Speech on organophosphorus poisoning
Following the Second World War, organochlorine pesticides (OP ) made a major
contribution to improvements in agricultural output and in the control of disease
vectors.
While the persistence of these compounds after application was of
considerable benefit to the user, it also introduced problems.
As these problems
became more widely appreciated, insect pest control began to rely more on the
anticholinesterase organophosphorus and carbamate ester pesticides.
A large
number of such substance have been introduced on the market, and are now still in
use. This chapter is to introduce organophosphorous pesticide poisoning.
OP are normally esters, amides, or thiol derivatives of phosphoric, phosphonic,
phosphorothioic, or phosphonothioic acids. Most are only sightly soluble in water and
have a high oil-to-water partition coefficient and low vapour pressure. All smell of
special odor of garlic. Most are more stable in the acidic environment (pH3-6), and
are easy to dispose in the alkalis or neural pH.
OP exert their acute effects in mammals by inhibiting acetylcholinesterase
(AChE) in the nervous system with subsequent accumulation of toxic levels of
acetylcholine (ACh), which is a neurotransmitter in the central nervous system (CNS)
and automnomic nervous system, thus causing muscarinic, nicotinic and CNS
symptoms. Death is caused by respiratory failure due to a combination of blocking of
the respiratory centre, bronchospasm, and paralysis of the respiratory muscles.
According to their oral LD50 in rats, the OPs can be divided into the following 4
classes:
1. super-high toxicity, LD50<10 mg/kg, i.e. Parathion,
2. high toxicity, LD50 10-100mg/kg, i.e. Methamidophos, DDVP (diethyl
dichlorovinyl phosphate]), parathion-methyl, Oxide Rogor
3. modest toxicity LD50100-1000mg/kg i.e. Rogor, dipterex, ethion
4. low toxicity LD50 1000-5000mg/kg , i.e.malathion
Etiology and Mechanism
1. Etiology
Uptake of OP in human may occur through the skin, respiratory system, or
gastrointestinal tract. Occupational exposure occurs during the process of producing,
transporting and applying the poisons. Living exposure is also common via foodstuffs,
polluted vegetable and water. Sometimes one is poisoned when he intends to suicide
or eat the poison by mistake.
2. Mechanism
1.1 Metabolism
OP distributes to allover the body quickly after absorption, esp. in the liver.
Metabolism occurs principally in the liver by oxidation, hydrolysis by esterases, and
by transfer of portions of the molecule to glutathione. Oxidation of organophosphorus
pesticides mostly results in more toxic products while hydrolytic reaction produces
products, that are, in most cases, of low toxicity. In general, phosphorothioates are not
directly toxic but require oxidative metabolism to the proximal toxin. Numerous
conjugation reactions follow the primary metabolic processes, and elimination of the
phosphorus-containing residue may be via the urine or faeces. No residues remain in
the body.
2.2 Mode of action
The
primary
biochemical
effect
associated
with
toxicity
caused
by
organophosphorus pesticides is inhibition of AChE (acetylcholine esterase). The
normal function of AChE is to terminate neurotransmission due to Acetylcholine
(Ach) that has been liberated at cholinergic nerve endings in response to nervous
stimuli.
Loss of AChE activity may lead to a range of effects resulting from
excessive nervous stimulation and culminating in respiratory failure and death. Ach is
the neurotransmitter at both pre and postganglionic synapses in the parasympathetic
system, sympathetic preganglionic synapses, some sympathetic postganglionic
synapses, the neuromuscular junction (somatic nervous system), and at some sites in
the CNS. Nerve fibers that release Ach from their endings are described as cholinergic
fibers. Sometimes OP would also affect Ach receptor directly.
Clinical Manifestation
1. Acute poisoning
The time of onset in acute OP poisoning is related to the chemical, dose, rout of
exposure and the amount of the gastric content. It takes 10 min to 2 hour for the
symptoms to occur if the poison is ingested, 30 minutes if the poison is taken by the
airway, and 2-6 hours if the toxin is absorbed via skin. Death is caused by respiratory
failure in serious cases.
Mild poisoning includes muscarinic symptoms; modest poisoning includes
nicotinic signs other than the muscarinic symptoms. Severe cases also show central
nervous system involvement.
The symptoms can be summarized in three groups as follows:
(a)
Muscarinic manifestations- manifestations caused by the spasm of smooth
muscle and over-excretion of the glands resulting from the continuous
stimulation of the parasynthetic nerves.
-
increased
bronchial
secretion,
excessive
sweating,salivation,
and
lachrymation,
-
pinpoint pupils, bronchoconstriction, abdominal cramps (vomiting and
diarrhoea); and
(b)
bradycardia.
Nicotinic manifestations- manifestations caused by the over-activation of
the ncotinic receptor
-
fasciculation of fine muscles and, in more severe cases, of diaphragm and
respiratory muscles; and
-
tachycardia,
(c)
Central nervous system manifestations
- headache, dizziness, restlessness, and anxiety;
-
mental confusion, convulsions, and coma; and
- depression of the respiratory centre.
According to the severity of the symptoms, the acute poisoning can be divided into
3 grades: mild, moderate, severe (Tab 1).
Table1 1. Classification of severity
Mild
Moderate
Severe
General symptoms
M-symptoms
N-symtoms
All more severe
Miosis
+
++
+++
Respiratory symtoms Chest tightness
Dyspnea
Acute lung edema
CNS symtoms
-
-
+
AchE activity
50-70%
30-50%
<30%
2. Organophosphorus Induced Delayed neuropathy (OPIDP)
Delayed neuropathy has occurred occasionally in the patients 2-3 weeks after the
diminishment of the symptoms of acute clinergic crisis in the intoxication of some
species of organophosphorus esters. Delayed neuropathy is initiated by attack on a
nervous tissue esterase distinct from AchE called neuropathy target esterase (NTE).
The initial symptoms are often sensory with tingling and burning sensations in the
lower limbs and feet followed by motor involvement of the lower limbs, manifested
by leg weakness, foot drop and muscle hypotonia. This progresses to paralysis, which,
in severe cases, affects the upper limbs also.
OPIDP is typically a “dying-back” neuropathy as revealed by clinical, electrophysiological and nerve biopsy data. The neuropathy has a typical “subacute” course
of progression over a two-week period. In addition, features of pyramidal tract and
posterior column involvement may be noted later in the course of illness.
The symptom of paresthesia will relieved gradually 3-12 months later. Dyskinesia
will recover totally or partially 6-18 months later. If the spinal cord and the brain are
involved, motor disfunction will be present permanently and result in disability.
3. Intermidate syndrome
Intermediate syndrome develops after the acute cholinergic crisis and before the
expected onset of the delayed neuropathy. It mainly occurs 24 to 96 hours after acute
poisoning, after a well-defined cholinergic phase. The patients have paralysis of
proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles.
The symptoms will be relieved in 4-18 days. In serious cases, death may occur
suddenly because of respiratory failure. About 5-10% of OP poisoning patients
develop intermediate syndrome. And it is more likely to occur with some liposoluble
organophosphates although it isn’t confined to some specific species.
The postsynaptic defect in the neuromuscular junction may be the predominant cause
of the paralytic symptoms, with neural and central components contributing to various
degrees.
Laboratory data
1. Determination of ChE activity
Determination of the blood/plasma ChE activity can confirm the diagnosis of OP
poisoning. There are two ChEs in the blood. AChE is present in human erythrocytes
(RBC) and is the same as the enzyme present in the target synapses. Thus, levels of
AChE in RBC are assumed to mirror the effects in the target organs.
However, it must be borne in mind that this assumption is only correct when the
organophosphate has equal access to blood and synapses.
In the case of acute
poisoning, a high inhibition of RBC-AChE is pathognomonic, but, in the follow-up of
the intoxication, it might not be correlated with the severity of symptoms.
Blood-plasma contains a related enzyme called ChE or pseudoChE, which contributes
to the whole-blood enzymatic activity; the contribution of plasma-ChE in assays of
AChE will depend on the type and concentration of the substrate used. PseudoChE
has no known physiological function and can be inhibited selectively by some
compounds without causing a toxic response. The sensitivities of AChE and ChE to
inhibitors differ, so that measurements of the ability of whole-blood samples to
hydrolyse the usual analytical substrates give only an approximate estimate of the
activity of the erythrocyte-AChE. However, under many kinds of field conditions,
procedures using whole blood are more practical than those using separated
erythrocytes.
Quite commonly, pseudoChE is more sensitive to inhibitors. Thus, if
separation of plasma and erythrocytes is possible, prior to assay, an indication of
exposure can be obtained by assay of pseudoChE only.
2.determination of urinary metabolites of the organophosphate
Methods for the determination of residues are simple and are helpful for the diagnosis.
Para-nitrophenol is the metabolic product of the many species of organophosphorous
pesticides, it can be detected in the urine soon after poisoning. Trichlorethanol can be
detected in the urine in the dipterex poisoned patients.
3.other examinations
In the patients suspicious of OPIDP,
electromyogram and nerve conduct function
should be done to confirm the diagnosis and differentiate with other neuropathy.
Diagnosis and differential diagnosis
Diagnosis
Clinical diagnosis is relatively easy and is based on:
(a) Medical history and circumstances of exposure; and
(b) Presence of several of the above-mentioned symptoms, in particular,
bronchoconstriction and pinpoint, pupils not reactive to the light. Pulse rate is not of
diagnostic value, because the AChE effects on the heart reflect the complex
innervations of this organ. On the other hand, since changes in the conduction and
excitability of the heart might be life-threatening, monitoring should be performed.
Confirmation of diagnosis is made by measurement of AChE in RBC or plasmapseudoChE, and, also, of the dibucaine number (to rule out genetic deficiencies).
Measurements of blood-ChE during therapy are also useful in assessing the treatment
with oximes, though there might not be a correlation between the severity of
symptoms and the degree of ChE inhibition: comparison should be made with
pre-exposure levels, wherever possible. Chemical analysis of body fluids (urine,
blood, gastric lavage) should be made in order to identify the compounds that caused
poisoning.
Differential diagnosis
The symptoms of tetrodotoxin poisoning and muscarine poisoning are similar to OP
poisoning. It also should be differentiate to acute gastricintestinitis, heat illness and
cephalnitis.
Therapy
Therapy of AChE poisoning by organophosphates may be graded according to the
severity of intoxication. Effective therapy for most compounds appears to consist of
co-administration of atropine with an oxime reactivating agent plus diazepam.
Useful physical measures include the maintenance of clear airways plus artificial
respiration. Efficacy of oximes may decline as the inhibited AChE ages. Oxime
therapy may continue to be effective in reactivating AChE, freshly inhibited by
inhibitor released from storage in body depots, long after the bulk of the inhibited
enzyme has aged.
There is no known therapy for severe delayed neuropathy. Mild neuropathies
tend to regress, presumably due to some regeneration or adaptation of peripheral
nerves.
All cases of organophosphorus poisoning should be dealt with as an emergency and
the patient sent to hospital as quickly as possible.
The treatment is based on:
(a) Minimizing the absorption;
(b) General supportive treatment; and
(c) Specific pharmacological treatment.
1. Minimizing the absorption
When dermal exposure occurs, decontamination procedures include removal of
contaminated clothes and washing of the skin with alkaline soap or with a sodium
bicarbonate solution. Particular care should be taken in cleaning the skin area where
venupuncture is performed.
Blood might be contaminated with direct-acting
organophosphorus esters, and, therefore, inaccurate measures of ChE inhibition might
result. Extensive eye irrigation with water or saline should also be performed. In the
case of ingestion, vomiting might be induced, if the patient is conscious, by the
administration of ipecacuanha syrup (10 - 30 ml) followed by 200 ml water. This
treatment is, however, contraindicated in the case of pesticides dissolved in
hydrocarbon solvents.
Gastric lavage (with addition of bicarbonate solution or
activated charcoal) can also be performed, particularly in unconscious patients, taking
care to prevent aspiration of fluids into the lungs (i.e., only after a tracheal tube has
been placed).
The volume of fluid introduced into the stomach should be recorded and samples
of gastric lavage frozen and stored for subsequent chemical analysis.
If the
formulation of the pesticide involved is available, it should also be stored for further
analysis (i.e., detection of toxicologically relevant impurities). A purge to remove
the ingested compound can be administered.
2. General supportive treatment
Artificial respiration (via a tracheal tube) should be started at the first sign of
respiratory failure and maintained for as long as necessary. Cautious administration of
fluids is advised, as well as general supportive and symptomatic pharmacological
treatment and absolute rest.
3. Specific pharmacological treatment
(a) Atropine
Atropine should be given, beginning with 2 mg iv and given at 15 to 30-min
intervals.
The dose and the frequency of atropine treatment vary from
case to case, but should maintain the patient fully atropinized (dilated
pupils, dry mouth, skin flushing, etc.).
Continuous infusion of atropine
may be necessary in extreme cases and total daily doses up to several
hundred mg may be necessary during the first few days of treatment.
Atropinization may manifest as dry mouth and skin, flush, mildly elevated
heart rate (90-100bpm), the distension of the minimized pupil, mild rise
of the body temperature, the disappear of the rales etc. While atropinism
appears to be the apparent dilation of the pupil, dry skin, irritation，
seizures, coma, hyperthermia(the oral temperature rise to 39-40degree),
tachycardia(heart rate more than 140 bpm) etc. The response of the eye pupil
may be unreliable in cases of organophosphorus poisoning. A flushed skin and drying
of secretions are the best guide to the effectiveness of atropinisation. Although
repeated dosing may well be necessary, excessive doses at any one time may cause
toxic side-effects. Pulse-rate should not exceed 120/min.
(b)Oxime reactivators
Cholinesterase reactivators (e.g., pralidoxime, obidoxime) specifically restore
AChE activity inhibited by organophosphates. The treatment should begin as soon as
possible, because oximes are not effective on "aged" phosphorylated ChEs. However,
if absorption, distribution, and metabolism are thought to be delayed for any reasons,
oximes can be administered for several days after intoxication. Effective treatment
with oximes reduces the required dose of atropine. Pralidoxime is the most widely
available oxime.
A dose of 1 g pralidoxime can be given either im or iv and
repeated 2 - 3 times per day or, in extreme cases, more often.
If possible, blood
samples should be taken for AChE determinations before and during treatment.
Skin
should be carefully cleansed before sampling. Results of the assays should influence
the decision whether to continue oxime therapy after the first 2 days.
Dosage of atropine and oxime
The recommended doses above pertain to exposures, usual for an occupational
setting, but, in the case of very severe exposure or massive ingestion (accidental or
deliberate), the therapeutic doses may be extended considerably. Warriner et al.
(1977) reported the case of a patient who drank a large quantity of dicrotophos, in
error, while drunk. Therapeutic dosages were progressively increased up to 6 mg
atropine iv every 15 min together with continuous iv infusion of pralidoxime chloride
at 0.5 g/h for 72 h, from days 3 to 6 after intoxication.
After considerable
improvement, the patient relapsed and further aggressive therapy was given at a
declining rate from days 10 to 16 (atropine) and to day 23 (oxime), respectively.
In
total, 92 g of pralidoxime chloride and 3912 mg of atropine were given and the patient
was discharged on the thirty-third day with no apparent sequelae.
Prophylaxis
To strengthen the administration of the poison maybe the key point of decreasing
OP intoxication cases.
Emphasis should be put on the self-protection in the occupational
exposed population. Lectures or booklet about self-protection and the
symptoms of poisoning and the urgent treatment should be given to them.
Table 2. Dosage of atropine and oxime
Drugs
mild
moderate
severe
PAM
0.4 iv, repeat 2hr 0.8 –1.2iv,
1.0-1.6iv, half dose
later if need
after
0.4-0.8 Q2hr*3
0.4ivgtt
30min;
Qhr
for
6hrs
PAM-Cl
0.25-0.5 iv, repeat 0.5-0.75
2hr later if need
iv,
0.5 0.75-1.0 half dose
Q2hr*3
after
0.5ivgtt
30min;
Qhr
for
6hrs
Atropine
1-2mg iH, 0.5mg 2-4mg
Q4-6hr iH after
Reference
1. 内科学 （七年制）人民卫生出版社
2. Cecil Textbook of Medicine，21st edition
iv
st, Depending
0.5-1mg iH Q4-6hr
actual situations
on