Rivastigmine

Rivastigmine (sold under the trade name Exelon among others) is a cholinesterase inhibitor used for the treatment of mild to moderate Alzheimer's disease.[1] The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects,[2] which typically include nausea and vomiting.[3]

Rivastigmine
Clinical data
Trade namesExelon, Prometax, others
AHFS/Drugs.comMonograph
MedlinePlusa602009
License data
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth, transdermal patch
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60 to 72%
Protein binding40%
MetabolismLiver, via pseudocholinesterase
Elimination half-life1.5 hours
Excretion97% in urine
Identifiers
IUPAC name
  • (S)-3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.120.679
Chemical and physical data
FormulaC14H22N2O2
Molar mass250.342 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 Y
  • Key:XSVMFMHYUFZWBK-NSHDSACASA-N Y
 NY (what is this?)  (verify)

The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.[3]

It was patented in 1985 and came into medical use in 1997.[4]

Medical uses

Rivastigmine capsules, liquid solution and patches are used for the treatment of mild to moderate dementia of the Alzheimer's type.

Rivastigmine has demonstrated treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems commonly associated with Alzheimer's.[5][6][7][8]

Efficacy

In people 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.[9] 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.[10][11] 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.[9][10] 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 AChE (BChE) esterase inhibitor is better in Parkinson's dementia, though rivastigmine is well-studied.

Side effects

Side effects may include nausea and vomiting, decreased appetite and weight loss.[3]

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.[3]

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.[2]

Usage of rivastigmine was associated with a higher frequency of reports of death as an adverse event in the Food and Drug Administration Adverse Event Reporting System database compared to the other acetylcholinesterase inhibiting drugs donepezil and galantamine.[12]

Administration

Rivastigmine tartrate is a white to off-white, fine crystalline powder that is both lipophilic (soluble in fats) and hydrophilic (soluble in water). It comes in a variety of administrations including a capsule, solution and a transdermal patch. Like other cholinesterase inhibitors, it requires doses to be increased gradually over several weeks; this is usually referred to as the titration phase.[3]

Pharmacodynamics

Rivastigmine, a cholinesterase 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.[13]

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.[14] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose).[14]

The compound does cross the blood–brain barrier. Plasma protein binding is 40%.[15] 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.[16] 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.[3]

History

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology at the Hebrew University of Jerusalem[17] and sold to Novartis by Yissum for commercial development. It is a semi-synthetic derivative of physostigmine.[18]

References
  1. Khoury, Rita; Rajamanickam, Jayashree; Grossberg, George T. (2018-01-08). "An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine". Therapeutic Advances in Drug Safety. SAGE Publications. 9 (3): 171–178. doi:10.1177/2042098617750555. ISSN 2042-0986. PMC 5810854. PMID 29492246.
  2. Winblad, B.; Grossberg, G.; Frölich, L.; Farlow, M.; Zechner, S.; Nagel, J.; Lane, R. (2007). "IDEAL: A 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease". Neurology. 69 (4 Suppl 1): S14–S22. doi:10.1212/01.wnl.0000281847.17519.e0. PMID 17646619. S2CID 38846813.
  3. Inglis, F. (2002). "The tolerability and safety of cholinesterase inhibitors in the treatment of dementia". International Journal of Clinical Practice. Supplement (127): 45–63. PMID 12139367.
  4. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 540. ISBN 9783527607495.
  5. Corey-Bloom, J.; Anand, R.; Veach, J. (1998). "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". International Journal of Geriatric Psychopharmacology. 1 (2): 55–65.
  6. Rosler, M.; Anand, R.; Cicin-Sain, A.; Gauthier, S.; Agid, Y.; Dal-Bianco, P.; Stähelin, H. B.; Hartman, R.; Gharabawi, M.; Bayer, T. (1999). "Efficacy and safety of rivastigmine in patients with Alzheimer's disease: International randomised controlled trial Commentary: Another piece of the Alzheimer's jigsaw". BMJ. 318 (7184): 633–638. doi:10.1136/bmj.318.7184.633. PMC 27767. PMID 10066203.
  7. Finkel, S. I. (2004). "Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease". Clinical Therapeutics. 26 (7): 980–990. doi:10.1016/S0149-2918(04)90172-5. PMID 15336465.
  8. Rösler, M.; Retz, W.; Retz-Junginger, P.; Dennler, H. J. (1998). "Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer's disease". Behavioural Neurology. 11 (4): 211–216. doi:10.1155/1999/168023. PMID 11568422.
  9. Gauthier, S.; Vellas, B.; Farlow, M.; Burn, D. (2006). "Aggressive course of disease in dementia". Alzheimer's & Dementia. 2 (3): 210–217. doi:10.1016/j.jalz.2006.03.002. PMID 19595889. S2CID 30562189.
  10. Touchon, J.; Bergman, H.; Bullock, R.; Rapatz, G. N.; Nagel, J.; Lane, R. (2006). "Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology". Current Medical Research and Opinion. 22 (1): 49–59. doi:10.1185/030079906X80279. PMID 16393430. S2CID 29977831.
  11. Burn, D.; Emre, M.; McKeith, I.; De Deyn, P. P.; Aarsland, D.; Hsu, C.; Lane, R. (2006). "Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease". Movement Disorders. 21 (11): 1899–1907. doi:10.1002/mds.21077. PMID 16960863. S2CID 24621350.
  12. Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R (2015). "Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada". PLOS ONE. 10 (12): e0144337. Bibcode:2015PLoSO..1044337A. doi:10.1371/journal.pone.0144337. PMC 4671709. PMID 26642212.
  13. Camps, P. Munoz-Torrero D. (Feb 2002). "Cholinergic drugs in pharmacotherapy of Alzheimer's disease". Mini Rev Med Chem. 2 (1): 11–25. doi:10.2174/1389557023406638. PMID 12369954.
  14. Cummings, J.; Lefevre, G.; Small, G.; Appel-Dingemanse, S. (2007). "Pharmacokinetic rationale for the rivastigmine patch". Neurology. 69 (4 Suppl 1): S10–13. doi:10.1212/01.wnl.0000281846.40390.50. PMID 17646618. S2CID 21290898.
  15. Jann, M. W.; Shirley, K. L.; Small, G. W. (2002). "Clinical Pharmacokinetics and Pharmacodynamics of Cholinesterase Inhibitors". Clinical Pharmacokinetics. 41 (10): 719–739. doi:10.2165/00003088-200241100-00003. PMID 12162759. S2CID 22768375.
  16. Jann, M. W. (2000). "Rivastigmine, a New-Generation Cholinesterase Inhibitor for the Treatment of Alzheimer's Disease". Pharmacotherapy. 20 (1): 1–12. doi:10.1592/phco.20.1.1.34664. PMID 10641971. S2CID 25007829.
  17. "Exelon". Yissum Technology Transfer. Retrieved 7 October 2010.
  18. Kumar, V. (2006). "Potential medicinal plants for CNS disorders: An overview". Phytotherapy Research. 20 (12): 1023–1035. doi:10.1002/ptr.1970. PMID 16909441. S2CID 25213417.
  • "Rivastigmine". Drug Information Portal. U.S. National Library of Medicine.
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