Obesity Pharmacology (Lect 10) Flashcards
What is the clinical definition of obesity?
• Defined clinically as having a body mass index >30
(kg/m2)
– Healthy range is 18.5 – 24.9 – Overweight is 25 – 30 – Obese is 30 – 40 – Severe obesity is >40
Obesity is a significant risk factor for
– Insulin resistance – Type 2 diabetes – Dyslipidemia – Hypertension – Heart diseases – Cancer
Non-Pharmacological Approaches to obesity
• Exercise
– Endurance aerobic exercise
• Dietary
– Calorie Restriction
– Ketogenic Diet
• Surgical/Medical Devices
– Gastric bypassWhat is an important region of the brain regulating appetite?
The hypothalamus
NPY/AgRP neurons are
orexigenic:
– Promote food intake
– Decrease energy expenditure
– In the hypothalamus
– Lead to weight GAIN
POMC/CART neurons are
anorexigenic:
– Inhibit food intake
– Increase energy expenditure
– In the hypothalamus
– Lead to weight LOSS
Criteria for Getting a Weight-Loss Medication
Approved in the Current Landscape
Therapeutic agent must:
– induce statistically significant placebo-adjusted weight loss of >5% at 1 year, or >35% of patients should achieve >5% weight loss (must at least twice that induced by placebo)
– also show evidence of improvement in metabolic biomarkers (e.g. blood pressure, blood lipids, blood sugar, etc.)
What is leptin?
– An adipokine (adipose tissue-derived peptide hormone)
that induces satiety
– Recently approved for the treatment of lipodystrophy (an abnormal distribution of fat in the body) (Myalept)
What is the MOA for leptin?
– Agonism of leptin receptors (related to class 1 cytokine receptors) present in the hypothalamus of the brain leads to potent suppression of appetite (reduced AMPK signaling) and causes weight loss – Only demonstrates real clinical utility in leptin or leptin receptor deficient humans
What is Liraglutide and what is its MOA?
– A GLP-1R agonist (normally used in the treatment of type 2 diabetes
(MOA)
– Activates GLP-1Rs that are expressed in the hypothalamus of the brain (G-protein coupled receptor linked to Gs proteins & increased cAMP production)
– Leads to REDUCED food intake/appetite
What is the dosing of Liraglutide?
Start with 0.6 mg subcutaneously once daily for 1-week; titrate upwards weekly to 1.2 mg, 2.4 mg, to max dose of 3.0 mg
(1.8mg for Type 2 Diabetes, 3.0 mg for obesity)
Adverse Effects of Liraglutide
- Increase in heart rate
- Pancreatitis?
(NOT AS IMPORTANT)
• Generally well tolerated
• Gastrointestinal upset (nausea, vomiting, diarrhea)
What is Orlistat and what is its MOA?
• A lipase inhibitor (saturated derivative of lipstatin isolated from Streptomyces toxytricini)
(MOA)
• Reacts with serine residues at the active sites for gastric and
pancreatic lipases to reversibly inhibit their enzymatic activity
• Prevents breakdown of dietary fat (triglycerides) into free fatty
acids and glycerol (decreases absorption of dietary fat)
• Only therapy that doesn’t act centrally for obesity
What is the dosing of Orlistat?
Over the counter dosage of 60 mg, prescription formulation is 120 mg (3x daily orally)
Adverse effects of Orlistat
- Flatulence/Fecal incontinence
- Intestinal borborygmic (stomach rumbling)
- Oily spotting (stool having oil-like appearance)
(NOT AS IMPORTANT)
• Abdominal cramps
Lorcaserin MOA?
• A selective 5-HT2C receptor agonist (will increase
proopiomelanocortin (POMC) expression in the hypothalamus which induces satiety)
Lorcaserin Dosing
10 mg twice daily or 20 mg extended release once daily
Adverse Effects of Lorcaserin
• Valvular heart disease?
(NOT AS IMPORTANT) • Gastrointestinal (nausea, constipation) • Headache • Dizziness • Fatigue • Dry mouth • Hypoglycemia • Hallucinogenic actions (Schedule IV Class Drug)
What is Phentermine/Topiramate?
The 1st combination therapy approved for obesity in the USA, provided as an adjunct to reduced caloric consumption and/or exercise (most potent pharmacotherapy for 1-year weight loss)
Phentermine/Topiramate MOA
- Phentermine is a sympathomimetic amine that acts as agonist for the trace amine-associated receptor (similar to amphetamine)
- Topiramate is an anticonvulsant agent (acts on sodium/calcium channels and inhibits carbonic anhydrase)
- Mechanism of action for how combination reduces body weight is unknown
Dosing for Phentermine/Topiramate
- 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
Adverse Effects for Phentermine/Topiramate
- Paresthesia (numbing tingling sensation in hands or feet)
- Insomnia
- Heart rate elevation
• Contraindicated:
▪ Pregnancy (teratogenic)
▪ If also taking monoamine oxidase inhibitors
(hypertension)
(NOT AS IMPORTANT) • Dizziness • Constipation • Dry mouth • Mood changes
• Contraindicated:
▪ Glaucoma
▪ Hyperthyroidism
What is Bupropion/Naltrexone (Contrave)?
A combination of low dose bupropion and naltrexone used in conjunction to exercise/dietary changes for weight loss
MOA for Bupropion/Naltrexone
• 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
- In combination, they modify the reward pathway to reduce appetite
Dosing for Bupropion/Naltrexone
- 16 mg/360 mg or 32 mg /360 mg Naltrexone/Bupropion
- Offered in 8 mg and 90 mg tablets Naltrexone/Bupropion
• 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
Adverse Effects of Bupropion/Naltrexone
• Increased heart rate & blood pressure
(NOT AS IMPORTANT)
• May affect mood and increase suicide risk
• Gastrointestinal upset (nausea, vomiting, diarrhea)
• Headache
• Dry mouth
• Contraindicated:
▪ History of seizures ▪ Eating disorders ▪ Taking other opioid medicines (e.g. for pain management) ▪ Pregnancy ▪ During withdrawal from barbiturates, benzodiazepines, and antiepileptic drugs
How to choose which pharmacotherapy for obesity?
- 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)
Gastric bypass surgery is a
Last resort and option for people with severe obesity
