The effect that a specific AChE inhibitor can have on the body depends largely on the chemical properties of the molecule and the strength of the bond it forms with AChE. Irreversible, or competitive AChE inhibitors are highly toxic. These chemicals, also known as organophosphorus compounds or nerve gases, form incredibly stable phosphorus bonds with AChE. These bonds can resist hydrolytic cleavage for up to several hours, meanwhile inhibiting all normal AChE activity and leading to an excessive, and possibly toxic, build-up of ACh at cholinergic synapses.
In the early 1930's, parathion, an irreversible AChE inhibitor, was manufactured for use as an insecticide. However, when it was discovered that this compound was toxic not only to insects, but to humans and other animals as well, i's use was discontinued. Its potential as a lethal weapon, however, did not go unnoticed. Several irreversible AChE inhibitors, including Sarin, Soman, and Tabun were secretly manufactured in Germany prior to and during World War II for use as chemical weapons. Though chemical warfare never actually broke out during this time, the Allied forces, in an effort to respond to the German threat, also manufactured their own nerve gas, called diisopropylfluoro-phosphate (DFP).
Organophosphorus compounds are stored as liquids but may be released as a vapor cloud or a spray. Whether they come into direct contact with the skin or they are inhaled, these deadly chemicals penetrate quickly into the bloodstream due to their high liquid solubility. They readily pass across the blood-brain barrier, inactivating AChE throughout the central and peripheral nervous systems and at all neuromuscular junctions. As little as one milligram of these noxious compounds causes profuse sweating, dimmed vision, uncontrollable vomiting and defecation, convulsions, filling of the bronchial passages with mucus, bronchial constriction, and at last, paralysis and asphyxiation from respiratory failure. (Feldman, Meyer, and Quenzer, 1997)
Though our bodies cannot naturally break the phosphate bond holding organophosphorus compounds to AChE, several antidotes, including pralidoxim and trimedoxime, can. These chemicals successfully break up the toxin-enzyme complex, freeing the enzyme and allowing for the breakdown of accumulated ACh.
Not all ACh inhibitors are as toxic as the irreversible/competitive compounds. Reversible AChE inhibitors are considered non-competitive because they can only bind to AChE for a limited amount of time before the unstable complex dissociates and ACh can once again bind to the enzyme. Because of the non-permanent nature of their action, reversible anti-AChEs can be safely administered as therapeutic agents in the treatment of disorders characterized by a decrease in cholinergic function. By transiently inhibiting the enzyme, these drugs allow for the multiple use of one molecule of ACh at the same receptor, thus compensating for the decrease in function caused by the condition. The bond formed with AChE is, however, broken before the accumulation of ACh in the synapse can become toxic.
Reversible AChE inhibitors are used to treat myasthenia gravis, an autoimmune disorder characterized by debilitating muscle weakness. This weakness is caused by a progressive breakdown of ACh receptor sites on the muscular endplate. Though ACh is present in normal concentrations, a lowered number of receptors on post-synaptic muscle cells limits the transmission of nerve signals at neuromuscular junctions, making muscle movement difficult. By causing a temporary excess of ACh at the synapse, non-competitive anti-AChEs are helpful in utilizing each remaining receptor molecule to its fullest capacity.
Pyridostigmine bromide, marketed under the name Mestinon or Regonol, is the most widely used anti-AChE in the treatment of Myasthenia gravis. Others include ambenonium chloride (Mytelase), and neostigmine methyl sulfate (Prostigmin). These drugs cannot pass the blood-brain barrier, so their action is limited to the inactivation of AChE at the neuromuscular junction. Because of this, they can be administered to treat muscle weakness, without causing the psychotropic side-effects they might if they could penetrate the cholinergic pathways of the central nervous system.
Reversible AChE inhibitors are also used in the treatment of Alzheimer's disease, a serious brain disorder in which the gradual death of cholinergic brain cells results in a progressive and significant loss of cognitive and behavioral function. Because Alzheimer's affects brain cells, drugs used to treat this condition must readily cross the blood-brain barrier. Tetrohydroaminoacridine (THA), known as Tacrine or Cognex, and Donepezil, known as Aricept, are both reversible anti-AChEs with the ability to penetrate the central nervous system. Though neither drug works as a cure or can be used to slow the progression of the condition, administering these compounds to Alzheimer's patients can help to ease some of the memory and language deficits characteristic of this devastating disease.