Cholinesterase inhibitors antagonists

The current gold standard of treatment for cognitive symptoms includes pharmacologic management with a cholinesterase inhibitor and/or an N-methyl-D-aspartate (NMDA) antagonist. 

The key to successful brain protection for Alzheimer s disease is the newly introduced NMDA receptor antagonist, memantine. Family members should be advised that the protection provided by memantine will slow the progression of Alzheimer s disease, but it does not halt or reverse the course of the illness. Memantine is now commonly coadministered with a cholinesterase inhibitor. 

Choudhary MI, Nawaz SA, Zaheer-uI-Haq Lodhi MA, et al, Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties, Biochem Biophys Res Comm 334 276—287, 2005. 

Tacrine has been found to be somewhat effective in patients with mild-to-moderate symptoms of this disease for improvement of cognitive functions. The drug is primarily a reversible cholinesterase inhibitor that increases the concentration of functional ACh in the brain. However, the pharmacology of tacrine is complex the drug also acts as a muscarinic receptor modulator in that it has partial agonistic activity, as well as weak antagonistic activity on muscarinic receptors in the CNS. In addition, tacrine appears to enhance the release of ACh from cholinergic nerves, and it may alter the concentrations of other neurotransmitters such as dopamine and NE. 

In this chapter, we use the term cognitive enhancers to refer to two classes of pharmacological agents used in the treatment of Alzheimer s disease the cholinesterase inhibitors and the A-methyl-D-aspartate (NMDA) receptor antagonists. 

Both the nicotinic and the muscarinic effects of the cholinesterase inhibitors can be life-threatening. Unfortunately, there is no effective method for directly blocking the nicotinic effects of cholinesterase inhibition, because nicotinic agonists and antagonists cause blockade of transmission (see Chapter 27). To reverse the muscarinic effects, a tertiary (not quaternary) amine drug must be used (preferably... 

Atropine Nonselective competitive antagonist at all muscarinic receptors in CNS and periphery Blocks muscarinic excess at exocrine glands, heart, smooth muscle Mandatory antidote for severe cholinesterase inhibitor poisoning Intravenous infusion until antimuscarinic signs appear continue as long as necessary Toxicity Insignificant as long as AChE inhibition continues... 

The classical synaptic clearance antagonist is the cholinesterase inhibitor physostigmine, from the calabar bean, Physostigma... 

The cholinesterase inhibitors have multiple practical applications - from medicine to warfare. Physostigmine was actually the first practically used cholinesterase antagonist. To describe its initial use as medical , however, would mean a bit of a stretch - instead, the seed containing it was used to extort confessions from persons accused of crimes or witchcraft in Guinea. This seed used to be called the ordeal bean by the local people. 

EEG and behavioral effects were modified in a parallel manner by the concurrent administration of antagonistic drugs. For Instance, when patients who exhibited a toxic delirium to Dlcran or atropine were given cecrafaydroamlnoacridlne, a cholinesterase inhibitor, the stupor was relieved and the EEG showed a decrease in both slow and fast frequencies. 

Recent studies have reported that galantamine also improves the cognitive performance of patients with autism (Nicolson et al., 2006) and, unlike other cholinesterase inhibitors, decreases the negative symptoms in patients with schizophrenia (Schubert et al., 2006). Eor more severe Alzheimer s disease, memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors, has also been approved. A number of newer drugs undergoing clinical trials for Alzheimer s disease work by a variety of other mechanisms, although a common theme appears to be neuroprotection (Robertson and Mucke, 2006). 

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