There are more than a hundred organophosphate compounds used regularly.
OVERVIEW
Organophosphates are extremely toxic chemicals which present with a myriad
of clinical problems all of which may lead to difficulties in determining
management. Much of what is written in textbooks relates to dermal or
occupational exposure to organophosphates. Oral ingestion of
organophosphate concentrates may involve doses 100-1000 fold greater and
requires an entirely different approach to management.
The organophosphate insecticides are an extremely toxic group of compounds
which are rapidly absorbed by the dermal, oral and pulmonary routes.
The exception to this is extremely lipid soluble organophosphate (eg
fenthion and dichlofenthion) which are rapidly taken into fat stores and
subsequently slowly and intermittently released and metabolised to more
active compounds. In this situation the symptoms of toxicity may not occur
for up to 48 hours and may continue for weeks.
MECHANISM OF TOXIC EFFECTS
The organophosphate compounds phosphorylate and inactivate
acetylcholinesterases. This causes an increase in acetylcholine with
stimulation of autonomic receptors and depolarising block of neuromuscular
junction receptors. This gives rise to a large number of clinical effects
in the central nervous system, autonomic nervous system and leads to
paralysis.
After the initial organophosphate acetylcholinesterase bonds are formed a
conformational change in the molecular structure of the organophosphate
occurs which increases the binding and subsequently makes the
organophosphate acetylcholinesterase complex irreversibly bound.
In addition to the inactivation of acetylcholinesterase and subsequent
acetylcholine accumulation there is also central nervous system antagonism
of GABA and Dopaminergic neurons.
KINETICS IN OVERDOSE
Absorption:
All organophosphates are rapidly absorbed from the small intestine or
dermal exposure. Peak levels may occur within a few hours.
Distribution:
This is a diverse group of compounds with a wide range of lipid/water
solubility characteristics and variable but usually large volumes of
distribution.
Metabolism & Elimination:
Some organophosphates (-thions) are metabolised in the liver to much more
active metabolites (-oxons). These poisons (eg parathion, fenthion,
chlorpyrifos) are also usually highly lipid soluble. Thus the slow
conversion of these substances, which are widely distributed into fat, may
lead to delayed and/or prolonged cholinesterase inhibition and toxic
effects. (This also may explain the intermediate syndrome which has only
been observed with -thion organophosphates).
The major route of elimination is paraoxonase. This is an enzyme which is
present in serum bound to lipoproteins (HDL).
CLINICAL EFFECTS
Three clinical syndromes have been described:
In addition there are long term neuropsychological sequelae that may result
from both acute & chronic exposure.
(see also Clinical Grading of Toxicity)
ACUTE CHOLINERGIC SYNDROME AND PARALYSIS
The clinical effects and symptomatology in acute poisoning results from
muscarinic, nicotinic and central nervous system effects. (see diagram)
MUSCARINIC effects are those mediated by stimulation of the parasympathetic
nervous system. This results in -
The mnemonic DUMBELS describes most of the significant muscarinic features.
* Diarrhoea
NICOTINIC effects are due to the accumulation of acetylcholine both at the
neuro-muscular junction and at the preganglionic synapses of the autonomic
nervous system.
The accumulation of acetylcholine at the neuro-muscular junction causes
initial stimulation followed by depolarisation and paralysis.
Stimulation of the sympathetic nervous system may produce sweating,
hypertension and tachycardia.
CENTRAL NERVOUS SYSTEM EFFECTS
These include initial cerebral stimulation followed by increasing central
nervous system depression leading to coma and occasional seizure activity.
CARDIOVASCULAR EFFECTSN
Severe organophosphate poisoning is often complicated by hypotension and
tachycardia. In addition, ischaemic sequelae may develop in patients with
pre-existing vascular disease.
The vascular effects of the excess ACh are mediated mainly through
muscarinic receptors of the endothelium evoking release of nitric oxide and
vasodilatation. ACh also acts on nicotinic receptors in the sympathetic
ganglia, muscarinic receptors in the muscle layer of medium size arteries
to cause vasoconstriction and on CNS muscarinic receptors which have less
predictable effects on blood vessels.
Thus the hypotension and tachycardia that occur are usually due to a low
total peripheral resistance with a partially compensating high cardiac
output. In this case the hypotension and vasodilatation are reversed by
atropine (Buckley et al 1993).
Ischaemic complications may be due to unopposed vasoconstriction by
acetylcholine at sites of endothelial injury (Buckley et al 1993).
Symptomatology varies between individuals and within the same individual at
different points of time. This relates to a varying balance of muscarinic
and nicotinic effects.
In addition to the neurologically related complications the patients may
also develop non cardiogenic pulmonary oedema, pancreatitis and the adult
respiratory distress syndrome.
SUBACUTE (Intermediate Syndrome)
A subacute syndrome has been described in which patients develop proximal
muscle weakness and cranial nerve lesions after recovery from cholinergic
effects. This has been thought to be due to primary motor end plate
degeneration due to prolonged inhibition of acetylcholinesterase. It has
not been reported where high doses of pralidoxime have been used.
LATE
Late neurological sequelae include a peripheral neuropathy which is due to
axonal degeneration. This may be due to the inhibition of the enzyme
neurotoxic esterase (reported in occupational exposures). It is much more
common with (though not limited to) certain compounds with a higher
affinity for this enzyme.
Long term neuropsychiatric sequelae have been described for all degrees of
exposure. Formal neuropsychological testing and regular follow up should be
performed.
INVESTIGATIONS
PLASMA CHOLINESTERASE (PChE):
Is a sensitive marker of exposure but on its own gives little idea of
severity of exposure. The normal range is 3000-7000 U/L. Its utility can be
improved in a number of novel ways in the following situations.
DOCUMENTATION OF EXPOSURE IN MILD POISONING
The test can be done sequentially to confirm exposure in patients whose
results fall within the low part of the normal range. Repeating the test a
few weeks later will show whether the levels rebound to a higher level.
DETERMINING IF SUFFICIENT PRALIDOXIME IS BEING GIVEN (Mixed cholinesterase
test)
PChE is measured in the patients plasma and in a normal plasma sample and
in a 50-50 mixture of the two samples. If there is no free organophosphate
in the patients plasma (ie adequate doses of pralidoxime are being given to
neutralise the organophosphate) then the mixed sample will have a PChE
value equal to the mean of the other two measures. Lower values indicate
insufficient pralidoxime has been given.
DETERMINING IF PRALIDOXIME CAN BE CEASED (Serial cholinesterase test)
If the patient appears to be clinically well on a pralidoxime infusion
(after atropine has been ceased) it is difficult to judge when to cease the
infusion. In this scenario, the PChE is measured in the patients plasma,
the pralidoxime is ceased and the PChE is measured 4-8 hours later.
Pralidoxime may be recommenced while awaiting results. If there is no
residual organophosphate in the patient then the second sample will be
similar to the first. If the second PChE value has fallen this indicates
continuing exposure to organophosphates (probably due to lipid soluble
organophosphates stored in the patients fat)
RED BLOOD CELL CHOLINESTERASE:
This correlates well with severity and prognosis. It is a better indicator
of tissue acetylcholinesterase inhibition and is much less sensitive than
plasma cholinesterase. (This is not available at many centres - send away
10 mls of blood in a Heparinised tube).
ECG
Should be done in moderate to severe poisonings as brady and
tachyarrhythmias may occur.
CXR & Blood Gases
These are indicated in all severe poisonings as aspiration pnuemonia
(contributed to by hydrocarbon diluents) is not uncommon
Plasma organophosphate levels:
These are unhelpful in aiding management.
DIFFERENTIAL DIAGNOSIS
Difficulties in diagnosis usually arise when an unconscious or delirious
patient is known to have ingested an unknown chemical from the garden shed
(see Differential diagnosis of garden shed poisoning).
The absence of miosis does not exclude significant organophosphate
poisoning. The presence of muscle fasciculations and associated weakness
strongly supports the diagnosis. Organophosphates often have an odour
similar to garlic though this may be masked by hydrocarbon diluents.
DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS
Often, organophosphates are listed according to their lethal dose in
animals as being low, moderate or high toxicity. As the compounds are
usually prepared in concentrations that account for their relative potency,
these lists do not give any indication of the likelihood of developing
clinical consequences from an exposure.
In deliberate ingestions of concentrates, these poisons vary from being
very poisonous to extremely poisonous. The major differences are that a
number of these poisons require metabolic activation and thus may have a
delayed or prolonged course.
DETERMINATION OF SEVERITY
The following table has been suggested as a guide to determining severity
by . However if a patient has any CNS signs or paralysis or has ingested a
concentrated preparation, the poisoning is likely to be severe irrespective
of other initial signs.
TREATMENT
Supportive:
Maintenance of airway, ventilation, IV access and fluids are an early
priority as patients may deteriorate rapidly.
Staff should also
ICU:
Patients with moderate or severe poisoning should be transferred to an
Intensive Care facility. Asymptomatic patients who have ingested
organophosphate concentrate should also be managed in ICU.
GASTROINTESTINAL DECONTAMINATION
Activated Charcoal:
Oral activated charcoal should be given to all patients ingesting
organophosphates. Patients with any history, signs or investigation
indicating severe poisoning should have elective intubation, gastric lavage
and activated charcoal and the specific treatment outlined below.
In addition some organophosphates & their active metabolites have
entero-hepatic circulation and therefore repeated doses of activated
charcoal should be given if not contraindicated.
Elimination enhancement is not useful.
,b>Specific Antidotes:
ATROPINE
Atropine is used to block muscarinic effects due to excessive
acetylcholine. Initial treatment is to give a test dose of 1-2 mg of
Atropine over 10 minutes (in adults). If the patient exhibits signs of
atropinisation after this test dose it is likely that they have mild
poisoning. In other patients this dose should be repeated at 10 minute
intervals until the patient is atropinised.
The end point of atropinisation is traditionally the absence of
oro-pharyngeal secretions. Pupil size can only be used as an end point if
miosis is present on admission. Patients will often require an atropine
infusion to maintain atropinisation and infusions of 10-20 mgs/hr are
commonly required with severe poisonings.
In severe poisonings, measurement of peripheral vascular resistance may be
a better method of measuring adequate atropinisation as, in some
circumstances, cholinergic features may be surprisingly minimal (perhaps
due to a depolarising block of the muscarinic receptors) and
hypotension/tachycardia due to circulating acetylcholine are dominant
clinical features.
PRALIDOXIME:
Pralidoxime binds to organophosphates and removes them from
acetylcholinesterase if ageing has not occurred. The
pralidoxime-organophosphate complex is water soluble and rapidly excreted
by the kidneys.
Patients with mild to moderate poisoning should receive Pralidoxime with an
initial dose of 2 gms intravenously over 30 minutes followed by 1 gm 8th
hourly for a minimum of 48 hours. Severe poisonings or oral exposures
should have an infusion of 500 mgs/hour after the initial dose. The success
of pralidoxime binding to available organophosphate may be determined by
the mixed plasma cholinesterase test and the infusion adjusted accordingly.
For the majority of organophosphate poisonings this treatment is only of
use in the first 36 hours but pralidoxime should be utilized in severe
poisonings regardless of the time of exposure.
For poisonings with highly lipid soluble organophosphates this treatment
may be commenced later and may need to be continued for up to 2-3 weeks.
The dose of Pralidoxime in children is 25-50 mg/kg. Pralidoxime undergoes
renal excretion, in patients with renal failure the dose may need to be
reduced.
Treatment of specific complications
SEIZURES:
Initially, diazepam 10-20 mg IV followed by phenobarbitone 15 mg/kg IV and
elective intubation and ventilation (without paralysis).
HAEMODYNAMIC COLLAPSE AND ISCHAEMIA
Patients who become hypotensive often have extremely low peripheral
vascular resistance which can respond to very large doses of atropine.
These patients should have a Swan-ganz catheter inserted to monitor the
effects of therapy. These patients may seem to be adequately atropinised
using the normal clinical criteria.
Paradoxical vasoconstriction can occur at atheromatous sites due to
endothelial dysfunction at these sites and unopposed action of
acetylcholine receptors in the arterial smooth muscle. In theory this
vasoconstriction should respond to atropine and be exacerbated by
adrenaline and dopamine. Also, most patients have high rather than low
cardiac output. Thus atropine, rather than inotropic drugs, should be used
for the treatment of hypotension. See hypertext article
VENTRICULAR TACHYCARDIA
Magnesium, isoprenaline or overdrive pacing (rate 120-140) are indicated
for torsade de pointes and should be considered for all tachyarrhythmias
Magnesium is normally the drug of choice for treating torsade de pointes
but its calcium channel blocking activity may aggravate the hypotension and
heart block that can also complicate organophosphate poisoning.
LATE/LONG TERM COMPLICATIONS & FOLLOW UP:
Late neurological sequelae include a peripheral neuropathy which is due to
axonal degeneration. This may be due to the inhibition of the enzyme
neurotoxic esterase (reported in occupational exposures).
Long term neuropsychiatric sequelae have been described for all degrees of
exposure.
Additional information
DETECTION LIMITS FOR COMMON ORGANOPHOSPHORUS COMPOUNDS
ORGANOPHOSPHORUS Compounds
Acephate (epa; cornell) 0.02
Note that no details are provided for glyphosate or for any toxic breakdown products.
Dated 27/9/1998 Updated 8/03/2016
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(Obtaining even clinically relevant data such as the lipid solubility, the
half life, the conversion to active metabolites, binding to antidotes and
whether they are associated with delayed neuropathy or neuropsychiatric
effects is difficult or impossible for many of these compounds).
Following significant exposure symptoms of toxicity generally occur within
4 hours.
This
process is called aging & occurs between 12-36 hours after binding.
* acute cholinergic symptoms and paralysis (most common)
* subacute proximal weakness (Intermediate Syndrome)
* late axonal degeneration
* contraction of intestinal & bronchial smooth muscles
* decreased pupil size
* increased secretions from all secretory glands
* decreased sinus node activity (bradycardia), AV conduction defects and
occasionally ventricular arrhythmias.
* Urination
* Miosis
* Bronchospasm
* Emesis
* Lacrimation
* Salivation.
Significant (ie not mild) poisoning will almost invariably be associated
with a low plasma cholinesterase. Similar but usually milder clinical
features may occur with poisoning with carbamate insecticides.
* Wear gown and gloves
* Remove (and destroy) patients clothes
* Wash the patient a number of times (soap, alcohol and soap)
It is much morecommon with (though not limited to) certain compounds with a higher affinity for this enzyme.
Formal neuropsychological testing and regular follow up should be
performed.
(From a recognised laboratory in 2004)
Normal detection limits in mg / kg
Azinphos 0.05
Azinphos methyl 0.05
Bromophos ethyl 0.05
Bromophos 0.05
Cadusafos 0.05
Carbophenothion (see products containing) 0.05
Chlorfenvinphos (and FAO data sheet) 0.05
Chlorpyrifos 0.05
Chlorpyrifos methyl 0.05
Demeton-S-methyl 0.05
Diazinon 0.02
Dichlorvos 0.05
Dimethoate 0.05
Ethion 0.05
Ethoprophos 0.05
Etrimfos 0.05
Fenchlorphos 0.01
Fenitrothion 0.05
Fensulfothion 0.05
Fenthion 0.05
Fonophos 0.05
Heptenophos 0.05
Iodofenphos 0.05
Malathion 0.05
Methacrifos 0.05
Methamidophos 0.01
Methidathion 0.02
Mevinphos 0.05
Monocrotophos 0.05
Omethoate 0.05
Parathion 0.05
Parathion methyl 0.05
Phosalone 0.05
Phosmet 0.05
Phosphamidon 0.05
Pirimiphos methyl 0.05
Quinalphos 0.05
Sulfotep 0.05
Terbufos 0.05
Tolclofos methyl 0.05
Triazophos 0.02
It was stated that only the manufacturers had access to the tests.