Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents Volume 1 (1982) / Chapter Skim
Currently Skimming:
Anticholinergics
Anticholinergics
Pages 51-76
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 51... ...
However, quaternary ammonium analoguea of atropine and related drugs generally have some degree of nicotinic blocking activity and consequently are more likely to interfere with ganglionic or neuromuscular transmission in doses only slightly greater than those that produce muscarinic block. In the central nervous system (CHSy, cholinergic transmission appears to be predominantly nicotinic in the spinal cord and both muscarinic and nicotinic at subcortical and cortical levels in the brain (23.
|
From page 52... ...
In animals, atropine antagonizes the action of ACh applies locally to the cerebral cortex ant Spinal cord. However, atropine also depresses the effects of noncholinergic stimuli, indicating that the t rug has central actions other than blocking cholinergic synapses.
|
From page 53... ...
Delirium ant toxic psychoses, without undue peripheral manifestations, have been reported in adults after instillation of atropine eyetrope. Fatalities from intoxication with atropine ant scopolamine are rare, but they sometimes occur in children, in whom lO mg or less may be lethal.
|
From page 54... ...
Only about 1Z of an oral dose of scopolamine is eliminated as such in the urines Traces of atropine are found in various aecretiona, lucluting milk. The total absorption of quaternary ammonium derivatives of the alkaloids after an oral dose is only about 10-25 percent (10,11)
|
From page 55... ...
-CH2OlI, -OCH3, -C1, -Br, -l, ~O2CCH3, R1 ant R2 ~ hydrogcs, phenyl, subetituted phenyl, alkyl, cycloallyl, e thylenic, olef inlc ~ thienyl, ant R3 - acyclic aminoallyl, cyclic aminoall~l, bicyclic amino aligl (e.g., tropine or scopine for atropine ant scopolamine, respectively)
|
From page 56... ...
found that a mitochondrial fraction prepared from rat brain adsorbed 3-4 timea as much BZ as a eropine in the physiologic range of pa. The optimal pH f or adsorption of BZ was about 8~0, whereas that for atropine was about 9.7; however, at their own optimal pH values, the adsorptions of the two anticholinergic compounds were about the settee THA, Ca2+ ant poll- decreased the adsorption of the benzilate by mitochondrta.
|
From page 57... ...
Mach of the information vea derived through a contract with Hacleton Laboratories, Falls Church. A summary of the preclinical pharmacology and toxicology in rata, dogs and monkeys is presented here; a fiat of other toxicity studies is given in Appendix F
|
From page 58... ...
Other measured indicators of pharmacologic effect included body weight, food consumption, hematology, "rosa ant microscopic pathologic aigns ant organ weights. No significant effect attributable to the repeated admintatratlon of BZ was found.
|
From page 59... ...
. A total of 20 daily intravenous injections of EA 3443 in mongrel dogs (two dogs per dose)
|
From page 60... ...
.. DO SING CONS MENTIONS Atropine Textbooks generally suggest that death from atropine poisoning may be expected after lugeation of doses above 100 ma.
|
From page 61... ...
' and four received 2 g/kg on three consecutive days (filth cumulative effects approaching incapacitation on the third day.) Thus, fewer than 10% of all subjects received more than a single dose.
|
From page 62... ...
In the features thus far described, BZ is a typical glycolate, indistinguishable qualitatively from atropine, acopolamine, EA 3834, EA 3443, EA 3580, EA 302,196, or any other compounds of the 21 in this family Studier In volunteers O EEG Effects ~ _ There is a close relationship between the changes in EEG patterns ant the behavioral effects of drug atminiatratlon. With high doses of atroplne (10-30 me)
|
From page 63... ...
The time course of action of the drug by this route was Pillar to that by intravenous injection; in fact, more symptoms were reported with this route, but this may have been due to differences in the completeness of reportinB. The time course was approximately as follows: o 10 my: Llght-headedness and giggling.
|
From page 64... ...
The mayor focus seemed to be on following heart rates and ttse BEG. Clinical manifestations noted with the other routes of administration probably also occurred here.
|
From page 65... ...
Testing of EA 3834 wee cautiously resumed in human subjects, and renal function wee monitored with frequent pretest and poatteat urine examinations. In a total of 69 subjects, including those who participated in field teat e, no additional ease a of bleeding were encountered, even though the subjects received up to 3 times the dose atminiatered to subjects with hematuria.
|
From page 66... ...
-- were accidentally exposes to unknown doses of EA 3167, the cost peralstent of the glycolates studied In each case, sub Active ant objective observations of perfoneance over a period of 6-12 ma inculcated that mlld-, but nontrivial, lolpair~ent of cognitive function could be tlacerned for approximately 6 Do, after which seemingly full recovery enamel. These patients were of Superior intellect ant had occupations that required optimal cognitive function for them to be successful.
|
From page 67... ...
None of the subjects has experienced any adverse sequclae that might be attributable to the drug experience. In the absence of additional reports of long-range consequences in subjects who had received the antlcholinergic teat compounds, data have been sought on delayed adverse reactions to other anticholinergic drugs used therapeutically, such as Ditran and atropine.
|
From page 68... ...
It is interesting that atropine ant scopolamine, truga with a long history of therapeutic use, had SMRa exceeding unity, whereas the four candidate chemical warfare agents (BZ, EA 3834, EA 3443, and EA 3580) had SMRs less than unity.
|
From page 69... ...
The high frequency of uncontrolled variables makes evaluation of behavioral effects difficult. On the basis of available data, in the Judgment of the panel, it is unlikely that a~iniatration of these anticholinergic compounds will have long-ter~ toxicity effects or delayed sequellae.
|
From page 70... ...
Tams 1 BISECTS 0, A=OPtNE IN EtELA~ION TO DOSE Dose ~ a;g Effects 0.5 Slight cardiac aloulag; cone dryness of couth; tshibltion of s - sting 1.0 Deflcite dryDese of mouth; thirst; lacrease In heart rates couetimes preceded by alowlog; mild dilatation of pupil 2~0 Rapit heart rate; palpitation; marlteddr~rness of - couth; dilated pupils; awe blurring of near vision 5.0 All the absve sy~pt~ Caulked; speech tlaturbet; difficulty in swallowing,, restIeseness and fatigue; headache; 4~9 ho: And, dlfflc~ty in ~icturitioD; reduced intestl - ] peristalsis 10.0 Above ·ysIptoma more earlier; rapid and weals pulse; iris practically obliterated; vision very blurred; skin flushed, hots 6~.
|
From page 71... ...
volunteere Total expocuresb No. records selected B1 BZ (EA 2277)
|
From page 72... ...
,o. Peripheral potency is in comparison to atropine (based on EDso to produce maximal heart rate of at lesat 100 beats/mint)
|
From page 74... ...
1974: Muscarinic Cholinergic Receptor Binding in the Longitudinal Muscle of the Guinea Pig Ilium with [3H] Quinuclidinyl Benzilate.
|
From page 75... ...
27. Bagdon, R.E., 1965: One year chronic toxicity studies of quartsan tr1 dogs, Dec.
|
From page 76... ...
and Garner, Z., 1966: One freer chronic toxicity studies of clidiniue bromide in rate. April 20.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.