Organophosphorus compounds are one of the most commonly used chemicals. They are used in agriculture to warfare( Sarin). These compounds are also used as therapeutic agents e.g. ecthiophate in glaucoma, field sprays, and house chemicals.
Exposure to organophosphate compounds in an attempt to commit suicide is the key problem in developing countrie and is a more common cause of poisoning than the chronic exposure experienced by farmers or sprayers in contact with pesticides. Estimates from the WHO indicate that each year, 1 million accidental poisonings and 2 million suicide attempts involving pesticides occur worldwide. Intoxication occurs following absorption through the skin, ingestion via the GI tract or inhalation through the respiratory tract.
There are more than a hundred organophosphorus compounds in common use.
WHO classifies organophosphates as follows:
1. Highly toxic organophosphates:
e.g. tetra-ethyl pyrophosphates, parathion
These are mainly used as agricultural insecticides.
2. Intermediately toxic organophosphates:
e.g. coumaphos, clorpyrifos, trichlorfon
These are used as animal insecticides.
3. Low toxicity:
e.g. diazinon, malathion, dichlorvos
These are used for household application and as field sprays.
· Classical description of a patient with OP poisoning is “unresponsive patient with pinpoint pupils, muscle fasciculation, diaphoresis, emesis, diarrhea, salivation, lacrimation, urinary incontinence and garlic odour.”
Organophosphorus compounds basically inhibit acetyl choline esterase enzyme. A covalent bond is formed when leaving group of organophosphate is split by Ach Esterase. This bond is stable but reversible. This complex becomes irreversibly bound during next 24-72 hrs when R groups leaves phosphate molecule. This is known as “AGING” . De novo synthesis of Ach Esterase is required to replenish it’s supply once aging has occurred.
But in carbamate compounds Ach Esterase undergoes carbamylation in a manner similar to phosphorylation, but without aging. As aging cannot occur, the carbamate-Ach Esterase bond hydrolyses spontaneously resulting in reactivation of enzyme within 24 hrs. Carbamate compounds donot cross blood brain barrier.
Ach is a neurotransmitter :
parasympathetic and sympathetic ganglia,
skeletal neuromuscular junction,
all post ganglionic parasympathetic nerves,
post ganglionic sympathetic to sweat glands and
Ach Esterase is an enzyme that hydrolyses Ach into acetic acid and choline immediately after release. OP compounds inhibit this choline esterase making more Ach available at the synapse/ NMJ – producing cholinergic symptoms.
Butyrylcholine esterase (pseudo choline esterase) is hepatic derived protein that is found in Human plasma, liver, heart, pancreas and brain. Exact function of this enzyme is not well understood.
· Caused by excessive stimulation of muscarinic and nicotinic cholinergic receptors.
· Onset of symptoms varies according to the agent, route and degree of exposure.
· Most patients become symptomatic within 8 hrs and almost all within 24 hrs.
· More lipophilic compounds such as dichlofenthion cause cholinergic effects for several days following oral ingestion.
· Anxiety, restlessness, insomnia, headache, dizziness, blurred vision, depression, tremors.
· Level of consciousness may deteriorate rapidly to confusion, lethargy and coma.
EXCESSIVE MUSCARINIC ACTIVITY
Mnemonic – “DUMBBELLS”
· D: Defecation
· U: Urination
· M: Miosis
· B: Bronchospasm
· B: Bronchorrhea
· E: Emesis
· L: Lacrimation
· S: Salivation.
Miosis is the most consistently encountered sign. Bronchorrhea can be so profuse that it may mimic pulmonary edema.
EXCESS NICOTINIC ACTIVITY
· At neuromuscular junction – behaves like a depolarizing neuromuscular blocking agent.
· Initially there is fasciculation followed by weakness and paralysis.
· It is the most reliable sign of organophosphate toxicity.
· With increasing severity paralysis ensues.
· Due to stimulation of nicotinic receptors causing catecholamine release.
· Mydriasis with bronchodilatation and urinary retention. Seen in 13% patients.
· May cause hyperglycemia with ketosis.
· Precipitation of margination-Leukocytosis.
· There may be hyperamylasemia- salivary gland stimulation. (Though pancreatitis can occur as a result spasm of sphincter of Oddi.
· There may be rise in Hepatic enzymes
· Initially sympathetic stimulation causes sinus tachycardia and hypertension
· As toxicity becomes more severe, bradycardia with prolonged PR interval with various degrees of blocks occur due to excess parasympathetic tone.
· Paralysis of respiratory muscles in combination with bronchorhea, bronchoconstriction and CNS depression lead to hypoxia and respiratory arrest which is the most common cause of death in OP poisoning.
· Another important cause is hypotension and circulatory failure.
· Liquid preparations of organophosphates are usually dissolved in hydrocarbon base.
· Therefore pulmonary aspiration following ingestion may cause hydrocarbon pneumonitis.
CARBAMATES : C/F
S Clinical features are same that of organophosphate poisoning except
1. Lack of CNS penetration and
2. Rapid hydrolysis of carbamate – Ach esterase bond.
However CNS symptoms may occur in victims of severe carbamate poisoning due to hypoxia.
A history of exposure to organophosphates and clinical manifestations are best clues to the diagnosis.
Routine investigations like – Hb, TC, DC, Electrolytes and CO2 levels.
Most reliable tests for confirming diagnosis are – Measuring level of insecticides and their metabolites in biologic tissues Or to measure Ach Esterase activity in neuronal tissues.However these tests are not practical. Measurement of RBC choline esterase ( true choline esterase)- which is similar to enzyme found in neuronal tissue.
Assessment of clinical condition of patient
· Level of consciousness
· BP, heart rate and temperature.
AIRWAY AND VENTILATION
1. Nasopharyngeal airway or intubation depending on clinical condition of the patient.
2. In comatose patient positive pressure ventilation should be used.
4. Maintain IV line.
5. If patient is on ventilator, non-depolarizing neuromuscular blockers should be used.
(with succinyl choline, paralysis can be prolonged up to 24 hrs.)
1. Rapid cutaneous absorption necessitates removal of all clothing.
2. Skin should be triple washed with water, soap, water and again rinsed with water.
3. Clothes should be washed with addition of washing soda/ baking soda.
4. Oily insecticides spilling on the hair may require repeated shampooing/shaving.
5. For oral ingestion: Gastric lavage should be given till the returning fluid is clear, followed by single oral dose of 1gm/kg of activated charcoal
TO CONTROL EXCESS MUSCARINIC ACTIVITY
S Before starting atropine its important to correct cyanosis and to catheterize the patient.
S Dose: Start with 1-5mg IV in Adolescent/ Adult or 0.05mg/kg in children up to adult dose.
S Repeat every 2-10 min interval until atropinisation occurs.
S Atropine can be started as continuous infusion- In children:0.025mg/kg/hr and In adults:0.5-1mg/hr.
Atropinisation is characterized by:
S Warm, dry, flushed skin (fever)
S Dry tongue and decreased secretions
S When antimuscarinic CNS toxicity becomes evident, yet peripheral cholinergic findings necessitate the administration of more atropine— Glycopyrrolate bromide can be substituted for atropine
S Because of its quaternary ammonium structure it can not cause CNS penetration.
S Dose:1-2mg IV repeated as needed in adolescent and adults
S 0.025mg/kg in children.
S Pralidoxime splits the complex by getting attached to anionic component of unaged organophosphate molecule and thus rejuvenating Ach Esterase.
S In addition to this PAM may also reverse Organophosphate toxicity by directly inactivating free organic phosphorus molecules and also by exhibiting antimuscarinic effect on nervous tissue.
S PAM is not useful once the Organophosphate-Ach esterase complex has undergone aging.
S Hence PAM therapy is most effective if started within first 24 hrs of ingestion.
S In children: 30-50mg/kg IV over 10-15 min
S Even after atropinisation, patient should be continuously observed for evidence of deteriorating neurological functions and the potential for paralysis.
S RBC choline esterase should be measured intermittently after the institution of PAM therapy.
S Discharge criteria: When a patient becomes asymptomatic and has not needed PAM and Atropine for 1-2 days and choline esterase activity is documented to be stable, patient may be discharged
S Treatment of carbamate poisoning is identical to that of organophosphate poisoning with except
Avoid PAM in monomethyl carbamate exposure
1. INTERMEDIATE SYNDROME:
- Delayed muscle weakness without fasciculation or cholinergic features noted in some patients 24-96 hrs after acute organophosphate poisoning.
Redistribution of lipophilic pesticide from adipose tissue is suggested as an etiology.
2. ENCEPHALOPATHY AND PERIPHERAL NEURITIS (OPIDN)
Several days or weeks after acute exposure.
Etiology: Inhibition of an enzyme within nervous tissue named Neurotoxic Esterase. Sympatientoms appear to be initiated by phosphorylation of this enzyme.
May even result from exposure to organophosphates that do not inhibit choline esterase. Ex: Merphos, Mipafox, Chlorpyrifos.
3. BEHAVIORAL TOXICITY
Behavioral changes may occur after acute and chronic exposure to organophosphate.
Symptoms include- confusion, psychosis, anxiety, drowsiness, depression, fatigue and irritability.
EEG may be abnormal.
Most psychological abnormalities resolve within 1 yr.