Toxicologia felina - carbamatos organofosforados

1. Small Animal Toxicology: Organophosphate and Carbamate Insecticide Toxicity
© Vet Education Pty Ltd 2016
Written by Dr. Philip R Judge
Organophosphate and Carbamate Insecticides
The Toxins
Organophosphate and carbamate insecticides interfere with the breakdown of the neurotransmitter
acetylcholine at cholinergic nerves. Specifically, these nerves are at the following locations:
1. Between preganglionic and postganglionic neurons of the autonomic nervous system
2. At the junction of postganglionic parasympathetic neurons in smooth muscle, cardiac muscle and
exocrine glands
3. At neuromuscular junctions of somatic nervous system
4. At cholinergic synapses in the central nervous system
Mechanism of Action
1. Organophosphate insecticides emulate the structure of acetylcholine, and bind to both the anionic and
esteratic sites of acetylcholinesterase. The phosphorus atom on the organophosphate molecule binds
strongly (half-life of binding is several hours, to days) at the esteratic site on acetylcholinesterase,
rendering the enzyme inactive for this time. As a result, synaptic acetylcholine remains active, and
results in continued stimulation of the post-synaptic membrane. Eventually, the stimulation of the post-
synaptic membrane progresses to paralysis, due to successive depolarizations and inadequate
repolarization as a result of continued stimulation. Note that at some point, the organic carbon groups
attached to the phosphorus molecule are hydrolyzed, leaving hydrogen bound to phosphorus, which
increases phosphorus binding to the acetylcholinesterase enzyme. This process is termed “aging” of
acetylcholinesterase – and the enzyme is considered permanently inactivated. New acetylcholinesterase
is produced at a rate of approximately 1% per day. Organophosphates with dimethoxy groups age
faster than those with diethyoxy groups.
2. Carbamates are similar in structure to Physostigmine and neostigmine, and also bind anionic and
esteratic sites of acetylcholinesterase. However, the end-product occupying the esteratic site is a
carbamylate residue, which has a binding half-life of only 30-40 minutes, and is therefore deemed to
be “reversible”. No aging of carbamate-acetylcholinesterase enzyme occurs
3. A syndrome of organophosphate-induced delayed neuropathy is described, following a single, or
multiple dose exposure to organophosphates.
a. The body contains numerous esterase enzymes, which can become bound to, inactivate, or
form complexes with organophosphate compounds. Type A esterase enzymes hydrolyse
organophosphates. Type B esterase enzymes are inactivated by organophosphates.
b. One type B esterase, neuropathy target esterase (NTE), when bound to organophosphates,
undergoes an ageing process and is inactivated. This inactivation is associated with loss of
myelin and axons in long nerves in the spinal cord, affecting both motor and sensory nerves.
The clinical syndrome is referred to as “organophosphate-induced delayed neuropathy, and
occurs 2-3 weeks after exposure to some organophosphate compounds
4. This results in continued stimulation of postsynaptic nerves, resulting in tremors, but eventual fatigue
of cholinergic end organs and muscles, resulting in paralysis and weakness
Clinical Signs
1. Result from over-stimulation of parasympathetic nervous system, muscles, and to a lesser degree, the
CNS
2. Muscarinic signs include
a. Salivation, lacrimation, urination, defaecation (SLUD)
b. Vomiting
c. Anorexia, coughing, miosis
d. Dyspnoea, abdominal pain, bradycardia

2. Small Animal Toxicology: Organophosphate and Carbamate Insecticide Toxicity
© Vet Education Pty Ltd 2016
Written by Dr. Philip R Judge
3. Nicotinic signs include
a. Muscle tremors
b. Muscle tetany
c. Stiffness
d. Weakness
e. Paralysis – caused by inability of cell membranes to repolarize adequately before the next action
potential
f. Sympathetic nervous system stimulation may produce mydriasis, and tachycardia
4. Central Nervous System signs include
a. Anxiety, apprehension
b. Restlessness, hyperactivity
c. Tonic-clonic seizures
d. Depressed respiration
e. Coma
5. Respiratory symptoms: occur due to both muscarinic and nicotinic signs, as well as CNS side-effects,
and include
a. Dyspnoea due to respiratory muscle fatigue
b. Excessive salivation – which may result in occlusion of the airway
c. Bronchoconstriction – due to parasympathetic nervous system stimulation
d. Respiratory arrest – due to paralysis of respiratory musculature secondary to continuous
nicotinic stimulation
6. Intermediate syndrome – may develop up to 24-72 hrs following acute toxicosis, usually in patients
following exposure to lipophilic organophosphates, with either a large, single dermal exposure, or
repeated small-dose exposures.
a. A phenomenon of ‘tolerance’ of cholinergic receptors may develop in muscarinic receptors,
leaving a predominance of symptoms relating to nicotinic receptor stimulation.
b. Persistent exposure to acetylcholine (as occurs with OP toxicity, and anticholinesterase
inhibition) leads to a down-regulation of cholinergic receptors through an internalization of the
receptors into cells – leaving less receptors available for binding
c. Muscarinic receptors are primarily affected, leaving a predominance of nicotinic clinical signs of
toxicity
i. Anorexia, diarrhoea
ii. Weakness
iii. Muscle tremors
iv. Depression and cervical ventro-flexion
v. Tonic-clonic seizures
Diagnosis
1. History
2. Clinical signs
3. Cholinesterase assay – most cases have cholinesterase activity less than 25% of normal
4. Detection of compound in gastric contents
Treatment
1. Provide oxygen supplementation during resuscitation and continue as required
2. Airway management
a. Clear airway
b. Sedate or lightly anaesthetise and intubate patients with evidence of airway obstruction
c. Provide positive pressure ventilation if required

3. Small Animal Toxicology: Organophosphate and Carbamate Insecticide Toxicity
© Vet Education Pty Ltd 2016
Written by Dr. Philip R Judge
3. Begin intravenous fluid therapy
a. Treat shock
b. Manage electrolyte disorders
c. correct dehydration deficits as required
4. Control CNS excitation and excessive muscle activity
a. Diazepam – 0.1-0.5 mg/kg IV bolus; 0.1-0.5 mg/kg/hr continuous infusion
b. Midazolam – 0.1-0.3 mg/kg IV bolus; 0.1-0.3 mg/kg/hr continuous infusion
5. Induce vomiting, or perform gastric lavage and catharsis
a. Activated charcoal may aid in reducing further absorption
b. Catharsis with sorbitol
c. Emesis – only recommended in patients with normal consciousness, and with normal gag and
swallow responses, having ingested the compound within the previous 2-3 hours. Alternatively,
gastric lavage under general anaesthesia should be performed
6. Atropine
a. Atropine is a non-competitive antagonist to acetylcholine. Its use decreases bombardment of
acetylcholine receptors during organophosphate or carbamate exposure.
b. Atropine has no effect on insecticide/acetylcholinesterase bond
c. Atropine does block muscarinic, and some CNS effects at nerve endings.
d. Atropine does not affect nicotinic effects of OP and carbamate poisons; hence, muscle tremors
persist. The use of atropine to manage tremors and seizures should be avoided
e. Atropine may be used at a dose of 0.01-0.02 mg/kg IV or IM to assist in controlling excessive
salivation; repeated q 1-6 hrs to effect. Some references cite higher doses (up to 30 times
higher) of atropine, however these doses are associated with urinary retention, gastrointestinal
stasis and excessive drying of respiratory secretions, and should generally be avoided.
7. Oximes (Protopam chloride)
a. Oximes such as Protopam chloride deconjugate insecticide/enzyme bond, and are useful in the
first 24 hours post exposure to organophosphate toxicity.
b. Oximes are not useful in carbamate toxicity, owing to the shorter duration of action of the
carbamate-acetylcholinesterase bond
c. May be used in acute toxicosis, and in intermediate syndrome
d. Dose: Protopam chloride 20 mg/kg IM, SC or very slow IV; repeated q 12 hrs if required
8. Antihistamines
a. Diphenhydramine (Benadryl)
i. Can relieve some nicotinic signs
ii. Reportedly prevents receptor paralysis at nicotinic receptor sites
iii. Relatively contraindicated in acute toxicosis, and is not currently recommended