Article: Sibutramine

Sibutramine
Systematic (IUPAC) name
1-(4-chlorophenyl)-N,N- dimethyl-a-(2-methylpropyl)- cyclobutanemethanamine
Identifiers
CAS number	106650-56-0
ATC code	A08AA10
PubChem	2215
DrugBank	APRD00456
Chemical data
Formula	C17H26ClN
Mol. weight	279.85
Pharmacokinetic data
Bioavailability	Resorption 77%, considerable first-pass metabolism
Metabolism	liver
Half life	sibutramine approx. 1h metabolite 1 14h metabolite 2 16h
Excretion	sibutramine and active metabolites : mainly biliar inactive metabolites : mainly urine
Therapeutic considerations
Pregnancy cat.	X, no human data existing, teratogenic potential in animal studies
Legal status	Schedule IV (USA)
Routes	Oral

Sibutramine (Meridia® in the USA, Reductil® in Europe), usually as sibutramide hydrochloride monohydrate, is an orally administered agent for the treatment of obesity. It is a centrally-acting stimulant chemically related to amphetamine, methamphetamine, and phentermine (one of the drugs in the Fen-Phen combination). Sibutramine is classified as a Schedule IV controlled substance in the United States.

Pharmacokinetics

Sibutramine is well absorbed from the GI-Tract (77%), but undergoes a considerable first-pass metabolism reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a halflife of 1 hour. Sibutramine is metabolized by cytochrome-P450-isoenzyme CYP3A4 resulting in 2 active primary and secondary amines (called active metabolites 1 and 2) with halflives of 14 and 16 hours, respectively. Peak plasma concentrations of active metabolites 1 and 2 are reached after 3 to 4 hours. The following metabolic pathway mainly results in two inactive conjugated and hydroxylated metabolites (called metabolites 5 and 6). Metabolites 5 and 6 are mainly excreted in the urine.

Pharmacological aspects

Sibutramine is a neurotransmitter reuptake inhibitor that helps enhance satiety by inhibiting the reuptake of serotonin (by 73%), norepinephrine (by 54%), and dopamine (by 16%); as such it is a satiety enhancer (i.e. it enhances satiety). Despite its actions upon the aforementioned neurotransmitters, sibutramine has never demonstrated any antidepressant properties. It was approved by the Food and Drug Administration (FDA) in November 1997^[1] for the treatment of obesity.

Sibutramine acts by increasing serotonin and noradrenaline levels in the brain. The serotonergic action, in particular, is thought to influence appetite.

Contraindications

Sibutramine is contraindicated in:

• Psychiatric conditions as bulimia nervosa, anorexia nervosa, serious depression or preexisting mania
• Patients with a history of or a predisposition to drug or alcohol abuse
• Hypersensitivity to the drug
• Patients below 18 years of age
• Concomitant treatment with a MAO inhibitor, antidepressant or other centrally active drugs, particular other anoretics
• Hypertension that is not sufficiently controlled (caution in controlled hypertension)
• Existing pulmonal hypertension
• Existing damage on heart valves, coronary heart disease, congestive heart failure, serious arrhythmias, previous myocardial infarction
• Stroke or transient ischemic attack (TIA)
• Hyperthyroidism (overactive thyroid gland)
• Closed angle glaucoma
• Seizure disorders
• Enlargement of the prostate gland with urinary retention
• Phaeochromocytoma
• Pregnant and lactating women

Side-effects

Frequently encountered side-effects are: dry mouth, paradoxically increased appetite, nausea, strange taste in the mouth, upset stomach, constipation, trouble sleeping, dizziness, drowsiness, menstrual cramps/pain, headache, flushing, or joint/muscle pain.

The following side effects are infrequent but serious and require immediate medical attention: cardiac arrhythmias, paresthesia, mental/mood changes (e.g., excitement, restlessness, confusion, depression, rare thoughts of suicide).

Symptoms that require urgent medical attention are seizures, problems urinating, abnormal bruising or bleeding, melena, hematemesis, jaundice, fever and rigors, chest pain, hemiplegia, abnormal vision, dyspnea and edema.

Currently, no case of pulmonary hypertension has been noted, although related compounds (such as Fen-Phen) have shown this rare but clinically significant problem.

Interactions

Sibutramine has a number of clinically significant interactions^{[citation needed]}.

Dosage

10mg once daily (usually in the morning), if this proves insufficient the dose may be increased to 15mg daily after 4 weeks.

Safety concerns

Studies are ongoing into reports of sudden death, heart failure, renal failure and gastrointenstinal problems. Despite a petitions by Ralph Nader-founded NGO Public Citizen^[2], the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005^[3].

A large randomized-controlled study with over 9000 patients (SCOUT) is currently ongoing to examine whether or not sibutramine reduces the risk for cardiovascular complications in people at high risk for heart disease.^[4]