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Rivastigmine


Rivastigmine

Article Author:
Parth Patel
Article Editor:
Vikas Gupta
Updated:
10/5/2020 10:04:28 AM
For CME on this topic:
Rivastigmine CME
PubMed Link:
Rivastigmine

Indications

With the rise in awareness of neurodegenerative diseases at the end of the 20th century, novel drugs were in development in hopes of countering the deleterious effects of these diseases. One of the main drugs that came into creation in 1985 was rivastigmine. With its approval by the FDA, rivastigmine is indicated to treat mild to moderate dementia of the Alzheimer’s type. Its indications also include the treatment of mild to moderate dementia that is associated with Parkinson disease. 

Recent studies have also shown that rivastigmine can improve gait stability to help reduce the risk of falls in patients with Parkinson disease.[1] Additionally, a study done in 2016 has shown that perioperative rivastigmine use can decrease the incidence of postoperative delirium in older patients that have cognitive dysfunction.[2] Researchers have also conducted small studies to see the effectiveness of acetylcholinesterase inhibitors like rivastigmine in hopes of helping cognitive dysfunction in multiple sclerosis patients. Overall, these studies showed that there were no significant benefits over placebo to improve cognitive function.[3]

Multiple studies have also shown that drugs like rivastigmine and other cholinesterase inhibitors can improve cognition in patients with dementia with Lewy bodies based on a computerized cognitive exam. Compared to the placebo group, patients receiving rivastigmine had an improvement of 30% or more as well as being overall less anxious and fewer episodes of hallucinations.[4]

Mechanism of Action

In the brain, two different cholinesterase enzymes hydrolyze acetylcholine. These two enzymes are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). AChE is mainly present at the synaptic nerve junctions, as well as areas that have high activity in the cerebral cortex. BuChE is found in the glial cells of the brain and helps mediate cholinergic activity. As humans age, the activity of both of these cholinesterase enzymes increases. In pathologic states like Alzheimer disease and Parkinson disease, the upregulation of cholinesterase enzymes is much higher than normal. Rivastigmine, unlike other cholinesterase inhibitors, has been shown to inhibit both of these enzymes, causing an overall increase in acetylcholine.[5] 

Administration

Rivastigmine indications include mild to moderate Alzheimer's dementia and dementia associated with Parkinson's disease. A mini-mental state examination (MMSE) is performed on patients to see if they qualify for cholinesterase inhibitor therapy. If the MMSE score is between 24 to 26 and 10 to 11 for mild to moderate dementia, respectively, the patient is a candidate for therapy. Studies show that long term treatment at a maximum dosage of rivastigmine has the greatest improvement in cognitive performance.[6] In addition, discontinuation of acetylcholinesterase inhibitors should be done carefully due to the possible worsening of cognitive impairment.[7]

Rivastigmine comes in two major formulations, an oral capsule, and a transdermal patch. 

  • Capsule
    • 1.5 mg - 6 mg
  • Transdermal Patch
    • 4.6 mg/24 hours - 13.3 mg/24 hours

The transdermal patch recommended starting dose is 4.6 mg/24 hours, and the prescriber can titrate the dose up every four weeks. The capsule formulation has a recommended starting dose of 1.5 mg twice daily and can be titrated up every four weeks as well by 1.5 mg per dose (total 3 mg increase per day). 

Adverse Effects

Adverse effects for this drug have received thorough study as it has been on the market for some time. The main adverse effects associated with the use of rivastigmine are gastrointestinal. The primary symptoms are nausea and vomiting. These acute effects primarily occur during the initial dose-escalation phase of therapy upward dose titration of the drug to achieve a therapeutic dose. These events can be minimized by using a slow titration schedule and taking the medication with food if prescribing an oral formulation. In a study done to analyze the safety and tolerability of cholinesterase inhibitors used to treat Alzheimer dementia, researchers found rivastigmine to be the drug to have the highest rate of gastrointestinal side effects.[8] 

Common adverse effects include extrapyramidal symptoms, sleep disturbances, as well as muscle cramps and weakness. These issues are less frequent during the maintenance phase of therapy when the dose is not adjusted, but when the drug is being taken for a long period, central nervous system effects can occur. However, these central nervous system effects are rather rare in rivastigmine and are more common with its counterpart drug, donepezil.[9]  

Studies have shown that using the transdermal patch to deliver rivastigmine is associated with fewer reports of nausea and vomiting.[10] Rivastigmine also has a rare case of angioedema related to its use, although overall very uncommon.[11] While the transdermal route offers decreased rates of gastrointestinal effects, reactions like contact dermatitis, are prevalent. Also, allergic reactions to the transdermal patch can manifest as vesicles and edema beyond the boundaries of the patch. 

Long term use of rivastigmine has also been associated with an increased risk of death when compared to patients treated with donepezil.[12]

Contraindications

Relatively few contraindications exist for the usage of rivastigmine in clinical practice. A patient with a history of hypersensitivity to rivastigmine or other drugs with carbamate derivatives should not be prescribed rivastigmine, and other treatment options should merit consideration. Also, severe reactions to other anticholinergic agents should lead clinicians to be on the lookout for similar effects. Patients who have taken anticholinergic medications before who have experienced a cholinergic crisis should also be wary of a potential repeat with the use of rivastigmine. 

Monitoring

Monitoring for this drug should be done primarily by evaluating the patient to see if the therapy will have the desired effect, and if there is a clinical improvement from the patient's baseline. Using assessments to evaluate a patient's cognition can be used to see the progression of the patient throughout the treatment. Clinical staff members should all be on the lookout for adverse reactions that can warrant discontinuation or alteration of the route of administration of the drug. Side effects like gastrointestinal disturbances can warrant a switch to the transdermal form of the drug. Cutaneous side effects also warrant prompt evaluation. Clinical staff members should be aware of the difference between a contact dermatitis reaction vs. an actual allergic reaction to the transdermal patch. Contact dermatitis occurs in the spot that the patch was placed and usually resolves. A true allergic reaction to the patch will present as the typical contact dermatitis symptoms in addition to erythema past the boundaries of the patch as well as the presence of vesicles and/or edema.  

Toxicity

Toxicity to the drug, while rare, should be carefully monitored. Common manifestations of toxicity include the presence of severe gastrointestinal reactions, allergic cutaneous reactions, as well as central nervous system effects. All cutaneous reactions due to usage of the patch should prompt immediate removal of the patch for at least 48 hours before reapplying in a new area. Therapy should be discontinued altogether if symptoms last longer than 48 hours, or a serious cutaneous reaction ensues. In addition to serious manifestations of common side effects, clinical staff members should always be on the lookout for cholinergic crises whenever prescribing anticholinergic medications. Classic manifestations of a patient in crisis can be remembered by the mnemonic DUMBELS - diarrhea, urination, miosis, bradycardia, excitability, lacrimation, salivation/excessive sweating prior to treatment. Patients that are experiencing a cholinergic crisis should have atropine followed by pralidoxime to reverse the anticholinergic effects of rivastigmine. While the usual treatment of the crisis involves giving atropine before pralidoxime, a case study done in 2009 showed a successful reversal of cholinergic crisis with just pralidoxime without atropine pretreatment.[13]

Enhancing Healthcare Team Outcomes

Patients on rivastigmine, and other anticholinergic medications, should have close follow up with the primary physician taking care of them. Physicians should work closely with nurses to keep proper follow up on patients to ensure the provision of optimal therapy along with being aware of the potential for adverse effects. Physicians can also work closely with pharmacists to help optimize treatment and prescribe the best regimen to their patients to achieve optimal therapy for their diagnoses; the pharmacist can consult on whether rivastigmine is best suited for the patient at hand or not. Nursing and pharmacy must both emphasize the importance of strict compliance to patients, as a lack of compliance can be devastating to therapy and, subsequently, their life. Concerns about compliance need to be brought to the prescribing clinician's attention immediately. All members of the interprofessional healthcare team are responsible for providing the best care to their patients as well as being on the lookout for adverse effects. An interprofessional team will result in the best outcomes.


References

[1] Henderson EJ,Lord SR,Brodie MA,Gaunt DM,Lawrence AD,Close JC,Whone AL,Ben-Shlomo Y, Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. Neurology. 2016 Mar;     [PubMed PMID: 26795874]
[2] Youn YC,Shin HW,Choi BS,Kim S,Lee JY,Ha YC, Rivastigmine patch reduces the incidence of postoperative delirium in older patients with cognitive impairment. International journal of geriatric psychiatry. 2017 Oct;     [PubMed PMID: 27561376]
[3] Cotter J,Muhlert N,Talwar A,Granger K, Examining the effectiveness of acetylcholinesterase inhibitors and stimulant-based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis. Neuroscience and biobehavioral reviews. 2018 Mar;     [PubMed PMID: 29406017]
[4] Hershey LA,Coleman-Jackson R, Pharmacological Management of Dementia with Lewy Bodies. Drugs     [PubMed PMID: 30680679]
[5] Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson's disease dementia., Kandiah N,Pai MC,Senanarong V,Looi I,Ampil E,Park KW,Karanam AK,Christopher S,, Clinical interventions in aging, 2017     [PubMed PMID: 28458525]
[6] Szeto JY,Lewis SJ, Current Treatment Options for Alzheimer's Disease and Parkinson's Disease Dementia. Current neuropharmacology. 2016;     [PubMed PMID: 26644155]
[7] Mohammad D,Chan P,Bradley J,Lanctôt K,Herrmann N, Acetylcholinesterase inhibitors for treating dementia symptoms - a safety evaluation. Expert opinion on drug safety. 2017 Sep;     [PubMed PMID: 28678552]
[8] Hansen RA,Gartlehner G,Webb AP,Morgan LC,Moore CG,Jonas DE, Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clinical interventions in aging. 2008;     [PubMed PMID: 18686744]
[9] Inglis F, The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. International journal of clinical practice. Supplement. 2002 Jun;     [PubMed PMID: 12139367]
[10] Winblad B,Grossberg G,Frölich 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;     [PubMed PMID: 17646619]
[11] Naharci MI,Tasci I, Angioedema Caused by Rivastigmine Patch: A Rare Case. Journal of clinical psychopharmacology. 2018 Jun;     [PubMed PMID: 29620690]
[12] Kazmierski J,Messini-Zachou C,Gkioka M,Tsolaki M, The Impact of a Long-Term Rivastigmine and Donepezil Treatment on All-Cause Mortality in Patients With Alzheimer's Disease. American journal of Alzheimer's disease and other dementias. 2018 Sep;     [PubMed PMID: 29742912]
[13] Hoffman RS,Manini AF,Russell-Haders AL,Felberbaum M,Mercurio-Zappala M, Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity. Human     [PubMed PMID: 19755437]