Weinbroum, Avi A. “Pathophysiological and clinical aspects of combat anticholinesterase poisoning.” British Medical Bulletin 72, no. 1 (2004): 119-133. Accessed March 24, 2013. http://bmb.oxfordjournals.org/content/72/
Anticholinesterase (AChE) is an enzyme and like all enzymes, their function is affected by several factors.
RECALL: Enzymes are affected by pH, temperature, substrate and enzyme concentration and inhibitors. These agents tend to disrupt the area of the enzyme called the active site by changing its conformation and hence hindering enzymatic activity.
Organophosphate – like compounds are inhibitors of the enzyme acetylcholine esterase (AChE) and are referred to as nerve agents (NAs). It is related to those used in pesticides. The extremely lethal irreversibly AChE inhibitors results in an inoperative AChE causing a buildup of acetylcholine (ACh) affecting the entire cholinergic system.
DID YOU KNOW
In the 1854, Wurtz synthesized the first organophosphate compound, tetraethyl pyrophosphate.
Sad to say…. organophosphates were used as weapons of mass destruction
1980 Iraq – Iran war
1994-95 – Terrorist attacks in Japan
The extent of absorption and contact with NA are vital issues in verifying biochemical intoxication route for the NA. NA can either be absorbed by the skin and mucous membrane or inhaled. The inhalation of the vapor results in instantaneous absorption due to the alveoli in the lungs causing respiratory ailments ranging from short breath to cardiovascular and respiratory failure and eventually death. Exposure to the skin has a nicotine-like effect causing muscle paralysis and continued developing respiratory indications and ultimately death.
BIOCHEMISTRY OF NAs
They are chemically obtained from phosphoric acids. They tend to differ slightly by substituting the -OH radical and the acid-base form but are still efficient of being both reversible and irreversible inhibitors to AChE. NAs chemical properties are such that it is both colorless and odorless in its volatile liquid state and denser that air in its gaseous state.
AChE enzyme is categorized as class three, Hydrolase and sub-class as esterase and therefore from the class it is determined that the enzyme hydrolyses esters, especially choline esters, ACh, a neurotransmitter for the cholinergic part of the nervous system.
AChE hydrolyses ACh swiftly and is located in the receptors sites of the nerves by the cholinergic nervous system. Reversible anticholinesterases are not lethal as compared to the irreversible anticholinesterases. Carbamates bind to anionic and the ester of the enzyme resulting in the separation of part of the carbamate and the formation at the location of the ester, an enzyme-cabamylated complex. Hence hydrolysis of ACh is no longer a rapid process. The most attractive binding sites for organophosphate compounds are the ester sites however the stability of the bonds depend on the correct orientation of the enzyme and inhibitor as well as other compounds are prevented from binding with the active site. They interfere with the cleft leaving the enzyme dysfunctional.
With irreversibly inhibition the NAs covalently binds (strongest bond formation) to the active site so therefore it is known as a completive inhibitor. This result in a buildup of the ACh in the neuro-effector junction hindering the synapse process in peripheral and the central cholinergic system causing toxic contamination to the nicotinic (CNS) and muscarinic cleft (muscle system). The covalent bond partakes in an instantaneous chemical reaction which stabilizes the molecule due to the surge in the thermodynamic stabilization resulting in the production of more hydrogen bridges between the phosphate and organic groups.
The skeletel muscles, the pre-ganglionic autonomic nerves and the post-ganglionic parasympathetic nerves are innervated by AChE. The cholinergic systems are bases on the muscarinic and nicotinic systems since they have receptors that display specificity to muscarinic alkaloids and nicotine alkaloids. The post-ganglionic parasympathetic fibers are innervated by the muscarinic sites which regulate the activity of the glands, smooth muscle of the respiratory, cardiovascular and gastrointestinal systems. Autonomic ganglia, part of the nicotinic sites are relied upon for the contractions of the skeletal muscle. When both muscarinic and nicotinic cholinergic neurotransmitter buildup it causes hyper-stimulation of the synaptic process and hence causes paralysis of the skeletal muscles. Comparably the buildup of AChE in the CNS nerve receptors leads to hyper-stimulation and paralysis cardiac brady-asystole, hyper-secretion from secretory glands, respirational collapse, seizures, coma and eventually it is fatal. A small window of opportunity allows antidote drugs, atropine and oximes to work against the inhibitor stimulated nicotinic and muscarinic cholinergic system correspondingly depending on the stage of poisoning.
NAs are highly poisonous complexes that result in fatality within mere seconds. The principal biochemical cause NAs is the capability to irreversible inhibit AChE enzyme resulting in the buildup of ACh in the synaptic cleavage. Antidotes such as atropine and oximes present a crucial windowed-opportunity to act against the inhibitor