Rivastigmine

Last updated
Rivastigmine
Rivastigmine chemical structure.svg
Rivastigmine ball-and-stick.png
Clinical data
Trade names Exelon, Prometax, 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 trade name Exelon among others) is a cholinesterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. [4] The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, [5] which typically include nausea and vomiting. [6]

Contents

The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions. [6]

It was patented in 1985 and came into medical use in 1997. [7]

Medical uses

Rivastigmine capsules, liquid solution and patches are used for the treatment of mild to moderate dementia of the Alzheimer's type, and in the UK for mild to moderate Parkinson's disease dementia. [8]

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

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. [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 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. [6]

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. [6]

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. [5]

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. [16]

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. [17]

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. [6]

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. [18]

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. [19] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose). [19]

The compound does cross the blood–brain barrier. Plasma protein binding is 40%. [20] 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. [21] 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. [6]

A QbD driven HPLC method was developed for the quantification of rivastigmine in rat plasma and brain for its pharmacokinetics study [ [22] ]. The developed method was selective and showed good linearity with recovery ranging between 96.73%–109.81% in plasma and 93.42%–108.39% in the brain.

History

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology at the Hebrew University of Jerusalem [23] and sold to Novartis by Yissum for commercial development. It is a semi-synthetic derivative of physostigmine. [24]

Related Research Articles

<span class="mw-page-title-main">Donepezil</span> Medication used for dementia

Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to change the progression of the disease. Treatment should be stopped if no benefit is seen. It is taken by mouth or via a transdermal patch.

<span class="mw-page-title-main">Galantamine</span> Neurological medication

Galantamine is an alkaloid extracted from the bulbs and flowers of Galanthus nivalis, Galanthus caucasicus, Galanthus woronowii, and other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata. It can also be produced synthetically.

<span class="mw-page-title-main">Selegiline</span> Monoamine oxidase inhibitor

Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Emsam, Selgin, among other names, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or tablet taken by mouth or orally disintegrating tablets taken on the tongue for Parkinson's disease and as a patch applied to skin for depression.

<span class="mw-page-title-main">Memantine</span> Medication used to treat Alzheimers disease

Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.

<span class="mw-page-title-main">Huperzine A</span> Chemical compound

Huperzine A is a naturally-occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata and in varying quantities in other food Huperzia species, including H. elmeri, H. carinat, and H. aqualupian. Huperzine A has been investigated as a treatment for neurological conditions such as Alzheimer's disease, but a 2013 meta-analysis of those studies concluded that they were of poor methodological quality and the findings should be interpreted with caution. Huperzine A inhibits the breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase. It is commonly available over the counter as a nutritional supplement and marketed as a memory and concentration enhancer.

<span class="mw-page-title-main">Cinnarizine</span> Antihistamine and calcium channel blocker medication

Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. It is prescribed for nausea and vomiting due to motion sickness or other sources such as chemotherapy, vertigo, or Ménière's disease.

<span class="mw-page-title-main">Oxybutynin</span> Medication for overactive bladder

Oxybutynin, sold as under the brand name Ditropan among others, is an anticholinergic drug primarily used to treat overactive bladder. It is widely considered a first-line therapy for overactive bladder due to its well-studied side effect profile, broad applicability, and continued efficacy over long periods of time. It works similar to tolterodine, darifenacin, and solifenacin, although it is usually preferred over these medications. It is sometimes used off-label for treatment of hyperhidrosis, or excessive sweating. It has also been used off-label to treat bed wetting in children, but this use has declined, as it is most likely ineffective in this role. It is taken by mouth or applied to the skin.

Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individual's age and education but which are not significant enough to interfere with instrumental activities of daily living. MCI may occur as a transitional stage between normal aging and dementia, especially Alzheimer's disease. It includes both memory and non-memory impairments. The cause of the disorder remains unclear, as well as both its prevention and treatment, with some 50 percent of people diagnosed with it going on to develop Alzheimer's disease within five years. The diagnosis can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.

<span class="mw-page-title-main">Tesofensine</span> Chemical compound

Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was originally developed by a Danish biotechnology company, NeuroSearch, who transferred the rights to Saniona in 2014.

Solanezumab is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but it has failed to show promise in Phase III trials.

<span class="mw-page-title-main">Pimavanserin</span> Atypical antipsychotic medication

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis and is also being studied for the treatment of Alzheimer's disease psychosis, schizophrenia, agitation, and major depressive disorder. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist.

<span class="mw-page-title-main">Acetylcholinesterase inhibitor</span> Drugs that inhibit acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors. Acetylcholinesterase is the primary member of the cholinesterase enzyme family.

<span class="mw-page-title-main">Cholinesterase inhibitor</span> Chemicals which prevent breakdown of acetylcholine and butyrylcholine

Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. This increases the amount of the acetylcholine or butyrylcholine in the synaptic cleft that can bind to muscarinic receptors, nicotinic receptors and others. This group of inhibitors is divided into two subgroups, acetylcholinesterase inhibitors (AChEIs) and butyrylcholinesterase inhibitors (BChEIs).

<span class="mw-page-title-main">Ladostigil</span> Chemical compound

Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders like Alzheimer's disease, Lewy body disease, and Parkinson's disease. It acts as a reversible acetylcholinesterase and butyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule. In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis. Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.

<span class="mw-page-title-main">Cymserine</span> Chemical compound

Cymserine is a drug related to physostigmine, which acts as a reversible cholinesterase inhibitor, with moderate selectivity (15×) for the plasma cholinesterase enzyme butyrylcholinesterase, and relatively weaker inhibition of the better-known acetylcholinesterase enzyme. This gives it a much more specific profile of effects that may be useful for treating Alzheimer's disease without producing side effects such as tremors, lacrimation, and salivation that are seen with the older nonselective cholinesterase inhibitors currently used for this application, such as donepezil. A number of cymserine derivatives have been developed with much greater selectivity for butyrylcholinesterase, and both cymserine and several of its analogues have been tested in animals, and found to increase brain acetylcholine levels and produce nootropic effects, as well as reducing levels of amyloid precursor protein and amyloid beta, which are commonly used biomarkers for the development of Alzheimer's disease.

Methanesulfonyl fluoride (MSF) has long been known to be a potent inhibitor of acetylcholinesterase (AChE), the enzyme that regulates acetylcholine, an important neurotransmitter in both the central and peripheral nervous systems.

<span class="mw-page-title-main">Phenserine</span> Chemical compound

Phenserine is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

<span class="mw-page-title-main">Buntanetap</span> Chemical compound

Buntanetap is an orally-administered small molecule inhibitor of several neurotoxic proteins that is under investigation in the treatment of Alzheimer's disease, frontotemporal dementia, chronic traumatic encephalopathy and Parkinson's disease. It is the (+) enantiomer of phenserine, as the (-) enantiomer also has unwanted anticholinergic effects. It is currently in phase III trials for the treatment of Parkinson's.

<span class="mw-page-title-main">Neuromuscular drug</span>

Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.

Memantine/donepezil, sold under the brand name Namzaric, is a fixed dose combination medication used for the treatment of dementia of the Alzheimer's type. It contains memantine, as the hydrochloride, a NMDA receptor antagonist; and donepezil as the hydrochloride, an acetylcholinesterase inhibitor. It is taken by mouth.

References

  1. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. ↑ Anvisa (2023-03-31). "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 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. ↑ "Product monograph brand safety updates". Health Canada . 7 July 2016. Retrieved 1 April 2024.
  4. ↑ Khoury R, Rajamanickam J, Grossberg GT (March 2018). "An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine". Therapeutic Advances in Drug Safety. 9 (3). SAGE Publications: 171–178. doi:10.1177/2042098617750555. PMC   5810854 . PMID   29492246.
  5. 1 2 Winblad B, Grossberg G, Frölich L, Farlow M, Zechner S, Nagel J, et al. (July 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.
  6. 1 2 3 4 5 6 Inglis F (June 2002). "The tolerability and safety of cholinesterase inhibitors in the treatment of dementia". International Journal of Clinical Practice. Supplement (127): 45–63. PMID   12139367.
  7. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 540. ISBN   9783527607495.
  8. ↑ "Recommendations - Parkinson's disease in adults". National Institute for Health and Care Excellence. 2017-07-19. Retrieved 2023-01-02.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Rösler M, Retz W, Retz-Junginger P, Dennler HJ (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.
  13. 1 2 Gauthier S, Vellas B, Farlow M, Burn D (July 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.
  14. 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.
  15. ↑ Burn D, Emre M, McKeith I, De Deyn PP, Aarsland D, Hsu C, et al. (November 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.
  16. ↑ 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.
  17. ↑ "Drug monograph: Rivastigmine". Clinical Key database. Elsevier. p. 8. Retrieved May 31, 2023.
  18. ↑ 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.
  19. 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Gopalan D, Patil PH, Jagadish PC, Kini SG, Alex AT, Udupa N, et al. (2022-06-05). "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.
  23. ↑ "Exelon". Yissum Technology Transfer. Archived from the original on 26 October 2011. Retrieved 7 October 2010.
  24. ↑ Kumar V (December 2006). "Potential medicinal plants for CNS disorders: an overview". Phytotherapy Research. 20 (12): 1023–1035. doi:10.1002/ptr.1970. PMID   16909441. S2CID   25213417.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.