Alvimopan

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Alvimopan
Alvimopan2DCSD.svg
Alvimopan3DanJ.gif
Systematic (IUPAC) name
2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl) -3-phenylpropanoyl]amino)acetic acid
Clinical data
Trade names Entereg
AHFS/Drugs.com monograph
MedlinePlus a608051
Licence data US FDA:link
Pregnancy cat. B (US)
Legal status -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 6%
Protein binding 80% (parent drug), 94% (metabolite)
Metabolism Gut microflora-mediated hydrolysis to active metabolite
Half-life 10-17 hours
Excretion Faeces, urine (35%)
Identifiers
CAS number 156053-89-3 N
ATC code A06AH02
PubChem CID 5488548
DrugBank DB06274
ChemSpider 4589864 YesY
UNII Q153V49P3Z N
ChEMBL CHEMBL270190 YesY
Synonyms Alvimopan, Entereg
Chemical data
Formula C25H32N2O4 
Mol. mass 424.53 g/mol
 N (what is this?)  (verify)

Alvimopan (trade name Entereg) is a drug which behaves as a peripherally acting μ-opioid antagonist. With limited ability to cross the blood–brain barrier, many of the undesirable side-effects of the opioid agonists such as constipation are minimized without affecting analgesia or precipitating withdrawal.[1][2] It is currently only Food and Drug Administration approved for the treatment of postoperative ileus which it received in May 2008.[3][4]

Indication[edit]

Alvimopan is indicated in patients to avoid postoperative ileus following partial large or small bowel resection with primary anastomosis. Alvimopan accelerates the gastrointestinal recovery period as defined by time to first bowel movement or flatus.[5]

Adverse effects[edit]

The most common side effects associated with alvimopan are:[1]

Adverse Effect Frequency (%) with placebo Frequency (%) with alvimpoan
Dyspepsia 4.6 7.0
Hypokalemia 8.5 9.5
Back Pain 1.7 3.3
Delayed Micturition 2.1 3.2

Contraindications[edit]

Alvimopan is absolutely contraindicated in patients who have taken therapeutic doses of opioids for more than seven consecutive days immediately prior to when alvimopan would be initiated because individuals with recent exposure to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists. The peripheral site of action of alvimopan suggests that such a heightened sensitivity would precipitate gastrointestinal effects beyond dyspepsia.[5]

Drug interactions[edit]

Alvimopan is not substrate for the cytochrome P450 enzyme system. Therefore, no interactions are expected with hepatically metabolized drugs. Alvimopan is substrate for p-glycoprotein. Expect interactions with known p-glycoprotein inhibitors such as amiodarone, depridil, diltiazem, cyclosporine, itraconazole, quinine, quinidine, spironolactone, and verapamil.[5]

Mechanism of action[edit]

Alvimopan competitively binds to mu-opioid receptor in the gastrointestinal tract. Unlike methylnaltrexone (another peripherally acting mu-receptor antagonist) that bears a quaternary amine, alvimopan owes its selectivity for peripheral receptors to its kinetics. Alvimopan binds to peripheral mu-receptors with a Ki of 0.2 ng/mL and dissociates slower than most other ligands.[5]

Pharmacokinetics[edit]

Absorption[edit]

Peak plasma concentration (Cmax) of alvimopan is reached approximately 2 hours after oral dosing, while the Cmax for metabolite occurs 36 hours after an oral dose. Alvimopan's high affinity for the peripheral mu-receptor results in an absolute bioavailability less than 7%. [5]

Distribution[edit]

80% to 90% of systemically available alvimopan is bound to plasma protein. At steady state, the volume of distribution is approximately 30 liters.[5]

Metabolism[edit]

Alvimopan undergoes no significant hepatic metabolism, but is metabolized by intestinal flora. Gut metabolism produces an active metabolite with no clinically significant contribution to drug effect.[5]

Elimination[edit]

Alvimopan undergoes 35% renal excretion and greater than 50% biliary excretion. Drug metabolized by intestinal flora is excreted in the feces. Alvimopan's half-life of elimination is 10 to 17 hours, while that of the gut metabolite is 10 to 18 hours.[5]

Dosing and administration[edit]

Alvimopan is only approved for short term use of no more than 15 doses. It is available on an inpatient basis at institutions approved by and registered with the Entereg Access Support and Education (E.A.S.E.) program. The drug is a 12 mg blue hard gelatin capsule. The recommended adult dose is to administer 12 mg 30 minutes to 5 hours preoperatively and 12 mg twice daily for seven days postoperatively. A patient should receive no more than 15 doses.[5]

References[edit]

  1. ^ a b Neary P, Delaney P (2005). "Alvimopan". Expert Opin Investig Drugs 14 (4): 479–88. doi:10.1517/13543784.14.4.479. PMID 15882122. 
  2. ^ Schmidt WK (2001). "Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist". Am J Surg 182 (5A Supp): 27S–38S. doi:10.1016/S0002-9610(01)00784-X. PMID 11755894. 
  3. ^ FDA press release - FDA Approves Entereg to Help Restore Bowel Function Following Surgery
  4. ^ Sharma, A; Jamal, MM (July 2013). "Opioid induced bowel disease: a twenty-first century physicians' dilemma. Considering pathophysiology and treatment strategies.". Current Gastroenterology Reports 15 (7): 334. doi:10.1007/s11894-013-0334-4. PMID 23836088. 
  5. ^ a b c d e f g h i Alvimopan Product Label as approved by the FDA on May 20, 2008.