Obesity Drugs

Question 1

Phen-fen

Answer 1

phentramine and fenfluramine, inhibits noradrenaline reuptake (fenfluramine also enhanced noradrenaline release). Withdrawn due to potentially fatal pulmonary hypertension

Question 2

Sibutramide

Answer 2

inhibits reuptake of noradrenaline, 5HT and dopamine. Modest weight loss of around 10-15lbs a year.
Withdrawn in 2010 over cardiovascular side-effect concerns

Question 3

Rimonabant

Answer 3

CB1 receptor antagonist
withdrawn in 2009 due to concerns about severe depression, anxiety and loss of neuroprotective endocannabinoid signalling.

Question 4

Orlistat

Answer 4

inhibits pancreatic lipase to decrease triglyceride absorption efficiency by about 30% in small intestine. Side effects include crampin, bloating, flatulence, pain, diarrhoea.
Need to take vitamin supplements due to loss of fat soluble vitamins A, D and E.
Limited effectiveness, around 3kg weight loss per year and tendancy to rebound after stopping taking it.

Question 5

Lorcaserin

Answer 5

5HT2c receptor agonist, approved by FDA but not EMA. Concerns about cardiovascular safety and psychiatric effects.
Very limited weight loss

Question 6

Contrave

Answer 6

bupropion (dopamine re-uptake inhibitor) and naltrexone (MOR antagonist)
Bupropion activates POMC neurones and naltrexone disinhibits POMC neurones. FDA rejected and EMA approved in 2015. Modest weight loss of about 5%.

Question 7

Liraglutide

Answer 7

GLP-1R agonist. licensed T2DM treatment, although higher doses are used for weight loss purposes. FDA approved in 2014 and EMA in 2015. Exact mechanism required confirmation, likely due to enhancement in POMC neurone activity.

Question 8

Bariatric surgery

Answer 8

Adjustable gastric band - at top of stomach to limit food intake
Gastric bypass - skips most of stomach and small section of small intestine to increase GI transit of food and reduce both feeding and absorption.
Vertical sleeve gastrectomy - most common, reduced stomach size greatly.
These produce a profound weight loss of around 60-70% in a year. Also 70-80% complete remission of T2DM, within a week, which is before weight loss has had a significant effect. Likely due to reduced calroic intake and works in similar way to 600cal/day diet.

Question 9

Celastrol

Answer 9

Leptin sensitisers.
Weight loss due to decreased food intake to begin with then higher energy expenditure later.
Promising mechanism, however, toxicity is an issue.

Question 10

2,4-dinitrophenol

Answer 10

Uncoupler, very potent.
Collapses proton gradient and results in energy being released as heat. Can cause hyperthermia.
Microdosing may be an option in future.

Question 11

Qsymia

Answer 11

Phentramine + topiramate
Better than sibutramide and rimonabant - 5-10% weight loss.
Concerns about psychiatric effects and CV endpoint