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- a toxic alkaloid extracted from belladonna and other members of the nightshade family, it is typically used to dilate the eye and to stop muscular spasms.
-Pharmacologic action: parasympatholytic (reducing activity of parasympathetic nervous system) by competitive blockade of acetylcholine at muscarinic receptors, increases sinus node automaticity and AV conduction
-Uses: treat bradycardia, asystole, and AV block
-Dose: 0.5 - 1 mg for bradycardia every 3-5 minutes to a total dose of 0.04 mg/kg; typically 3 mg is adequate to completely block vagal effects. Atropine is well absorbed via endotracheal route (administer 1-2 mg diluted in 10mL sterile water or normal saline)
Potential complications: tachyarrhythmias, exacerbation of myocardial ischemia, low dose may cause paradoxical bardycardia ( < 0.5 mg), dry mouth, urinary retention, flushed and hot skin, crosses blood-brain barrier which can cause delirium -Pralidoxime (not equally effective, found to be successful with parathion, diazinon, methyl parathion, EPN, TEPP, dimethoate, and dichlorvos while dimethy compounds: malathion and methyl demeton are more resistant to reversal with pralidoxime)
-Diazepam (may improve survival in severe poisonings; diazepam co-administration with oximes in the treatment of organic phosphorus nerve gases (sarin, soman, tabun): decrease the incidence of seizures and neuropathy, decrease cerebral morphologic damage resulting from related convulsions) -Chronic exposure to insecticide: causes illness, workers regularly coming in contact, insecticides in living enviroments
-Tolerance may develop in long-term exposures: symptomatic after variable lengths of time, symptoms can range from vague neurologic complaints, weakness, blurred vision, miosis, nausea, vomiting, diarrhea, diaphoresis, other cholinergic effects, red blood cell cholinesterase activity is the most sensitive measure of chronic poisoning.
-contaminated foods
-contaminated beverages (responsible for epidemics of delayed polyneuropathies and encephalopathy)
-vague distal muscle weakness and pain are often the presenting symptoms, but weakness may progress to paralysis
-the onset and clinical course of these symptoms do not seem to be altered by the administration of atropine or pralidoxime
-pyramidal tract signs may appear weeks to months after exposure
-recovery in these patients is variable over months to years -relates to their ability to stimulate the parasympathetic and to a lesser extent the sympathetic branches of the autonomic nervous system
-early clinical findings may be mixed: weakness, fasciculations (muscle twitch), tachycardia, hypertension, vomiting, diaphoresis, diarrhea, salivation, small pupils, urinary retention
-as acetylcholine levels rise the clinical course usually changes mainly reflect muscarinic, skeletal muscle, and CNS abnormalities (bradycardia, heart block, hypotension, bronchospasm, lacrimation)
-secretions may become copious from every orifice and hinder resuscitation efforts
-with supportive care some patients with anticholinesterase poisoning improve rapidly (signs and symptoms resolving within 2-3 days)
-in other cases redistribution and absorption of these chemicals may continue for days, leads to prolonged or recurrent cholinergic symptoms and lengthy hospitalizations.
-measuring cholinesterase activity can be helpful when diagnosis of poisoning is not clear, but most labs are unable to rapidly produce results of tests
-recognition of cholinergic syndromes and appropriate therapy with atropine to control muscarinic activity and oxime to regenerate AChE can be coupled with supportive care to improve clinical outcome. DDT analogues
DDT - used to control typhus and eradication of malaria and was the most important factor in the population explosion that occurred between 1950-1970
-DDT/ Dichlorodiphenyltrichloroethane (Neocid, Ixodex, Anofex, others), canceled, low to moderate acute oral toxicity, low dermal absorption, highest lipid storage, tremors, CNS excitation; odorless
-Methoxychlor (Marlate), suspended, low acute oral toxicity, low dermal absorption, moderate lipid storage, and less toxic DDT substitute
-Dicofol (Kelthane), residential use banned, cotton, citrus, apple; low acute oral toxicity, low dermal absorption, low lipid storage
-Chlorbenzilate (Benzilan, Benzo-Chlor), citrus miticide, low acute oral toxicity, low dermal absorption, low lipid storage, and much less environmental persistence than DDT
*Look at structures toxaphene (isomers aldrin, dieldrin, endrin, heptachlor, endosulfan)
-Aldrin (Aldrex, Octalene, Toxadrin), canceled, high acute oral toxicity, high dermal absorption, high lipid storage, rapidly metabolized to dieldrin; mild "chemical" odor
-Dieldrin (Dieldrite, Octalox, Quintox), canceled, high acute oral toxicity, high dermal absorption, high lipid storage, stereoisomer of endrin; early and late seizures; odorless
-Endrin (hexadrin), Canceled, highest acute oral toxicity, high dermal absorption, no lipid storage, most toxic organochlorine; rapid onset seizures; status epilepticus
-Chlordane (octachlor, toxichlor, others), canceled, moderate acute oral toxicity, high dermal absorption, high lipid storage, early and late seizures occur
-Endosulfan ( thiodan, cyclodan, others) high acute oral toxicity, high dermal absorption, low lipid storage, strong sulfur odor
- Heptachlor (Drinox), restriced; fire ant control; soil treatment, moderate acute oral toxicity, high dermal absorption, high lipid storage, toxic metabolite heptachlor epoxide; odor of camphor
- Isobenzan (Telodrin), never registered in US, high acute oral toxicity, moderate dermal absorption, high lipid storage, also inhibits Mg++-ATPase; mild "chemical" odor
-Dienochlor (Pentact), canceled, N/A acute oral toxicity, low dermal absorption, low lipid storage, toxic metabolite binds to GSH
-Toxaphene (Polychlorinated Camphene) (Alltox, Chemphene, Toxakil, others), canceled, moderate-high acute oral toxicity, low dermal absorption, low lipid storage, seizures; terpene odor, often mixed with parathion.
*Look at structures -Chlordecone (Kepone), canceled, moderate acute oral toxicity, high dermal absorption, high lipid storage, "kepone shakes", seizures not seen; structurally similar to mirex
-Mirex (Dechlorane) canceled, low oral toxicity, high dermal absorption, high lipid storage, converted to chlordecone; toxicity identical
-Mechanism of action not as well understood: appear to inhibit sodium, potassium- ATPase and calcium-ATPase pumps
-they are poor inhibitors of the GABA-dependent chloride channel
*look at structures -Pre- 1940s: highly toxic arsenicals, mercurials, lead, sulfur, nicotine
-Early 1940s: Chemist Paul Muller demonstrated insecticidal properties of DDT creating a whole new class of pesticides
-1940s-1970s: widespread use: inexpensive, environmentally stable, low acute toxicity
-DDT help to control typhus, eradicaiton of malaria, increase human population 1950-1970
-In 1962 Rachel Carson, Biologist wrote about biomagnification up the food chain - insects to birds then found DDT in human residues, severe restriction or total ban in USA and Europe -a non-competitive antagonist at GABA-A receptors: convulsant
-blocks the GABA-activated chloride ionophore
- used as a research tool
-CNS stimulant
-Antidote in poisoning by CNS depressants, especially the barbiturate poisoning.
-obtained from cocculus indicus- this is a fruit of the anamirta paniculata, used externally as an antiparasitic, powerful poison, high dose causes (unconsciousness, delirium, convulsions, gastro-enteritis, stimulation of the respiratory center, paralysis, death) pyrethrins - natural plant extracts
pyrethroids - synthetic pyrethrin deriviatives, are more stable than natural pyrethrins, absorption by the oral route resulting toxicity has occurred, most exposures are from dermal absorption direct exposure to the peripheral sensory nerves, accounts for facial paresthesias, and absorbed via inhalation
-organic solvent extraction: ground chrysanthemum flowers
-pyrethrum = consists of 6 ester derived from chrysanthemic acid and pyrethric acid
-are highly effective, contact poison, lipophilic, penetrate exoskeleton, paralyzes nervous systems (sodium channel blockade)
-no mammalian toxicity (low acute toxicity)
-rapidly hydrolyzed in intestine and liver (carboxylesterase)
-break down rapidly in light and water (no environmental persistence, no bioaccumulation)
Oral toxicity in mammals: extremely low, LD50 is high, dermal toxicity is even lower
*mass production techniques come close to this ideal patented by the US army in 1946, marketed in the US since 1956
concentrations ranging from 5-100%, multiple formulations (solutions, creams, lotions, gels, sprays)
EPA estimates: 38% of the US population uses DEET each year
it repels insects by interfering with the chemo-receptors that attract insects to hosts
it is absorbed via skin and GI tract, skin absorption is significant (somewhat depend upon vehicle and concentration)
0.08% of dose remains on the skin after 8 hours
DEET is lipophilic skin absorption occurs within 2 hours, it is extensively metabolized by oxidation and hydroxylation (hepatic microsomal enzymes, excreted in the urine within 12 hours, metabolites and parent compound)
exact mechanism of toxicity is unknown 