ORGANOPHOSPHOR

US
POISONING
- Environmental protection agency(EPA) :
80 % of all hospitalizations from poisoning : Due to the
Organophosphate group..

- Acc. to WHO , more than 3 million cases of serious pesticide

poisoning annually worldwide.

- Majority caused by organophosphates

especially in the developing countries.
 Estimated 5,00,000 deaths in Rural Asia from Deliberate
Self – Harm (DSH) each year.

 Deliberate self harm ???

 60 % are due to pesticide poisoning..

 Acc. to studies , Organophosphorus Compounds are

responsible for 2/3rds of these i.e 2,00,000 deaths..
 Survey of self-reported minor poisoning
(Asian region)

Approx. 25 million agricultural workers in the

developing world suffer from an episode of poisoning
each year..

Fatality rate in DSH with OP compounds :

as high as 46% in some hospital-based studies.
O.P POISONING IN NEPAL

 31 % of all suicidal deaths in 1999-2000 : Due to

Poisoning.

 Acc. To 12 Hospital- based studies from 5 Major

Hospitals (1999-2000) :

OP compounds : The most common form of

poisoning comprising 52% of total cases..
O.P. PESTICIDES
 Popular because:

- Highly effective ..

- Lack of persistence in the environment due to their

unstable chemical nature..
HISTORY:
 TETRAETHYL PYROPHOSPHATE (TEPP) :
- First organophosphate to be synthesised (1954)

- Used as an agricultural substitute for nicotine.

- For possible use as a nerve gas in chemical warfare in

Germany during World War II..

- Most highly toxic of the organophosphorus

insecticides.. ( death recorded within 5 min. of
ingestion)
GINGER - JAKE PARALYSIS
 Also known as JAKE LEG.

In 1920s , contamination of a beverage

( JAMAICA GINGER ) with the insecticide
TOCP( Triorthocresyl Phosphate),used to fortify the
extracts..

Rapid development of flaccid paralysis of lower and

upper extremities( demyelination of nerve sheaths)..
CLASSIFICATION: (ACC. TO
TOXICITY)
1. Highly toxic organophosphates:
TEPP(5 g), Parathion (15 – 30 mg) , Phorate, Mevinphos,
Disulfoton.
- Used as agricultural insecticides.
fatal dose = 15 mg to 05 grams..

2. Intermediately toxic organophosphates: Coumaphos ,

Chlorpyrifos , Trichlorfon , Ronnel.
- Used as animal insecticides.
fatal dose = 10 to 25 grams..

3. Low toxicity:
Diazinon, Malathion, Dichlorvos , Acephate.
- Used for household application and as field (golf course)sprays.
fatal dose = 25 grams to 60 grams ..
CHEMICAL PROPERTIES
O (S)
ІІ
R1--P--R2
І
X

X Group (Leaving group):

 Differ b/w different OP agents

 Determine its physical & chemical properties

R1 & R2 :
 Alkoxy groups

 Account for toxicokinetics of different OP agents.

P=S
 When Central Phosphorous atom is linked with Sulphur it is called
‘PHOSPHOROTHIOATES’.
 e.g Parathion/Malathion
CLASSIFICATION ( ACC. TO CHEMICAL
STRUCTURE):

1. ALKYL PHOSPHATES :
TEPP , HETP
OMPA (Octomethyl pyrophosphoramide)
DIMEFOX , ISOPESTOX , SULFOTEPP
DEMETON , MALATHION.

2. ARYL PHOSPHATES :
PARATHION
METHYL PARATHION
PARAOXON , DIAZINON
CHLORTHION
FACTORS DETERMINING ONSET ,
DURATION AND INTENSITY
 Nature of compound:
Water soluble : acute and shorter duration of symptoms
eg: TEPP.
Lipid soluble : delayed and more sustained effect
eg: Chlorfenthion.
 Nature of binding:

Reversible : short lived effects

Irreversible : persistent effects eg: Parathion
 Mode of action:

Direct agent: Direct acetylcholinesterase inhibition.

eg : Sarin
 Indirect agent: needs to be converted to an active
metabolite. eg parathion.
 Route/degree of exposure :

Cutaneous: chronic toxicity

Oral/GIT : acute symptoms
Inhaled: may be acute or chronic depending on poison
load
 Relative toxicity of the compound

 Rate of metabolic degradation

Malathion : more accelerated rate of metabolism in

higher animals.
MECHANISM OF ACTION
Organophosphorous compounds bind to
acetylcholinesterase
Overabundance of acetylcholine in the synapse
By time the compound undergoes a
conformational change (aging) renders the
enzyme irreversibly resistant to reactivation.
 Carbamate compounds unlike
organophosphates, are transient cholinesterase
inhibitors.
PATHOPHYSIOLOGY & CLINICAL FEATURES
ageing
A
Choline
c R₁
h
A Ac OP
Ac

c hE
hE

Agent
h
Acetic Acid
R₂

AchR

Muscarinic Effect Nicotinic Effect CNS toxicity

SITES OF ABSORPTION:
 Transdermal

 Transconjnctival

 Inhalational

 Direct injection

 Across the G.I mucosa

CLINICAL FEATURES
 Onset of systemic symptoms is most rapid
following inhalation and least following
percutaneous absorption.

 Generally oral or respiratory exposures result in

signs or symptoms within three hours.

 Symptoms of toxicity from dermal absorption

may be delayed up to 12 hours.
CLINICAL FEATURES (ACUTE
TOXICITY)

 In children :Common presenting signs :

 Seizures are more common (22%-25%).

 Lethargy and coma (54%-96%).

 Flaccid muscle weakness

 Miosis

 Excessive salivation
CLINICAL FEATURES (ACUTE
TOXICITY)

ACH: acetylcholine; Epi: epinephrine; NE: norepinephrine; NMJ: neuromuscular junction.

CLINICAL FEATURES CONTD..
Due to overstimulation of muscarinic acetylcholine receptors in
the parasympathetic system
(SLUDGE / DUMBELS)

- Bronchospasm
- Bronchorrhoea
- Miosis
- Lacrimation
- Urination
- Diarrhoea
- Hypotension
- Bradycardia
- Vomiting
- Salivation
 Features due to overstimulation of nicotinic
acetylcholine receptors in the sympathetic system :

- Tachycardia
- Mydriasis
- Hypertension
- Sweating
 Features due to overstimulation of nicotinic and
muscarinic acetylcholine receptors in the CNS

- Confusion
- Agitation
- Coma
- Respiratory failure
 Features due to overstimulation of nicotinic
acetylcholine receptors at the neuromuscular junction

- Muscle weakness
- Paralysis
- Fasciculations
PERADENIYA O.P POISONING SCALE

CLINICAL CRITERIA SCORE

PUPIL SIZE > 2 mm 0
< 2 mm 1
Pin point 2
RESP. RATE < 20 /min 0
> 20 /min 1
> 20 with central cyanosis 2
HEART RATE >60 /min 0
41 – 60 /min 1
< 40 /min 2
FASCICULATION none 0
Present, generalised or continuous 1

both 2
PERADENIYA SCALE CONTD...
CLINICAL CRITERIA SCORE
LEVEL OF Conscious and rationale 0
CONSCIOUSNESS
Impaired response to verbal 1
commands
No response to verbal commands 2
SEIZURES absent 0
present 1
 A score of 0 to 3 is considered as Mild poisoning.

 4 to 7 as Moderate poisoning

 8 to 11 as Severe poisoning.
CARDIAC TOXICITY: (LUDOMIRSKY ET
AL)
 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 torsades de pointes,

ventricular tachycardia and ventricular fibrillation..
MECHANISM OF CARDIAC TOXICITY:
 A direct toxic effect on the myocardium

 Overactivity of cholinergic or nicotinic receptors causing

haemodynamic alteration.

 Hypoxia

 Acidosis

 Electrolyte abnormalities

 High dose atropine therapy (used as treatment for

organophosphate poisoning).
NEUROLOGICAL MANIFESTATIONS:

 Type I paralysis or Acute paralysis.

 Type II paralysis or Intermediate syndrome.

 Type III paralysis or Organophosphate- induced

delayed polyneuropathy(OPIDP)
TYPE I PARALYSIS OR ACUTE PARALYSIS :
 Occurs along with the initial cholinergic symptoms.
 Result of persistent depolarisation at the neuromuscular
junction due to blockade of acetylcholinisterase >
desensitisation.
 Features:

- Muscle fasciculations.
- Cramps
- Twitching
- Weakness.
- Respiratory muscle paralysis > Respiratory arrest ..
- Bronchorrhoea – Pneumonia..
INTERMEDIATE SYNDROME ( TYPE II
PARALYSIS)
 Term 'intermediate syndrome' first coined by Senanayake
from Srilanka in 1987.

 But first described by Wadia as type II paralysis in 1974.

 Appears after the acute cholinergic phase but before the

expected onset of delayed neuropathy.

 Develops 24-96 hours after the poisoning.

 But may occur even in the subsequent week..

DEFINITION:
Defined as “proximal muscle paralysis of grade 3 or less,
72 h after ingestion of organophosphate with or without
requirement of mechanical ventilation (along with
extraocular, neck,and respiratory muscle weakness).”

 Affects conscious patients without fasciculations or other

cholinergic manifestations..

 Agents:
Fenthion , Monocrotophos & Dimethoate..
DURATION OF I.S :
Defined as “the time from onset of intermediate
syndrome to regaining proximal muscle power of both
shoulder and hip of grade 4”..
 Observed in a series of 10 patients..

 In 70 % pts. Respiratory insufficiency drew attention to

its onset..

 Various degrees of cranial nerve palsies and proximal

muscle weakness seen.

 Reported incidence varies between 8 to 49%..

 Muscle weakness affecting the proximal limb muscles
and neck flexors.

 A relative sparing of the distal muscle group.

 Inability to lift head from the pillow (due to a marked

weakness in neck flexion).

 Cranial nerves supplying the extra-ocular muscles are

mostly involved (i.e III , IV , VI)

 Cranial nerves VII and X less frequently affected.

 EMG:
Combination of pre and post synaptic dysfunction of
neuromuscular transmission..

 Senanayake:
Fade on tetanic stimulation..
Absence of fade on low frequency stimulation.
Absence of post – tetanic facilitation..
 Primary type is an axonal neuropathy..

 Also,
Nm transmission defect
Anterior horn cell defect
Toxin induced musclar inability..

 Syndrome persists for about 4 to 18 days..

TYPE III PARALYSIS (OPIDP): (GINGER
PARALYSIS SYNDROME)
 Sensory motor distal axonopathy

 Two distinct entities:

1. Pure motor polyneuropathy
2. Mild sensory with severe motor type..

 Pure sensory type not observed..

 Occurs 2 – 3 weeks after the acute poisoning episode.

 Distal muscle weakness..

 Relative sparing of neck muscles, cranial nerves and proximal

muscle groups..

 EMG:
Suggests of denervation..

 Recovery is delayed for up to 6 to 12 months.

 High dose methyl prednisolone shown to be beneficial in

experimental animals..
OTHER NEUROLOGICAL
MANIFESTATIONS:

 COPIND :

- Impaired memory
- Confusion
- Irritability
- Lethargy
- Psychoses

 EXTRAPYRAMIDAL MANIFESTATIONS :

- Dystonia
- Resting tremor
- Cog wheel rigidity
- Choreoathetosis
CONTD…
 Neuro – ophthalmic manfestations:
Optic neuropathy
Degeneration of retina
Myopia due to spasm or paresis of accomodation.

 Rarer manifestations:
G.B SYNDROME
Sphincter involvement
Ototoxicity
Isolated b/l recurrent laryngeal nerve paralysis
Myonecrosis
Schizophrenia
PANCREATITIS:
10%–12% patients develop pancreatitis following OP
ingestion.

Painless pancreatitis often goes unnoticed ..

Rarely, formation of a pseudopancreatic cyst ..

 Reference:
( Rizos E, Liberopoulos E, Kosta P, Efremidis S, Elisaf
M. Carbofuran-induced acutepancreatitis. JOP
2004;5:44–7.)
O.P POISONING & PREGNANCY :
 Experimental animals : Causes pre natal and postnatal
death and congenital abnormalities ,
eg: Vertebral deformities
Limb defects
Polydactyly
Intestinal herniae
Cleft palate
Hydroureter
 Human pregnancy :

- Poisoning in 3rd month : abortion done as continuation

may be hazardous…

- 2nd and 3rd trimester : successfully managed cases :

may allow pregnancy to continue till term unaffected..
DIAGNOSIS:
 No specific clinical features..

 High index of suspicion required.

 History of exposure and typical clinical features..

 Response to atropine therapy..( tolerance to atropine)

 Signs:
Pungent garlic like odour in breath and vomitus.
Miosis
Bradycardia.
Muscle fasciculations.
Excessive salivation
Excessive respiratory tract secretions
Lacrimation.

 Nicotinic effects:
Tachycardia
Hypertension
Mydriasis
LAB. INVESIGATIONS :
 Cholinesterase levels:
true and pseudo..
 Red-cell acetylcholinesterase is a good marker of
synaptic function and atropine needs in patients poisoned
with organophosphorus.
- Probably a good marker of severity..

PseudoCholineEsterase
 Plasma AchE = ButyrylAchE (BchE)

 Both ‘True’ & ‘Pseudo’ AchE are ↓ed in OP poisoning.

ACUTE POISONING :
 Approx. upto 50% AchE activity- Subclinical Poisoning

 20 – 50% AchE activity- Mild Poisoning

 < 10% AchE activity- Severe Poisoning

Clinical recovery correlates well with RBC – AChE

recovery to 30 % of normal..
CHRONIC EXPOSURE :
Depression of cholinesterase activity to 80 %

Intoxication

70 % or less activity

Hazard..
DIAGNOSIS (LABORATORY
ABNORMALITIES)

D o not delay the treatment until laboratory

confirmation is obtained.
MANAGEMENT:
 Patient should be placed in the left lateral position, with the
neck extended and head - end below the level of body..

Benefits:

- Reduces risk of aspiration .

- Helps keep the airway patent .
- Could decrease pyloric emptying and absorption of poison .
DECONTAMINATION:

- Remove pt. from site of exposure and clothes removed.

- Body thoroughly washed with soap and water to prevent

further absorption.

- Staff protection by wearing gloves, gowns and eye

protectors .

- No mouth to mouth respiration..

CAREFULLY WASH :

Skin folds

Areas under the fingernails,

Axillae and groins &

Other areas of the body that trap and retain chemicals

 Oxygen should be provided at the first opportunity.

 Little evidence supports the common advice that atropine must not
be given until oxygen is available.
(ventricular tachycardia in hypoxic dogs given atropine)

** Hospitals having no access to oxygen :

Atropine should be given early ...

(Reduce secretions and improve respiratory function)..

 Gastric lavage may be useful within 1–2 hours of ingestion..

 Done after aspiration of the gastric contents with an

orogastric tube using 200–300 ml of tap water ...

(5 ml/kg of normal saline in young children).

 Large quantities of saline avoided :

- Push the gastric contents into the intestine.. - May
induce vomiting leading to aspiration.
Comatose patients :
Intubate prior to gastric lavage ...

Latex gloves give inadequate protection and rubber

gloves should be used while decontaminating patients.

Label of the pesticide container :

- Invaluable resource to guide management ..
- Should be inspected whenever available..
 ANTICHOLINERGICS:
 Mainstay of treatment..

 Antagonize the muscarinic effects of the organophosphate on the

CNS, CVS and gastrointestinal tract..

 Should be started as soon as the airway is secured ..

 Recommended starting dose:

2 mg i.v bolus
Subsequent doses of 2 – 5 mg i.v every 5 – 15 minutes..(0.05
mg/kg in adults & 0.02 mg/kg in children)
If the effect of atropine is not seen after 3–5 minutes of
the initial dose & features of cholinergic poisoning
persist

Double every subsequent dose of atropine compared to

the previous dose till such time as the desired effect is
achieved.
SIGNS OF ADEQUATE ATROPINIZATION
:

- Decrease in bronchial secretions..

- Dry mouth..

- Moderately dilated pupils ( i.e no longer constricted)..

- Increased heart rate(> 100 beats/min)..

- Reduction in bowel sounds..

- Systolic B.P > 80 mm of Hg..

 REMEMBER:
 Pupils may remain constricted if the eyes have been exposed to the poison..

 Persistent crepitations in the chest may be due to aspiration pneumonia ..

Tachycardia : (may not always be adequate

atropinisation)

Hypoxia..
Agitation..
Alcohol withdrawal
Pneumonia
Fast Oxime administration.
MAINTENANCE DOSE OF ATROPINE :

Calculated at 10%–20% of the total dose required for

initial atropinization

Given in divided doses every hour.

OR

Continuous infusion of atropine (0.02 – 0.08 mg/kg/hour)

** Avoid heart rate > 140/min..

ATROPINE TOXICITY:
 Agitation

 Confusion

 Urinary retention

 Hyperthermia

 Bowel ileus

 Tachycardia
# Blind as a bat.

# Mad as a hatter.

# Hot as a hare.

# Looney as a tune.

# Red as a beet.

# Dry as a bone.
MANAGEMENT :

Reduce or stop atropine temporarily..

After the atropine toxicity subsides, three-fourth of the

previous dose should be started.
GLYCOPYRROLATE:
 Quarternary ammonium antimuscarinic agent..

 Peripheral effects similar to those of atropine..

 Longer acting drug , does not cross the blood–brain

barrier..

 Does not counteract the central nervous system effects of

the poison..

 More effective Antisialagogue...

 Cost also a limiting factor to its routine use..

 0.2 mg of glycopyrrolate costs two times that of 0.6 mg

atropine..
 CHOLINESTERASE REACTIVATOR

 Pralidoxime (PAM, 2-pyridine aldoxime methyl chloride).

 Obidoxime

 Diacetyl monoxime (DAM)

 Nucleophilic agents.

 Reactivate the phosphorylated acetylcholinesterase by binding to the

organophosphate molecule.
 M.O.A :

Three main actions:

- Direct reaction converting the organophosphate to a harmless

compound.

- Transient reaction protecting the enzyme from further

inhibition.

- Reactivation of the inhibited alkyl phosphorylated enzyme to

free the active unit (if given early enough)
 Action most marked at the nicotinic skeletal NM junction.

 Does not reverse the muscarinic manifestations.

 Recommended dosage:
# 1 gram i.v every 6 – 12 hours(adults)
(maximum dosage = 12 gram/24hours)
# 30 mg/kg in adults….
# 10 - 20 mg/kg in children.

 Continue till adequate spontaneous ventilation .

ACC. TO WHO :
World Health Organization(WHO) recommends:

30 mg/kg loading dose of PAM (chloride salt) over 15

minutes..

Followed by a continuous infusion of 10 mg/kg/ hour till

clinical recovery or for 7 days..
(whichever is later.)

** Chloride salt about 1.53 times more potent than the iodide
salt..
 Effective plasma concentration : 4 mg / litre.

 Patient should show signs of improvement 10 - 40 minutes after

administration.

 Elimination half life : 1.2 hours.

 Side effects:
Drowsiness
Visual disturbances
Nausea
Tachycardia
Muscle weakness
PAM :
Salts :

- Iodide
- Chloride
- Mesylate
- Methyl sulphate

 Routes :
i.v
i.m
s.c
sublingual as a first aid
OBLIDOXIME:
 Used in some countries……

 250 mg i.v bolus followed by an infusion of 750

mg every 24 hours..

 In Children:
3 – 6 mg / kg bolus..

Followed by a 0.5 mg/kg/hour infusion….

AGEING :
 Ageing of the phosphorylated enzyme after which the enzyme
cannot be reactivated by oximes.

 Probably a result of loss of one alkyl or alkoxy group..

 Half-life of ageing ::

- Dimethyl phosphorylated AChE: 3.7 hours

- Diethyl phosphorylated AChE : 33 hours..

(particularly benefit from oxime therapy)
RATES OF AGEING :
 Diethyl < Diisopropyl < Dimethyl < Isopropyl -
methyl
BENZODIAZEPINES  :
 Prophylactic
diazepam has been shown to decrease
neurocognitive dysfunction after poisoning.

 Diazepam 0.1-0.2 mg/kg IV, repeat as necessary if

seizures occur.

 Phenytoinhas no effect on organophosphate agent-

induced seizures.
ADJUNCTS IN O.P POISONING
BIOSCAVENGER THERAPY:
A ) OP hydrolases and anhydrases — enzymes
catalytically hydrolysing and inactivating OP
compounds..

B ) Cholinesterases and related enzymes—those

stoichiometrically binding and neutralising OP..

C ) Pseudocatalytic— a combination of ChE and oxime

pre-treatment
MAGNESIUM :
 Magnesium reversed the decrement in the force of
contraction and compound muscle action potential in rat
diaphragm..
 PLASMAPHERESIS:

 Plasma exchange therapy may be considered for patients with

organophosphate poisoning unresponsive to atropine and
pralidoxime.
(Human & Experimental Toxicology (2004) 23, 365- 368)

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