Rivastigmine

drugbox
IUPAC_name = (S)-N-Ethyl-N-methyl-3- [1-(dimethylamino)ethyl] -phenyl carbamate hydrogen-(2R,3R)-tartrate

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CAS_number = 123441-03-2
ATC_prefix = N06
ATC_suffix = DA03
ATC_supplemental =
PubChem = 77991
DrugBank = APRD00321
C = 14 | H = 22 | N = 2 | O = 2
molecular_weight = 250.337 g/mol
bioavailability = 96%
protein_bound = 40%
metabolism = Hepatic, via pseudocholinesterase
elimination_half-life = 1.5 hours
excretion = Renal, 97%
pregnancy_US = B
legal_US = Rx-only
routes_of_administration = Oral, Transdermal

Rivastigmine (sold under the trade name Exelon) is a parasympathomimetic or cholinergic agent that was developed by Novartis for the treatment of mild to moderate dementia of the Alzheimer’s type. In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's Disease. [ “FDA Approves the First Treatment for Dementia of Parkinson’s Disease” U.S. FDA News Release [http://www.fda.gov/bbs/topics/NEWS/2006/NEW01399.html] ] Rivastigmine has been available in capsule and liquid formulations since 1997. Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [http://www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf] ] In 2007 the rivastigmine transdermal patch became the first patch treatment for dementia.

Rivastigmine tartrate is a white to off-white fine crystalline powder that is both lipophilic (soluble in fats) and hydrophilic (soluble in water). Rivastigmine is a cholinesterase inhibitor that inhibits both butyrylcholinesterase and acetylcholinesterase (unlike donepezil which is selective for acetylcholinesterase). It is thought that rivastigmine works by inhibiting these cholinesterase enzymes, which would otherwise break down the brain chemical acetylcholine. [ 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 ] Its efficacy is similar to donepezil and tacrine. Doses below 6mg/d may be ineffective.The effects of this kind of drugs 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.We still do not have enough postmarketing clinical experience with rivastigmine patch, but initial reports are encouraging.

Clinical use

The FDA has approved rivastigmine capsules and rivastigmine patch 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 world-wide.

Rivastigmine has demonstrated significant treatment effects on the cognitive (thinking and memory), functional (activities of daily living) and behavioural problems that are commonly associated with Alzheimer’s [ 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. ] [ Rösler M, Anand R, Cicin-Sain A, et al. “Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial.” Br Med J. 1999;318:633-640. PMID 10066203 ] [ Finkel SI. “Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer's disease.” Clin Ther. 2004;26:980-990. PMID 15336465 ] [ Rosler M, Retz W, Retz-Junginger P, Dennler HJ. ”Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer's disease.” Behav Neurol. 1998;11(4):211-216. PMID 11568422 ] and Parkinson's disease dementias. [ Emre M, Aarsland D, Albanese A, et al. “Rivastigmine for dementia associated with Parkinson’s disease.” N Engl J Med. 2004;351:2509-2518. PMID 15590953 ]

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, rivastigmine appears to show marked treatment effects in patients showing a more course of aggressive disease, such as those with a younger age of onset, a poor nutritional status, or those experiencing symptoms such as delusions or hallucinations. [ Gauthier S, Vellas B, Farlow M, Burn D. “An aggressive course of disease in dementia.” Alzheimer's & Dementia 2006;2:210–17. ] For example, the presence of hallucinations appears to be a predictor of especially strong responses to rivastigmine, both in Alzheimer’s and Parkinson's disease patients. [ Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R. Response to rivastigmine or donepezil in patients with Alzheimer’s disease and symptoms suggestive of concomitant Lewy body pathology. Curr Med Res Opin 2006;22:49-59. PMID 16393430 ] [ Burn D, Emre M, McKeith I, et al. “Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease.” Mov Disord. 2006;21:1899-1907. PMID 16960863 ] It has been proposed that 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. [ Gauthier S, Vellas B, Farlow M, Burn D. “An aggressive course of disease in dementia.” Alzheimer's & Dementia 2006;2:210–17. ] [ Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R. Response to rivastigmine or donepezil in patients with Alzheimer’s disease and symptoms suggestive of concomitant Lewy body pathology. Curr Med Res Opin 2006;22:49-59. PMID 16393430 ] Multi-infarct dementia - may be slight improvement in executive functions and behaviour. The usage in schizophrenia patients - there are no firm evidences.

On the other hand, it has been postulated that the strong potency of rivastigmine, provided by its dual inhibitory mechanism, leads to more nausea and vomiting during the titration phase of oral rivastigmine treatment (all cholinesterase inhibitors require doses to be increased gradually over several weeks, and this is usually referred to as the ‘titration phase’). [ Inglis F. “The tolerability and safety of cholinesterase inhibitors in the treatment of dementia.” Int J Clin Pract. 2002;(127):45-63. PMID 12139367] This enforces the importance of taking oral forms of these drugs as prescribed with food. Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [http://www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf] ] 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 three times fewer reports of nausea and vomiting. [ Winblad B, Grossberg G, Frolich L, Farlow M, Zechner S, Nagel J, Lane R. “IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease.” Neurology 2007 Jul 24;69(4 Suppl 1):S14-22. PMID 17646619] .

Oral doses of rivastigmine should be titrated, with a 3mg per day step 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 was used to reverse bradycardia. Dialysis is ineffective due to the half-life of the drug.

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 non-linear at higher doses. Elimination is through the urine. Peak plasma concentrations are seen in about one hour, with peak CSF 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. [ 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] The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose). [ 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]

The compound does cross the blood-brain barrier. Plasma protein binding is 40%. [ Jann MW, Shirley KL, Small GW. “Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors.” Clin Pharmacokinet. 2002;41(10):719-739. PMID 12162759 ] The major route of metabolism for rivastigmine is by its target enzymes via cholinesterase-mediated hydrolysis. Elimination bypasses the hepatic system so hepatic cytochrome P450 (CYP) isoenzymes are not involved. [ Jann MW. “Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease.” Pharmacotherapy. 2000 20(1):1-12. PMID 10641971 ] It has been suggested that this means there is a low potential for drug-drug interactions (which could lead to adverse effects) between rivastigmine and the many common drugs that use the cytochrome P450 metabolic pathway. [ Inglis F. “The tolerability and safety of cholinesterase inhibitors in the treatment of dementia.” Int J Clin Pract. 2002;(127):45-63. PMID 12139367]

Notes

ee also

* "Cholinesterase inhibitors" section of the "Cholinesterase" article
* Dimebon
* Memantine