ORGANOPHOSPHATE TOXICITY
Demetre C. Daskalakis, M.D.
February 14,2003
Introduction
Organophosphates are responsible for about 100,000 cases of poisoning victims per year world-wide.
These agents are used commercially as pesticides but also used for more sinister purposes as chemical
warfare agents. The most famous agent in this group is sarin, developed and produced by Germany in
1938 as an insecticide and used in the mid-1990s in two terrorist attacks in Japan. Though no longer
produced in the United States stockpiles of sarin (GB) and VX (another nerve gas) still exist, although
they are being incinerated with a planned complete depletion of these stockpiles by 2004. Though not
produced by most countries, concern exists that nerve gas may be a cheap and effective weapon that can
be cheaply and easily produced by terrorist groups. The 100,000 cases are mostly due to suicide attempts
and exposures in agricultural workers. The lessons we learn from insecticide poisoning are important to
extend to the difficult reality of potential chemical attack.
Mechanism of Toxicity
 Routes: Organophosphates can cause injury through three routes: inhalation,
skin/mucous membrane absorption, and ingestion. Nerve gases are volatile
agents that can vaporize and be inhaled. The margin between the dose of nerve
gas required to cause incapacitation and death is very narrow. Multiple
mechanisms (explosion, aerosolization) may be used to disperse these
chemicals. Dermal absorption may cause immediate or delayed illness.
Ingestion is the most frequent route used in suicide attempts utilizing these
agents.
 Biochemical target: The organophosphates are irreversible cholinesterase
inhibitors that bind the enzyme acetylcholinesterase. Another class of
chemicals called carbamates are also cholinesterase inhibitors, however they
are reversible binders of the same enzyme. Inhibition of this enzyme causes
build-up of its target molecule, acetylcholine, at the synaptic junction causing
continuous activation of post-synaptic cholinergic receptors.
 Review of cholinergic receptors: Muscarinic receptors are located in the CNS
and in the peripheral nervous system at junctions between nerves and target
organ (glands, muscles, etc.) Nicotinic receptors are located in the CNS,
autonomic nervous system, and the NMJ. These agents work on both kinds of
receptors both centrally and peripherally causing a myriad of symptoms.
Clinical Presentation-mneumonics
Peripheral Muscarinic Receptors
Diarrhea
Urination
Miosis
Bradycardia, bronchorrhea, bronchospasm
Emesis
Lacrimation
Salivation, secretion, sweating
Peripheral Nicotinic Receptors
Mydriasis
Tachycardia
Weakness
Hpertension, hyperglycemia
Fasciculations
Insecticides
Chlorpyrifos
Phosphorothioic acid
Dichlorvos
Fenthion
Malathion
Parathion
Nerve Gases
Tabun
Sarin
Soman
VX
CNS
Confusion
Coma
Convulsions
Anxiety
Restlessness
Seizures
The nicotinic signs predominate in the early course of exposure, but muscarinic signs may also be present
causing a more confusing and contradictory presentation. Later in the course, the muscarinic signs are
usually more prominent. Time of exposure to onset of toxicity may be minutes to hours but usually
occurs between 30-120 minutes. The majority of patients die of the pulmonary and cardiac toxicities of
these agents (called the “killer B’s”. . .bradycardia, bronchorrhea, and bronchospasm).
When
appropriately managed, the majority of patients recover in 24-48 hrs. A minority of patients develop an
Beth Israel Deaconess Medical Center Residents’ Report
“intermediate syndrome” that may occur 1-4 days after poisoning that consists of proximal limb, neck
flexor, and respiratory muscle paralysis with cranial nerve palsies. 2-3 weeks after poisoning, some
patients will develop peripheral neuropathy that initially presents as lower limb parasthesias and may
proceed to ascending paresis. A few sources also site later onset extrapyramidal/parkinsonian symptoms
after poisoning.
Diagnosis
The diagnosis is clinical.
There is a lab test available in some centers that measures RBC
acetylcholinesterase activity as a surrogate for this enzyme’s activity in more difficult to access sites such
as synapses. <50% normal activity confirms the diagnosis of organophosphate poisoning.
Treatment
Initial treatment begins with decontamination by removal of contaminated clothing and washing of the
skin with soap and water. GI decontamination may also be undertaken with use of activated charcoal.
Supportive measures include ventilator support, oxygen, and treatment of seizures as they present.
Medications used to treat organophosphate poisoning include atropine and oximes.
 Atropine is a symptomatic antidote for muscarinic signs and symptoms by competing for muscarinic
receptos with acetylcholine.
It is a parasympatholytic.
Atropine does not regenerate
acetylcholinesterase, so it is truly symptomatic. Atropine doses required to treat the longer acting
insecticides are higher than those needed to treat nerve gas exposures. Atropine should be reserved to
treat patients with severe symptoms of exposure. Patients in respiratory distress should be observed
for 15-30 minutes after removal of the offensive agent. If they do not improve, they should get 12mg of atropine IV or IM. These doses should be repeated every 5-10 minutes until breathing
becomes easier. A single dose of 6mg may be used in severe cases followed by boluses of 1-2mg or
continuous infusions. Hypoxia should be corrected before administration of atropine when possible
given the theoretical risk of ventricular fibrillation observed in animals. Atropine has no nicotinic
activity.
 Pralidoxime (2-PAM) is an oxime. This drug works on the bound acetylcholinesterase in two steps.
In the first a phosphorylenzyme-oxime complex is formed. The second step is reactivation of the
enzyme. It is critical to treat early because inhibited enzyme is relatively irreversibly bound by these
poisons until it completes a process called “ageing” after which it is truly irreversibly inhibited.
Different organophosphates will have different rates of ageing (ranging from 2 minutes to 5 hrs) and
it appears as if oxime therapy itself may slow the ageing process. All cases of moderate to severe
organophosphate poisoning should be treated. Dosage depends on agent to which the patient has
been exposed, time since exposure, and intrinsic RBC cholinesterase activity (if measured). Patients
are usually loaded with 1-2g of 2-PAM followed by a 500mg/hr infusion for about 24 hrs. Some
sources recommend testing for RBC acetylcholinesterase activity and reversibility in vitro with
oximes as a criterion for treatment.
Some source also recommend following RBC
acetylcholinesterase activity to guide therapy.
Oxime therapy in carbamate poisoning is
controversial, with some sources citing an adverse effect.
 Ipratropium can be used in treating bronchospasm/bronchorrhea.
 Benzodiazepines are preferred management for seizures.
Take home message. . .
Toxicology consult is important when dealing with these agents since half lives and solubility will
influence duration of therapy. If organophosphate toxicity is suspected etiology of agent should be sought
after where possible.
Bibliography
Available by request.
Beth Israel Deaconess Medical Center Residents’ Report
Beth Israel Deaconess Medical Center Residents’ Report