Drugs for Obesity

Drugs for Obesity Dr.Entisar Al-Mukhtar

Obesity [body mass index (BMI) ? 30 kg/m2] is due in part to an energy imbalance (calorie consumption exceeds calorie expenditure).
• Genetics, metabolism, behavior, environment, culture & socioeconomic status play a role in obesity.
• BMI > 30 or > 27 with at least two comorbidities (e.g, HT & DM) then the pharmacological treatment of obesity is candidate.
Two classes of drugs are used in treating obesity the anorexiants (appetite suppressants including Phentermine and Diethylpropion) & lipase inhibitor (Orlistat).
• The majority of drugs approved to treat obesity have short-term indications for usage including the older medications (Phentermine and Diethylpropion).
However, some of the newer medications have been approved for long-term weight management (up to 4 years ) such as the lipase inhibitor orlistat.
Recently, a serotonin agonist, lorcaserin, and a combination drug, phentermine and topiramate, were also approved for the treatment of obesity.
• Drugs for obesity are considered effective if they demonstrate at least a 5% greater reduction in body weight as compared to placebo. The medications discussed in this chapter have been shown in clinical trials to help patients lose approximately 5% - 10% of their body weight.

Anorexiants (appetite suppressants): Phentermine & Diethylpropion
MOA:
• Phentermine increases NE and dopamine release and inhibiting their reuptake, the increase in NE signals a “fight-or-flight” response, in turn decreases appetite.
• Diethylpropion has similar effects on NE. Tolerance to the weight loss effect develops within weeks. Discontinuation of the drug is usually recommended once the weight loss plateau is reached.

Pharmacokinetics:
• Diethylpropion undergoes extensive 1st pass metabolism. Many of the metabolites are active, excreted mainly via the kidneys.
Adverse effects:
• The anorexiants are controlled substances (potential for dependence or abuse).
• HR and BP may be increased (should be avoided in patients with a history of uncontrolled HT, CV disease, arrhythmias, HF, or stroke).
• anorexiants used with MAOIs or other sympathomimetics should be avoided.
Lipase inhibitors
Orlistat is the only available lipase inhibitors, its indicated for long-term weight management (up to 4 years ).
• gastrointestinal adverse effects limits its clinical utility.
MOA:
Inhibits gastric & pancreatic lipases decreasing dietary fat break-down, decreasing fat absorption by about 30%. Its GI adverse effects may also contribute to an overall decreased intake of food.
Pharmacokinetics:
• Taken orally with each fatty meal.
• save in patients with renal or hepatic dysfunction.
Adverse effects:
• Oily spotting, flatulence with discharge, fecal urgency & increased defecation, low-fat diet & concomitant cholestyramine use minimized these effects.
• Contraindication: (1) pregnancy (2) chronic malabsorption syndrome (3) cholestasis.

Drug interaction:
• interferes with fat-soluble vitamins (A, D, E, and K) and ?-carotene absorption, thus multivitamin supplement and ?-carotene should be taken (after at least 2 hours of orlistat).
• interfere with the absorption of amiodarone, cyclosporine & levothyroxine.

Serotonin agonists
Lorcaserin is a newer serotonin agonist, has selectivity for 5-HT2C, used for chronic weight management.
Previous serotonin agonists used for weight loss were pulled from the market due to an increase in potentially fatal adverse effects, including valvular heart disease which may lead to pulmonary hypertension. It is believed that valvulopathy, is linked to 5-HT2B receptors.

MOA:
• activates 5-HT2C receptors (in the CNS ), thereby activate melanocortin receptors & decreasing appetite.
Pharmacokinetics:
not recommended in severe renal impairment.

Adverse effects:
• Patients should be monitored for the emergence of life-threatening serotonin syndrome or neuroleptic malignant syndrome.
• concomitant use of lorcaserin with SSRIs, serotonin–NE reuptake inhibitors, MAOIs, or other serotonergic drugs should be avoided.
the incidence of valvulopathy was not significantly increased in studies of lorcaserin (5-HT2C receptor agonist).
• patients should be monitored for the development of valvulopathy (hence, lorcaserin should be used cautiously with a history of HF).

Combination drugs
• The phentermine / topiramate combination has been approved for long-term use.
• the stimulant phentermine was added to counteract the sedating effects of topiramate and promote additional weight loss.
• dose of phentermine/ topiramate combination is escalated every 2 weeks, depending on the response.
• If a 5% weight loss not achieved after 12 weeks (on the highest dose), the combination should be discontinued.

• This medication should not be stopped abruptly as seizures may be precipitated.
• Topiramate has been associated with birth defects including cleft palate, thus, the combination is contraindicated in pregnancy.
• Topiramate can cause paresthesias, suicidal ideation, and cognitive dysfunction.
• increased HR may be observed with the phentermine component.

Drug interactions:
• MAOIs should be avoided (possibility of serotonin syndrome with phentermine).
• Non–potassium-sparing diuretics used with this combination may increase hypokalemia risk.
• Topiramate is a weak carbonic anhydrase inhibitor, thus the use of other carbonic anhydrase inhibitors with this combination increases the risk of kidney stones.
• Topiramate may reduce OCs efficacy, given a risk of birth defects.