ORGANOPHOSPHOROU

S POISONING
 ORGANOPHOSPHATES

Potent cholinesterase inhibitors capable of

causing severe cholinergic toxicity following
cutaneous exposure, inhalation, or ingestion.
 Usually from insecticides or nerve agents.
 Most common causes of poisoning worldwide, and are
frequently intentionally used in suicides
 Comprises of ester, amide or thiol derivatives of phosphoric
acid and are
 Most commonly used as pesticides in commercial agriculture,
field sprays and as household chemicals

Significant importance due to their practical

usefulness and chemical instability
Curtis D. Klaassen, CASARETT AND DOULL’S TOXICOLOGY The Basic Science Of Poisons 7 th Edition, McGraw-
Hill
STRUCTURE OF ORGANOPHOSPHATES (1
of 3)

 Degradable organic compounds

containing carbon- phosphorus bonds
(thus excluding phosphates and
phosphite esters, which lack this kind
of bonding) Organophosphates
structure
 Where X is the so-called “leaving
group,” that is displaced when the OP
phosphorylates acetylcholinesterase
(AChE), and is the most sensitive to
hydrolysis;R1 andR2 are most
commonly alkoxy groups (i.e., OCH3 or
OC2H5),

 Either an oxygen or a sulfur are also

attached to the phosphorus with a
Curtis D. Klaassen, CASARETT AND DOULL’S TOXICOLOGY The Basic Science Of Poisons 7 th Edition, McGraw-
Hill
STRUCTURE OF ORGANOPHOSPHATES (2
of 3)

Specific agents linked to human poisoning

include

Curtis D. Klaassen, CASARETT AND DOULL’S TOXICOLOGY The Basic Science Of Poisons 7 th Edition, McGraw-
Hill
STRUCTURE OF ORGANOPHOSPHATES (3
of 3)

Specific agents linked to human poisoning

include

Curtis D. Klaassen, CASARETT AND DOULL’S TOXICOLOGY The Basic Science Of Poisons 7 th Edition,
McGraw-Hill
 EPIDEMIOLOGY AND SOURCES OF
EXPOSURE

 Used as insecticides worldwide for more than 50 years.

 Use has declined in last 10 to 20 years, in part due to development of

carbamate insecticides, which are associated with similar toxicities .

 Medical applications include

 Reversal of neuromuscular blockade (neostigmine, pyridostigmine, edrophonium)
 Treatment of glaucoma, myasthenia gravis, and Alzheimer disease (echothiophate, pyridostigmine,
tacrine, and donepezil).

 Worldwide, an estimated 3,000,000 people exposed each year,

 Up to 300,000 fatalities yearly.
 Toxicity generally results from accidental or intentional ingestion

 Other potential causes of organophosphate toxicity include ingestion

of contaminated fruit, flour, or cooking oil, and wearing contaminated
clothing.
Curtis D. Klaassen, CASARETT AND DOULL’S TOXICOLOGY The Basic Science Of Poisons 7 th Edition,
McGraw-Hill
 CLASSIFICATION

 More than a 100 organophosphorus compounds in

use

 Classified according to toxicity & clinical use:

 Highly toxic organophosphates: (e.g. tetra-ethyl
pyrophosphates, parathion). These are mainly used as agricultural
insecticides.

 Intermediately toxic organophosphates: (e.g. coumaphos,

clorpyrifos, trichlorfon). These are used as animal insecticides.

 Low toxicity: (e.g. diazinon, malathion, dichlorvos). These are

used for household application and as field sprays.

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 MECHANISM OF ACTION (1 of 2)

 These agents are well absorbed through skin, lungs, and

gastrointestinal tract.

 They bind to acetylcholinesterase (AChE), also known as red blood cell

(RBC) acetylcholinesterase, and render this enzyme non-functional.

 AChE is enzyme responsible for hydrolysis of acetylcholine to choline

and acetic acid, and inhibition leads to an overabundance of
acetylcholine at the neuronal synapses and the neuromuscular junction.

 After some period of time (dependent on chemical structure of

organophosphorus agent), acetlycholinesterase-organophosphorus
compound undergoes a conformational change, known as "aging," which
renders enzyme irreversibly resistant to reactivation by an antidotal
oxime .

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 MECHANISM OF ACTION (2 of 2)

 In addition, plasma cholinesterase (also called butylcholinesterase [BuChE] or

pseudocholinesterase) and neuropathy target esterase (NTE) are inhibited by
organophosphorus agents; however, the clinical significance of these
interactions are less certain.

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 CLINICAL FEATURES

 Onset and duration of AChE inhibition varies depending on organophosphorus

agent's rate of AChE inhibition, route of absorption, enzymatic conversion to
active metabolites, and lipophilicity of organophosphorus agent.

 For most agents, oral or respiratory exposures generally result in signs or

symptoms within three hours, while symptoms of toxicity from dermal
absorption may be delayed up to 12 hours.

 Lipophilic agents such as dichlofenthion, fenthion, and malathion are associated

with delayed onset of symptoms (up to five days) and prolonged illness (greater
than 30 days),
 Which may be related to rapid adipose fat uptake and delayed redistribution from fat stores.

 Toxicity is produced by rapid absorption of compound through gastrointestinal,

respiratory tracts and skin.

 Clinical symptoms & signs are non-specific and will depend on specific agent,
quantity and route of entry.

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 SIGNS & SYMPTOMS (1 of 2)

Nicotinic receptors Central receptors

Cardiovascular General effects
Tachycardia Anxiety
Hypertension Restlessness
Ataxia
Musculoskeletal Convulsions
Weakness Insomnia
Fasciculations Dysarthria
Cramps Tremors
Paralysis Coma
Absent reflexes
Respiratory depression
Circulatory collapse

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 SIGNS & SYMPTOMS (2 of 2)

Muscarinic receptors
Cardiovascular Genitourinary
Bradycardia Urinary continence
Hypotension
Eyes
Respiratory Blurred vision
Rhinorrhoea Increased lacrimation
Bronchorrhoea Miosis
Bronchospasm
Cough Glands
Excessive salivation
Gastrointestinal
Nausea/vomiting
Increased salivation
Abdominal cramps
Diarrhoea
Faecal incontinence

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 Cardiac manifestations (1 of 2)

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 blockade.

Cardiac manifestations are often the cause of serious

complications and fatality.

There may also be rhythm abnormalities such as sinus

bradycardia , ventricular extra-systoles, ventricular
tachycardia and fibrillation.

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 Cardiac manifestations (2 of 2)

Mechanism of cardiac toxicity is unclear and

the following have all been postulated:
 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
 Respiratory & Gastrointestinal manifestations

 Respiratory manifestations
 Respiratory manifestations of acute organophosphorus poisoning

include bronchorrhoea, rhinorrhoea, bronchospasm & laryngeal spasm.

 This is due to action of organophosphate on muscarinic receptors.
 Integrity of airway may be compromised by excessive secretions.
 Nicotinic effects lead to weakness & subsequent paralysis of
respiratory & oropharyngeal muscles.
 This increases the likelihood of both airway obstruction and aspiration of
gastric contents.
 Finally, central neurological depression may lead to respiratory arrest.

 Gastrointestinal manifestations
 Symptoms resembling gastroenteritis such as vomiting, diarrhea and

abdominal cramps are the first to occur after oral ingestion of an

organophosphorus compound.

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 Neurological manifestations

 A large number of patients, following acute exposure to

organophosphorus compounds, will require prolonged ventilatory
support in the intensive care unit due to neuromuscular weakness.

 The neurological manifestations have therefore been a primary

focus of interest.

 There has been an emphasis on reducing the incidence of neuro-

muscular respiratory failure.

 Three different types of manifestations are recognized based largely

on the time of occurrence and their differing pathophysiology:
 Acute toxicity
 Intermediate syndrome
 Organophosphate- induced delayed Neuropathy(OPIDN)

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 Acute toxicity (1 of 3)

 Acute toxicity from organophosphorus agents presents with

manifestations of cholinergic excess.
 Primary toxic effects involve autonomic nervous system,
neuromuscular junction, and central nervous system (CNS).
 The parasympathetic nervous system is particularly dependent on
acetylcholine regulation, since both autonomic ganglia & end organs
of parasympathetic nervous system are regulated by nicotinic and
muscarinic cholinergic receptor subtypes, respectively.
 The dominant clinical features of acute cholinergic toxicity include

Bradycardia Bronchospas
Miosis, m,
Lacrimation Urination
Salivation Emesis
Bronchorrhea Diarrhea.

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 Acute toxicity (2 of 3)

 Diaphoresis occurs because sweat glands are regulated

through sympathetic activation of postganglionic muscarinic
receptors.

 At times, however, mydriasis and tachycardia may be

observed, as sympathetic ganglia also contain nicotinic
receptors .

 Muscarinic signs mnemonics:

 SLUDGE/BBB
– Salivation, Lacrimation, Urination, Defecation, Gastric Emesis, Br
onchorrhea, Bronchospasm, Bradycardia
 DUMBELS
– Defecation, Urination, Miosis, Bronchorrhea/Bronchospasm/Brady
cardia, Emesis, Lacrimation, Salivation
 It2013
should be noted
[Link] that these mnemonics do not take into
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 Acute toxicity (3 of 3)

 Nicotinic effects include fasciculations, muscle weakness, and

paralysis via acetylcholine stimulation of receptors at the
neuromuscular junction.

 This mechanism is analogous to the depolarizing effects

of succinylcholine in producing neuromuscular blockade.

 Nicotinic and muscarinic receptors also have been identified in

the brain, and may contribute to central respiratory
depression, lethargy, seizures, and coma.

 Cardiac arrhythmias, including heart block and QTc

prolongation, are occasionally observed in organophosphorus
agent poisoning.
 Intermediate syndrome

10 to 40 % of poisoned patients develop a

distinct neurologic disorder within 24 to 96
hours after exposure.

Referred to as "intermediate syndrome,"

consists of characteristic neurological findings
including :
 neck flexion weakness,
 decreased deep tendon reflexes,
 cranial nerve abnormalities,
 proximal muscle weakness, and
 respiratory insufficiency.
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 Intermediate syndrome

 Risk factors for development of intermediate syndrome appear

to include exposure to highly fat-soluble organophosphorus
agent, & may be related to inadequate doses of oximes

 With adequate supportive care, including prolonged

mechanical ventilation, patients have complete resolution of
neurologic dysfunction within 2 to 3 weeks

 Clinical deterioration & improvement appear to correlate with

red blood cell (RBC) acetylcholinesterase levels

 Nerve conduction studies on patients with intermediate

syndrome reveal unique postsynaptic abnormalities that
differentiate this disorder from delayed neurotoxicity

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 Delayed neurotoxicity (1 of 2)

 Organophosphorus agent induced delayed neuropathy (OPIDN) typically

occurs 1 to 3 weeks after ingestion of one of small number of specific
organophosphorus agents, including chlorpyrifos

 Mechanism involve inhibition of neuropathy target esterase (NTE), rather

than alterations in RBC acetylcholinesterase function .
 This enzyme, which is found in brain, peripheral nerves, & lymphocytes, is responsible for
the metabolism of various esters within cell.

 Affected patients present with transient, painful "stocking-glove" paresthesias

followed by symmetrical motor polyneuropathy characterized by flaccid
weakness of the lower extremities, which ascends to involve upper
extremities.

 Sensory disturbances are usually mild.

 Delayed neurotoxicity primarily affects distal muscle groups, but in severe

neurotoxicity, proximal muscles groups may also be affected.

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 Delayed neurotoxicity (2 of 2)

 The risk of developing OPIDN is independent of the severity of acute

cholinergic toxicity.
 Some organophosphorus agents, such as parathion, are potent cholinergic
agents but are not associated with OPIDN.
 Others, such as triorthocresyl phosphate (TOCP), produce few clinical signs
of cholinergic excess but are frequently implicated in OPIDN .

 Most cases of mild delayed neurotoxicity improve with time, in

severe cases, an upper motor neuron syndrome with spasticity of
lower extremities usually causes permanent disability.

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 DIAGNOSIS (1 of 2)

 No clinical features specific to organophosphorus poisoning(OP),

diagnosis requires a high index of suspicion

 History of exposure may be denied by suicidalpatients, or unavailable

in unconscious patients.

 Helpful signs of poisoning include pungent garliclike odour of

organophosphorus in breath and vomitus, miosis, bradycardia and
muscle fasciculations.

 Excessive salivation, excessive respiratory tract secretions &

lacrimation are other helpful signs.

 Some patients may present with nicotinic effects of tachycardia,

hypertension and mydiasis (rather that anticipated bradycardia and
hypotension).
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 DIAGNOSIS (2 of 2)

 Treatment is initiated immediately on clinical suspicion,

without waiting for blood investigations (although these are
important, to confirm diagnosis, & rule out multiple poisonings
& other metabolic causes of an altered neurological state).

 Both true and pseudocholinesterase levels can be estimated

to assess poisoning.
 These levels are markedly reduced in organophosphorus
poisoning.
 While true cholinesterase correlates with the severity of poisoning
at presentation, pseudocholinesterase levels do not.
 A 25% or greater reduction in true cholinesterase level is
indicative of organophosphorus poisoning.

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 MANAGEMENT (1 0f 7)

Decontamination
 Skin decontamination is very important step that should never be
neglected or hurried.
 Patient should be removed from site of exposure & their clothes
removed.
 Patient’s body should then be thoroughly washed with soap & water to
prevent further absorption from skin.
 Prior to treating patient, staff should be protected from the
organophosphate by wearing gloves, gowns and eye protectors.
 Gastric emptying should then be considered if patient presents within
1 hour of ingestion.
 Gastric lavage is only means of emptying the stomach in unconscious
patients in which case airway needs to be protected.
 Patient should receive activated charcoal 0.5-1 gm/ kg every four hours
to promote adsorption in gastrointestinal tract.
 Lavage is preferred to enforced emesis as this may precipitate seizures.

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 MANAGEMENT (2 0f 7)

 ICU management
 Airway: protection, prevention of aspiration, clearance of secretions

and adequate ventilation.

 If unable to protect airway - intubate and ventilate; do not use neuromuscular
blocking (NMB) agent succinylcholine, as it may result in prolonged paralysis
of hours to days.
 If using non-depolarising NMBs, there may be delayed onset with higher
dosage required to obtain effect.

 Breathing: Improve tissue oxygenation prior to administration of

atropine - minimises risk of ventricular fibrillation.
 If ventilated - establish a "gas scavenger" set-up: an external reservoir of
exhaled gas that is 'suctioned' away; see Protocol in the ICU Clinical Resource
Manual.

 Circulation: Blood pressure support with cautious use of noradrenaline.

 Blood pressure may be high or low.

[Link] Review date: February

2006
 MANAGEMENT (3 0f 7)

Drug Therapy:
 Atropine competitively blocks effects of acetylcholine.
 1-2mg IV in moderate poisoning; 2-5mg IV in severe poisoning for adults, 0.05
mg/kg IV for children
 Continue stat doses every 10 - 30 minutes until muscarinic signs (sweating,
salivation, bronchorrhoea) subside.
 Infusion: 60mg atropine in a 50mL syringe: 50 x 1.2mg ampoules.
 In patients with severe poisoning, HUNDREDS of milligrams of atropine by
bolus and continuous infusion may be required over the course of several days.
 Nebulised atropine may improve respiratory distress & oxygenation by
decreasing bronchial secretions, however; where ingestion results in
hydrocarbon aspiration, an ARDS picture occurs (refractory pulmonary oedema
and poor oxygenation).
 Tachycardia is not contraindication to therapy (it may be secondary to hypoxia
or sympathetic stimulation).
 Pupillary dilatation is not a sign of adequate therapy.
 Atropine is ineffective against nicotinic effects - (thus respiratory depression,
muscle weakness remain in presence of atropine).

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 MANAGEMENT (4 0f 7)

Pralidoxime
 Pralidoxime(2-PAM) and other oximes, such as HI-6 and obidoxime, are
cholinesterase reactivating agents that are effective in treating both
muscarinic and nicotinic symptoms.

 It should NOT be administered without concurrent atropine in order to

prevent worsening symptoms due to transient oxime-induced
acetylcholinesterase inhibition.

 Oxime therapy be given to all patients with evidence of cholinergic

toxicity, patients with neuromuscular dysfunction, or patients with
exposures to organophosphorus agents known to cause delayed
neurotoxicity.

 Current WHO recommendation for IV bolus therapy with pralidoxime is at

least 30 mg/kg in adults, and 25 to 50 mg/kg for children, based upon the
severity of symptoms.

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 MANAGEMENT (5 0f 7)

 Pralidoxime (continue…)
 No treatments have been shown to prevent intermediate syndrome
or organophosphorus agent-induced delayed neuropathy (OIDN),
early oxime treatment may be of benefit in this situation.

 It should be administered slowly over 30 minutes, since rapid

administration has occasionally been associated with cardiac arrest,
& slow administration prevents muscle weakness that results from
transient inhibition of acetylcholinesterase as pralidoxime binds to
the enzyme .

 After bolus dose, it appears that superior antidotal effects

occur with pralidoxime given as continuous infusion of at least
8 mg/kg/hour in adults & 10 to 20 mg/kg/hour for children.
 MANAGEMENT (6 0f 7)

Pralidoxime (continue…)
 Severe poisonings may result in prolonged redistribution of toxin;
therefore, continuous IV therapy should be adjusted based upon
patient's clinical response, & several days of therapy required.

 If rapidly available, serial red blood cell acetylcholinesterase (RBC

AChE) concentrations may be valuable in determining efficacy of
oxime-induced acetylcholinesterase regeneration.

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 MANAGEMENT (7 0f 7)

 Benzodiazepines —
 Organophosphorus agent-induced seizures should be treated with
a benzodiazepine.
 Prophylactic diazepam has been shown to decrease neurocognitive
dysfunction after organophosphorus agent poisoning .
 This led, in part, to the US military development of a 10 mg
autoinjector of diazepam for use in the setting of chemical attack .
 There is no evidence that phenytoin has any effect on
organophosphorus agent-induced seizures, and this agent is not
recommended.

 Frusemide
 Considered for persistent pulmonary oedema after full
atropinization.

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SUMMARY AND RECOMMENDATIONS
(1 of 3)

 While diagnosis of organophosphorus agent poisoning is often not

subtle, the management of these patients may be complex and
protracted.

 All symptomatic patients should receive therapy with

oxygen, atropine, an oxime (eg, pralidoxime), and a benzodiazepine.

 Acute toxicity from organophosphorus agents presents with

manifestations of cholinergic excess.

 This disorder consists of characteristic neurological findings including

neck flexion weakness, decreased deep tendon reflexes, cranial nerve
abnormalities, proximal muscle weakness, and respiratory
insufficiency.

 Due to significant variability in toxicity and treatment, every effort

should be made to precisely identify the agent.
SUMMARY AND RECOMMENDATIONS
(2 of 3)

 Moderately to severely poisoned patients with markedly depressed

mental status require 100 percent oxygen and immediate tracheal
intubation.

 In addition, patients who appear mildly poisoned may rapidly

develop respiratory failure.

 Succinylcholine should be avoided when performing rapid sequence

intubation in patients with OP poisoning.

 Adequate volume resuscitation with isotonic crystalloid should be

performed concomitantly with other resuscitative and diagnostic
efforts.

 We recommend atropine therapy for all patients with moderate to

severe cholinergic toxicity from OP poisoning .
SUMMARY AND RECOMMENDATIONS
(3 of 3)

 We suggest that oxime therapy (eg, pralidoxime) be given to all patients

with evidence of cholinergic toxicity, patients with neuromuscular
dysfunction, or patients with exposures to organophosphorus agents
known to cause delayed neurotoxicity .

 The current WHO recommendation for IV bolus therapy with pralidoxime

is at least 30 mg/kg in adults, and 25 to 50 mg/kg for children, based on
severity of symptoms, administered slowly over 30 minutes.

 In cases of topical exposure with potential dermal absorption, aggressive

decontamination with complete removal of the patient's clothes and
vigorous irrigation of the affected areas should be performed.

 Transfer of moderately to severely ill patients to a regional toxicology

treatment center is encouraged.
Thank you