Introduction

Rivastigmine is a pseudo-irreversible, carbamate-type,brain-selective, dual AChE?BuChE inhibitor (the structure and properties are shown in Table 1). The pharmacokinetic profile showed that compared with the oral formulation,rivastigmine transdermal patch provides smoother and continuous as well as controlled drug delivery over 24 h,thereby resulting in fewer side effects.The transdermal patch formulation of rivastigmine has been approved in the US (FDA) for the treatment of mild, moderate, and severe Alzheimer’s disease (AD) and mild-to-moderate Parkinson’s disease dementia(PDD), and in the European Union, it is approved for the treatment of mild-to-moderately severe AD. Both AD and PDD are associated with cortical cholinergic deficits and therefore form the rationale for the use of pharmacological symptomatic treatment. The findings from an in vivo positron emission tomography (PET) imaging study showed greater cortical AChE deficit in patients with PDD than in those with AD. Rivastigmine exerts symptomatic the rapeutic effects through increasing acetylcholine levels in the brain,thereby making more acetylcholine available for synaptic transmission. This increase in brain acetylcholine levels is believed to be responsible for the clinical improvements in AD and PDD.[1]

Mechanism of action

Rivastigmine: dual inhibitorAChE/BuChE

AChE and BuChE are two different cholinesterase enzymes located in the brain that are responsible for acetylcholine hydrolysis. Of these, AChE is the primary cholinesterase mostly found at the nerve synaptic junctions and the areas that express intense activity in the adult human cerebral cortex, whereas BuChE is mainly located in the glial cells of the brain and plays an important role in cholinergic mediation. As AD progresses, BuChE activity increases in the hippocampus and temporal cortex in contrast to the AChE activity, which decreases in these specific regions of the brain, thereby supporting the key role of BuChE in regulating brain acetylcholine levels. Moreover, while BuChE activity increased with age in the AD brain, no correlation was observed in AChE activity with increasing age. Studies have also shown that BuChE inhibition with rivastigmine correlated with improved cognition in patients with AD. Initially, treatment efforts were focused on the inhibition of AChE; however, several studies have demonstrated the importance of both AChE and BuChE inhibition in the pathophysiology and pharmacological treatment of AD.Further to the evidence of BuChE involvement in cholinergic regulation and the suggested role of BuChE (K-variantallele) in the progression of AD, dual inhibition may offer additional benefits,especially over a long term.Rivastigmine has been shown to inhibit AChE in the brain in preclinical and clinical studies. Several large clinical studies and meta-analyses have demonstrated that rivastigmine improves cognitive function in AD. Studies inpatients with AD have shown that rivastigmine exhibited dose-dependent efficacy, and further investigations suggested that a higher dose of rivastigmine patch 13.3 mg/24 h(15cm2) conferred greater benefits on cognition, ADL,and global function than the 4.6 mg/24 h patch (5cm2) inpatients with severe AD.[1]

Pharmacodynamic Properties

Rivastigmine inhibits acetylcholinesterase less potently than physostigmine in vitro and in vivo (in rats). However, unlike physostigmine, rivastigmine has selectivity for the hippocampus and cortex (rather than the striatum and pons/medulla) in the brain, and selectivity for the brain (rather than the heart or skeletal muscle) in rats. This increased inhibitory activity in the hippocampus and cortex,which are the areas of the brain most affected by Alzheimer’s disease, may result from preferential activity at the globular G1 form of acetylcholinesterase.Rivastigmine has no affinity for muscarinic, α- or β-adrenergic, dopaminergic or opioid receptors.Results of studies conducted in animal models indicate that rivastigmine has central cholinergic activity, but little peripheral activity. The ratio of central to peripheral cholinergic effects was about 5 times greater than that of physostigmine.

CSF acetylcholinesterase and butyrylcholinesterase activity is dose-dependently reduced by rivastigmine 1 to 6mg twice daily in patients with Alzheimer’sdisease. Significant inhibition of acetylcholinesterase is maintained for up to 11.6hours (with the 6mg twice daily dosage). Inhibition of butyrylcholinesterase activity in the plasma is numerically lower than in the CSF at all dosage levels and inhibition of this enzyme is generally more variable than inhibition of acetylcholinesterase.In old rats, rivastigmine increased depressed acetylcholine levels and choline acetyltransferase activity to levels found in younger rats. Reductions in choline acetyltransferase activity in basal forebrain-lesioned rats were also attenuated byrivastigmine, but not tacrine or physostigmine. Rivastigmine increased the number of muscarinic M1 receptor binding sites in the frontal cortex of aged rats and attenuated the decreases in cortical muscarinic acetylcholine receptor binding ability (without changes in binding affinity) seen in aged rats.Rivastigmine attenuated spatial memory and/or learning impairment induced by basal forebrain lesions in rats as shown in the water maze test and a step-down avoidance paradigm.Rivastigmine demonstrated no abuse potential and did not cause physical dependence in rhesus monkeys.[2]

Pharmacokinetic Properties

After oral administration, rivastigmine is rapidly absorbed and extensively biotransformed to the decarbamylated metabolite NAP 226-90 (ZNS 114-666)which is soon detected in the CSF [time (tmax) to CSF maximum concentration(Cmax) of 1.4 to 3.8 hours]. In patients, plasma and CSF Cmax values and areas under the concentration-time curves for the first 12 hours (AUC12) for both rivastigmine and NAP 226-90 are significantly correlated with oral dose. Concomitant food slows the absorption of rivastigmine and results in a decrease in Cmax values of approximately 30% and an increase in AUC values of about 30%.Systemic exposure to rivastigmine is not affected by age, but drug concentrations are inversely related to body surface area and nicotine consumption. Concentrations of NAP 226-90 are also inversely related to body surface area.Cholinergic adverse events, such as anorexia, diarrhoea, nausea and vomiting,are correlated more with NAP 226-90 than rivastigmine concentrations. Inhibition of acetylcholinesterase activity tends to be directly related to CSF rivastigmine and NAP 226-90 concentrations.Rivastigmine is rapidly and extensively metabolised, primarily by cholinesterases, to NAP 226-90. NAP 226-90 may then undergo N-demethylation and/or sulphate conjugation. After metabolism, rivastigmine undergoes rapid renal elimination. Repeated administration of rivastigmine (1 to 6mg twice daily) does not result in accumulation of the parent drug or NAP 226-90.Coexisting hypertension, dyspepsia, diabetes mellitus, arthritis or neoplasia do not significantly affect plasma concentrations of rivastigmine or NAP 226-90.Age does not consistently affect the absorption of rivastigmine, but elimination is slightly prolonged in the elderly. As the metabolism of rivastigmine and elimination of NAP 226-90 appear to be reduced in patients with renal and mild to moderate hepatic impairment, dosage recommendations to titrate according to individual tolerability should be closely followed in these patients. Patients with severe hepatic impairment have not been studied.[2]

References

1.Kandiah N, Pai MC, Senanarong V, et al. Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson's disease dementia. Clin Interv Aging. 2017;12:697-707. Published 2017 Apr 18. doi:10.2147/CIA.S129145

2.Spencer CM, Noble S. Rivastigmine. A review of its use in Alzheimer's disease. Drugs Aging. 1998;13(5):391-411. doi:10.2165/00002512-199813050-00005