Rivastigmine
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Rivastigmine
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| Systematic (IUPAC) name | |
| (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate hydrogen-(2R,3R)-tartrate | |
| Identifiers | |
| CAS number | |
| ATC code | N06 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C14H22N2O2 |
| Mol. mass | 250.337 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 96% |
| Protein binding | 40% |
| Metabolism | Hepatic, via pseudocholinesterase |
| Half life | 1.5 hours |
| Excretion | Renal, 97% |
| Therapeutic considerations | |
| Pregnancy cat. |
B(US) |
| Legal status | |
| Routes | Oral |
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. Rivastigmine has been available in capsule and liquid formulations since 1997.[1] In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's Disease.[2]
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.[3]
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[edit] Clinical use
Rivastigmine is approved for 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[4][5][6][7] and Parkinson's disease dementias.[8]
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.[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 disease patients.[10][11] 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.[12][13]
On the other hand, it has been postulated that the strong potency of rivastigmine, provided by its dual inhibitory mechanism, might lead to more nausea and vomiting during the titration phase of treatment (all cholinesterase inhibitors require doses to be increased gradually over several weeks, and this is usually referred to as the ‘titration phase’).[14] This enforces the importance of taking the drug as prescribed with food.[15] Taking rivastigmine twice daily at meal times, and titrating (increasing) the dose in long titration steps (at least 4-week gaps between each dose increase) has been shown to markedly improve the tolerability of rivastigmine.[16] In addition, the future holds the promise of a rivastigmine patch, which would offer the benefits of smooth and continuous dual inhibition, but with a pharmacokinetic profile that is expected to provide greatly improved tolerability.
[edit] Pharmacokinetics
When given orally, rivastigmine is well absorbed with a bioavailabilty 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. The compound does cross the blood-brain barrier. Plasma protein binding is 40%.[17]
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.[18] 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.[19]
A transdermal patch formulation for rivastigmine has also been developed. Pharmacokinetic studies have not yet been published but it seems reasonable to expect that the rivastigmine patch will provide smooth continuous inhibition of target enzymes with fewer ‘peaks and troughs’ of drug levels in the blood. This would lead to optimal tolerability, and subsequently higher doses and better efficacy.
[edit] References
- ^ Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [1]
- ^ “FDA Approves the First Treatment for Dementia of Parkinson’s Disease” U.S. FDA News Release [2]
- ^ 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
- ^ 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
- ^ 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
- ^ 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
- ^ 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
- ^ 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
- ^ Inglis F. “The tolerability and safety of cholinesterase inhibitors in the treatment of dementia.” Int J Clin Pract. 2002;(127):45-63. PMID 12139367
- ^ Novartis Pharmaceuticals Corporation “Exelon Product Insert” June 2006. [3]
- ^ Grossberg GT. “Cholinesterase inhibitors for the treatment of Alzheimer’s disease: getting on and staying on.” Curr Ther Res. 2003;64:216-35.
- ^ Jann MW, Shirley KL, Small GW. “Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors.” Clin Pharmacokinet. 2002;41(10):719-739. PMID 12162759
- ^ Jann MW. “Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease.” Pharmacotherapy. 2000 20(1):1-12. PMID 10641971
- ^ Inglis F. “The tolerability and safety of cholinesterase inhibitors in the treatment of dementia.” Int J Clin Pract. 2002;(127):45-63. PMID 12139367
[edit] See also
| Anticholinesterases (N06DA, N07AA) edit |
| Metrifonate - Physostigmine - Neostigmine - Pyridostigmine - Ambenonium - Demarcarium - Rivastigmine - Galantamine - Donepezil - Tacrine - Edrophonium |
