ORGANOPHOSPHORUS

POISONING
DR. SUBODH KUMAR MAHTO
P G I M E R , D R . R M L H O S P I TA L .
NEW DELHI
 Uses
 Classification
 Types
 Metabolism and mode of absobption
 Mechanism
 Clinical features- nicotinin/muscarnic/central receptor
and neurological:acute .IMS. Delayed neuropathy
 Management: diagnosis=pseudocholinesterase n atropine
test.—decontamination..atropine..PAM..metabolic
correction..suppotive eg NaHCO3, Mgso4, antiibotics,
clonidine, recom bacterial hydrolases.
 Mortality
 INTRODUCTION

 Organophosphorus compounds are chemical agents

in wide-spread use throughout the world, mainly in
agriculture.
 They are also used as nerve agents in chemical warfare
(e.g. Sarin gas), and as therapeutic agents, such as
ecothiopate used in the treatment of glaucoma.
 They comprise the ester, amide or thiol derivatives of
phosphoric acid and are most commonly used as
pesticides in commercial agriculture, field sprays
and as household chemicals.
 There are no rules and regulations governing the
purchase of these products, and they are therefore
readily available “over the counter”, despite them
being a major cause of morbidity and mortality.

 Exposure to organophosphates in an attempt to

commit suicide is a key problem, particularly in the
developing countries, and is a more common cause
of poisoning than the chronic exposure
experienced by farmers or sprayers in contact with
pesticides.
 CLASSIFICATION

 There are more than a hundred organophosphorus compounds

in common use. These are classified according to their toxicity
and clinical use:

 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.
 Types of organophosphate
Insecticides Nerve gases Antihelminthic Herbicides
agents
Malathion Soman Trichlorfon Tribufos
[DEF]
Parathion Sarin Merphos

Diazinon Tabun
Fenthion VX
Dichlorvos

Chlorpyrifos

Ethion
 Exposure

Home Exposure Occupational Exposure Other Exposure

Accidental ingestion Farms & Farm worker Dietary exposure-

Pesticide residues on
crops
Lawn and garden use Pesticide applicator Leaching from soils to
ground water

Insect control Manufacture Community exposure

Food supply Mixing and handling Airborne drift from

commercial
app

Water supply Landscapers Contaminated

drinking water
Absorption route

Cutaneous
Ingestion (Accidental Or Suicidal)
Inhalation
Injection
 Pharmacokinetics

o Most organophosphates are highly lipid soluble

compounds and are well absorbed from intact skin,
oral mucous membranes, conjunctiva and the
gastrointestinal and respiratory tracts.

o They are rapidly redistributed to all body tissues.

o The highest concentrations are found in the liver and

kidneys.
 .

 This high lipid solubility means that they easily cross

the blood/brain barrier and therefore produce potent
effects on the CNS.

 Metabolism occurs principally by oxidation in the liver

with conjugation and esterase hydrolysis producing a
half-life of minutes - hours.
 .

 The oxidative metabolites of malathion and

parathion (malaoxon and paraoxon) are active forms
and are subsequently hydrolyzed into inactive
metabolites.

 Elimination of organophosphorus compounds and

its metabolites occur mainly via urine, bile and
faeces
 mechanism of action

 OP Inactivate Acetyl Cholinesterase (Ach E).

Establishment Of A Covalent Bond With AchE.

 Ach E Is An Enzyme That Degrades The

Neurotransmitter Acetylcholine (Ach) Into Choline
And Acetic Acid.
 Ach Is Found In CNS & PNS, Neuromuscular
Junctions, And Red Blood Cells (RBCS).
 Once Ach E - Inactivated, Ach Accumulates
Throughout The Nervous System →
Overstimulation Of Muscarinic And Nicotinic
Receptors.
Once an organophosphate binds to AChE, the enzyme can undergo
one of the following:

• Endogenous hydrolysis of the phosphorylated enzyme by

esterases or paraoxonases
• Reactivation by a strong nucleophile such as pralidoxime (2-
PAM)
• Irreversible binding and permanent enzyme inactivation (aging)

The onset and severity of symptoms depend on the specific

compound, amount, route of exposure, and rate of metabolic
degradation
 Clinical features of Organophosphorus Poisoning

 Following exposure to organophosphorus compounds, the

toxic features are usually obvious within 30 minutes to 3
hours.

 This may be delayed in some cases depending on the rate

and amount of systemic absorption.

 The majority of patients give a history of intentional or

accidental ingestion of organophosphorus compounds.

 Toxicity is produced by the rapid absorption of the

compound through the gastrointestinal, respiratory tracts
and skin.
 Cont…

 The clinical symptoms and signs are non-specific and will

depend on the specific agent, the quantity and the route of
entry.

 Some patients present with vomiting, diarrhoea and

abdominal pain, whilst others may be unconscious on arrival
at the hospital. A high index of suspicion is therefore needed to
make an early diagnosis.

 The clinical features can be broadly classified as secondary to

the
(a) muscarinic effects
(b) nicotinic effects and
(c) central receptor stimulation.
 Cont…

 Early cases present predominantly with

parasympathetic over-activity, and a characteristic
garlic smell.

 The end result may be a multi-system manifestation

involving the gastrointestinal, respiratory,
cardiovascular and nervous systems, as well as
involvement of skeletal muscle, other organs and
metabolic effects such as hypo- or hyperglycemia.

 Most fatalities occur within 24 hours and those who

recover usually do so within 10 days.
Symptoms and signs
 Who classification for severity

MILD MODERATE SEVERE

Serum/rbc cholinesterase 0.8-2 u/l <0.8 u/l
level 2-8 u/l
Walks and talks Talks with soft voice Coma convulsions
Abd pain nausea vomit Cannot walk profuse bronchial
headache Fasiculations present secretions
Salivation sweating Miosis restlessness
anxiety
 Cardiac manifestations

 The commonest cardiac manifestations following

poisoning are hypotension (with warm, dilated
peripheries), and bradycardia. Patients seldom present
with tachycardia and hypertension due to predominant
nicotinic receptor stimulation.
 Cardiac manifestations are often the cause of serious
complications and fatality.

 Electrocardiographic manifestations include prolonged Q-

Tc intervals, elevation of the ST segment, inverted T waves
and a prolonged PR interval. There may also be rhythm
abnormalities such as sinus bradycardia , ventricular extra-
systoles, ventricular tachycardia and fibrillation.
 .

 Ludomirsky et al described three phases of cardiac

toxicity following organophosphate poisoning:

 Phase I: A brief period of increased sympathetic

tone

 Phase II: A prolonged period of parasympathetic

activity including AV node blockade

 Phase III: Q-T prolongation followed by torsade

de pointes, ventricular tachycardia and
ventricular fibrillation
 Respiratory manifestations

 Respiratory manifestations of acute

organophosphorus poisoning include
bronchorrhoea, rhinorrhoea, bronchospasm and
laryngeal spasm.

 This is due to the action of the organophosphate on

muscarinic receptors.

 The integrity of the airway may be compromised by

excessive secretions.
 .

 The nicotinic effects lead to weakness and

subsequent paralysis of respiratory and
oropharyngeal muscles.

 This increases the likelihood of both airway

obstruction and aspiration of gastric contents.

 Finally, central neurological depression may lead to

respiratory arrest
 .
Neurological manifestations
 Three different types of paralysis are recognized
based largely on the time of occurrence and their
differing pathophysiology:

 Type I paralysis or acute paralysis

 Type II paralysis or Intermediate syndrome
 Type III paralysis or Organophosphate- induced
delayed polyneuropathy
 Type I paralysis or acute paralysis

 is seen during the initial cholinergic phase.

 This is when large numbers of both muscarinic and
nicotinic receptors are occupied by acetylcholine,
leading to persistent depolarization at the
neuromuscular junction.
 Clinical features include muscle fasciculation,
cramps, twitching and weakness.
 At this stage the patient may require ventilatory
support due to the weakness of the respiratory
muscles leading to respiratory depression and arrest.
 Type II Paralysis/Intermediate syndrome

 The intermediate syndrome is a distinct clinical entity that

occurs 24 to 96 hours after the ingestion of an OP compound.
 Approximately 10-40% of patients treated for acute poisoning
develop this illness.
 The onset of the IMS is often rapid, with progression of muscle
weakness from the:
 ocular muscles
 neck muscle (the patient cannot raise their head from the
pillow)
 proximal limbs
 respiratory muscles (intercostals and diaphragm) over the
course of 24 hours.
 Clinical feature

 clinical manifestations of IMS typically occur within 24 to 96

hours, and affect conscious patients without fasciculation or
other cholinergic signs.
 Marked weakness of neck flexion and varying degree of
proximal limb muscle weakness, manifesting as weakness of
shoulder abduction and hip flexion, are the constant clinical
features.
 Respiratory insufficiency is common and frequently draws
medical attention to the onset of the syndrome.
 Other possible manifestations are involvement of muscles
innervated by motor cranial nerves and decreased deep
tendon reflexes.
 Sensory impairment is not a clinical manifestation of
IMS.
 Type III paralysis or organophosphate- induced
delayed polyneuropathy. (OPIDP)

 is a sensory-motor distal axonopathy that usually

occurs after ingestion of large doses of an
organophosphorus compound.

 The neuropathy presents as weakness and ataxia

following a latent period of 2-4 weeks.

 Initial stimulation causes excitatory fasciculation,

which then progresses to an inhibitory paralysis. The
cardinal symptoms are distal weakness of the hands
and feet.
 .

 This is often preceded by calf pain, and in some

cases, parasthesia of the distal part of the limbs.
Delayed CNS signs include tremor, anxiety and
coma.
 MANAGEMENT

DIAGNOSIS
 Diagnosis of OP poisoning based on the H/O
exposure to OP compounds, characteristics
manifestation of toxicitiy and improvement of sign
and symptoms after administration of atropine.
 Garlic-like smell is an added clinical sign especially if
the patient has ingested sulphur containing OP
compound.
 This may be aided by insisting the patient attendant
to search for a possible poison container in the
vicinity of the patient.
Contd.

 Cholinesterase (ChE) estimations (plasma butyryl

cholinesterase and red cell AChE) are the only useful
biochemical tool for confirming exposure to OP.
 Clinical severity graded on the basis of the
pseudocholinesterase level :-
 Mild - 20-50% enzyme activity.
 Moderate 10-20% enzyme activity.
 Severe <10% enzyme activity.
• Though the enzyme activity does not correlate well
with clinical severity.
Contd.

Plasma Butyrylcholinestrase Red cell acetylcholinestrase

Easily assayed Difficult to assay
Doesn’t correlate well with neuronal Correlate well with neuronal activity
activity . 30% activity – normal muscle function
< 10% activity – grossly deranged
muscle function.
Response to antidotal therapy is less Increased activity after
pralidoxime therapy.
Levels altered in malnutrition, chronic Levels altered in hemoglobinopathies
illness, chronic liver disease and and thalassemia.
infection.
Contd.

 Analytical identification of OP compound in gastric

aspirate or in the body fluids gives the clue that
patient has been exposed to OP compound.
 However in doubtful cases and especially if
laboratory facilities are not available, 1 mg atropine
can be given intravenously. If this does not
produce marked anticholinergic
manifestations, anticholinesterase poisoning
should be strongly suspected.
 Treatment

 Decontamination and Supportive therapy

 Blockade of Muscarinic activity with ATROPINE.
 Reversal of cholinesterase inhibition with OXIME.
 Correction of Metabolic abnormalities
 Prevention of infection.
 Management of complication.
 Decontamination and Supportive therapy

 Comatose or vomiting patients should be kept in left

lateral, preferably head down position with neck
extension to reduce the risk of aspiration.
 Patent airway should be secured with placement of
airway or with endotracheal intubation especially if
the patient is unconscious or having seizure.
 Frequent suctioning is essential as excessive
oropharyngeal and respiratory secretions may
occlude the airway.
 Need for oxygen therapy can be assessed by frequent
assessment of arterial oxygen saturation.
Contd.

 All clothing, hair accessories are to be removed and placed

in appropriate waste bags. The person is to be washed
with copious amount of water and soap.
 Skin folds and underside of fingernails and long hairs
require particular attention. Ocular decontamination is to
be carried out by washing eyes with water/normal saline.
 The health care workers need protection through personnel
protecting equipments. Rubber Gloves and gowns are
recommended as these compounds are known to penetrate
latex /vinyl gloves.
Contd

 Gastric lavage
 should be considered in patients presenting within 1-2 hours of
ingestion of poison.
 Risks of gastric lavage include aspiration, hypoxia, and laryngeal
spasm.
 reduced with proper management of airway.

 Activated charcoal
 reduce the poison load by adsorbing it.
 Its efficacy has not been conclusively proven in humans.
 single to multiple dose activated charcoal is routinely used in clinical
practice.(25gm 2 hourly).
 AVOID cathartics and induced emesis.
Blockade of muscarinic activity with atropine

 Specific antidote for muscarinic effects, no effect on

nicotinic symptoms.
 It reverses life threatening features that can result in
death :
 central respiratory depression
 bronchospasm, excessive bronchosecretion
 severe bradycardia, and hypotension.
 Current guidelines recommend the use of incremental
dose regimen to attain target end points, followed by
setting up an infusion to maintain these end-points.
 Bolus dose regimen (2-5 mg atropine every 10-15 min)
found inferior to standard regimen.
 Continous infusion regimen ( 1 mg/min till full
atropinisation) can be used in resource poor setting.
Contd.

 Target end-points for Atropine therapy :

 Heart rate >80/ min.
 Dilated pupils.
 Dry axillae.
 Systolic blood pressure >80 mm Hg.
 Clear chest on auscultation with resolution of bronchorrhea (absence of
wheeze and crepts).
• Recommended dose is an initial iv bolus of 1.8-3mg with
subsequent doses doubled every 5 minutes if there is no response
or repeat same dose until atropinization is achieved.
• Maintenance dose: 20% of initial atropinizing dose per hour for
first 48 hours and gradually taper over 5 -10 days, continuously
monitoring the adequacy of therapy.
Contd.

 Look for atropine TOXICITY

 Agitation, confusion, hyperthermia, urinary retention and severe
tachycardia.
 can precipitate ischaemic events in patients with underlying coronary
artery disease.

 Over atropinisation may necessitate discontinuation of

the atropine infusion, followed by frequent observation.
 When they settle down the infusion is to be started at 70-
80 % of the previous rate.
 Anticholinergic agent glycopyrrolate along with atropine
can be used in order to limit the central stimulation
produced by atropine.
Contd.

 Since glycopyrrolate does not enter CNS initial

muscarinic signs like coma or drowsiness will not
respond.
 It’s use is recommended
 when there is copious secretion as an adjunct to atropine
 when features of atropine toxicity like delirium etc are confused with
CNS effects of poison
 when atropine is not available.

 Dose : 7.5 mg of glycopyrolate in 200ml of saline is started as

infusion and is titrated to the desired effects of dry mucus membranes.
Reversal of cholinesterase inhibition by OXIMES.

 Oximes work by reactivating acetylcholinesterase that

has been bound to the OP molecule.
 Pralidoxime
 most frequently used oxime worldwide
 Nucleophilic agent
 other members include obidoxime and trimedoxime and experimental
HI 6 and HLO 7.
 The therapeutic window for oximes is limited by the time taken for
‘ageing’ of the enzyme-OP complex, because ‘aged’ enzyme can no
longer be reactivated by oximes.
 Mechanism of action :
 Oximes get attached to the free anionic site of the enzyme ChE. The
oxime end then reacts with the phosphorus atom of OP attached at the
esteratic site of the enzyme. This oxime phosphate so formed
diffuses away leaving the enzyme intact (Reactivated ChE).
Contd.

 Dose :
 WHO recommends pralidoxime dose of 30 mg/kg bolus iv over 20-
30 min followed by continuous infusion of 8mg/kg/hour Infusion
continued until recovery : 12 hrs after atropine has been stopped and
BChE noted to increase.
 Largest oximes trial recommends 2gm loading dose followed by
500mg/hr maximum for 7 days .

 Side effects : Dizziness, headache, blurred vision, and

diplopia, are common side effects of oxime therapy.
 Formation of stable phosphoryl oximes – high anticholinesterase
activity.
 Rapid administration may lead to tachycardia, laryngospasm,
muscle spasm, and transient neuromuscular blockade.
 Treatment of complication

 Cardiovascular complication :
 Muscarinic receptor stimulation cause bradycardia and hypotension
usually responds to atropine. Severe hypotension might benefit from
vasopressors. The value of vasopressors versus higher doses of
atropine is not yet clear.
 While nicotinic receptor stimulation cause sinus tachycardia and
hypertension.
 ECG changes: Prolonged QTc interval, ST segment elevation, low
amplitude T waves, extrasystole and prolonged PR interval.

 Respiratory complication :
 Regular and close observation in initial course will guide when to
ventilate. Regular suctioning and high flow oxygen should be given
to all patients with respiratory distress. Further, ABG should be
done to guide the therapy.
Contd.

 Indication of ventilator support :

I. Respiratory Gas Tensions
i Direct Indices
Arterial Oxygen Tension < 50 mm Hg on room air
Arterial Co2 Tension > 50 mm Hg in the absence of metabolic alkalosis
ii Derived Indices
P a o2/ Fio2 < 250 mm of Hg
PA-aOo2 ( Pulmonary arterial-alveolar O2 gradient) > 350 mm of Hg

II. Clinical - Respiratory Rate (RR)> 35 breaths/min

III. Mechanical Indices

Vital capacity < 15 ml/kg.
Maximum inspiratory force <- 25 cm of H2O.
Contd.

 CNS complication :
 Patients poisoned with organophosphorus frequently develop agitated
delirium.
 The cause is complex, with contributions from the pesticide itself,
atropine toxicity, hypoxia, alcohol ingested with the poison, and medical
complications.
 Diazepam is first-line therapy for seizures; however, seizures are
uncommon in well oxygenated patients with pesticide poisoning.
Seizures seem to be more common with organophosphorus nerve agents
(such as soman and tabun).
 Animal studies suggest that diazepam reduces neural damage and
prevents respiratory failure and death, but studies in humans are few.
 Gacyclidine : anti-glutamatergic compound, inh. Seizure caused by nerve
gas poison.
 Dose : 10 mg IV slowly which can be repeated up to 30-40 mg/24
hrs.
 Supportive treatment

 Antibiotic prophylaxis :-
 Broad spectrum antibiotics
 risk of infection due to frequent and multiple interventions.

 Hydrocarbon Aspiration :-
 ingestion of liquid concentrates of OP, hydrocarbon solvent
aspiration causes chemical pneumonitis.
 These cases are to be managed as a case of Acute Respiratory
Distress Syndrome.

 Furosemide :- It is recommended if pulmonary oedema

persists, even after full atropinisation.
 Magnesium sulphate :-
 blocks ligand-gated calcium channels, resulting in reduced
acetylcholine release from pre-synaptic terminals, thus
improving function at neuromuscular junctions, and reduced CNS
overstimulation mediated via NMDA receptor activation.
 I/V MgSo4 (4gm) on first day shown to decrease hospitalization
period and improve outcome.

 Clonidine :-
 alpha2-adrenergic receptor agonist.
 reduces acetylcholine synthesis and release from presynaptic
terminals.
 Animal studies show benefit of clonidine treatment, especially in
combination with atropine, but effects in human beings are
unknown.
 Dose : 0.15-.30 mg i/v bolus f/b 0.5 mg over 24hr.
 Sodium bicarbonate :-
 Increases in blood pH (up to 7·45–7·55) have been reported to improve
outcome in animals through an unknown mechanism.
 Useful in nerve gas poisoning.
 Dose : 5 meq/kg over 1 hour f/b 5-6 meq/kg/day.

 The roles of FFP, haemodialysis and haemofiltration are

not yet clear.
 a recent non-randomised controlled study in China suggested a benefit
of haemofiltration after poisoning with dichlorvos, which has poor
solubility in fat, and therefore should have a relatively small volume of
distribution.
 A systematic review of these therapies in organophosphorus poisoning is
underway, but randomised controlled trials will be needed to establish
good evidence-based treatment guidelines.
 A better approach than use of butylcholinesterase
might be to give recombinant bacterial
phosphotriesterases or hydrolases.
 These proteins break down organophosphorus pesticides
enzymatically and protect animals from pesticide poisoning.
 Future clinical development of such enzymes could reduce blood
concentrations of organophosphorus, allowing optimum activity of
other treatments.
 Mechanism of INTERMEDIATE SX

 IMS is well recognized as a disorder of the neuromuscular

junction; however, its exact underlying mechanisms are not
clearly defined.
 Senanayake and Karalliedde in their first report of IMS
suggested that the syndrome might be caused by pathologic
change in the postsynaptic end-plate region of striated
muscles.
 Proposed mechanism of IMS are:
 Downregulation or desensitization of postsyneptic Ach Receptors.
 Prolonged Ach esterase inhibition.
 Failure of postsyneptic Ach release.
 Oxidative stress related myopathy.
 Muscle necrosis.
 Treatment of IMS

 Treatment of IMS is mainly supportive and there are

no specific antidotes available for this devastating
syndrome.
 With supportive therapy, recovery from IMS occurs 5–18 days after
the onset of weakness.
 Regression of toxic signs among patients who survived IMS followed
a distinct pattern. Muscle power first resumed in cranial
nerve-innervated muscles, followed by respiratory
muscles, proximal muscles, and neck flexors.
 Organophosphate induced delayed
polyneuropathy (OPIDN )
 Occurs 1-3 weeks after acute exposure.
 Usually present with symptoms of cramping muscle pain followed by
numbness and paraesthesia in distal upper and lower limb.
 Can cause foot drop, wrist drop, muscle wasting and deformity such as
clawing of the hands.
 Physical examination :
 Symmetrical flaccid weakness of the distal muscle

 Variable sensory loss

 Dominant hand affected more

 Tendon reflex are lost or reduced ; absent ankle reflex being a

constant feature
 Pathophysiology of OPIDN

 Neuropathy inducing OP compounds cause inhibition of

carboxylesterase i.e. NTE (neuropathy target esterase).
 Inhibition should be irreversible and significant.
 degeneration of distal regions of large, long myelinated axons as the
primary lesion, which progresses to Wallerian-like degeneration of
affected fiber regions.

 Inhibition of NTE is necessary antecedent to OPIDN but

precise relationship has not been defined till now.
 Physiological function of NTE is not known.
 Dichlorovos and nerve agent are not associated with
OPIDN.
 Treatment

 Recovery from OPIDN is incomplete and may be limited to the hands

and feets, although substantial functional recovery after 1-2 years may
occur in younger patient.
 Currently no drug is approved for treatment of OPIDN.
 Following drugs are under trial :
 Phenylmethylsulfonyl fluoride (PMSF)- serine protease inhibitor.
 Corticosteroid and vitamin
 Calcium channel blocker
 Ganglioside mixture
 Mortality

Worldwide Mortality 3-25%.

Mortality Rates Depend On The

 Type Of Compound Used,

 Amount Ingested,
 General Health Of The Patient,
 Delay In Discovery And Transport,
 Insufficient Respiratory Management,
 Delay In Intubation, And
 Failure In Weaning Off Ventilatory Support.