²⁶The use of Sibutramine in treating Obesity

²⁶Current data shows that in 1998, 17% of men and 21% of women in the UK were clinically obese, and over 50% of the UK population was overweight. Sibutramine is recommended to patients with a BMI of 30kg m^-2 or more for aiding weight loss by reducing appetite and increasing satiety. Sibutramine increases blood pressure in some patients and therefore blood pressure must be monitored during treatment to ensure that it does not become dangerously high.

16 clinical trials involving over 5000 patients have shown that in randomised, controlled trials, Sibutramine was more effective than a placebo at promoting weight loss; by 3kg at 8 weeks, by between 4 and 9kg at 24 weeks and by between 4 and 5kg at 1 year. While this demonstrates Sibutramine's effectiveness, it still shows that over a longer period of time behavioural change becomes a more predominant factor in weight loss.

Side effects of Sibutramine include dry mouth, constipation and insomnia. Less common side effects include headache, increased sweating, increased blood pressure and increased heart rate. Of these, the issue of increased blood pressure is the most concerning, but it is less common and since patients with obesity are regularly monitored by their doctors for changes in blood pressure, this risk is mitigated somewhat. ²⁶References for Sibutramine recommend terminating treatment if blood pressure increases above 145/90.

Sibutramine is incompatible with the following drugs (Information from ²⁸Medline Plus):

• Other appetite suppressants, (benzphetamine [e.g., Didrex], diethylpropion [e.g., Tenuate], mazindol [e.g., Sanorex], phendimetrazine [e.g., Phendiet], phentermine [e.g., Ionamin])—The effects of using sibutramine in combination with another appetite suppressant are not known.
• Bromocriptine (e.g., Parlodel)
• Buspirone (e.g., BuSpar)
• Certain tricyclic antidepressants (amitriptyline [e.g., Elavil], clomipramine [e.g., Anafranil], imipramine [e.g., Tofranil])
• Dextromethorphan (cough medicine)
• Levodopa (e.g., Sinemet)
• Lithium (e.g., Eskalith)
• Meperidine (e.g., Demerol)
• Nefazodone (e.g., Serzone)
• Pentazocine (e.g., Talwin)
• Selective serotonin reuptake inhibitors (citalopram [e.g., Celexa], fluoxetine [e.g., Prozac], fluvoxamine [e.g., Luvox], paroxetine [e.g., Paxil], sertraline [e.g., Zoloft])
• Street drugs (LSD, MDMA [e.g., ecstasy], marijuana)
• Sumatriptan (e.g., Imitrex)
• Tramadol (e.g., Ultram)
• Trazodone (e.g., Desyrel)
• Tryptophan
• Venlafaxine (e.g., Effexor)—Using these medicines with sibutramine may increase the chance of developing a rare, but very serious, unwanted effect known as the serotonin syndrome. Symptoms of this syndrome include confusion, diarrhea, fever, poor coordination, restlessness, shivering, sweating, talking or acting with excitement you cannot control, trembling or shaking, or twitching.
• Moclobemide (e.g., Manerex)—Taking moclobemide and sibutramine together or less than 3 days apart may increase the chance of developing serious unwanted effects, including the serotonin syndrome.
• Monoamine oxidase (MAO) inhibitors (furazolidone [e.g., Furoxone], phenelzine [e.g., Nardil], procarbazine [e.g., Matulane], selegiline [e.g., Eldepryl], tranylcypromine [e.g., Parnate]). This combination in particular has been shown to considerably increase the likelihood of developing the serotonin syndrome

In addition, Sibutramine should not be prescribed for people with a history of coronary artery disease, congestive heart failure, arrhythmias or stroke, as it may dangerously increase the individual's heart rate and/or blood pressure.

²⁹Clinical Pharmacology

It has been discovered that Sibutramine produces its therapeutic effects by inhibiting the reuptake of seratonin, norepinephrin and dopamine. It has two metabolites, DMS and DDMS. Both Sibutramine and it's metabolites are effective in vivo however in vitro Sibutramine is not effective. This is because the pharmacologically active substances are the metabolites, and in the in vitro studies, there is nothing to metabolise sibutramine, so it remains inactive.

Pharmacokinetics

Absorption

Sibutramine is rapidly absorbed from the gastro-intestinal tract and is first metabolised in the liver to DMS and DDMS, with a half-life of 1.1 hours. Peak plasma concentrations of the metabolites are reached within 3-4 hours, and overall it has been determined that 77% of a single dose of sibutramine is absorbed by the body.

Metabolism

Sibutramine is primarily metabolised by the cytochrome P450(3A₄) enzyme. DMS and DDMS are also metabolised by the liver by hydroxylation and conjugation to pharmcologically inactive forms, which are then excreted from the body. The elimination half life of DMS is 16 hours and the elimination half-life of DDMS is 14 hours.

Excretion

Approximately 85% of a dose of sibutramine is excreted over a 15 day period, 77% of which is excreted in the urine.