Sibutramine
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Sibutramine
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| Systematic (IUPAC) name | |
| 1-(4-chlorophenyl)-N,N-dimethyl-a-(2-methylpropyl)- cyclobutanemethanamine |
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| Identifiers | |
| CAS number | 106650-56-0 |
| ATC code | A08AA10 |
| PubChem | 5210 |
| DrugBank | APRD00456 |
| Chemical data | |
| Formula | C17H26NCl |
| Mol. weight | 279.85 g/mol |
| Pharmacokinetic data | |
| Bioavailability | Resorption 77%, considerable first-pass metabolism |
| Metabolism | Hepatic (CYP3A4-mediated) |
| Half life | sibutramine approx. 1 hour Metabolite 1: 14 hours Metabolite 2: 16 hours |
| Excretion | Biliary (sibutramine and active metabolites), renal (inactive metabolites) |
| Therapeutic considerations | |
| Pregnancy cat. |
X, no human data existing, teratogenic potential in animal studies |
| Legal status | |
| Routes | Oral |
Sibutramine (trade name 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.
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[edit] Pharmacokinetics
Sibutramine is well absorbed from the GI tract (77%), but undergoes considerable first-pass metabolism reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a half-life of 1 hour. Sibutramine is metabolized by cytochrome P450 isozyme CYP3A4 resulting in 2 active primary and secondary amines (called active metabolites 1 and 2) with half-lives 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.
[edit] Pharmacological aspects
Sibutramine is a neurotransmitter reuptake inhibitor that helps enhance satiety by inhibiting the reuptake of serotonin (by 53%), norepinephrine (by 54%), and dopamine (by 16%). Despite its actions upon the aforementioned neurotransmitters, sibutramine has never demonstrated any antidepressant properties. It was approved by the U.S. Food and Drug Administration (FDA) in November 1997[1] for the treatment of obesity.
Sibutramine acts by increasing serotonin and norepinephrine levels in the brain. The serotonergic action, in particular, is thought to influence appetite.
[edit] 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 pulmonary 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
[edit] 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.
Sibutramine can substantially increase blood pressure and pulse in some patients. Therefore all patients treated with sibutramine should have regular monitoring of blood pressure and pulse.
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.
[edit] Interactions
Sibutramine has a number of clinically significant interactions.[citation needed]
[edit] Dosage
10mg once daily (usually in the morning), if this proves insufficient the dose may be increased to 15mg daily after 4 weeks.
[edit] Safety concerns
Studies are ongoing into reports of sudden death, heart failure, renal failure and gastrointestinal problems. Despite a petition 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] Similarly, Dr. David Graham, FDA "whistleblower", testified before a Senate Finance Committee hearing that sibutramine may be more dangerous that the conditions it is used for.[4]
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.[5]
[edit] References
- ^ FDA 1997 approval.
- ^ Petition by Public Citizen to FDA to withdraw sibutramine
- ^ Bruce Japsen. "FDA weighs decision on Meridia ; Health advisory likely for Abbott obesity drug". Chicago Tribune. Chicago, Ill.: Mar 13, 2005. pg. 1.
- ^ Hearing of 17 November 2004. Related CBS news item 19 November 2004.
- ^ James WPT. The SCOUT study: risk-benefit profile of sibutramine in overweight high-risk cardiovascular patients. Eur Heart J 2005;7 Suppl;L44-48. Abstract.
[edit] External links
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