Pharmacology + Pharmacotherapy for Obesity Flashcards
Pathophysiology
What is clinically defined as obese?
healthy range?
How can you gain weight?
BMI > 30 kg/m2 healthy range: 18.5-24.9 overweight: 25-30 obese: 30-40 severe obesity > 40
- gain weight if calorie intake (energy in) is greater than calories you burn (energy out)
- eat more than body reuqires
- physical inactivity
Pathophysiology
What disorders is obesity a risk factor for? (6)
- insulin resistance
- Type 2 diabetes
- dyslipidemia
- hypertension
- heart diseases
- cancer
What Non-Pharm Approaches can help? (3)
What is the last resort?
- exercise (endurance aerobic exercise good even w/o weight loss
- dietary (calorie restriction, ketogenic diet)
- surgical/medical devices (gastric bypass)
gastric bypass is last resort option
What part of the brain is important for regulating appetite?
Hypothalamus
What neurons are orexigenic?
NPY/AgRP neurons
- promote food intake
- decrease energy expenditure
What neurons are anorexigenic?
POMC/CART neurons
- inhibit food intake
- increase energy expenditure
What is dinitrophenol?
What is the problem with it?
- mitochondrial uncouple that increases metabolism, but instead of ATP, heat is generated (thermogenesis)
- used in 1930s as a diet pill but was banned in US in 1938 as it increases heart rate
What is dinitrophenol? (don’t need to know)
What is the problem with it?
- mitochondrial uncouple that increases metabolism, but instead of ATP, heat is generated (thermogenesis)
- used in 1930s as a diet pill but was banned in US in 1938 as it increases heart rate
What is dexfenfluramine? (don’t need to know)
What is the problem with it?
a serotonergic drug approved in 1996 by US FDA for weight loss despite preclinical studies demonstrating neurotoxicity
- reports of cardiac valvopathy or pulmonary hypertension resulting in immediate withdrawal from the market
What is sibutramine? (don’t need to know)
What is the problem with it?
a serotonin and noradrenaline reuptake inhibitor that promotes satiety and approved in US and Health Canada in 1997
- suspended first in Europe due to CV adverse events
- US voluntarily withraw from market
What is the criteria for getting a weight-loss med approved?
- must induce statistically significant placebo adjusted weight loss of >5% at 1 year of >35% of patients should achieve >5% weight loss (twice that induced by placebo)
- must show evidence of improvement in metabolic biomarkers (bp, blood lipids, blood sugar)
Pharm approaches
Leptin
MOA?
- an adipokine (adipose tissue-derived peptide hormone) that induces satiety, recently approved for lipodystrophy
- one of the first discovered
MOA
- agonism of leptin receptors (related to class 1 cytokine receptors) present in hypothalamus of brain leads to potent suppression of appetite (reduced AMPK signaling energy sensor) and suppression of body weight gain
- only clinical utility in leptin or leptin receptor deficient humans
- leptin resistance in obese people, high circulating leptin in obese people
- AMPK = 5’AMP activated protein kinase
Pharm approaches
Liraglutide
what is the receptor?
MOA?
originally used for?
- GLP-1R agonist (normally used to Type 2 diabetes)
MOA
- activate GLP-1Rs that are expressed in hypothalamus
- G-protein coupled receptor linked to Gs proteins and increased cAMP production
- reduce food intake/appetite
- studies done show primary endpoints were proportion of patients losing at least 5% or more than 10% of their body weight
Pharm approaches
Liraglutide
Dosage?
1.8 mg for Type 2 diabetes, 3.0 mg for obesity
Start w/ 0.6 mg subq once daily for 1 week; titrate upwards weekly to 1.2, 2.4 to max dose of 3.0mg
pk: acylated to prolong half-life
only injectable med for weight loss
Pharm approaches
Liraglutide
AE? (2)
- well tolerated
- GI upset
- *increase in HR
- *pancreatitis
