Organophosphates

Organophosphorous compounds are used as insecticides and parasiticides. They include malathion, parathion, tetraethyl pyrophosphate, dimethoate, coumaphos, fenchlorphos, trichlorphon etc

On the basis of their activity, organophosphates are classified as directly acting and indirectly acting.

• The metabolite is responsible for the toxicological actions in indirectly acting organophosphorus compounds.
• Directly acting include TEPP, DFP, tabun, serin, soman and diazinon.
• Indirectly acting includes malathion, parathion, fenithion and fenitrothion.

Sources:

Organophosphorus compounds are used in the control of pests on crops and stored grains.

• They are used to treat parasitic infestations in animals.
• They are also used as flea collars in pets and as fly repellents and cockroach baits.
• Feed may be contaminated with OPC, animal premises may be dusted or sprayed, systemic over dosage of antiparasitic compounds, drinking water may be contaminated, empty pesticide containers are never empty and animals can be poisoned if they are fed or watered with these container of poisoning.

Kinetics

• The cholinesterase inhibitors tend to be well absorbed from any exposure route.
• Rapidly distributed to tissues throughout the body.
• The cholinesterase inhibitors are metabolized primarily in the liver .
• In most cases the metabolic process detoxifies the compound, but some organophosphorus insecticides may be activated or have an increase in activity following metabolism.

 ✓ Phosphorothioates and phosphorodithioates (sulfur – containing compounds) undergo oxidative desulfuration reactions to form the oxon derivatives that have increased potency. 

✓ General oxidation and hydrolysis reactions, the cleavage of the ester linkage, markedly reduce toxicity.

• Excreted as degradation products in the urine.

Mechanism Of action:

Acetylcholine (ACh) is the mediator at junctions including those between:

o Preganglionic and postganglionic neurons in both parasympathetic and sympathetic nervous system.

o Postganglionic parasympathetic fibers and smooth muscles or glands.

o Motor nerves and skeletal muscles. o Some neuron to neuron junctions in the CNS.

• ACh has a cationic site and an esteric site.
• ACh is immediately metabolised by the enzyme acetylcholinesterase (AChE) which has a anionic site and an esteratic site.
• The binding of acetylcholinesterase by different organophosphous inhibitors varies somewhat in affinity and reversibility.
• After binding, the enzyme is ‘phosphorylated’, and thus inhibited. Generally speaking, much of the binding of AChE by an OP is regarded as ‘irreversible’.
• There are four stages of anticholinesterase action produced by these compounds.

They are – inhibition (phosphorylation), reactivation, aging and regeneration/recovery • Phosphorylation: Organophosphorus compounds react only at the esteratic site of cholinesterase to form a phosphorylated enzyme.

• Reactivation: Following alkylphosphorylation, spontaneous reactivation can occur. But, the rate is dependent on the nature of the alkyl group.
• Aging : Aging is the loss of one alkyl group, which generally occurs more rapidly than spontaneous hydrolysis. Aging makes the product more resistant to regeneration by pralidoxime. The rate is dependent on the R group of the organophosphorus compound. Pralidoxime was a compound that was generated to reactivate the enzyme cholinesterase. This agent combines with the cation binding site which orients the oxime group of this agent to react with the elecrophillic phosphorus atom. The oxime-phosphonate is split off, leaving the regenerated enzyme.
• Regeneration: If the enzyme is not reactivated, new acetylcholinesterase must be synthesized. This takes weeks or months. However, recovery can occur more rapidly since only a small fraction of acetylcholinesterase is needed to be resynthesized. • Irreversible inhibition of acetylcholinesterase causes accumulation of acetylcholine in the neuromuscular junction, parasympathetic postganglionic terminals in smooth muscles, cardiac muscle and glands and in all autonomic ganglia and in cholinergic synapses in the CNS.

  Organophosphate compound forms irreversible complex compound with acetylcholinestarase   

                               Enzyme

                                                              ê

                                   As., acetylcholinesterase enzymes converts , acetylcholine to acetic and choline 

                                                               ê

                There is excessive accumulation of acetylcholine due to OP poisoning.

                                                              ê

                         This may lead to excessive CNS stimulation, Atropine being a parasympatholytics.  Block muscarinic receptors , due to which acetylcholine cannot bind with muscarinic receptors to show its action.

Clinical Signs:

Three categories of effects occur in poisoned animals: muscarinic, nicotinic, and central nervous system effects.

o Muscarinic effects include profuse salivation, lacrimation, serous or seromucous nasal discharge, increased respiratory sounds due to bronchoconstriction and excess bronchial secretions, pronounced gastrointestinal sounds, colic and diarrhoea due to increased gastrointestinal motility, bradycardia, pupil constriction, sweating, coughing, vomiting and frequent urination. These parasympathetic signs usually begin appearing first.

o Signs of nicotinic cholinergic overstimulation occur soon after the onset of muscarinic signs and include muscle fasciculation, tremors, twitching, spasm and hypertonicity causing a stiff gait or rigid stance.

o Central nervous system effects vary with species and severe CNS depression common in any species. Anxiety, restlessness and hyperactivity may also be noticed. o Death is usually due to respiratory failure, but, bronchoconstriction and convulsions may be life threatening.

• Chronic organophosphorus poisoning

o The symptoms of chronic poisoning include polyneuritis, demyelination, sensory disturbances, muscle weakness, tenderness, depressed tendon reflexes, lower and upper motor neuron paralysis. The mechanism of action is not very clear. But, it is not due to anticholinesterase activity. No specific treatment is available.

Treatment :

• Emergency (rapid progression) .
• Atropine treats muscarinic effects (0.1 mg/kg IV), Repeat SQ every 2 hours may be necessary (irreversible action of OPs) .

✓ Doesn’t affect nicotinic signs, muscle fasciculations and muscle paralysis .

• Pralidoxime chloride (2-PAM; protopam chloride) 20mg/kg IV every 4-6 hours (IM or SC twice daily) for nicotinic or neuromuscular signs .
• If dermal route, bath with soap & water .
• Oral route

 ✓ Activated charcoal by nasogastric tube, mineral oil .

✓ Osmotic laxatives (magnesium sulfate).

• IV fluids .
• Respiratory support (May be) .
• Contraindicated: morphine, succinylcholine & phenothiazine and tranquilizers.

Prognosis

• Guarded

DDx

• CHC (convulsive seizures, no response to atropine)
• Carbamate
• Fog fever
• Urea
• Nitrate
• Hypomagnesemia.