Drugs Used in Obesity Flashcards
What are the problems associated with obesity?
increased risk of T2D, CVD, cancer, hypertension, osteoarthritis, asthma, sleep apnoea; increased burden on health care system
Leptin is released from
white adipose tissue
Where does leptin act in the brain to regulate body weight and energy expenditure?
hypothalamus - regulates neuropeptides
What are the current drugs approved for treatment of obesity?
Orlistat and Phentermine
What percent of the population is predicted to be obese by 2025?
1/3rd
What population is rapidly gaining weight?
ages 25-34; younger people
What are satiety signals?
afferent sympathetic (liver and stomach) or vagal signals (stomach) to the medulla - short-term
Satiety signals function by
afferent sympathetic or vagal signals to the medulla, medulla to hypothalamus; hypothalamus alters neuropeptides that signal to stop eating
CCK is produced
in the GIT in response to digested fats and carbs
CCK signals via the ______ nerve to the ______ to ________ eating
vagus; medulla & hypothalamus; stop eating
What are adiposity signals?
long-term; provide the brain with information on fat stores (leptin, insulin)
Leptin levels are proportional to
fat mass/BMI
How is leptin transported across the BBB?
It is large tf it needs to be actively transported
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
Examples of central peptides that increase feeding (orexigenic) are
NPY, melanin-concentrating hormone, agouti-related peptide, Orexin A and B, endocannabinoids
Examples of peripheral peptides that increase feeding (orexigenic) are
ghrelin
Examples of central peptides that decrease feeding (anorexigenic) are
alpha-MSH, urocortin, corticotrophin releasing hormone, serotonin, NA
Examples of peripheral peptides that decrease feeding (anorexigenic) are
leptin, insulin, CCK
Why is it hard to alter eating behaviours via single neuropeptides?
Altering one leads to compensation by others
Leptin inhibits food intake via ______ mechanism
CNS
Plasma leptin has a ________ rhythm
circadian
Why does the elevated leptin in obesity not affect the brain?
saturation of transport - leptin must be actively transported through the BBB
High leptin ______ food intake; low leptin ______ food intake
decreases; increases
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
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
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)
What are the current central drug targets of food intake?
inhibitors: NA, serotonin; stimulators: CB1 antagonists, NPY & AgRP antagonists, aMSH antagonists
What are the current peripheral drug targets of food intake?
Leptin
What are the current drug targets of fat absorption?
lipase inhibitors (orlistat)
What are the current drug targets to increase thermogenesis?
B3-aR agonists - B3s on skeletal muscle and fat
Phentermine is a ___________
sympathomimetic amine
What is the action of phentermine?
acts within the CNS to increase NA (also DA and 5HT) known to inhibit food intake
What is the limitation of phentermine use?
can only be used for 3 weeks and tolerance develops; bc sympathomimetic, higher doses can be dangerous
Orlistat is a ____________
lipase inhibitor: pancreatic and gastric
What is the benefit of orlistat over phentermine?
It can be used in the long-term
What is the action of orlistat?
Inhibits dietary fat absorption by inhibiting pancreatic and gastric lipases
For obesity drugs to be effective they must be combined with ________ and ________
low calorie diet; increased exercise
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]
Phentermine use is indicated for patients
BMI > 30 or >/ 27 with one co-moribidity (diabetes, cardiac HT)
What are the adverse effects of phentermine?
sympathomimetic effects: increased BP, HR, insomnia, nervousness; headache, dry mouth; may have addictive euphoric properties
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
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
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)
What is the mechanism of Topiramate?
unknown; but it increases energy expenditure and suppresses appetite, and also insulin sensitivity
Use of Topiramate is indicated in patients with
BMI > 30 or >/27 with one co-morbidity
What are the adverse effects of Topiramate?
dizziness, taste alteration, teratogenic effects (cleft palate), parasthesia
Use of Orlistat is indicated in patients with
BMI > 30
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
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%
What is the dosing of Orlistat?
3x daily with meals, 120mg
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
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
Orlistat must be combined with
a low fat diet (prevents GI side effects) and fat-soluble vitamin supplements (D & E)
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
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
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
