Physostigmine toxicity

Heptylphysostigmine (eptastigmine) (17) has been shown to be as active as physostigmine in AChE inhibition, but superior to physostigmine in terms of oral bioavadabihty and half-life (118—120). However, further clinical evaluation of this compound has been halted because of dmg-related hematological toxicity. 

The carbamate and OP insecticides and the organophosphorous nerve gases soman, sarin, and tabun all act as anticholinesterases, and most of their toxicity is attributed to this property. The naturally occurring carbamate physostigmine, which has been used in medicine, is also an anticholinesterase. Some OP compounds can cause relatively long-lasting inhibition of the enzyme because of the phenomenon of... 

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

An alternative to THA was welcome, since both Ostfeld s group and our own had noted changes in liver function following the use of THA, even though these indications of liver toxicity cleared rapidly after discontinuation of the drug s use. Physostigmine, fortunately, did not manifest such changes. 

Carbamates are sold at a lesser volume than are organophosphorus compounds. The first carbamate (urethane) insecticides were developed in the late 1940s at Geigy Chemical Co. in Switzerland. Research on carbamates was inspired by the known toxicity of the alkaloid physostigmine, which occurs naturally in a West African bean. 

A number of drugs in addition to atropine and scopolamine have antimuscarinic properties. Tbese include tricyclic antidepressants, phenothiazines, and antihistamines. Physostigmine has been used in the treatment of acute toxicity produced by these compounds. However, physostigmine can produce cardiac arrhythmias and other serious toxic effects of its own, and therefore, it should be considered as an antidote only in life-threatening cases of anticholinergic drug overdose. 

Absorption of the quaternary carbamates from the conjunctiva, skin, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7-4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. 

One of the best-understood autoimmune diseases is myasthenia gravis, a condition associated with a decrease in the number of functional post-synaptic nicotinic acetylcholine receptors (Fig. 30-23) in neuromuscular junctions. e The resulting extreme muscular weakness can be fatal. Myasthenia gravis is not rare and affects about one in 10,000 peopled An interesting treatment consists of the administration of physostigmine, diisopropyl-phosphofluoridate (Chapter 12, Section C,l), or other acetylcholinesterase inhibitors (Box 12-E). These very toxic compounds, when administered in controlled amounts, permit accumulation of higher acetylcholine concentration with a resultant activation of muscular contraction. The same compounds... 

Physostigmine Antilirium, Eserine, Isopto Eserine Glaucoma, reversal of CNS toxicity caused by anticholinergic drugs... 

Physostigmine (eserine sulfate) causes miosis and spasm of accommodation it also lowers intraocular pressure and hence can be used in the treatment of wide-angle glaucoma. As it is lipid soluble, it penetrates into the brain rapidly, raises the acetylcholine concentration and, in toxic amounts, may cause cholinergic CNS toxicity, which is characterized by restlessness, insomnia, tremors, confusion, ataxia, convulsions, respiratory depression, and circulatory collapse. These effects are reversed by atropine. 

In the mid-19th century the Calabar bean was sent to Scotland and the two principal alkaloids were extracted in a number of European laboratories. There the formulae were determined and toxic and medicinal properties intensively studied. By the early 20th century the formula for physostigmine and the presence of two... 

Physostigmine is one of the major alkaloids in calabar bean. It has been shown to inhibit acetylcholinesterase at low concentration and to reverse the toxic effects resulting from diazepam overdose. The phytostigmine skeleton is easily obtained in very good yields from an appropriate non-stabilized imidate methylide.162,292,465... 

Since physostigmine causes these peripheral and central activities, and is also able to activate nicotinic receptors in the neuromuscular junction (NMJ) [8], it is no wonder that the alkaloid is relatively toxic. Indeed, the LD50 of physostigmine in mice is about 0.6 mg kg-1 [9]. 

---