Toxic Disruption of the Cholinergic Nervous System

Toxic agents can interfere with each of the stages of cholinergic transmission given in the previous section involving the release, action at the post-junctional mem-brance and removal of ACh. 

There are a number of strains of BoTx. They act by preventing the formation of vesicles containing ACh which leads to reduced release. This in turn means that insufficient ACh is released with the arrival of a nerve impulse to ensure that a post-junctional electric impulse will be generated and therefore synaptic transmission becomes blocked. The most striking consequence of this is a descending neuromuscular paralysis which may be life-threatening due to the effects on the respiratory muscles. At the autonomic level, prodromal symptoms such as dry mouth are related to synaptic block. The toxidromes produced by BoTx are considered in Chap. 7. The most important clinical consequence of the pathophysiology of the toxin is the production of a potentially fatal respiratory failure and arrest. More information about BoTx will be found in Chap. 11. 

As noted above, ACh produces an electrical impulse at the post-junctional membrane of the chohnergic synapse which is either transmitted on to another neurone or to smooth or skeletal muscle causing contraction. This occurs by binding of the ACh molecules at special receptor sites which control entiy of ions into a channel. At the NMJ, there are two such sites at the entrance of an ion channel in the post-junctional membrane. When ACh combines with these, the channel is opened and there is an ion flow through it leading to depolarisation of the membrane. In the case of NMJ, this causes the associated muscle fibre to contract. The action of the ACh is terminated by AChE. If, however, the ACh receptor sites are blocked, the transmitter cannot attach to them and depolarisation cannot take place. Toxic substances such as curare, alpha-bungarotoxin from krait snakes and black widow spider venom can do this. The overall main chnical effect is the same as for BoTx, namely a paralysis which leads to respiratory failure and arrest. However, the timescale of a post-junctional block is shorter than a pre-junctional ACh release block and the 

Increased ACh concentrations in autonomic synapses give rise to a variety of other signs and symptoms which are characteristic of the classic cholinergic tox-idrome which is discussed in Chap. 7. The important clinical outcome of AChE inhibition is respiratory failure and arrest. With both carbamate and organophosphate anticholinesterases, this is due to a double action (1) by causing depolarizing 

Also in the CNS, increased ACh levels give rise to overactivity of central neurons causing spike discharges and fitting. This is sign of serious anticholinesterase poisoning and acts with peripheral NM paralysis to worsen the developing h3T)oxia. 

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