Rivastigmine

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Rivastigmine
Rivastigmine chemical structure.svg
Rivastigmine ball-and-stick.png
Clinical data
Trade names Exelon, others
AHFS/Drugs.com Monograph
MedlinePlus a602009
License data
Pregnancy
category
  • AU:B2
Routes of
administration 		By mouth, transdermal patch
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60 to 72%
Protein binding 40%
Metabolism Liver, via pseudocholinesterase
Elimination half-life 1.5 hours
Excretion 97% in urine
Identifiers
  • (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 InfoCard 100.120.679 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H22N2O2
Molar mass 250.342 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 Yes check.svgY
  • Key:XSVMFMHYUFZWBK-NSHDSACASA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Rivastigmine, sold under the brand name Exelon among others, is an acetylcholinesterase inhibitor used for the treatment of dementia associated with Alzheimer's disease and with Parkinson's disease. [4] [6] [7] Rivastigmine can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, [8] which typically include nausea and vomiting. [9]

Contents

Rivastigmine is eliminated through the urine, and appears to have relatively few drug-drug interactions. [9]

It was patented in 1985 and came into medical use in 1997. [10]

Medical uses

Rivastigmine is indicated for the treatment of dementia of the Alzheimer's type; [4] and for the treatment of dementia associated with Parkinson's disease. [4]

Rivastigmine capsules, liquid solution and patches are used for the treatment of mild to moderate dementia of the Alzheimer's type, and for mild to moderate Parkinson's disease dementia. [11]

Rivastigmine has demonstrated treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems commonly associated with Alzheimer's. [12] [13] [14] [15]

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. [16] 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. [17] [18] 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. [16] [17] 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. [9]

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. [9]

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. [8]

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; this increase could be related to improper application of the transdermal patch, or because rivastigmine is more often used during advanced illness. [19]

Rivastigmine can increase gastric acid; it is discontinued if there are signs of gastrointestinal bleeding, particularly in individuals using nonsteroidal anti-inflammatory drugs (NSAIDs) or who have a history of peptic ulcer disease. [20]

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. [9]

Pharmacology

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. [21]

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 twice daily, 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. [22] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose). [22]

The compound does cross the blood–brain barrier. Plasma protein binding is 40%. [23] 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. [24] 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. [9]

A QbD driven HPLC method was developed for the quantification of rivastigmine in rat plasma and brain for its pharmacokinetics study [ [25] ].

History

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology at the Hebrew University of Jerusalem [26] and sold to Novartis by Yissum for commercial development. It is a semi-synthetic derivative of physostigmine. [27]

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References

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  2. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ↑ "Product monograph brand safety updates". Health Canada . 7 July 2016. Archived from the original on 29 March 2024. Retrieved 1 April 2024.
  4. 1 2 3 4 "Exelon- rivastigmine patch, extended release". DailyMed. 8 May 2024. Retrieved 16 August 2024.
  5. ↑ "Prometax EPAR". European Medicines Agency (EMA). 4 December 1998. Archived from the original on 22 June 2021. Retrieved 16 August 2024.
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  13. ↑ Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al. (March 1999). "Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial". BMJ. 318 (7184): 633–638. doi:10.1136/bmj.318.7184.633. PMC   27767 . PMID   10066203.
  14. ↑ Finkel SI (July 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.
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  17. 1 2 Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R (January 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.
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  19. ↑ 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.
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  21. ↑ Camps P, Muñoz-Torrero D (February 2002). "Cholinergic drugs in pharmacotherapy of Alzheimer's disease". Mini Reviews in Medicinal Chemistry. 2 (1): 11–25. doi:10.2174/1389557023406638. PMID   12369954.
  22. 1 2 Cummings J, Lefèvre G, Small G, Appel-Dingemanse S (July 2007). "Pharmacokinetic rationale for the rivastigmine patch". Neurology. 69 (4 Suppl 1): S10–S13. doi:10.1212/01.wnl.0000281846.40390.50. PMID   17646618. S2CID   21290898.
  23. ↑ Jann MW, Shirley KL, Small GW (2002). "Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors". Clinical Pharmacokinetics. 41 (10): 719–739. doi:10.2165/00003088-200241100-00003. PMID   12162759. S2CID   22768375.
  24. ↑ Jann MW (January 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.
  25. ↑ Gopalan D, Patil PH, Jagadish PC, Kini SG, Alex AT, Udupa N, et al. (5 June 2022). "QbD-driven HPLC method for the quantification of rivastigmine in rat plasma and brain for pharmacokinetics study". Journal of Applied Pharmaceutical Science. 12 (6): 056–067. doi: 10.7324/JAPS.2022.120606 . eISSN   2231-3354. Archived from the original on 23 May 2024. Retrieved 6 March 2024.
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