  • fecal incontinence
  • intestinal borborygmic
  • oily spotting
58
Q

Rimonabant:

A
  • a cannabinoid receptor antagonist

- withdrawn from the market

59
Q

Rimonabant mechanism of action:

A
  • agnism of cannabinoid receptors (CB1) in the brain (hypothalamus) stimulates appetite, thus antagonism of these receptors will reduce appetite and body weight gain
  • CB1 receptors are also expressed in adipose tissue (antagonism decreases lipogenesis and increase circulating adiponectin levels)
60
Q

Adverse effects of rimonabant:

A
  • nausea

- depression/suicidality (mechanism unknown)

61
Q

Why are therapies that can induce weight gain in overweight/obese individuals important to consider?

A

obese individuals are often receiving polypharmacy for numerous pathologies (eg. T2D, depression)

62
Q

Therapies that can induce weight gain in overweight/obese individuals:

A
  • sulfonylureas (for T2D)
  • insulin analogues (for T2D)
  • thiazolidinediones (for T2D)
63
Q

Name 4 surgical approaches:

A
  • gastric bypass surgery
  • Roux-en-Y gastric bypass (RYGB)
  • sleeve gastrectomy
  • laparoscopic adjustable gastric band (LAGB)
64
Q

Gastric bypass surgery:

A

stomach is divided into a small upper pouch and much larger lower remnant pouch, following which the small intestine is rearranged to connect to both

65
Q

RYGB:

A
  • Roux-en-Y gastric bypass
  • stomach is divided into 2 compartments, where food goes into the smaller pouch portion, which then directly connects to the jejunum (bypass)
66
Q

Sleeve gastrectomy:

A

irreversible procedure in which a large portion of the stomach is removed (~15% of original size)

67
Q

Laparoscopic adjustable gastric band (LAGB):

A

adjustable silicone rubber band wrapped around the upper portion of the stomach to decrease its functional size

68
Q

Pros of LAGB:

A
  • short outpatient procedure
  • adjustable and reversible
  • low rate of complications
  • low risk of malabsorption of vitamins and minerals
69
Q

Cons of LAGB:

A
  • less long term weight loss than other procedures
  • high rates of reoperation for band slippage, obstruction, or erosion
  • possible progressive dilation of esophagus due to band obstruction
70
Q

Pros of RYGB:

A
  • large and sustained long term weight loss

- high rates of T2D remission

71
Q

Cons of RYGB:

A
  • complex procedure requiring skill
  • requires hospital stay of 1-2 days
  • higher rate of perioperative complications
  • late complications
  • needs long term vitamin and mineral supplementation
72
Q

Pros of sleeve gastrectomy:

A
  • significant weight loss
  • less complex procedure compared with RYGB
  • can be converted to RYGB at a later stage
  • less risk of vitamin and mineral deficiencies
73
Q

Cons of sleeve gastrectomy:

A
  • somewhat higher risk of weight regain compared with RYGB
  • higher rate of complications compared with LAGB
  • post-operative GERD
  • late complications that include chronic obstructive symptoms
74
Q

Name 3 medical devices:

A
  • intragastric balloon
  • electrical stimulation system
  • gastric emptying system
75
Q

Intragastric balloon:

A

a single balloon is indroduced into the stomach via endoscopic procedure and filled with saline (400-700 mL) to expand

76
Q

Electrical stimulation system:

A

electrodes are placed on the trunks of the vagus nerve at the gastroesophageal junction, which act to block the vagal nerve and suppress communication between the stomach and the brain

77
Q

Gastric emptying system:

A

a gastric tube that connects to a skin port outside your abdomen, which allows the individual to flush food out (20-30 min after meal intake) when they open the port valve

78
Q

Indications for intragastric balloons:

A
  • BMI 30-40

- up to 6 months

79
Q

Indications for electrical simulation systems:

A
  • BMI 35-45

- long term use

80
Q

Indications for gastric emptying systems:

A
  • age > 22 yrs
  • BMI 35-55
  • long term use
81
Q

Adverse effects of intragastric balloons:

A
  • abdominal pain
  • bloating
  • nausea
  • rare cases of GI obstruction
82
Q

Adverse effects of electrical simulation systems:

A
  • pain at neuroregulator disc site
  • heart burn
  • abdominal pain
  • nausea
  • belching
83
Q

Adverse effects of gastric emptying systems:

A
  • pain
  • abdominal discomfort
  • nausea
  • change in bowel habits
  • electrolyte abnormalities
  • irritation or infection at site
84
Q

Unimolecular co-agonists:

A
  • research in the science of how gastric bypass surgery improves metabolic syndrome has focused significantly on gut-derived hormones
  • a promising approach involves co-agonists for both the GLP-1 receptor and the GIP receptor
85
Q

A novel GLP-1 receptor and GIP receptor co-agonist has been shown to cause….

A

greater weight loss than a GLP-1 receptor agonist in a phase 2 trial

86
Q

Gastric bypass surgery is a ____ ____ and option for people with ____ ____.

A
  • last resort

- severe obesity

KIN 334 (14 decks)

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