Rivastigmine

Pharmacology
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By K K Jain MD

Cholinesterase inhibitors with potential or established clinical effects can be classified as follows:

  • Reversible inhibitors: donepezil, galantamine.
  • Pseudoreversible inhibitors (carbamate derivatives): physostigmine, rivastigmine.
  • Irreversible inhibitors: metrifonate.

Pharmacodynamics. Rivastigmine is an acetylcholinesterase inhibitor that facilitates cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits associated with Alzheimer disease. Rivastigmine is a carbamate derivative that binds to the steric site of the acetylcholinesterase and dissociates slowly; thus, it provides a longer duration of action than tacrine and donepezil, which are short-acting agents, because binding to acetylcholinesterase is hydrolyzed within minutes. In addition to acetylcholinesterase, rivastigmine inhibits butylcholinesterase, and as a result of this dual inhibition, it can optimize cholinergic function. Rivastigmine markedly inhibits cerebrospinal fluid acetylcholinesterase after a single oral dose of 3 mg; it also has central nervous system selectivity over the peripheral inhibition of acetylcholinesterase.

An oral 3 mg dose decreases acetylcholinesterase activity in cerebrospinal fluid by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer disease, inhibition of acetylcholinesterase in cerebrospinal fluid by rivastigmine was found to be dose-dependent up to 6 mg given twice a day (the highest dose tested).

Alterations in the clinical and cognitive status of patients receiving rivastigmine are paralleled by changes in regional cerebral blood flow as measured by SPECT. These values are enhanced in responders and reduced in nonresponders.

Various studies indicate that rivastigmine improves cognition and activities of daily living in patients with dementia associated with Parkinson disease, resulting in a clinically meaningful benefit (Moretti et al 2007).

Pharmacokinetics. Important points pertaining to pharmacokinetics include the following:

  • Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of the drug’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose.
  • Rivastigmine is weakly bound to plasma proteins (approximately 40%). It readily crosses the blood-brain barrier.
  • Rivastigmine is rapidly and extensively metabolized (half-life in plasma approximately 1 hour) primarily through cholinesterase-mediated hydrolysis to the decarbamoylated metabolite. Total plasma clearance of rivastigmine was approximately 130 L/h after a 0.2 mg intravenous dose, and it decreased to 70 L/h after a 2.7 mg intravenous dose.
  • Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14-C-rivastigmine, renal elimination was rapid and essentially complete (greater than 90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. No accumulation of rivastigmine or the decarbamoylated metabolite is present in patients with Alzheimer disease.
  • Transdermal rivastigmine maintains steady drug levels in the bloodstream as compared to fluctuations with the capsule form of the drug (Mercier et al 2007). Transdermal rivastigmine enables maintenance of a lower peak of drug concentration, fewer gastrointestinal side effects, and an efficacy similar to the oral capsules of rivastigmine (Salmon 2008). Despite the advantages of transdermal rivastigmine, the effects of environmental factors such as fever or skin abrasions or tears on drug pharmacokinetics are unknown, and the need for titration to the target dose is not eliminated (Guay 2008).