CARBAMATES

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.

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.

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.

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).