Rivastigmine
Encyclopedia
Rivastigmine 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, which typically include nausea and vomiting. The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.
and sold to Novartis
for commercial development. It has been available in capsule and liquid formulations since 1997. In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's Disease
; and in 2007 the rivastigmine transdermal patch became the first patch treatment for dementia.
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. 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.
and acetylcholinesterase
(unlike donepezil
, which selectively inhibits acetylcholinesterase). It is thought that rivastigmine works by inhibiting these cholinesterase enzymes, which would otherwise break down the brain chemical acetylcholine.
. It has been used in more than 6 million patients worldwide.
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 and Parkinson's disease
dementias.
patients. 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.
Multi-infarct dementia—may be slight improvement in executive functions and behaviour. There are no firm evidences supporting 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 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.
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. This enforces the importance of taking oral forms of these drugs as prescribed with food. 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..
The compound does cross the blood-brain barrier. Plasma protein binding is 40%. 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. 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.
Parasympathomimetics
A parasympathomimetic drug is a drug or poison that acts by stimulating or mimicking the parasympathetic nervous system . These chemicals are also called cholinergic drugs because acetylcholine is the neurotransmitter used by the PSNS...
or cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
agent for the treatment of mild to moderate dementia of the Alzheimer’s type
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and dementia due to Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. The drug can be administered orally or via a transdermal patch
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
; the latter form reduces the prevalence of side effects, which typically include nausea and vomiting. The drug is eliminated through the urine, and appears to have relatively few drug-drug interactions.
History
Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology, at the Hebrew University of JerusalemHebrew University of Jerusalem
The Hebrew University of Jerusalem ; ; abbreviated HUJI) is Israel's second-oldest university, after the Technion – Israel Institute of Technology. The Hebrew University has three campuses in Jerusalem and one in Rehovot. The world's largest Jewish studies library is located on its Edmond J...
and sold to Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
for commercial development. It has been available in capsule and liquid formulations since 1997. In 2006, it became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's Disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
; and in 2007 the rivastigmine transdermal patch became the first patch treatment for dementia.
Administration
Rivastigmine tartrateTartrate
A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. Its formula is O−OC-CH-CH-COO− or C4H4O62−.As food additives, tartrates are used as antioxidants, acidity regulators, and emulsifiers...
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. 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
Pregnancy category
The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast...
B, with insufficient data on risks associated with breastfeeding. In cases of overdose, atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
is used to reverse bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
. Dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
is ineffective due to the drug's half-life.
Pharmacodynamics
Rivastigmine is a cholinesterase inhibitor that inhibits both butyrylcholinesteraseButyrylcholinesterase
Butyrylcholinesterase is a non-specific cholinesterase enzyme that hydrolyses many different choline esters...
and acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
(unlike donepezil
Donepezil
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...
, which selectively inhibits acetylcholinesterase). It is thought that rivastigmine works by inhibiting these cholinesterase enzymes, which would otherwise break down the brain chemical acetylcholine.
Indication
The U.S. Food and Drug Administration has approved rivastigmine capsules and the 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 diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. It has been used in more than 6 million patients worldwide.
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 and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
dementias.
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, rivastigmine appears to show marked treatment effects in patients showing a more aggressive course of disease, such as those with a younger age of onset, a poor nutritional status, or those experiencing symptoms such as delusions or hallucinations. For example, the presence of hallucinations appears to be a predictor of especially strong responses to rivastigmine, both in Alzheimer’s and Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
patients. 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.
Multi-infarct dementia—may be slight improvement in executive functions and behaviour. There are no firm evidences supporting usage in schizophrenia patients.
Its efficacy is similar to donepezil and tacrine
Tacrine
Tacrine is a centrally acting anticholinesterase and indirect cholinergic agonist . It was the first centrally-acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the...
. Doses below 6 mg/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.
Side effects
Side effects may include nausea and vomiting.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. This enforces the importance of taking oral forms of these drugs as prescribed with food. 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..
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. The 9.5 mg/24 h rivastigmine patch provides comparable exposure to 12 mg/day capsules (the highest recommended oral dose).The compound does cross the blood-brain barrier. Plasma protein binding is 40%. 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. 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.