Dr Syed Hussain Azhar Rizvi

OP compounds: What do we know?

 Organophosphorus pesticide self-poisoning is

an important clinical problem in rural regions
of the developing world

 A killer Poison - it kills an estimated 200 000

people every year

 These are class Ia Toxic compounds ,

according to WHO ( i.e. Highly Hazardous)
WHO Toxicity Classifcation
Major Issue in Medical ICU,
CHK
 Major Issue in Medical ICU, CHK is
NOT occupational exposure,
But
Self Poisoning or
Suicidal Poisoning
Self Inflicted Violence

 Self inflicted violence accounts for around

half of the 1.6 million violent deaths that
occur every year worldwide.

 About 63% of global deaths from self harm

occur in the Asia Pacific region.
Comparison Of Methods Used For
Fatal Self Harm
Pathophysiology of Toxicity
 Pathophysiology of OP
Compounds
 Organophosphorus pesticides inhibit esterase
enzymes, especially acetylcholinesterase in
synapses and on red-cell membranes, and
butyrylcholinesterase in plasma

 But, there are multiple factors influencing the

effects of OP on the body and measurement
of assays for diagnosis …
Mechanism

of OP
 Simplified Acute OP Toxicity
 Inactivation of acetylcholinesterase enzyme
Organophosphate
Generally Accepted
Mechanism Of OP Toxicity
(TD): Interaction And
Subsequent Inhibition Of
 It is accepted
Tissue AChethat blood and tissue
cholinesterase’s inhibition represents OP
exposure marker and initiating mechanisms
for toxicodynamic effects, characteristic for
cholinergic crisis
OP Toxicity and Cholinesterase

1. The symptomatology appears at more than

50% inhibition of RBC AChE

2. Blood ChE – RBC AChE and BuChE

(apparently with no cholinergic physiological
significance) are a redundant system

3. Erythrocyte AChE inhibition is more closely

correlated with OP toxic symptomatology
and represents a biomarker for exposure
OP Toxicity and Cholinesterase
... Cont’d

4. There is no clear correlation between blood

ChE and symtomatology
(Total inhibition may be without symptoms!)

 There is a net discrepancy between RBC

AChE and brain AChE inhibition:
cholinesterase activity restoration in blood
and brain is very different, approx. 1%⁄ day
for blood and re-synthesis half-life of 5–7
days for brain
OP Toxicity and Cholinesterase
... Cont’d

6. Toxic syndrome: resultant of cholinergic effects

(cholinergic crisis) sequentially associated with
non-cholinergic effects and neurotoxicity
(excitotoxicity)

7. The treatment targeting exclusively the

cholinergic segment (cholinergic crisis) leads to
partial results only
(Completion of treatment with anticonvulsants
(such as diazepam) improves the antidotal
results)
OP Toxicity and Cholinesterase
... Cont’d

8. Antidotism improvement by admitting the

following premises:
- OP complex mechanism of action: cholinergic,
non-cholinergic, excitotoxicity, etc.
- evaluation of OP TK⁄TD correlations and their
toxic consequences.
- evaluation of antidote PK⁄PD correlations as
major determinants of their antidotal effects
(anticholinergic, ChE reactivation, GABA agonism,
glutamatergic excitotoxicity antagonism, etc.).
Thus, 3 Groups of Effects
after OP Poisoning
1. Muscarinic
2. Nicotinic
3. Excitotoxic
 Clinical Syndrome
 Clinical Syndrome

}
 Acute Cholinergic:
 Central Respiratory
Respiratory
 Peripheral Muscarinic failure
failure
 Peripheral Nicotinic
 Intermediate Syndrome
 OPIDN: Delayed peripheral neuropathy
 Neurocognitive dysfunction
Muscarinic Nicotinic Central nervous
symptomatology symptomatology symptoms
(Postsynaptic (Postsynaptic Nicotinic ( Excitotoxic)
Muscarinic R R
excessive excessive stimulation)
stimulation)
Myosis Muscular fasciculation -anxiety, agitation, tremor;
Bradicardia Muscular weakness -consciousness alteration;
Hypotension Muscular paralysis -hallucinations;
Bronchorrhoea Respiratory insufficiency -seizures;
Salivation (ventilatory component) -respiratory centre inhibition
Emesis Pallor – respiratory insufficiency
Diarrhoea, abdominal Perspiration (synergistic with
pain Mydriasys* skeletal muscle paralysis)
Urinary frequency Tachycardia* -hypothermia
Cardiac rhythm Hypertension* -intermediate syndrome –
disturbance *(Transient symptoms usually type II paralysis –
masked by muscarinic appears few days later
Symtomatology)
OP Mechanisms Of Action

 It is generally accepted that irreversible AChE

inhibition, whatever the location, represents
the OP characteristic mechanism.
 Red blood cells AChE and plasma BChE
inhibition has practically no direct functional
consequence in the cholinergic system, being
first used as OP exposure biomarker
 Importance of RBC AChe
Redundancy

 The most important clinical implication of

RBC Ache Redundancy is the high threshold
of clinical symtomatology after OP exposure
i.e. symptoms occur when 50% or even higher
levels of cholinesterases are inhibited
AChE inhibition by OP –
biomarker of organism
exposure, followed by
complex disturbances
OP Poisoning is Not just
Cholinergic Crisis
• Primary mechanism of OP toxic effects: cholinergic crisis
• The cholinergic crisis initiates a complex pathological process and
consequences: Non-cholinergic mechanism – other targets
- Ischaemia – hypoxia – stress
- Acidosis
- Shock state
- Energetic metabolism perturbation and ATP depletion
- ATP depletion
- Excitotoxicity – Neurotoxicity
- Convulsions, induced by synergistic sequential events:
- Cholinergic crisis
- Hypoxia, anoxia
- GABA inhibition
- Glutamatergic mechanism (excitotoxic effects)
 OP Targets Than AChe, Correlated With
The Toxic Effects
Targets
M cholinergic receptor
N cholinergic receptor
M2 and M3 receptors at GABA
neurons level
Neuronal M and N receptors
Nicotinic cholinergic receptors
DFP irreversibly blocked
NMDA receptors
Energetic metabolism
Glutamate excessive release
Serotonin receptors and
transport blocked
GABA-ergic system
Functional consequences
Activation, neurotoxicity
Partial agonist
M3 receptors facilitate GABA transmission
Direct effects M1 and 2 receptors facilitate GABA
transmission
Blocking effects
M receptors decreased in cortex and hippocampus
Acidosis, oxidative metabolism blocked, ATP
decreased
Glutamate e.c. increased, excitotoxicity, neuronal
lesions
Neurotoxicity
Inhibitory effects
 The Unequal Efficacy Of
Oximes
 Oximes are reactivators of peripheral, but not cerebral
AChE
 Distribution predominantly plasmatic

 No reactivator is active against all major AChE inhibitors

 Very low lipophilicity, therefore, very low penetrability
 Oximes BBB penetration represents 4–10% of its plasma
concentration and is selective

 2-PAM T1 ⁄ 2 in humans = 1–2 hrs , therefore, given as a

continuous infusion
Diagnosis of OP Poisoning

 Diagnosis is made on the basis of:

 Clinical suspicion
 The characteristic clinical signs
 Smell of pesticides or solvents
 Reduced butyrylcholinesterase or
acetylcholinesterase activity in the blood.
Cholinesterase assays

 Red cell acetylcholinesterase assays

 Plasma butyrylcholinesterase assays
Use of butyrylcholinesterase recovery as a marker of organophosphorus
pesticide elimination

(A) dimethoate
and

(B) fenthion
poisoning
Red cell acetylcholinesterase assays
 These assays measure acetylcholinesterase expressed
on the surface of red cells

 Red-cell acetylcholinesterase inhibition is a good marker

of such inhibition in synapses and of poisoning severity

 This enzyme is measured in whole blood in which

butyrylcholinesterase activity has been blocked by an
inhibitor

 Acetylcholinesterase is present at very low levels in

human plasma and serum
Red cell acetylcholinesterase assays
. . . cont’d

 Once red-cell acetylcholinesterase has aged, it only

recovers via erythropoeisis

 Regeneration at less than 1% per day is therefore much

slower than butyrylcholinesterase regeneration

 The rate of spontaneous neuronal acetylcholinesterase

recovery is unclear, and thus red-cell
acetylcholinesterase could be a less useful marker of
synaptic acetylcholinesterase activity as recovery occurs
Red cell acetylcholinesterase assays
. . . cont’d
 Reactions between acetylcholinesterase,
organophosphorus and oximes will continue if a blood
sample is left at room temperature after sampling
 The measured acetylcholinesterase activity will then not
represent the exact activity in the blood at the time of
sampling; leaving samples for different times will give
variation in assays
 Blood samples must be diluted and cooled immediately
after sampling, to stop the reactions.
 We routinely dilute by a factor of 20 at the bedside by
mixing 200 μL of blood freshly drawn into an EDTA tube
with 4 mL of cold saline (at 4˚C) and then place the
sample in a freezer at −20˚C within 5 min
 Therapeutic Monitoring by
Acetylcholinesterase Assays
 Monitoring a patient’s cholinesterase status
after organophosphate poisoning enables the
verification of substantial exposure to
anticholinesterase agents
 In future, such assays could facilitate the
decision about when to stop oxime treatment
and allow cautious weaning of a patient from
a ventilator when butyrylcholinesterase
activity is increasing
 Principles Of Therapy

 Resuscitation of patients and giving oxygen and fluids

 A muscarinic antagonist (usually atropine)
 An acetylcholinesterase reactivator (an oxime that
reactivates acetylcholinesterase by removal of the
phosphate group)
 Respiratory support is given as necessary
 Gastric decontamination should be considered only after
the patient has been fully resuscitated and stabilised.
 Initial Resuscitation
 Check airway, breathing, and circulation.

 Place patient in the left lateral position, preferably with

head lower than the feet, to reduce risk of aspiration of
stomach contents.

 Provide high flow oxygen, if available.

 Intubate the patient if their airway or breathing is
compromised

 Set up an infusion of 0.9% normal saline; aim to keep the

systolic blood pressure above 80 mm Hg and urine output
above 0.5 mL/kg/h
Initial Resuscitation
... Cont’d
 Continuous cardiac monitoring and pulse
oximetry should be established; an ECG should
be performed

 Remove all clothing and gently cleanse patients

suspected of organophosphate exposure with
soap and water because organophosphates are
hydrolyzed readily in aqueous solutions with a
high pH. Consider clothing as hazardous waste
and discard accordingly.
Muscarinic Antagonist –
Atropine
 Give 1–3 mg of atropine as a bolus, depending on severity
 Record pulse rate, blood pressure, pupil size, presence of
sweat, and auscultatory findings at time of first atropine
dose

 5 min after giving atropine, check pulse, blood pressure,

pupil size, sweat, and chest sounds
 If no improvement has taken place, give double the
original dose of atropine
Muscarinic Antagonist –
Atropine ... Cont’d
 Continue to review every 5 min; give doubling
doses of atropine if response is still absent

 Once parameters have begun to improve, cease

dose doubling. Similar or smaller doses can be
used
Muscarinic Antagonist –
Atropine ... Cont’d
 Give atropine boluses until the heart rate is more than 80
beats per minute, the systolic blood pressure is more
than 80 mm Hg, and the chest is clear (appreciating that
atropine will not clear focal areas of aspiration)

 Sweating stops in most cases

 Tachycardia is not a contraindication to atropine since it

can be caused by many factors
Muscarinic Antagonist –
Atropine ... Cont’d
 The pupils will commonly dilate; however, this
sign is not a useful endpoint for initial atropine
treatment because a delay exists before
maximum effect.

 However, very dilated pupils are an indicator of

atropine toxicity
 Scheme Of Atropinization
(Endpoints To Be Reached)
2 4 8 16 Atropine requirement Atropinization

Poor air entry into lungs caused by Clear lungs

40
bronchospasm and bronchorrhoea

Exces sive sweating Dry axillae

30
(Hypotension) Systol. BP >
80 mm Hg
20
(Bradycardia) Heart rate >
80/min
10 (Miosis) No miosis

0
0 5 10 15
min after fir st atropine
dose

 Eddleston M, Buckley NA, Mohamed F, Senarathna L, Hittarage A, Dissanayake W, Azhar

S, Sheriff MHR, Dawson AH. Speed of initial atropinisation in significant organophosphorus
pesticide poisoning - a comparison of recommended regimens. Journal of Toxicology – Clinical
Toxicology 2004;6:865-875.
Monitoring of Atropine
Infusion
 Once the patient is stable, start an infusion of atropine
giving every hour about 10–20% of the total dose needed
to stabilize the patient
 If too little is given, cholinergic features will re-emerge
after some time
 If too much is given, patients will become agitated and
pyrexial, and develop absent bowel sounds and urinary
retention
 If this happens, stop the infusion and wait 30–60 min for
these features to settle before starting again at a lower
infusion rate
Atropine ... Summary
 Loading
 Doubling dose regime e.g. 2 4 8 16 mgs every 5
minutes
 Maintenance
 Continuous infusion < 3mg/hr
 10-20% of loading dose/hour
 Endpoints
 Clear chest on auscultation with no wheeze
 Heart rate >80 beats/min
 Withdrawal
 Atropine toxicity
 Clinical Improvement
Acetylcholinesterase
Reactivator
 Give pralidoxime chloride 2 g intravenously over
20–30 min into a second cannula

 Follow with an infusion of pralidoxime 0.5–1 g/h

in 0.9% normal saline

 Continue the oxime infusion until atropine has

not been needed for 12–24 h and the patient has
been extubated
Reactions Of Acetylcholinesterase
After Inhibition With Organophosphorus

 Inhibited acetylcholinesterase reactivates spontaneously

but slowly
 Oximes speed up this reactivation

 Unfortunately, if the organophosphorus is present in

high concentrations, newly reactivated
acetylcholinesterase will be rapidly reinhibited

 Whether reactivation or inhibition predominates

depends on the type of organophosphorus and relative
concentrations and affinities of organophosphorus and
oxime
Concept of Aging of AChe
 Inhibited acetylcholinesterase can also become aged, by
loss of one of the two alkyl groups attached to the bound
phosphate

 Aged acetylcholinesterase cannot be reactivated by

oximes

 The half-life of ageing varies according to the inhibiting

pesticide: if dimethyl, the half-life is around 3 h; if diethyl,
the half-life is around 33 h

 Thus ageing has important clinical consequences

Evidence of Benefit of
Pralidoxime
 A randomised controlled trial* in Baramati, India studied
the effect of very-high-dose pralidoxime iodide (2 g
loading dose, then 1 g either every hour or every 4 h for
48 h, then 1 g every 4 h until recovery) in 200 patients
with moderate organophosphorus poisoning (excluding
severely ill patients)
 The high-dose regimen was associated with reduced case
fatality (1% vs 8%; odds ratio [OR] 0·12, 95% CI 0·003–
0·90), fewer cases of pneumonia (8% vs 35%; 0·16, 0·06–
0·39), and reduced time on mechanical ventilation
(median 5 days vs 10 days).
*Continuous pralidoxime infusion versus repeated bolus injection to treat
organophosphorus pesticide poisoning: a randomised controlled trial.
Lancet 2006; 368: 2136–41.
Is There Convincing
Evidence Of Benefit Of
Pralidoxime?
 We look at the 2011 Cohrane Review. . .
 The Cochrane Database of
Systematic Reviews 2011
Conclusion
 Seven pralidoxime RCTs were found

 Three RCTs including 366 patients studied pralidoxime vs

placebo and four RCTs including 479 patients compared
two or more different doses. These trials found quite
disparate results with treatment effects ranging from
benefit to harm. However, many studies did not take into
account several issues important for outcomes..

 Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. Oximes for acute

organophosphate pesticide poisoning. Cochrane Database of Systematic
Reviews 2011, Issue 2
 The Cochrane Database of
Systematic Reviews 2011
 In particular, baseline characteristics were not balanced,
oxime doses varied widely, there were substantial delays
to treatment, and the type of organophosphate was not
taken into account

 Only one RCT compared the World Health Organization

(WHO) recommended doses with placebo. This trial
showed no clinical benefits and a trend towards harm in
all sub-groups, despite clear evidence that these doses
reactivated acetylcholinesterase in the blood

 Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. Oximes for acute

organophosphate pesticide poisoning. Cochrane Database of Systematic
Reviews 2011, Issue 2
 The Cochrane Database of
Systematic Reviews 2011

 Summary:
No evidence that oximes are a useful
treatment for organophosphate pesticide
poisoning
 Current evidence is insufficient to indicate
whether oximes are harmful or beneficial
 Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. Oximes for acute
organophosphate pesticide poisoning. Cochrane Database of Systematic
Reviews 2011, Issue 2
Special Situations In
Giving Pralidoxime
 Pregnancy Category: C

 A:Generally acceptable. Controlled studies in pregnant

women show no evidence of fetal risk.
 B:May be acceptable. Either animal studies show no risk
but human studies not available or animal studies showed
minor risks and human studies done and showed no risk.
 C:Use with caution if benefits outweigh risks. Animal
studies show risk and human studies not available or
neither animal nor human studies done.
 D:Use in LIFE-THREATENING emergencies when no safer
drug available. Positive evidence of human fetal risk.
Indications for Respiratory
Support
 Intubate and ventilate patients if:

 Tidal volume is below 5 mL/kg, or

 Vital capacity is below 15 mL/kg, or
 If they have apnoeic spells, or
 PaO2 is less than 8 kPa (60 mm Hg) on FiO2 of
more than 60%
Intermediate Syndrome
 Delayed Respiratory Failure
 Proximal muscle weakness and cranial nerve lesions
 Typically 1-4 days after cholinergic crisis has resolved

 Prolonged Effects on Nicotinic receptors

 Primary motor end plate degeneration

 Clinical importance
 Delayed respiratory failure leads to death if not aware of
it or prepared for it
Wadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde
1987
Chronic Effects
 Organophosphate induced delayed
neuropathy (OPIDN)
 1-3weeks
 Peripheral neuropathy
 Axonopathy due to Neuropathy Target Esterases
(NTE)

 Chronic organophosphate induced

neuropsychiatric disorder (COPIND)
How To Monitor For Onset Of
Intermediate Syndrome
 Assess flexor neck strength regularly in conscious patients
by asking them to lift their head off the bed and hold it in
that position while pressure is applied to their forehead.

 Any sign of weakness is a sign that the patient is at risk of

developing peripheral respiratory failure (Intermediate
Syndrome).

 Tidal volume should be checked every 4 h in such

patients. Values less than 5 mL/kg suggest a need for
intubation and ventilation
Intermediate Syndrome (IMS)
A Disorder Of Neuromuscular Junctions
 Acute organophosphate insecticide poisoning
can manifest 3 different phases of toxic
effects, namely:
 Acute cholinergic crisis
 Intermediate syndrome (IMS), and
 Delayed neuropathy

 Intermediate syndrome (IMS) is a major cause

of death from respiratory failure following
acute organophosphate poisoning.
Intermediate syndrome (IMS)
... Cont’d
 Proposed mechanisms of IMS include:
 Different susceptibility of various cholinergic
receptors
 Muscle necrosis
 Prolonged acetylcholinesterase inhibition
 Inadequate oxime therapy
 Downregulation or desensitization of postsynaptic
acetylcholine receptors, failure of postsynaptic
acetylcholine release, and oxidative stress-related
myopathy
The clinical manifestations
of IMS
 Typically occur within 24 to 96 hours

 Affecting conscious patients without

cholinergic signs

 Involve the muscles of respiration, proximal

limb muscles, neck flexors, and muscles
innervated by motor cranial nerves
The Duration of IMS

 Complete recovery develops 5–18 days later

Comparison of RNS Changes with Neck
Power
Proposed Treatments for IMS
other than Supportive i.e.
Mechanical Ventilation
1. Therapy with obidoxime, a more potent
oxime compared to pralidoxime,
significantly decreased the incidence of
respiratory failure, the length of
hospitalization, and mortality
2. Whole blood transfusion of 400–800mL/day
for up to 5 days
3. FFPs
Organophosphate - Induced Delayed
Neurotoxicity (OPIDN)
 Occurs 2–3 weeks after acute exposure to certain
organophosphate insecticides

 The clinical features are predominantly motor

neuropathy and primarily manifest as numbness and
weakness of the lower extremities, followed by
progressive ascending weakness of limb muscles.

 The disease entity is believed to be due to the inhibition

of a poorly characterized esterase called the
“Neuropathy Target Esterase”
Supportive Measures

 Benzodiazepines
 Gastrointestinal decontamination
 Other therapies
Benzodiazepines

 Treat agitation by reviewing the dose of

atropine being given and provide adequate
sedation with benzodiazepines

 Physical restraint of agitated patients in

warm conditions risks severe hyperthermia,
which is exacerbated greatly by atropine
because it inhibits normal thermoregulatory
responses, including sweating

 Adequate sedation is therefore important

Gastrointestinal
Decontamination
 No evidence shows any form of gastric
decontamination to benefit patients poisoned
with organophosphorus

 Lavage should be considered only if the patient

arrives within 1 hour of ingesting poison

 Gastric decontamination should only be done

after the patient has been stabilised and treated
with oxygen, atropine, and an oxime
Role of Magnesium Sulphate
in OP Poisoning
 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

 A trial in people poisoned with organophosphorus

pesticides recorded reduced mortality with magnesium
sulphate (0/11 [0%] vs 5/34 [14·7%]; p<0·01).
Role Of Other Substances is
Controversial In OP Poisoning
 Clonidine
 Sodium Bicarbonate
 FFPs (A small controlled study (12 patients given fresh frozen
plasma with 21 control patients) recorded benefit, but this trial was
not randomised and allocation decisions were unclear)
 Recombinant Bacterial Phosphotriesterases (break
down organophosphorus pesticides enzymatically)
Interventions To Reduce /
Prevent OP Self-Poisoning
 Love Marriages Law
 Rights to Affairs Law
 Parents Restraints Law/ Child protection
 Learn to Live with cockroaches
Thank You