Rivastigmine

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Rivastigmine
Systematic (IUPAC) name
(S)-3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate
Clinical data
Trade names Exelon
AHFS/Drugs.com monograph
MedlinePlus a602009
Pregnancy cat. B (US)
Legal status ℞-only (US)
Routes Oral, Transdermal
Pharmacokinetic data
Bioavailability 60 to 72%
Protein binding 40%
Metabolism Hepatic, via pseudocholinesterase
Half-life 1.5 hours
Excretion Renal, 97%
Identifiers
CAS number 123441-03-2 YesY
ATC code N06DA03
PubChem CID 77991
DrugBank DB00989
ChemSpider 70377 YesY
UNII PKI06M3IW0 YesY
KEGG D03822 YesY
ChEBI CHEBI:8874 N
ChEMBL CHEMBL636 YesY
Chemical data
Formula C14H22N2O2 
Mol. mass 250.337 g/mol
 N (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,[2] which typically include nausea and vomiting.[3] The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.[3]

History

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology, at the Hebrew University of Jerusalem[4] and sold to Novartis by Yissum for commercial development.(It is a semi-synthetic derivative of physostigmine)[5] It has been available in capsule and liquid formulations since 1997.[6] In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's disease;[7] 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.[3] 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.[8]

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[9][10][11][12] and Parkinson's disease dementias.[13]

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.[14] 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.[15][16] 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.[14][15] 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.[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] This enforces the importance of taking oral forms of these drugs with food as prescribed.[6] 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.[2]

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.[17] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose).[17]

The compound does cross the blood–brain barrier. Plasma protein binding is 40%.[18] 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.[19] 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]

Synthesis

R. Amstutz, A. Enz, M. Marzi, M. Boelsterli, M. Walsinshaw [1]


See also

References

  1. ↑ Amstutz, R.; Enz, A.; Marzi, M.; Boelsterli, J.; Walkinshaw, M. (1990). "Cyclische Phenyl-carbamate des Miotin-Typs und ihre Wirkung auf die Acetylcholinesterase". Helvetica Chimica Acta (in German) 73 (3): 739. doi:10.1002/hlca.19900730323. 
  2. ↑ 2.0 2.1 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. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 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. ↑ "Exelon". Yissum Technology Transfer. Retrieved 7 October 2010. 
  5. ↑ Kumar, V. (2006). "Potential medicinal plants for CNS disorders: An overview". Phytotherapy Research 20 (12): 1023–1035. doi:10.1002/ptr.1970. PMID 16909441. 
  6. ↑ 6.0 6.1 Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006
  7. ↑ Approves the First Treatment for Dementia of Parkinson’s Disease U.S. FDA News Release
  8. ↑ 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
  9. ↑ 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.
  10. ↑ 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. 
  11. ↑ 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. 
  12. ↑ 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. PMID 11568422. 
  13. ↑ Emre, M.; Aarsland, D.; Albanese, A.; Byrne, E. J.; Deuschl, G. N.; De Deyn, P. P.; Durif, F.; Kulisevsky, J.; Van Laar, T.; Lees, A.; Poewe, W.; Robillard, A.; Rosa, M. M.; Wolters, E.; Quarg, P.; Tekin, S.; Lane, R. (2004). "Rivastigmine for Dementia Associated with Parkinson's Disease". New England Journal of Medicine 351 (24): 2509–2518. doi:10.1056/NEJMoa041470. PMID 15590953. 
  14. ↑ 14.0 14.1 Gauthier, S.; Vellas, B.; Farlow, M.; Burn, D. (2006). "Aggressive course of disease in dementia". Alzheimer's & Dementia 2 (3): 210. doi:10.1016/j.jalz.2006.03.002. 
  15. ↑ 15.0 15.1 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. 
  16. ↑ 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. 
  17. ↑ 17.0 17.1 Cummings, J.; Lefevre, G.; Small, G.; Appel-Dingemanse, S. (2007). "Pharmacokinetic rationale for the rivastigmine patch". Neurology 69: S10. doi:10.1212/01.wnl.0000281846.40390.50. 
  18. ↑ 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. 
  19. ↑ 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. 
Psychoanaleptics: Antidementia agents (N06D)
Anticholinesterases
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M: PSO/PSI

mepr

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