Description
The first carbamate esters to exhibit insecticidal activity
were derivatives of dithiocarbamic acid. A few
of these were contact poisons to soft-bodied insects
(aphids), whereas others, including thiram, demonstrated
antifeedant properties. In subsequent studies
with physostigmine and related carbamate compounds,
the charge of amine salts and quaternary structures was
shown to prevent their penetration through the waxy cuticle
and into the fatty nervous system of insects. Several
substituted-phenyl monomethylcarbamates were shown to
be effective contact toxins for aphids, flies, and thrips. Still
later, the oxime carbamates were discovered and shown to
be effective contact and systemic insecticides, nematocides
and/or miticides.
Pharmacology
Carbamate anticholinesterase agents are carbamic acid
esters that are hydrolyzed by AChE in a manner similar
to that of ACh. Carbamates have this general structure:
The clinically useful carbamates generally contain a
tertiary or quaternary amine group that can bind noncovalently
to the anionic site of the enzyme.The inhibition
of AChE by neostigmine (Prostigmin) illustrates
the general mechanism. The quaternary ammonium
group of neostigmine binds electrostatically to the anionic
site of the enzyme, thereby orienting the drug. The carbamates generally inhibit pseudo-ChE as well as true AChE, and their suicidal degradation by cholinesterases contributes importantly to terminating their duration of effect. Physostigmine (also called eserine) (Antilirium) is a tertiary amine that can inhibit AChE in the CNS, and it can be used in life-threatening
cases to treat antimuscarinic poisoning.
Pyridostigmine (Mestinon) is a quaternary ammonium
carbamate. Neostigmine and pyridostigmine also
have direct agonist activity at nicotinic receptors on
skeletal muscle. Rivastigmine (Exelon) is a carbamate
cholinesterase inhibitor with good penetration into the
brain.
Metabolism
The carbamates are generally broken down by hydrolysis
into the parent alcohol/phenol and a substituted carbamic
acid. The substituted carbamic acid formed is unstable and decomposes with loss of carbon dioxide to give an amine
derivative.
Numerous microorganisms in vitro have the ability
to hydrolyze promacyl either at the amide bond to form
promecarb or at the ester bond to form isothymol(16).
McDougall and Makin (17) reported that microbial degradation
accounts for seasonal declines observed in promacyl
concentrations in cattle plunge dips and that stabilization
of promacyl can be achieved by adjusting the dip wash pH
to <4.5.
Toxicity evaluation
Inappropriate storage of carbamate insecticides for home
and garden applications accounts for many cases of poisoning
of companion animals. Toxicoses in food-producing
animals may result from the use of ectoparasiticides,
ingestion of treated stored grain, grazing of treated crops,
and direct contact with insecticides in animal housing.
In mammals, acetylcholine is a neurotransmitter
released at the synapses of parasympathetic nerves and
myoneural junctions . The released acetylcholine
is quickly hydrolyzed by acetylcholinesterase and other
cholinesterases including erythrocyte cholinesterase and
plasma cholinesterase (also referred to as a pseudocholinesterase).
Inhibition of these hydrolysing enzymes
by carbamates results in continued nerve stimulation and
fatigue of cholinergic end-organs and muscles. Symptoms
of toxicity include salivation, diarrhea, miosis, accommodation
failure, bronchospasm, and muscle cramps.
Death is due to respiratory failure. Because of the rapid
progression of clinical symptoms, the treatment of animals
poisoned with carbamates should be considered an
emergency. Repeat doses of atropine are administered
to block the effects of accumulated acetylcholine at the
synapses of the parasympathetic nerves and myoneural
junctions. The administration of 2-PAM (pralidoxime
chloride) is contraindicated in carbamate intoxication.
A slurry of activated charcoal is administered orally
following accidental ingestion of carbamates, whereas
bathing of the animal is considered appropriate following
intoxication from dermal exposure. In addition
to inhibiting cholinesterases, carbaryl is teratogenic in
the chicken embryo test (75) and carcinogenic in chronic
rodent studies (76). Although carbaryl has not shown any
convincing evidence of genotoxic or carcinogenic activity
in humans, the human relevance of vascular tumors
(hemangiomas and hemangiosarcomas) in mice cannot be
dismissed (76).
