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
Pharm approaches
Orlistat
what is it?
MOA (2)
what is special about it?
- lipase inhibitor (saturated derivative of lipstatin isolated from Streptomyces toxytricini)
MOA
- reacts with serine residues at active sites for gastric, pancreatic lipases to reversible inhibit their enzymatic activity
- prevents breakdown of dietary fat (triglycerides) into free fatty acids and glycerol (decrease absorption of dietary fat)
- not absorbing the fat you are eating
- *only therapy that does not act centrally for obesity
- least potent of all weight loss meds
Pharm approaches
Orlistat
Dosage?
OTC dosage of 60mg, prescription formulation is 120mg (3x daily orally)
pk: excreted in feces (97%), minimal metabolism
Pharm approaches
Orlistat
AE? (3)
- flatulence/fecal incontinence: cannot control
- intestinal borborygmic: a rumbling sound made by the movement of gas in the intestine
- oily spotting: fat is eliminated in stool
abdominal cramps
Pharm approaches
Lorcaserin
MOA? receptor and response
Dose?
MOA:
- 5-HT2C receptor agonist (selective so safer than dexfluramine which is a failed drug)
- 2A is hallucogenic, 2B pulm hypertension
- increase POMC expression in hypothalamus to induce satiety
Dose
- 10 mg twice daily or 20mg extended release once daily
Pharm approaches
Lorcaserin
AE?
- valvular heart disease
- GI, headache, dizziness, fatigue, dry mouth, hypoglycemia (noticeable in Type 2 diabetes), hallucinogenic actions
Pharm approaches
Phentermine/Topiramate
what is special about it?
MOA
phen?
top?
combo?
- 1st combo therapy approved in US for obesity as an adjunct to reduced caloric consumption and/or exercise
- most potent pharm for 1 year weight loss
MOA
- Phentermine is a sympathomimetic amine that acts as agonist for trace amine-associated receptor (similar to amphetamine)
- topiramate is anticonvulsant agent (acts on Na+/Ca channels and inhibits carbonic anhydrase
- MOA for how combo works is unknown
Pharm approaches
Phentermine/Topiramate
Dosage?
- 3.75/23, 7.5/46, 11.25/69, 15/92 mg extended release once daily
- Needs to be carefully titrated; start 3.75/23 mg for 14-days, increase to 7/46 mg and titrate monthly to 11.25/69 mg then 15/92 mg
- Discontinue if weight loss <3% on 11.25/69 mg, or <5% on 15/92 mg after 12-weeks
- Graduated titration over 3-5 days is recommended due to seizure risk with abrupt withdrawal - down-titrate carefully
Pharm approaches
Phentermine/Topiramate
AE (3)
Contraindicated? (2)
AE
- *paresthesia
- *insomnia - taken in morning, amphetamine like
- *heart rate elevation
- dizziness, constipation, dry mouth, mood changes
Contraindicated
- *pregnancy (teratogenic)
- *if taking monoamine oxidase inhibitors (hypertension
- glaucoma, hyperthyroidism
Pharm approaches
Bupropion/Naltrexone (Contrave)
MOA
- combo of low dose bup and nalt used in conjuction to exercise/diet changes
MOA
- Bupropion is noradrenaline-dopamine reuptake inhibitor (normally used for treating depression)
- (Active metabolites can also antagonize the nicotinic
acetylcholine receptor (hydroxybupropion))
- Naltrexone is a competitive opioid receptor antagonist (u and k)
- combo - modify reward pathway to reduce appetite
Pharm approaches
Bupropion/Naltrexone (Contrave)
Dosage
- 16 mg/360 mg or 32 mg /360 mg Naltrexone/Bupropion
- Offered in 8 mg and 90 mg tablets
- Start first week 1 tablet once daily in the morning for wk 1, then 1 tablet twice daily for wk 2, then 2 tablets in the morning and 1 tablet at night for wk 3, followed by 2 tablets twice daily
Pharm approaches
Bupropion/Naltrexone (Contrave)
AE (1)
- *increased HR and BP
- affect mood, increase suicide risk
- contraindicated in history of seizures, eating disorders, taking other opioids, etc.
How to choose which pharmacotherapy?
What is the best predictor for success?
- Don’t have enough clinical guidance yet on which therapy a patient should start on
- Weight loss in the first 3-4 months is the only consistent predictor of further success with available medications
- If 5% weight loss not achieved in first 3-4 months, change medications (unless improvement in comorbidities)
Name the currently available anti-obesity medications (5)
Liraglutide Orlistat Lorcaserin Phentermine/Topiramate Bupropion/Naltrexone (Contrave) Leptin?
What is a GLP-1 receptor agonist?
Liraglutide
What is a lipase inhibitor?
Orlistat
What is a selective 5-HT2C receptor agonist
Lorcaserin
Name 2 combination therapies
Phentermine/Topiramate
Bupropion/Naltrexone (Contrave)
Leptin, GLP-1, insulin, 5-HT have _________ actions on __________ neurons
positive, POMC/CART (aniorexigenic)
Opiods, NPY, Orexin have _________ actions on __________ neurons
negative, POMC/CART (aniorexigenic)
