Nerve agents central nervous system effects

Another very important site for drug delivery is the central nervous system (CNS). The blood-brain barrier presents a formidable barrier to the effective delivery of most agents to the brain. Interesting work is now advancing in such areas as direct convective delivery of macromolecules (and presumably in the future macromolecular drug carriers) to the spinal cord [238] and even to peripheral nerves [239]. For the interested reader, the delivery of therapeutic molecules into the CNS has also been recently comprehensively reviewed... 

Target Organ Toxicity. -Hexane exposure is documented to cause toxicity in peripheral nerves of humans (both sensory and motor). In rats, -hexane exposure causes toxicity in the peripheral and central nervous system and in male reproductive tissues. Effects on respiratory tissue have been observed in mice and rabbits. The toxic agent in nervous system and reproductive tissues is believed to be the -hexane metabolite 2,5-hexanedione (Graham et al. 1995). 

The actions of p-blockers on blood pressure are complex. After acute administration, blood pressure is only slightly altered. This is because of the compensatory reflex increase in peripheral vascular resistance that results from a (3-blocker-induced decrease in cardiac output. Vasoconstriction is mediated by a-receptors, and a-receptors are not antagonized by (3-receptor blocking agents. Chronic administration of (3-blockers, however, results in a reduction of blood pressure, and this is the reason for their use in primary hypertension (see Chapter 20). The mechanism of this effect is not well understood, but it may include such actions as a reduction in renin release, antagonism of (3-receptors in the central nervous system, or antagonism of presynaptic facilita-tory (3-receptors on sympathetic nerves. 

In addition to battlefield trauma, there is also the risk of exposure to chemical weapons such as the nerve agents, notably the organophosphorus gases (soman, sarin, VX, tabun) [6]. Organophosphorus toxicity arises largely from their ability to irreversibly inhibit acetyl-cholinesterases, leading to effects associated with peripheral acetyl-choline accumulation (muscarinic syndrome) such as meiosis, profuse sweating, bradychardia, bronchioconstriction, hypotension, and diarrhoea. Central nervous system effects include anxiety, restlessness, confusion, ataxia, tremors. 

Little is known about the nervous systems of cestodes and trematodes except that they probably differ from those of nematodes, since milbemycins and avermectins have no effect on them. However, a highly effective anti schistosomal and antitapeworm agent, praziquantel (see Chapter 54 Clinical Pharmacology of the Anthelmintic Drugs), is known to enhance Ca2+ influx and induce muscular contraction in those parasites, though it exerts no action on nematodes or insects. Some benzodiazepine derivatives have activities similar to those of praziquantel these activities are unrelated to the anxiolytic activities in the mammalian central nervous system. The nerves and muscles in schistosomes and tapeworms are thus interesting subjects for future chemotherapeutic studies. 

Notes X = A known adverse effect by an agent CNS = Central nervous system ANS = Autonomic nervous system CV = Cardiovascular system PB = Pyridostigmine bromide OP = Organophosphates CB = Carbamates Pyreth = Pyrethroids Lind = Lindane NA = Nerve agents Mus = Mustard agents Du = Depleted uranium. 

Nerve agents are OP compounds, which irreversibly inhibit AChE, leading to ACh accumulation, and cause over-stimulation of muscarinic and nicotinic ACh receptors. The effect at the SA node, the primary heart control site, is inhibitory and bradycardia results. VX primarily affects neurotransmitter receptors, those of norepinephrine, and also affects the central nervous system (CNS) not related to AChE inhibition. 

The binding of the nerve agent to the enzyme is considered irreversible unless removed by therapy. The accumulation of acetylcholine in the peripheral nervous system and central nervous system (CNS) leads to depression of the respiratory center in the brain, followed by peripheral neuromuscular blockade causing respiratory depression and death. The pharmacologic and toxicologic effects of the nerve agents are dependent on their stability, rates of absorption by the various routes of exposure, distribution, ability to cross the blood-brain barrier, rate of reaction and selectivity with the enzyme at specific foci, and their behavior at the active site on the enzyme. 

The initial effects of nerve agents depend on the dose and route of exposure. A small inhalation exposure from nerve agent vapor causes a response in the eyes, nose and airway, such as miosis, conjunctival injection, eye pain, rhinorrhea, bron-choconstriction, excessive bronchial secretions, and mild to moderate dyspnea (9,13,18). Larger exposures cause central nervous system effects within seconds to minutes, including loss of consciousness, seizures, and central apnea. Death can occur within 5-lOmin of a lethal dose, usually due to respiratory failure from the combined effects of respiratory muscle paralysis, loss of airway control and profuse bronchorrhea (13,14). 

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