Organophosphates

Classification of OPs

are based on the leaving group (X)

Severity of toxicity depends on

the compound, the dose, the route, the frequency and duration of exposure, and the time of observation relative to the time of peak toxic effect. Effects may be immediate or delayed by hours or even days.

Oxime

• A nucleophilic chemical structure. The family of oxime chemicals include aldoximes and ketoximes. • 2-PAM (2-pyridine aldoxime methyl chloride, or called pralidoxime), in the form of chloride or iodide salts, belongs to a family of compounds called oximes, and specifically, it is a aldoxime. • Not to be confused with oxon, the phosphorus- oxygen (p=o) bond in organophosphates.

Organophosphorus-ester Induced Delayed Neurotoxicity (OPIDN)

• Certain OP classes (e.g., phosphoroamidates and phosphonates) cause central-peripheral distal axonopathy ("dying back polyneuropathy") in association with phosphorylation of a second enzyme, neuropathy target esterase (NTE). • Delayed onset: 2-3 wks after a single exposure • Backward degeneration of the axons of long and large nerve fibers in the central and peripheral nervous system, i.e. the neurotoxic degeneration develops in the feet and hands then progress with time to the legs and arms. • NTE is an integral membrane protein in all neurons. NTE controls interactions between neurons and glia in developing animals. Its physiological role is unknown in adults.

Cause of Death from OP Poisoning

• Exposure to even small amounts of an OP compound can be fatal • Respiratory paralysis and cardiac arrest are the most common causes of death in acute OPs poisoning patients

Developmental and Reproductive Toxicity

• Many reproductive studies demonstrated no definitive effects. • Young children and animal are more susceptible because of limited detoxification capacity, not because of the elevated sensitivity to the inhibitory effects of AChE.

Known detoxication reactions:

• Oxidative cleavage of the leaving group detoxifies phosphorothionate through metabolic intermediate • Hydrolytic cleavage of the leaving group detoxifieds the active oxon ▪ PON1: serum paraoxonase, a phosphotriesterase ▪ CE (CarbE): carboxylesterases ▪ BChE: Butyrylcholinesterase • Glutathione-S-transferase

Acute symptoms of AChE inhibition through overstimulation at muscarinic receptors

▪ Hypersalivation ▪ Excess lacrimation (tea flow) ▪ Hyperhidrosis (sweating) ▪ Miosis (pupil constriction) ▪ Intestinal cramps ▪ Vomiting ▪ Diarrhea ▪ Urinary and fecal incontinence ▪ Bronchorrhea and bronchoconstriction

Acute symptoms of AChE inhibition through overstimulation at nicotinic receptors

▪ Muscle cramps ▪ Muscle fiber fasciculation ▪ Weakness & Paralysis ▪ Pallor ▪ Anxiety, restlessness, dizziness, confusion, ataxia, convulsions, and respiratory and circulatory depression

Species Difference in PON1 and CarbE

• Serum paraoxonase 1 (PON1) is present in human and mammalian species, but not in the serum of birds, fish and reptiles, or in insects. • Insects have relatively low activity of carboxylesterases (CarbE).

OPs are selectively effective and inexpensive insecticides because

-Species differences in cholinesterase (ChE) targets -Rapid detoxification in mammals than insects -Delivered as pro-insecticides which are activated in insects in higher amounts or faster than in mammals -Faster rate of biodegradation in the environment (short half-life)

Group II compounds, fluorophosphates

-X, a fluoride leaving group -Generally highly toxic (e.g., diisopropyl fluorophosphate)

Group I compounds, phosphorylcholines

-X, a quaternary nitrogen -Most potent organophosphates (e.g., Shradan)

Treatment of OP Poisoning

-Atropine, pralidoxime (2-PAM), and benzodiazepines (eg, diazepam) are the mainstays of medical therapy -Initial management must focus on adequate use of atropine. -Optimizing oxygenation prior to the use of atropine is recommended to minimize the potential for dysrhythmias.

Types of nicotinic receptors

-N1 nicotinic receptors at neuromuscular junctions (for muscle movement) -N2 nicotinic receptors in the brain, and in the autonomic and parasympathetic nervous systems

Long-term Effects after Acute Poisoning

-OP poisoning has been associated with long-term effects on cardiovascular diseases such as arrhythmia, coronary artery disease (CAD), congestive heart failure (CHF). The overall database is rather weak. -Long-term neurobehavioral abnormalities at the cognitive levels have also be suspected.

Chemical structure of OPs

-OPs are esters of phosphoric acid and its derivatives with varying combinations of oxygen, carbon and sulfur or with nitrogen attached. -The general chemical structure of an OP comprises a central phosphorus atom with a double bound to oxygen or sulfur -R1 and R2 are commonly alkyl or aryl groups bound to the phosphorus atom either through an oxygen or sulfur -X represents a variety of groups and is called the leaving group, which is displaced (usually by nucleophilic substitution) by the oxygen of the serine residue at the target protein active site.

Purposes of OPs

-Pesicides in ag -Flame retardants -Meds for elimination parasitic worms and surface parasites -Gasoline additives -Hydraulic fluids -Cotton defoliants -Plastic components -Growth regulators -Industrial intermediates -Warfare chemical agents

Group IV compounds

-X, alkoxy, alkylthio, aryloxy, arylthio, or heterocyclic group -Most of the organophosphates used as insecticides today

Group III compounds

-X, cyanide or a halogen other than fluoride -Generally less potent than groups I or II (e.g., Parathion)

Muscarinic receptors

-g-protein coupled receptors, regulating phosphorylation of various second messengers -Located in brain, heart, smooth muscle, found in both the parasympathetic and sympathetic nervous system

Oxidative Desulfuration of organophosphate pesticides

1. Breakdown of acetylcholine 2. Partially electropositive phosphorus is 3. Transition state, bonds break and bones forming 4. OP attached to AChE, preventing attached to the partially electronegative serine the attachment of ACh

Organophosphates (OPs)

A large diverse class of chemicals that have been synthesized since the 19th century for several purposes

The use of OPs is __________.

Declining *However continue to be one of the most important classes of insecticides today

Organophosphate mechanism

Inhibits the enzyme acetylcholinesterase (AChE)

Nicotinic receptors

Ionotropic receptors, activation allows positively charged ions (mainly Na+) flow through the receptors to causes depolarization of the cells.

Acetylcholine receptors can be either

Nicotinic or muscarinic receptors

Detoxication of Organophosphate Pesticides

Ops binding to other esterases (1) may contribute to toxicity (not well studied), and (2) does contributes to detoxification.

Inhibition of acetylcholinesterase

Results in overstimulation at muscarinic and nicotinic cholinergic synapses

Intermediate Syndrome after Acute Toxicity

Symptoms (1 to several days after exposure): • Weakness of respiratory, neck, and proximal limb muscles • Death due to respiratory paralysis may happen • Underlying mechanism of intermediate syndrome is unknown and dose not appear to be AChE related. ▪ Nicotinic receptor desensitization due to prolonged cholinergic stimulation is hypothesized.