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Flashcards in Drugs Used in Obesity Deck (56):
1

What are the problems associated with obesity?

increased risk of T2D, CVD, cancer, hypertension, osteoarthritis, asthma, sleep apnoea; increased burden on health care system

2

Leptin is released from

white adipose tissue

3

Where does leptin act in the brain to regulate body weight and energy expenditure?

hypothalamus - regulates neuropeptides

4

What are the current drugs approved for treatment of obesity?

Orlistat and Phentermine

5

What percent of the population is predicted to be obese by 2025?

1/3rd

6

What population is rapidly gaining weight?

ages 25-34; younger people

7

What are satiety signals?

afferent sympathetic (liver and stomach) or vagal signals (stomach) to the medulla - short-term

8

Satiety signals function by

afferent sympathetic or vagal signals to the medulla, medulla to hypothalamus; hypothalamus alters neuropeptides that signal to stop eating

9

CCK is produced

in the GIT in response to digested fats and carbs

10

CCK signals via the ______ nerve to the ______ to ________ eating

vagus; medulla & hypothalamus; stop eating

11

What are adiposity signals?

long-term; provide the brain with information on fat stores (leptin, insulin)

12

Leptin levels are proportional to

fat mass/BMI

13

How is leptin transported across the BBB?

It is large tf it needs to be actively transported

14

How does leptin function once inside the brain?

activates receptors on the hypothalamus to inhibit feeding by inhibiting neuropeptides that promote food intake, or promote neuropeptides that inhibit food intake

15

Examples of central peptides that increase feeding (orexigenic) are

NPY, melanin-concentrating hormone, agouti-related peptide, Orexin A and B, endocannabinoids

16

Examples of peripheral peptides that increase feeding (orexigenic) are

ghrelin

17

Examples of central peptides that decrease feeding (anorexigenic) are

alpha-MSH, urocortin, corticotrophin releasing hormone, serotonin, NA

18

Examples of peripheral peptides that decrease feeding (anorexigenic) are

leptin, insulin, CCK

19

Why is it hard to alter eating behaviours via single neuropeptides?

Altering one leads to compensation by others

20

Leptin inhibits food intake via ______ mechanism

CNS

21

Plasma leptin has a ________ rhythm

circadian

22

Why does the elevated leptin in obesity not affect the brain?

saturation of transport - leptin must be actively transported through the BBB

23

High leptin ______ food intake; low leptin ______ food intake

decreases; increases

24

T/F leptin deficiency and receptor defects are the primary cause of obesity in humans

False; few patients are leptin-deficient or have receptor defects

25

How does leptin regulate body weight and energy expenditure?

High circulating leptin from white adipose tissue signals to the hypothalamus, binding to receptors to alter neuropeptides such that food intake is decreased and energy usage is increased to restore fat stores to normal; the opposite occurs when circulating leptin is low

26

What are the effects of elevated leptin levels in obesity?

leptin resistance due to: decrease in sensitivity of hypothalamic leptin receptors; failure/insensitivity of second messenger systems; decrease in sensitivity of BBB transport systems because they are saturated (tf less leptin gets into the brain)

27

What are the current central drug targets of food intake?

inhibitors: NA, serotonin; stimulators: CB1 antagonists, NPY & AgRP antagonists, aMSH antagonists

28

What are the current peripheral drug targets of food intake?

Leptin

29

What are the current drug targets of fat absorption?

lipase inhibitors (orlistat)

30

What are the current drug targets to increase thermogenesis?

B3-aR agonists - B3s on skeletal muscle and fat

31

Phentermine is a ___________

sympathomimetic amine

32

What is the action of phentermine?

acts within the CNS to increase NA (also DA and 5HT) known to inhibit food intake

33

What is the limitation of phentermine use?

can only be used for 3 weeks and tolerance develops; bc sympathomimetic, higher doses can be dangerous

34

Orlistat is a ____________

lipase inhibitor: pancreatic and gastric

35

What is the benefit of orlistat over phentermine?

It can be used in the long-term

36

What is the action of orlistat?

Inhibits dietary fat absorption by inhibiting pancreatic and gastric lipases

37

For obesity drugs to be effective they must be combined with ________ and ________

low calorie diet; increased exercise

38

What is the mechanism of phentermine?

selective for increasing NA availability at post-synaptic receptors (also DA and 5HT) by blocking neuronal re-uptake by the presynaptic neuron; this suppresses appetite [may increase energy expenditure]

39

Phentermine use is indicated for patients

BMI > 30 or >/ 27 with one co-moribidity (diabetes, cardiac HT)

40

What are the adverse effects of phentermine?

sympathomimetic effects: increased BP, HR, insomnia, nervousness; headache, dry mouth; may have addictive euphoric properties

41

What are the contraindications for phentermine?

cannot be combined with other drugs that increase catecholamines in the brain eg MAO inhibitor antidepressants; cannot be used in pregnancy

42

What is the primary use of Topiramate?

epilepsy and migraine, it blocks VG Na+ and Ca2+ channels, reducing firing; weight loss is a side effect

43

What is the use of Topiramate in obesity?

in combination with phentermine it creates a slow-release hormone with a longer half life and a longer time to steady-state (increased tolerability)

44

What is the mechanism of Topiramate?

unknown; but it increases energy expenditure and suppresses appetite, and also insulin sensitivity

45

Use of Topiramate is indicated in patients with

BMI > 30 or >/27 with one co-morbidity

46

What are the adverse effects of Topiramate?

dizziness, taste alteration, teratogenic effects (cleft palate), parasthesia

47

Use of Orlistat is indicated in patients with

BMI > 30

48

What are the unique aspects of Orlistat?

only drug available for long-term use, and only drug that targets dietary fat intake rather than food intake

49

What is the mechanism of Orlistat?

inhibits gastric and pancreatic lipases via covalent binding, preventing hydrolysis of TAGs to FFAs - this decreases dietary fat absorption by ~30%

50

What is the dosing of Orlistat?

3x daily with meals, 120mg

51

Orlistat has been shown to improve

body weight (60% 5% decrease, 40% 10% decrease) and WHR - 5% reductions in body weight improve BP, blood lipids, glucose and insulin tolerance

52

What are the adverse effects of Orlistat?

limited to the GI bc not systemically absorbed; minimal if low-fat diet is adhered to, but after high fat meals they get explosive diarrhoea and faecal fat leakage - this conditions them to eat a lower fat diet

53

Orlistat must be combined with

a low fat diet (prevents GI side effects) and fat-soluble vitamin supplements (D & E)

54

The basis for amylin + leptin analogue drugs is

amylin works synergistically with insulin to increase the brain's sensitivity to insulin, creating feelings of satiety and fullness

55

Mechanisms of potential new drugs in obesity include

DA & NA reuptake inhibitors; analogues of amylin and leptin; pancreatic lipase inhibitors; long-acting glucagon like peptide analogs; 5HT, DA, and NA reuptake inhibitors; Agouti-related protein inhibitors; Diglyceride acyltransferase inhibitors; NPY receptor antagonist

56

To be effective, drugs used in obesity

should have a known mechanism of action of reducing appetite and increasing energy expenditure to limit side effects; reduce body weight and associated medical complications; benefits should outweigh side effects; no addictive properties; should be able to be used long-term