BACKGROUND:

Rivastigmine is a cholinestrase inhibitor drug. It inhibits the enzymes acetylcholinesterase and butryl cholinesterase by reversibly covalent binding to these enzymes. Generally, in Alzheimer’s patients as the illness advances the amount of butryl cholinestrase increases, so inhibition of this enzyme cures the Alzheimer disease. Rivastigmine have A 9-hour synaptic half-life, supporting BID dosing every 18 hours, hence it is a known therapeutic effect for Alzheimer, Parkinson, Dementia¹.

History:

Rivastigmine was Formulated and extracted by Marta Weinstock – Rosin of the pharmacology department at the Hebrew university of Jerusalem. Next it was Purchased by Novartis pharmaceuticals for further development and research and commercial purpose. It was developed as a semi-synthetic variation of physostigmine. Currently Rivastigmine is released under the name of Exelon by Novartis. Back in 1993, doctors started using Tacrine as the first inhibitor for Alzheimer's disease after physostigmine was phased out in 1979 due to issues with Low Bio-availability and Short Half life. Then, in 1986, Summers reported that Tacrine seemed to make a big difference for 16 Alzheimer's patients, saying they felt better overall. And amazingly, 10 of them actually showed clear improvements in their condition. The support of Parke-Davis to Summers finally led to the commercialization of Tacrine as hydro chloride. However, the treatment did not affect the disease progression, although some cognitive improvements could be described compared to placebo in the early stage of the dementia. Nevertheless, a high rate of hepatic side effects was found out, so this drug has been beaten by others, a second generation of Ch E inhibitors, i.e., Donepezil, galantamine, and the previously commented Rivastigmine; this is the unique carbamate clinically used for Alzheimer’s Disease².

Pharmacokinetic Pharameters:

Pharmacokinetics of Rivastigmine in human is different in individual with renal and hepatic impairment and in mild to moderate Alzheimer’s Disease patients. To study pharmacokinetics in healthy volunteers is subjected to administration of Rivastigmine through IV and the dose is less than equal to 2.7mg and the oral dose include less than 4.2mg in both fasting conditions and in presence of meal. Single and multiple doses and even higher doses are given to the patients affected by Alzheimer’s Disease.Rivastigmine shows nonlinear pharmacokinetics.

Absorption:

Rivastigmine is easily absorbed in healthy individual through oral administration where T max= 0.8 to 1.2 hours. As absorption complete bio-availability is decreased by pre systemic metabolism (First pass). AUC of Rivastigmine in humans is 35.5% (oral to IV). Administration of second dose leads to steady state conditions. Alzheimer disease patients shows 30% to 50% higher plasma concentration of Rivastigmine and principal metabolite, NAP 226-90 than healthy elderly volunteers. Administration of Rivastigmine along with food slower the absorption (T max is increased by 1.4 to 1.6hours) where C max is reduced where bio-availability is increased by 30% compared to fasting state.

Distribution:

Administration of Rivastigmine through IV dose of 48 healthy elderly volunteers the apparent volume of distribution ranges between 1.8 to 2.7L/Kg. This exceeds total body water volume, Rivastigmine is distributed to an extra-vascular compartment. The principal metabolite is NAP 226-90, has same volume of distribution = 4.3 to 5.9 l/Kg.

Distribution of Rivastigmine in Cns:

· Plasma concentration of Rivastigmine is highly increased after administration of Rivastigmine and high levels are not maintained

· Study of Rivastigmine is done on young healthy volunteers.

· The cleavage fragment NAP 226-90, also appeared rapid in the plasma but shows undetectable fall levels up to 15hours.

· Rivastigmine is barely detectable in Cerebro spinal fluid (0.65ng/ml).

· Where concentration of NAP 226-90 is raised rapidly with measurable levels.

· Rivastigmine causes inhibition of Ach E in CSF by 1.2hours (P<0.05). which reaches peak by 2.4hours & inhibits slowly declines until approx. 8.5hrs.

· Rivastigmine is selective far Ach E. As it shows weak inhibition of Butryl Cholinestrase³.

Metabolism:

· Rivastigmine is rapidly metabolized by cholinesterase – mediated hydrolysis.⁴

· A carbamate moiety remains bound to the enzyme and the cleavage product NAP 226 – 90 is produced.

· The activity of the parent compound (NAP 226-90 has 10%) and is metabolized through liver by N-demethylation (or) sulphate conjugation and excretion is through kidneys.

· The carbamate moiety of Rivastigmine is attaches to Ach E inhibits the action if enzyme for 10hours and slowly metabolizes through sulphate conjugation.

· In vitro studies have demonstrated that Rivastigmine at concentration up to 200µM doesn’t inhibit cytochrome P450 metabolism, but it has low plasma protein binding and low (or) short duration of Ach E inhibition⁵.

Elimination:

· Rivastigmine elimination is through renal elimination of drug’s metabolite is rapidly and complete after 24 hours.

· The sulphate conjugation can be seen in urine.

· Less than 1% of the administration of Rivastigmine is observed in the faces.

· Half-life – 1.5hours

· Renal clearance = 2.1 – 2.8L/hr⁶.

PHARMACOLOGICAL PARAMETERS:

The Rivastigmine is available in various dosage forms such as capsules, Liquid intended for oral use. And Trans-dermal Patches for Dermal administration. Before prescribing Rivastigmine to patient mini-mental state examination (MMSE) is conducted on patients to determine their eligibility for cholinestrase inhibitor treatment. Research has shown that extended use of the highest dosage of Rivastigmine can enhance cognitive function. The cessation of acetylcholinesterase inhibitors should be done carefully due to passable worsening of cognitive impairment. Rivastigmine should be taken after food. No need of dose adjustment during Renal Failure⁷.

· Adverse drug reactions:

Rivastigmine causes nausea, vomiting during initial dose escalation phase of therapy with upward dose tit-ration of the drug to achieve a desired therapeutic dose. The conditions like nausea can be reduced by using slow tit-ration schedule & taking the medicament after food in case of oral administration. The cholinesterase inhibitor mostly causes extra pyramidal symptom, Muscle cramps, sleep disturbances, weakness^. Administration of Rivastigmine through trans-dermal patches decrease the symptoms of nausea & vomiting but may lead to contact dermatitis⁸.

· Contraindications:

Rivastigmine shows only few contraindication reactions: Due to the drug trans-dermal patches, it may resul to contact dermatitis. Patients hypersensitive to cholinesterase inhibitors should be careful about Rivastigmine. Patients such as cardiac disease, sinus syndrome, COPD & Asthma, Bleeding Ulcer, Seizures Etc. must be cautious during the prescription of Rivastigmine⁹.

· Mechanism of action:

Rivastigmine is an acetyl cholinesterase inhibitor. Acetyl cholinesterase is the substance which hydrolysis acetyl choline. Acetyl choline is generally hydrolyzed by two enzymes i.e., acetyl cholinesterase, butyryl cholinesterase. Acetylcholinesterase is primarily found at the synaptic nerve junctions and tends to increase with age in humans age the activity of both enzyme increases leading to decreased in acetyl choline levels in the body. Rivastigmine reversibly bind & inhibit both the enzymes Ache &BuchE, which lead to overall Increase In acetyl choline¹⁰.

Physicochemical Parameters:

Synonyms: Rivastigmine, Exelon, Prometax;

Molecular formula- C₁₄H₂₂N₂O_2;Molecular weight- 250.34 g/mol;

Hydrogen Bond Donor – 0;

Hydrogen Bond Acceptor Count – 3;

Rotable Bond Count- 5;

Heavy atom count- 18;

Solubility- 2.04e+00g/L;

log P- 2.3; Basic pKa- 8.8^;¹¹

It is white crystalline powder, very much dissolves in water, Soluble in Ethanol and acetone, slightly soluble in n- octane, and very slightly soluble in Ethyl acetate;

Melting point- 123 to 125 ^oC. Till now tow Polymorphic forms have been identified¹².

Synthesis:

IUPAC Name of Rivastigmine is - [(S)-N-ethyl-N-methyl-3-[1-(diethylamino)ethyl] - carbamic acid. 3Methoxy acetophenone and α methyl benzylamine undergo reduction in presence of catalyst such as Raney Ni/H2, result in the formation of 1-(3-methyoxy phenyl)-N-[(S)-1-phenylethyl]Ethan amine, this intermediate on N-methylation using formic acid and formaldehyde lead to the formation of (S)-1-(3-methyoxy phenyl)-N- methyl-N-[(S)-1-phenylethyl]Ethan amine, this on dehydration in presence of HBr lead to formation of 3-[(S)-1-[methyl-[(S)-1-phenylethyl]amino]ethyl]phenol, on reduction of this intermediate it lead to the production of (S)-N-ethyl-N-methyl-3-[1-(methylamino)ethyl]-phenyl carbamate, on treating this with L- tartaric acid it lead to the formation of (S)-Nethyl-N-methyl-3-[1-(dimethylamine)ethyl]-phenyl carbamate^[13].

Overdose Treatment:

CASE REPORT 01: A patient of 87 – years old male has dementia shown symptoms such as nausea, vomiting and renal failure leading to death after the unintentional overdose of Rivastigmine/Exelon patches. He was found to use 6 Exelon patches on his upper body but his dose was 9.5mg patch per 24hrs. The staff unintentionally administered 6 patches on the day (day before death). Next day morning the same person subjected to change with 6 new patches. Patient had confusion, nausea, vomiting, but these symptoms were not associated with the use of drug at that point. All the patches were removed and discharged from hospital and be monitored for bradycardia. 9hours later patient experienced dizziness and pulse was discovered to be fluctuating with 45beats/min. At emergency department in the hospital the serum creatinine level of patient was discovered to be 149µmol/L and the patient effected with urinary tract infection moreover patient also effected by renal failure after few days. Patient shown that rise in potassium and calcium levels. After 19 days of the condition, it is determined as the symptoms are due to over dose (after the death of the patient). The reason of the death is uremia due to the acute tubercular necrosis occurred due to dehydration as a result of vomiting¹⁴.

Drug- Drug Interactions:

Rivastigmine is metabolized through hydrolysis by esterase and only minimally metabolized through the CYP450 ISO-enzymes. No pharmacokinetics interactions with drugs metabolized through the CYP 450 ISO enzymes are expected. Drugs that can produce additive pharmacodynamic effect (ex: Cholinestrase inhibitors, Parasympathomimetics).

These types of drugs should not administer with Rivastigmine they increase the effect and increase the toxicity potential. In contrast, anti-cholinergic drugs may decrease the effect of Rivastigmine because the latter increase the cholinergic effect. Combined data from a clinical trial (N=2459) showed that antispasmodics, anti-cholinergic agents, and propulsive agents were more likely to cause adverse effects and necessitate treatment in patients taking Rivastigmine compared to those on a placebo (P=0.017). Additionally, combinations of Salicyclates and Rivastigmine were linked to body weight loss¹⁵.

1) Amantadine	The therapeutic efficacy of Amantadine can be decreased when used in combination with Rivastigmine
2) Amlodipine	Amlodipine may increase the Bradycardia activities of Rivastigmine
3) Chlorpromazine	The therapeutic efficacy of Chlorpromazine can be low when used in combination with Rivastigmine
4) Diphenhydramine	The therapeutic efficacy of Diphenhydramine can be decreased when used in combination with Rivastigmine¹⁶.

PATENTS:

1. PATENT NO: US9585862B2

Filed on 21-5-2012, Application filled by SK chemicals co.3-02-2012 assigned to SK chemicals co LTD.

2. PATENT NO: US8324429B2

Preparation method of Rivastigmine, Its intermediates method of preparation.

3. PATENT NO: US9585862B2

Dermal Preparation of Rivastigmine.

4. PATENT NO: WO2014152454A1

Trans dermal drug Delivery system containing Rivastigmine¹⁷.

SPECIAL POPULATIONS: (Dementia in Down Syndrome)

The most common genetic disorder identified at birth is Down syndrome, caused by the presence of an extra copy of chromosome 21. This chromosome can lead to decrease in areas of assimilation and adaptation, along with cognitive impairment. There are well established and recognized Neuropathological and neurochemical links There are connections between Down syndrome and Alzheimer's disease with both associated with chromosome 21¹⁸In Down syndrome, this additional chromosome can lead to fewer neurons and decrease the levels of Acetyl Choline as compared to natural and general population. Research suggests that cholinergic deficits have been linked to loss of neurons in the nucleus of a minor patients with Alzheimer’s disease. People with Down syndrome have more risk of getting dementia of Alzheimer’s type earlier, about 30 years than general population¹⁹.

The Working of Intervention:

Unlike Donepezil, Rivastigmine acts on both acetyl choline and butyl cholinesterase, but it effects are short lived. It occupies the receptors and unbind to them temporarily. It reverses itself over the time. Therefore, this type of phenomena is called Pseudo irreversible. The drug appears to affect enzymes within the central nervous system more than the peripheral. It has potential advantage of absorption, trans dermally and can be dispensed as a skin patch. It can be absorbed, unaltered, even patient with renal and hepatic impairment can use this method. In Cochrane review of Rivastigmine for Alzheimer’s disease in people who did not have Down syndrome. Rivastigmine was found to be benefit for people with mild to moderate Alzheimer’s disease. Through the increase of dosage, the risk of the side effects is increased²⁰.

Safety Profile of Rivastigmine:

A study was conducted by the Novartis Pharmaceutical company in association with University Hospital in France. The results are:

The main daily dose of drug impatience for the study was 9±3.1mg per day with 91.4% of patients receiving nearly 6mg/day. More than 13% of the patient’s dose was maintained at 12mg/day. Overall, 313 patients were judged as being related to complete study. Five patients died during the treatment Among all of them, none of them was judged as being related to Rivastigmine. The Most repeated adverse reactions are nausea, vomiting, agitation, weight loss, anorexia.

Among these 313 patients about 29.8% took as a Metaclopramide or Domeperidone during the study to alleviate ADR symptoms. Majority of these patients were receiving the high doses of Rivastigmine. This strategy has been successful of taking Metaclopramide during Rivastigmine. Serious ADRs were reported in sixty patients they include: Vomiting, gastritis, malaise, personality disorder, agitation, Supra-ventricular tachycardia and more²⁰.

CONCLUSION:

The drug Rivastigmine is available in various dosage forms such as liquid capsules intended for oral use and trans dermal patches. To study the pharmacokinetic characteristics of Rivastigmine it is given through IV dose ≤ 2.7mg and oral > 4.2mg. It is essential to perform MMSE before prescribing Rivastigmine it should be taken after food, hence to prevent the common ADRs like Nausea, Vomiting. The mechanism involved in the Rivastigmine is by inhibiting Acetyl cholinesterase and butyryl cholinesterase enzymes. The synthesis of Rivastigmine is done by reducing the 3-methoxy Acetophenone and α-methyl Benzyl amine. Overdose of Rivastigmine is found to be lethal. The administration of Rivastigmine should be avoided in combination with few drugs like amantadine, Amlodipine, Chlorpromazine, Diphenhydramine.

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17. Stanford University, Last Updated March 2024, Google patents, Accessed on April 4th 2024, URL: https://patents.google.com/patent/US9585862B2/en?oq=+US9585862B2++

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Received on 12.11.2024 Revised on 10.02.2025

Accepted on 22.04.2025 Published on 10.07.2025

Available online from July 17, 2025

Asian J. Pharm. Res. 2025; 15(3):316-320.

DOI: 10.52711/2231-5691.2025.00049

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