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==Pharmacokinetics==
==Pharmacokinetics==


When given orally, rivastigmine is well absorbed, with a bioavailability of about 40% in the 3-mg dose. Pharmacokinetics are linear up to 3&nbsp;mg [[List of medical abbreviations: B|BID]], but nonlinear at higher doses. Elimination is through the urine. Peak plasma concentrations are seen in about one hour, with peak cerebrospinal fluid concentrations at 1.4–3.8 hours. When given by once-daily transdermal patch, the pharmacokinetic profile of rivastigmine is much smoother, compared with capsules, with lower peak plasma concentrations and reduced fluctuations.<ref name= Cummings>Cummings J, Lefevre G, Small G, Appel-Dingemanse S. “Pharmacokinetic rationale for the rivastigmine patch”. Neurology. 2007 Jul 24;69(4 Suppl 1):S10–3. PMID 17646618</ref> The 9.5&nbsp;mg/24 h rivastigmine patch provides comparable exposure to 12&nbsp;mg/day capsules (the highest recommended oral dose).<ref name=Cummings />
When given orally, rivastigmine is well absorbed, with a bioavailability of about 40% in the 3-mg dose. Pharmacokinetics are linear up to 3&nbsp;mg [[List of medical abbreviations: B|BID]], but nonlinear at higher doses. Elimination is through the urine. Peak plasma concentrations are seen in about one hour, with peak cerebrospinal fluid concentrations at 1.4–3.8 hours. When given by once-daily transdermal patch, the pharmacokinetic profile of rivastigmine is much smoother, compared with capsules, with lower peak plasma concentrations and reduced fluctuations.<ref name= Cummings>{{Cite doi| 10.1212/01.wnl.0000281846.40390.50}}</ref> The 9.5&nbsp;mg/24 h rivastigmine patch provides comparable exposure to 12&nbsp;mg/day capsules (the highest recommended oral dose).<ref name=Cummings />


The compound does cross the blood–brain barrier. Plasma protein binding is 40%.<ref>Jann MW, Shirley KL, Small GW. “Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors”. Clin Pharmacokinet. 2002;41(10):719–739. PMID 12162759</ref> The major route of metabolism is by its target enzymes via cholinesterase-mediated hydrolysis. Elimination bypasses the hepatic system, so hepatic cytochrome P450 (CYP) isoenzymes are not involved.<ref>Jann MW. “Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease”. Pharmacotherapy. 2000 20(1):1–12. PMID 10641971.</ref> The low potential for drug-drug interactions (which could lead to adverse effects) has been suggested as due to this pathway compared to the many common drugs that use the cytochrome P450 metabolic pathway.<ref name=Inglis/>
The compound does cross the blood–brain barrier. Plasma protein binding is 40%.<ref>{{Cite doi|10.2165/00003088-200241100-00003}}</ref> The major route of metabolism is by its target enzymes via cholinesterase-mediated hydrolysis. Elimination bypasses the hepatic system, so hepatic cytochrome P450 (CYP) isoenzymes are not involved.<ref>{{Cite doi|10.1592/phco.20.1.1.34664}}</ref> The low potential for drug-drug interactions (which could lead to adverse effects) has been suggested as due to this pathway compared to the many common drugs that use the cytochrome P450 metabolic pathway.<ref name=Inglis/>


==Synthesis==
==Synthesis==

Revision as of 23:39, 26 November 2013

Rivastigmine
Clinical data
Trade namesExelon
AHFS/Drugs.comMonograph
MedlinePlusa602009
Routes of
administration		Oral, Transdermal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability96%
Protein binding40%
MetabolismHepatic, via pseudocholinesterase
Elimination half-life1.5 hours
ExcretionRenal, 97%
Identifiers
  • (S)-3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.120.679 Edit this at Wikidata
Chemical and physical data
FormulaC14H22N2O2
Molar mass250.337 g/mol g·mol−1
3D model (JSmol)
  • O=C(Oc1cc(ccc1)[C@@H](N(C)C)C)N(CC)C
  • InChI=1S/C14H22N2O2/c1-6-16(5)14(17)18-13-9-7-8-12(10-13)11(2)15(3)4/h7-11H,6H2,1-5H3/t11-/m0/s1 checkY
  • Key:XSVMFMHYUFZWBK-NSHDSACASA-N checkY
 ☒NcheckY (what is this?)  (verify)

Rivastigmine (sold under the trade name Exelon) is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects,[1] which typically include nausea and vomiting.[2] The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.[2]

History

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology, at the Hebrew University of Jerusalem[3] and sold to Novartis by Yissum for commercial development.(It is a semi-synthetic derivative of physostigmine)[4] It has been available in capsule and liquid formulations since 1997.[5] In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's disease;[6] and in 2007 the rivastigmine transdermal patch became the first patch treatment for dementia.

Administration

Rivastigmine tartrate is a white to off-white, fine crystalline powder that is both lipophilic (soluble in fats) and hydrophilic (soluble in water). Like other cholinesterase inhibitors, it requires doses to be increased gradually over several weeks; this is usually referred to as the titration phase.[2] Oral doses of rivastigmine should be titrated with a 3 mg per day increment every 2 to 4 weeks.

Rivastigmine is classified as pregnancy category B, with insufficient data on risks associated with breastfeeding. In cases of overdose, atropine is used to reverse bradycardia. Dialysis is ineffective due to the drug's half-life.

Pharmacodynamics

Rivastigmine, an acetylcholinesterase inhibitor, inhibits both butyrylcholinesterase and acetylcholinesterase (unlike donepezil, which selectively inhibits acetylcholinesterase). It is thought to work by inhibiting these cholinesterase enzymes, which would otherwise break down the brain neurotransmitter acetylcholine.[7]

Indication

The U.S. Food and Drug Administration has approved rivastigmine capsules and patches for the treatment of mild to moderate dementia of the Alzheimer’s type and for mild to moderate dementia related to Parkinson's disease. It has been used in more than 6 million patients worldwide.[citation needed]

Rivastigmine has demonstrated significant treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems commonly associated with Alzheimer’s[8][9][10][11] and Parkinson's disease dementias.[12]

Efficacy

In patients with either type of dementia, rivastigmine has been shown to provide meaningful symptomatic effects that may allow patients to remain independent and ‘be themselves’ for longer. In particular, it appears to show marked treatment effects in patients showing a more aggressive course of disease, such as those with younger onset ages, poor nutritional status, or those experiencing symptoms such as delusions or hallucinations.[13] For example, the presence of hallucinations appears to be a predictor of especially strong responses to rivastigmine, both in Alzheimer’s and Parkinson's patients.[14][15] These effects might reflect the additional inhibition of butyrylcholinesterase, which is implicated in symptom progression and might provide added benefits over acetylcholinesterase-selective drugs in some patients.[13][14] Multiple-infarct dementia patients may show slight improvement in executive functions and behaviour. No firm evidence supports usage in schizophrenia patients.

Its efficacy is similar to donepezil and tacrine. Doses below 6 mg/d may be ineffective. The effects of this kind of drug in different kinds of dementia (including Alzheimer's dementia) are modest, and it is still unclear which AcCh(ButCh) esterase inhibitor is better in Parkinson's dementia, though rivastigmine is well-studied.

Side effects

Side effects may include nausea and vomiting.[2]

The strong potency of rivastigmine, provided by its dual inhibitory mechanism, has been postulated to lead to more nausea and vomiting during the titration phase of oral rivastigmine treatment.[2] This enforces the importance of taking oral forms of these drugs with food as prescribed.[5] However, rates of nausea and vomiting are markedly reduced with the once-daily rivastigmine patch (which can be applied at any time of the day, with or without food).

In a large clinical trial of the rivastigmine patch in 1,195 patients with Alzheimer’s disease, the target dose of 9.5 mg/24-hour patch provided similar clinical effects (e.g. memory and thinking, activities of daily living, concentration) as the highest doses of rivastigmine capsules, but with one-third fewer reports of nausea and vomiting.[1]

Pharmacokinetics

When given orally, rivastigmine is well absorbed, with a bioavailability of about 40% in the 3-mg dose. Pharmacokinetics are linear up to 3 mg BID, but nonlinear at higher doses. Elimination is through the urine. Peak plasma concentrations are seen in about one hour, with peak cerebrospinal fluid concentrations at 1.4–3.8 hours. When given by once-daily transdermal patch, the pharmacokinetic profile of rivastigmine is much smoother, compared with capsules, with lower peak plasma concentrations and reduced fluctuations.[16] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose).[16]

The compound does cross the blood–brain barrier. Plasma protein binding is 40%.[17] The major route of metabolism is by its target enzymes via cholinesterase-mediated hydrolysis. Elimination bypasses the hepatic system, so hepatic cytochrome P450 (CYP) isoenzymes are not involved.[18] The low potential for drug-drug interactions (which could lead to adverse effects) has been suggested as due to this pathway compared to the many common drugs that use the cytochrome P450 metabolic pathway.[2]

Synthesis

R. Amstutz, A. Enz, M. Marzi, M. Boelsterli, M. Walsinshaw [19]


See also

References

  1. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1212/01.wnl.0000281847.17519.e0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1212/01.wnl.0000281847.17519.e0 instead.
  2. ^ a b c d e f Template:Cite PMID
  3. ^ "Exelon". Yissum Technology Transfer. Retrieved 7 October 2010.
  4. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/ptr.1970, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/ptr.1970 instead.
  5. ^ a b Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006
  6. ^ “FDA Approves the First Treatment for Dementia of Parkinson’s Disease” U.S. FDA News Release [1]
  7. ^ Camps P. Munoz-Torrero D. “Cholinergic drugs in pharmacotherapy of Alzheimer's disease”. Mini Rev Med Chem. 2002 Feb;2(1):11–25. PMID 12369954
  8. ^ Corey-Bloom J, Anand R, Veach J. “A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease”. Int J Geriatr Psychopharmacol. 1998;1:55–65.
  9. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1136/bmj.318.7184.633, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1136/bmj.318.7184.633 instead.
  10. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S0149-2918(04)90172-5, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S0149-2918(04)90172-5 instead.
  11. ^ Template:Cite PMID
  12. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1056/NEJMoa041470, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1056/NEJMoa041470 instead.
  13. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.jalz.2006.03.002, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.jalz.2006.03.002 instead.
  14. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1185/030079906X80279, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1185/030079906X80279 instead.
  15. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/mds.21077, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/mds.21077 instead.
  16. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1212/01.wnl.0000281846.40390.50, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1212/01.wnl.0000281846.40390.50 instead.
  17. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.2165/00003088-200241100-00003, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.2165/00003088-200241100-00003 instead.
  18. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1592/phco.20.1.1.34664, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1592/phco.20.1.1.34664 instead.
  19. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/hlca.19900730323, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/hlca.19900730323 instead.
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