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Chapter: Modern Pharmacology with Clinical Applications: Local Anesthetics

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Depression of Acetylcholine Release

Botulinum Toxin, Lambert-Eaton Myasthenic Syndrome.


Botulinum Toxin

Botulism is most commonly caused by ingestion of a neurotoxin produced by Clostridium botulinum in im-properly canned food. Poisoning may also occur after wound contamination with the organism. Infant botu-lism may occur when spores of the organism germinate and manufacture the toxin in the intestinal tract of in-fants. Botulinum toxin works by inhibiting ACh release at all cholinergic synapses.

Botulinum toxins are classified into seven antigeni-cally distinct types, A through G. Each consists of a polypeptide chain of about 150,000 daltons. All but one is nicked by trypsin-type enzymes to yield a light and heavy chain linked by a disulfide bridge. One end of the heavy chain mediates binding to the nerve terminal, and the other initiates internalization of the toxin. The light chain produces the intracellular inhibition of ACh re-lease. This involves a Zn -dependent endopeptidase action to cleave synaptic target proteins that control vesicle docking and fusion with the prejunctional mem-brane.

Neuromuscular paralysis occurs 12 to 36 hours after ingestion of the toxin. Early symptoms include diplopia, dysphagia, and dysarthria. Paralysis may descend to in-clude proximal and limb muscles and result in dyspnea and respiratory depression. The toxins do not cross the placental barrier but do enter the central nervous sys-tem (CNS). Pupil size may or may not be normal, but mental and sensory functions are not impaired. Re-covery from paralysis requires days to weeks.

Reliable antidotes for botulism are not available. In some cases, anticholinesterase drugs may improve muscle strength, albeit temporarily. Guanidine and 4-aminopyri-dine also have limited usefulness. Management depends primarily on supportive measures, such as administering antitoxin and maintaining respiration.

Botulinum toxin is used clinically in the treatment of blepharospasm, writer’s cramp, spasticities of various origins, and rigidity due to extrapyramidal disorders. It is also used to treat gustatory sweating and cosmetically to decrease facial wrinkles. Botulinum toxin A (Botox, Oculinum) injected intramuscularly produces func-tional denervation that lasts about 3 months. Clinical benefit is seen within 1 to 3 days. Adverse effects range from diplopia and irritation with blepharospasm to muscle weakness with dystonias.

Botulinum toxin is the most toxic substance known. One gram of crystalline toxin adequately dispersed can kill a population of a million people, so its use in bioter-rorism is a possibility. The toxin can be introduced through inhalation or ingestion but not through dermal exposure. The threat of mass inhalation poisoning is limited by the ability or inability to aerosolize the toxin for widespread dispersion. Contaminating the water or food supply is also a possibility, although the toxin is degraded by standard water treatment and by heating of foods to 85°C (185°F) for 5 minutes. Prior immuniza-tion with toxoid vaccine is advisable for personnel at risk, but prophylactic administration of trivalent equine antitoxin is not recommended.

Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an au-toimmune disease that is often associated with small-cell lung carcinoma. It is characterized by fatigability, hyporeflexia, and autonomic dysfunction. The neuro-muscular junction appears normal in morphology, and postjunctional receptor function is unchanged. How-ever, particles at the active zones of nerve terminals that correspond to Ca++ channels are reduced in number and disorganized, and patients with LEMS have high titers of antibodies against the prejunctional P/Q-type Ca++ channel. Thus, muscle weakness results from im-paired influx of Ca++ and diminished release of ACh. Diagnosis is confirmed by an incremental increase in electromyographic recordings upon repetitive stimula-tion.

Treatment with guanidine may produce clinical im-provement within 3 to 4 days. Side effects include pares-thesia, gastrointestinal distress, renal tubular necrosis, and hyperirritability. The most serious effect is bone marrow depression, which is dose-related and poten-tially fatal. Aminopyridines have been used in clinical studies with some positive results. Corticosteroids and plasmapheresis may also be of some benefit, whereas anticholinesterase agents are only marginally effective.

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