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Sibutramine

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Sibutramine chemical structure
Sibutramine

1-(4-chlorophenyl)-N,N-dimethyl-a-(2-methylpropyl)-
cyclobutanemethanamine
IUPAC name
CAS number
106650-56-0
ATC code

A08AA10

PubChem
5210
DrugBank
APRD00456
Chemical formula {{{chemical_formula}}}
Molecular weight 279.85 g/mol
Bioavailability Resorption 77%, considerable first-pass metabolism
Metabolism Hepatic (CYP3A4-mediated)
Elimination half-life sibutramine approx. 1 hour</br>Metabolite 1: 14 hours</br>Metabolite 2: 16 hours
Excretion Biliary (sibutramine and active metabolites), renal (inactive metabolites)
Pregnancy category X, no human data existing, teratogenic potential in animal studies
Legal status {{{legal_status}}}
Routes of administration 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 amphetamines.[1] Sibutramine is classified as a Schedule IV controlled substance in the United States.

Sibutramine's manufacturer is Abbott Laboratories.

PharmacokineticsEdit

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.

Pharmacological aspectsEdit

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[2] 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.

ContraindicationsEdit

Sibutramine is contraindicated in:

Side effectsEdit

Frequently encountered side effects are: dry mouth, paradoxically increased appetite, nausea, strange taste in the mouth, anorgasmia and delayed ejaculation, 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.

InteractionsEdit

Sibutramine has a number of clinically significant interactions. The concomitant use of sibutramine and monoamine oxidase inhibitors (MAOIs, such as selegiline) is not indicated, as it may increase the risk of serotonin syndrome, a somewhat rare but serious adverse drug reaction.[3] Sibutramine should not be taken less than two weeks after stopping or before starting use of an MAOI. Taking both sibutramine and certain medications used in the treatment of migraines—such as ergolines and triptans—, as well as opioids, may also increase the risk for serotonin syndrome, as may the use of more than one serotonin reuptake inhibitor at the same time.[3]

The concomitant use of sibutramine and drugs which inhibit CYP3A4, such as ketoconazole and erythromycin, may increase plasma levels of sibutramine.[4] Sibutramine has no effect on the efficacy of oral contraceptives.[3]

DosageEdit

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

Safety concernsEdit

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,[5] the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005.[6] Similarly, Dr. David Graham, FDA "whistleblower", testified before a Senate Finance Committee hearing that sibutramine may be more dangerous than the conditions it is used for.[7]

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.[8]

ReferencesEdit

  1. (2002). New Drugs. Australian Prescriber 25 (1): 22. PDF
  2. U.S. Food and Drug Administration (November 24 1997). FDA APPROVES SIBUTRAMINE TO TREAT OBESITY. Press release. Retrieved on 2007-04-29.
  3. 3.0 3.1 3.2 (2007). Meridia Side Effects, and Drug Interactions. RxList.com. URL accessed on 2007-04-29.
  4. (Portuguese) Cloridrato de sibutramina monoidratado. Bula. [Sibutramine hydrochloride monohydrate—label information]. Medley (2007).
  5. Wolfe, Sidney M., Larry D. Sasich, Elizabeth Barbehenn Petition to FDA to ban the diet drug sibutramine (MERIDIA) (HRG Publication #1613). Public Citizen. URL accessed on 2007-04-29.
  6. Bruce Japsen. "FDA weighs decision on Meridia ; Health advisory likely for Abbott obesity drug". Chicago Tribune. Chicago, Ill.: Mar 13, 2005. pg. 1.
  7. Hearing of 17 November 2004. Related CBS news item 19 November 2004.
  8. 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.

External linksEdit


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