87 - Drugs Used in Obesity Flashcards
Examples of peptides that increase feeding (central)
1-5
Neuropeptide Y Melanin concentrating hormone Agouti-related peptide Orexin A and B Endocannabinoids
Examples of peptides that promote satiety (central)
1-5
Alpha-melanocyte stimulating hormone Urocortin Corticotrophin releasing hormone Serotonin Noradrenaline
Examples of peptides that increase feeding (peripheral)
Ghrelin
Examples of peripheral peptides that promote satiety
1-3
Leptin
Insulin
Cholecystokinin
How do leptin and insulin reach the hypothalamus to modulate hunger?
Are transported across the BBB, because they are large peptides.
How do satiety signals reach the brain?
CCK released from GIT following fatty meals.
CCK binds vagus nerve receptors, signal sent along vagus to nucleus tractus solitarius, which signals to hypothalamus to decrease appetite.
Liver also sends sympathetic signals to NTS.
Rhythm of leptin release
Circadian rhythm (highest at midnight, reduce until noon)
How does leptin cross BBB?
Via a saturable process (transporter)
Where are leptin receptors located?
Hypothalamus
What secrete leptin?
Predominantly adipocytes.
Also released by lung cells, immune cells, albeit at much lesser levels.
Three ways in which leptin resistance can arise
Saturation of leptin transporters.
Hypothalamic leptin receptors become desensitised
Leptin receptor 2nd messenger systems become less sensitive
Three targets for possible obesity treatments
Food intake
Fat
Thermogenesis
Way in which thermogenesis might be targeted for obesity treatment
Beta3 adrenoceptor agonists
Why in which fat absorption might be targeted for obesity treatment
Lipase inhibitors
TGA-approved anti-obesity drugs
1) Phentermine
2) Orlistat
Phentermine
Sympathomimetic amine
TGA approved
Can only be used short term
Orlistat
Decrease dietary fat absorption
TGA approved
Can be used long term
Sibutramine
Decrease NA and 5-HT uptake
Anti-obesity drug
TGA approval has been withdrawn (increases MI risk)
Rimonabant
CB1 antagonist.
No TGA approval, as increases risk of suicide
Uses of phentermine
BMI over 30.
Can only be used short term (amphetamine derivative).
Effect of phentermine
Non Ca2+-dependent NA release from neurons.
This suppresses appetite
Adverse effects of phentermine
Increased BP Increased HR Insomnia Nervousness Headache Dry mouth Addictive, induces tolerance
Contraindications of phentermine
Other weight loss drugs
MAO inhibitors (and other antidepressants)
Not safe in pregnancy
When is orlistat prescribed?
BMI over 30kg/m^2
Dosing of orlistat
Three times per day with meal (120mg)
Mechanism of orlistat action
Inhibits gastric and pancreatic lipases.
Triglycerides need to be broken down into free fatty acids and monoglycerides to be absorbed by gut wall.
This cannot occur if lipases are inhibited.
Effect of orlistat
Decreases dietary fat absorption by ~30%
Clinical effects of orlistat
Decrease body weight, waist circumference
Restoration of insulin sensitivity
Help resolve dislipidaemia, blood pressure
Side effects of orlistat
Limited to GIT, because not absorbed systemically.
If eat fatty meals, can have explosive diarrhoea, faecal fat leakage.
What must be combined with orlistat treatment?
Low fat diet Vitamin supplementation (D and E)
Anti-epilepsy drug that is FDA approved for anti-obesity, in combination with phentermine
Topiramate
Mechanism of topiramate
Unknown.
Maybe increases energy expenditure, suppresses appetite, but the mechanism for these is unknown.
Increases half-life of phentermine.
Adverse affects of topiramate
Dizziness
Taste alteration
Teratogenic
Anti-diabetes drug that is FDA approved for anti-obesity
Glucagon-like peptide-1 receptor agonist.
Administration of glucagon-like peptide-1 receptor agonist
Injection (a peptide, so can’t be digested without hydrolysis)
Actions of GLP-1 receptor agonists
Increased insulin secretion and synthesis Decreased glucagon secretion. Reduces gastric emptying Liver decreases glucose production Increased glucose uptake into muscles
Mechanism of GLP-1 agonist
1-4
–Potentiates glucose mediated insulin secretion
–Suppress glucagon secretion
–Slows gastric emptying
–Loss of appetite (central action)
Adverse effects of GLP-1 agonist
Nausea Vomiting Diarrhoea Pancreatitis Hypoglycaemia (if patient doesn't have hyperglycaemia)
