Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
52 Cards in this Set
- Front
- Back
|
FDA approved drugs (know these in detail)
|
Phentermine
Sibutramine Orlistat |
|
|
Why is obestiy a chronic disease?
|
Dysfunc of neurochemical regulator of food intake and fat storage.
Compensatory mechanisms make weight loss difficult (once you have been obese for a while, your body changes and weight loss becomes difficult) |
|
|
Indications for pharmacotherapy
|
Obese pts who can't lose 0.5kg/week with first line therapy (diet, exercise, behavior modification)
Obese is considered BMI >= 30 --- Or overweight pts (BMI>=27 with comoribidities (T2DM, CHD, athero, sleep apnea), risk factors, excessive waist circumference. NOT RECOMMENDED FOR EATING DISORDERS!!! |
|
|
non-responders to pharmacotherapy
|
Pts who fail to lose >=2 kg in first 4 weeks.
Must either inc dosage or switch the other approved drug. |
|
|
SNPs
|
can predict pts who will respond well to sibutramine
|
|
|
Support services
|
help with outcomes of pharmacotherapy
|
|
|
Goals of pharmacotherapy
|
reduce risk factors and comorbidities. and improve QOL.
so you don't have to reach ideal weight. |
|
|
Drugs no longer used
|
thyroid hormone
dinitrophenol d-amphetamine phenylpropanolamine (PPA) phentermine/fenfluramine Fenfluramine caused valvular heart disease and pulmonary HTN. but phentermine alone is still in use. Ephedra FDA ban (stresses heart) |
|
|
False claims
|
Xenadrine (placebo was more effective)
One a day weight smart cortislim and cortistress trimspa |
|
|
Phentermine
|
CNS acting
Stimulates NE and DA release in hypothal feeding center to suppress appetite QUICK TOLERANCE!!!! - so short term use only (12 weeks) 0.5 kg weight loss per week (modest) |
|
|
AEs of phentermine
|
HTN, anxiety, nervousness, dry mouth, constipation
|
|
|
Sibutramine
|
Long term therapy - CNS acting
Strucutre similar to amphetamines but less addiction risk. Inhib reuptake of serotonin, NE, and DA - suppresses appetite Modest weight loss can occur even without low calorie diet. Has a big placebo effect. Decreases CV risk factors (Chol, LDL, TGs) Convenient dosing schedule (once a day) 8% body weight reduction at 6 months - pretty good. All weight will come back once tx is stopped. |
|
|
Sibutramine interactions
|
MAO-Is, SSRIs, drugs that increase BP
|
|
|
Sibutramine AEs
|
Inc HR and BP. But long term weight loss can reverse the BP effect.
May increase CV events. Similar minor effects to pherntermine (another CNS acting one - short term) - dry mouth, HA, insomnia, nausea, constipation |
|
|
How to improve sibutramine's actions
|
Give lifestlye and diet advice. (can get 15% weight loss)
Give chronic or intermittent therapy to avoid weight coming back. |
|
|
Orlistat
|
long acting - GI lipase inhibitor
Inhibits lipases to prevent hydrolysis of fat into TGs Has a less potent OTC version (alli - a comprehensive system with diet and exercise tips too) Reduces CV risk factors (HTN, hyperglycemia, hyperlipidemia) 1 capsule with each meal. |
|
|
Only anti-obesity drug covered by medicaid
|
orlistat - because it reduces comorbidities
|
|
|
AEs of orlistat
|
not absorbed, so few systemic side effects compared to CNS acting drugs.
Supplement with multivit though to get abs of vit A,D,E. Flatulence, oily spotting (fecal excretion of fat), urgency (lessens with time) |
|
|
Preferred drug for HTN pts (most of your pts)
|
orlistat
|
|
|
Compliance with orlistat
|
The pt may eat less fatty foods to avoid SEs, but may also eat fatty foods and just not take the drug.
|
|
|
Dosing of orlistat
|
with each meal, not sure about intermittent dosing in this drug, pts can gain weight back if they dont have lifestyle modification
|
|
|
How to make orlistat more effective
|
Supervised lifestyle modification - maintains weight loss after discontinuation of orlistat.
|
|
|
Cetilistat
|
Next generation - similar to orlistat.
has less AEs. |
|
|
Sibutramine vs. orlistat
|
sibutramine slight more effective at BMI reduction
orlistat better for waist circumference reduction. no major benefit to combo therapy. |
|
|
Limitations of sibutramine or orlistat therapy
|
5-10% initial weight loss at 6 months, 15% at one year.
Setting realistic goals are key. |
|
|
Losing 2.2 pounds will
|
increase life expectancy by 3-4 months.
|
|
|
Practical advice to help pts
|
frequent follow ups
patient support (get them an exercise buddy) eat breakfast pts may have psychiatric side effects. |
|
|
Now new drugs coming downt he pipeline..
New benchmarks for FDA approval |
Mean weight loss greater than 5% compared to placebo
35% of subjects on drug must show 5% loss of baseline body weight and number of subjects must at least double that achieved this in placebo group. |
|
|
Rimonabant
|
Cannabinoid receptor antagonist
Leads to ideation of suicide |
|
|
Exenatide
|
Incretin/Glp-1 mimetic.
Slows gastric emptying to signal satiety |
|
|
Tesofensine
|
Inhib serotonin, DA, NE reuptake
Huge decrease in weight (twice as effective as the FDA approved ones) |
|
|
Lorcaserin
|
5HT(2c) agonist to suppress appetite, increase satiety.
This specific serotonin receptor will not give AEs of fenfluramine (heart valve defects of hallucigenic) |
|
|
Combo therapy of new drugs
|
Use low dose FDA approved drugs iwth a newer drug to avoid compensatory homeostatic mechanisms
or juts combine two random drugs... |
|
|
Contrave
|
Buproprion (DA reuptake inhibitor - less food cravings) and naltrexone (opioid antagonist)
|
|
|
Empatic
|
bupropion (DA reuptake inhibitor - less food cravings) and zonisamide (anticonvulsant)
|
|
|
Qnexa (pronounced kenexa)
|
phentermine + topiramate (GABA agonist - anticonvulsant)
|
|
|
Slide 60 - review of some new drugs
|
decent, not great
|
|
|
Summary
|
Obesity must be viewed as a chronic condition
Long term pharmacotherapy may be necessary Current FDA approved drugs promote 2.5-5 kg weight loss above placebo Loss of 5-10% initial body weight is a realistic and clinically significant goal New drugs are in development Combination therapy may be an effective new strategy |
|
|
Fat
|
not just a storage depot,but a dynamic endocrine organ
|
|
|
Leptin deficient
|
Morbidly obese
|
|
|
Leptin actions (centrally)
|
With excess energy, it is secreted and acts on feeding center and suppresses appetite.
Inhibits NPY, AgRP, orexins and MCH - normally stimualtes feeding Activates alpha-MSH (melanocyte stimulating hormone), CART, CRH (corticotropin releasing hormone) - inhibits appetite All the things that leptin directly inhibit/activate are hypothalamus 1st order neurons and they act on hypothal 2nd order neurons. |
|
|
Leptin in periphery
|
Activates AMP kinase which leads to oxidation of FAs in mitochondria.
(normally AMP goes up when energy is low to increase ATP production by burning FAs in mitochondria) |
|
|
Activating AMP kinase is like...
|
"exercise in a bottle"
|
|
|
Will most obese people benefit from leptin therapy?
|
no
due to acquired leptin resistance. |
|
|
Notes for this lecture
|
tied in with the obesity notes it seems like
|
|
|
Ghrelin
|
stimulates appetite
as you lose weight, ghrelin levels go up, metabolic rate goes down. |
|
|
gut derived satiety signals
|
PYY
CCK GLP1 |
|
|
NPY
|
stimulates food intake and promotes fat storage
|
|
|
alpha melanocyte stimulating hormone
|
inhibits feeding
|
|
|
adiponectin
|
most abundant transcript in adipocytes
low levels in T2DM and obesity anti-inf and anti-atherosclerotic lean people have high levels |
|
|
Conclusions (again)
|
Genetic deletion of feeding stimuli (Ghrelin, AgRP, or NPY) does not result in leanness
But, mutation or deletion in fat storage pathways (POMC, MCR4, leptin, leptin R) results in severe obesity Homeostatic mechanisms have evolved to promote feeding in times of plenty to avoid starvation when food is scarce. We have not evolved protective mechanisms to prevent obesity when food is plentiful |
|
|
Exercising will...
|
activate AMPK
|
