Organophosphates, Pralidoxime, Atropine

Which characteristic distinguishes direct-acting organic phosphorus agents from indirect-acting agents? a. Direct-acting agents can inhibit acetylcholinesterase without being structurally altered by the body b. Direct-acting agents can pass freely through intact epidermis c. Direct-acting agents move into the brain through the BBB despite protein binding d. Direct-acting agents are not reabsorbed from the proximal tubule e. Direct-acting agents are acted upon directly by CYP enzymes prior to cholinesterase metabolism

a. Direct-acting agents can inhibit acetylcholinesterase without being structurally altered by the body

What is the aging half-life of a dimethyoxy OP? a. 1-4 hour b. 4-8 hours c. 8-12 hours d. 12-24 hours

a. Half life of dimethoxy OPs is ~ 4 hours

Which of the following is true regarding "intermediate syndrome" following an exposure to organophosphate exposure? a. Arises 1-3 days after the resolution of cholinergic signs. b. Begins during the peak of the cholinergic crisis. c. Characterized by mild toxicity d. Prevented with the use of antimuscarinic medications.

a. Intermediate syndrome arises 1-3 days after the acute presentation and may be related to the severity of the initial cholinergic presentation. Starts in the proximal muscles and involves the neck flexors, facial muscles, and muscles of respiration. Use of atropine does not prevent the syndrome. An inability to raise the head from the pillow has been described as a first sign of OP intermediate syndrome. Mortality due to respiratory paralysis ranges from 15 - 40%.

Organic phosphorus compound-induced delayed neuropathy (OPIDN) is associated with which of the following? a. Neuropathic esterase depression greater than 70% b. Acetylcholine depression greater than 50% c. Immediate onset after exposure to OP agent d. Initial onset of muscle weakness within 24-48 hours after exposure to OP agent e. Response to pralidoxime

a. Neuropathic esterase depression greater than 70%

Describe the "intermediate syndrome"

as soon as 4d after exposure. Delayed NMJ dysfunction after OP exposure that manifests as muscle weakness without muscarinic features or fasciculations. Proximal weakness is a feature. Idiosyncratic.

Organophosphate-induced delayed peripheral neuropathy is characterized by all of the following except: a. Mixed neurologic picture that clinically appears similar to ALS b. Associated seizure activity c. A dying back neuropathy d. Both central and peripheral lesions, histologically e. A history of exposure to agents with neuropathy target esterase

b. Associated seizure activity

Deaths from Atropine use are generally associated with: a. Renal failure b. Hyperthermia c. Dysrhythmias d. Respiratory failure

b. Hyperthermia

Physostigmine, one of the first carbamates discovered in a Calabar bean, was first used medicinally in 1877 to treat what disease? a. cataracts b. glaucoma c. uveitis d. ocular hypertension

b. glaucoma

Which cholinesterase activity level will be the first to drop after OP exposure? (RBC, butyrl, plasma, psudocholinesterase)

butyrlChE will plummet first. butyrl = plasma = psudocholinesterase

Which of the following causes irreversible cholinesterase inhibition? a. Aldicarb b. Carbaryl c. Chlorpyrifos d. Imidacloprid

c. Chlorpyriphos is an organophosphate that, like all OP agents will age and cause irreversible cholinesterase inhibition. OP age because they do undergo hydrolysis while bonded to the series "esteric" site on cholinesterase. Carbamates do not undergo this transition and do not bind irreversibly. Imidacloprid is a neonicotinoid and can cause neuronal hyperexcitability and seizures.

For cases of severe OP poisoning, how should atropine be administered? a. Give bolus of atropine 2 to 5mg every 10-15 minutes until atropinization b. Start with an infusion @ 5mg/hr c. Double atropine dosage until atropinization is achieved every 5 minutes starting at 1-3mg. d. Bolus 10mg then start infusion at 5mg/hr

c. Double atropine dosage until atropinization is achieved every 5 minutes starting at 1-3mg.

Acetylcholinesterase activity is increased in which of the following scenarios? a. Antimalarial therapy b. Iron deficiency anemia c. Malnutrition d. Oral contraceptive therapy e. Post exposure to a organophosphate compound

d. Acetylchoninesterase activity can be increased in the presence of oral contraceptive therapy. The remaining choices could decrease activity.

What is true about intermediate syndrome? a. First sign is weakness of the neck flexion b. It is delayed muscle weakness about 24-96 hours after acute cholinergic poisoning resulting in respiratory failure c. Stable patients can suddenly develop respiratory arrest d. All the above

d. All the above

When interpreting plasma and RBC cholinesterase levels it is important to note that: a. Carbamate insecticide poisoning reliably inhibits plasma and RBC cholinesterase. b. Cholinesterase levels vary little between persons and are maintained at a relatively constant level in each individual c. Red cell cholinesterase always recovers before plasma cholinesterase. d. Serum and RBC cholinesterase concentrations correlate poorly with clinical state. e. Subtle (5-10%) changes in cholinesterase levels are diagnostic for OP poisoning.

d. Cholinesterase concentrations correlate poorly with acute toxicity. Chronic exposure can cause severe cholinesterase depression without apparent clinical symptoms. High potency OP's (warfare agents) may cause mortality before plasma or RBC cholinesterase drop. There is a wide normal range of butyrcholinesterase with day to day variation in otherwise healthy people.

The "intermediate syndrome" associated with organophosphate poisoning: a. Consists of respiratory failure and cholinergic crisis b. Has been associated with white matter degeneration and progressive dementia c. Is treated with an extended duration of intravenous pralidoxime d. May cause EMG changes in organophosphate exposed patients e. Results in irreversible muscle paralysis

d. May cause EMG changes in organophosphate exposed patient. The exact pathophysiology of intermediate syndrome is unknown but dysfunction at the NMJ and respiratory failure from weakness of the diaphragm and intercostal muscles result. The syndrome generally does not develop for a few days after organophosphate exposure. As such, the cholinergic crises has generally ended. High doses of pralidoxime are postulated to prevent the syndrome but not necessarily treat it. Neuropathy target esterase is the enzyme involved in organic phosphorous induced delayed neuropathy and not intermediate syndrome. The weakness and paralysis commonly resolve in 5-18 days.

Which of the following is true regarding organophosphate induced peripheral neuropathy (OPIDN)? a. Is a dying-back neuropathy with typical stocking-glove onset in most cases that most often affects small, proximal neurons. b. Is believed to be due to activation of a specific neuro-toxic esterase (neuropathic target esterase, NTE) c. Is only sensory in nature, and resolves in most cases. d. Patients may go on to permanent and severe motor and sensory loss. e. Results from a severe cholinergic crisis after organophosphate exposure

d. OPIDN is caused by INHIBITION of neuropathy target esterase. It primarily affects large, distal neurons with axon degeneration occurring before demyelination.

A 12 yo boy was admitted to the hospital with bradycardia, vomiting, pinpoint pupils, and paralysis after ingesting parathion. It is now eight days after admission. He has been off of atropine and pralidoxime for three days and he is asymptomatic. The serum and RBC cholinesterase values have been stable, but they remain markedly depressed. Which of the following is the best course of action? a. restart pralidoxime b. repeat skin decontamination c. start repeat dose charcoal and continue to monitor in-house until cholinesterase levels rebound d. send him home e. atropinize him with IV atropine and then restart pralidoxime

d. send him home. clinical resolution of cholinergic symptoms is the most important marker of improvement. Recrudescence is rare.

What is the aging half-life of a diethyoxy OP? a. 5 hrs b. 10 hours c. 20 hours d. 30 hours e. > 30 hours

e. Half life of diethoxy OP's is 31-57 hours

Regarding oxime therapy for agricultural/home-use organophosphate poisonings, which of the following is true? a. Human data clearly establish which oxime works best for each OP agent. b. Most hospitals in the United States have access to 2-PAM (pralidoxime), obidoxime, and HI-6. c. Only warfare agents undergo "aging" and oximes will work at any time. d. Oximes cannot be administered until carbamate poisoning has been excluded e. The use of oxime therapy in OP poisonings is controversial

e. The use of oxime therapy in OP poisonings is controversial. Depending on the organophosphate agent, aging can occur at variable times. Multiple papers have conflicting data regarding the efficacy of oxime therapy and the effective dose strategy. Carbamates do not age and oximes may be useful at any time after carbamate exposure.

Two pesticide applicators walk into a bar. One has a beer, the other has a soda. While talking about the size of their latest fungicide application, the one with the beer develops flushing, tachycardia, nausea, and palpitations. They were most likely applying: a. Benomyl - a thiabendazole b. "Flowers of sulfur" - inorganic sulfur powder c. Nitenpyram - a neonicotinoid d. Phenylmercuric acetate e. Thiram - a dithiocarbamate

e. Thiram and the other dithiocarbamate herbicides are structural analogs of disulfiram (Antabuse). Alcohol ingestion after exposure will result in a characteristic response including flushing, tachycardia and nausea due to acetaldehyde dehydrogenase inhibition.

Poisoning with this specific OP can lead to significant hypotension, believed to be caused by the solvent cyclohexone: a. Malathion b. Parathion c. Triorthocresyl phosphate d. Dimethoate e. Sarin and Tabun f. a-d g. b and d h. all of the above

g. b and d contain cyclohexane

Name 4 mechanisms of OP-induced respiratory failure

1) bronchoconstriction 2) bronchorrhea 3) diaphragmatic paralysis 4) intermediate syndrome

Atropine is a competitive antagonist of acetylcholine at which receptors? a. only at nicotinic receptors b. only at muscarinic receptors c. at nicotinic and muscarinic receptors d. at only metabotropic G-protein linked nicotinic receptors e. at only ionotropic muscarinic receptors

B. only at muscarinic receptors Atropine is not effective at nicotinic acetylcholine receptors. Muscarinic receptors are G-protein coupled and nicotinic receptors are ionotropic.

Which 2 features of an OP poisonings predict whether or not Intermediate Syndrome will occur?

1) How quickly oxime (2PAM) therapy is administered. 2) Characteristics of the OP itself. Some OPs don't respond to oximes at all. Some OPs age AChE very quickly. Others are inherently resistant to oxime therapy. Lipid-soluble OPs are notoriously resistant to 2PAM. OPs that need to be bioactivated allow for a greater time window to administer oximes.

Describe the main differences between the two main types of AChE

1) RBC AChE - more accurately reflects CNS AChE activity. NMJ dysfunction occurs when activity falls < 30% baseline. 2) Plasma/Butyrl/Pseudo-cholinesterase - levels are effectuated quickly by OPs, but recover quickly.

Sort the following by their aging T 1/2: Tabun Sarin Soman VX

1) Soman - 2min 2) Sarin - 3hrs 3) Tabun - 14 hrs 4) VX - 48 hrs

Describe 4 main categories of OPs

1) mainly inhibit AChE 2) mainly inhibit NTE (neuropathy target esterase or neuropathy target enzyme) 3) inhibit both AChE and NTE 4) do nothing (like glyphosate in Round-up)

Although AChE inhibition can present with any of the DUMBELLS or SLUDGE symptoms, which are the 3 most commonly described (via case reports) symptoms?

1) miosis 2) diaphoresis 3) respiratory distress

Describe 3 main types of carbamates

1) regular (meprobamate, carisoprodol) 2) N-methyl carbamates (cholinesterase inhibitors) 3) thiocarbamates (disulfiram, dithiocarb; which cause antabuse-like reactions)

Name 3 proposed mechanisms of 2PAM

1) rejuvenation of AChE 2) atropine-like 3) inactivates free OP

Glycopyrrolate bromide can be used in the treatment of OP and carbamate poisoning instead of atropine to prevent what adverse sequelae of atropine? a. Urinary rentention b. Supraventricular tachycardia c. Ileus d. CNS toxicity e. Hepatotoxicity

D. CNS Toxicity

Which of the following statements regarding the use of pralidoxime to treat symptoms of organophosphate poisoning is true? a. Pralidoxime dosing must be adjusted if it is given after atropine has been given. b. Pralidoxime should only be used if atropine is unavailable. c. Pralidoxime should be used after 10 mg of atropine have been ineffective. d. Pralidoxime should only be used in conjunction with atropine, never alone. e. Pralidoxime and atropine should never be used together.

D. Pralidoxime should only be used in conjunction with atropine, never alone. There is disputed evidence that pralidoxime, when used without atropine, may worsen carbamate poisoning. Pralidoxime should not be used without atropine. Regardless of what the exposure is (organophosphate vs. carbamate), the effects of atropine and pralidoxime are synergistic.

Which of these statements is a true regarding different groups of organic phosphorous compounds? a. Phosphorylcholines (Group 1 OP's) possess a quaternary nitrogen and are capable of directly stimulating acetylcholine receptors b. Fluorophosphates (Group 2 OP's) possess a fluorine as the leaving group which is makes them of low toxicity. c. Group 3 OP's possess a benzene ring allowing them to cross the blood brain barrier more easily d. Group 4 OP's are rarely clinically encountered and possess dimethoxy, diethoxy, or other substituted compounds e. Thion organic phosphorous compounds are mostly safe after GI exposures

A. Group 1 OP's are capable of directly stimulating ACh receptors. Group 2 OP's are highly volatile and very toxic. Group 3 OP's contain a halogen other than fluoride or they contain a cyanide molecule. Group 4 contains dimethoxy and/or diethoxy groups and are the most commonly encountered groups. Thion organic phosphorous compounds reuqire metabolism via intestinal mucosa or liver to became the active "direct acting" oxon version.

The products of normal acetylcholine metabolism

Acetic Acid + Choline

The term which describes the process by which AChE is permanently inhibited by OPs

Aging

Which benzodiazepine should be administered for sedation in cases of OP poisonings?

Animal studies suggest increased survival and decreased in the incidence of seizures and neuropathy when DIAZEPAM is administered.

Describe the "antidote" function of administering an N-methyl carbamates to a patient who is poisoned by an organophosphate

By temporarily inhibiting NTE, they "protect" it from permanent inhibition by OP.

Which of these statements is true regarding acetylcholinesterase inhibition? a. The half-life of spontaneous reactivation of human acetylcholinesterase after inhibition by dimethoxy OP's is 31-57 hours b. The half-life of spontaneous reactivation of human acetylcholinesterase after inhibition by diethoxy OP's is <1 hour c. After undergoing carbamylation nonenzymatic loss of another alkyl group leads to permanent inactivation of acetylcholinesterase d. Thiocarbamates are known to be the worse kind of acetylcholinesterase inhibitors

C. This is the process called aging. The aging is not a part of carbamate exposures and thiocarbamates (as well as some carbamate derivatives) do not produce cholinergic symptoms. The half-life of dimethoxy OP's for spontaneous reactivation is is <1 hour and the half-life for diethoxy OP's is 31-57 hours

How long does it take for AchE levels to rise following OP poisoning in the absence of oximes? (hint: whats the life span of an RBC) a. Hours b. Days c. Weeks d. Months

D. After poisoning, in the absence of oximes, red cell AChE may take many weeks to recover since erythrocytes in circulation at the time of OP exposure must be replaced. An average of 66 days may be necessary for red cell AChE activity to recover following severe inhibition.

Which of these is an uncommon finding after ingestion of an OP insecticide? a. Bradycardia & bronchorrea b. Tachycardia & diaphoresis c. Hyperglycemia & leukocytosis d. Seizures e. Pancreatitis

D. Seizures are uncommonly associated with OP insecticide as opposed to nerve agents. Seizures may occur however in the setting of hypoxia. Parasympathetic stimulation usually leads to the expected bradycardia, bronchorrea, bronchoconstriction, miosis, and GI symptoms. Stimulation of nicotinic adrenal receptors however may offset this and cause sympathomimetic symptoms as well hyperglycemia and leukocytosis. Hypovolemia can also cause tachycardia. Pancreatic edema and necrotizing pancreatitis as well as hepatic transaminitis are also common. Co-formulant solvents are commonly hydrocarbons and can be associated with aspiration as well as surfactant poisoning.

Describe the clinical effects of TOCP poisoning

Delayed distal, symmetric, predominantly motor polyneuropathy

Which of the following nerve agents is a persistent agent; i.e. it remains in the environment for a long time? a. Chlorine gas b. Sarin c. Soman d. Tabun e. VX

E. VX is a cholinesterase inhibiting nerve agent which has the consistency of motor oil, and is much more persistent than the other agents listed. The V series also includes VE, VG, and VM

Name a historically significant example of an outbreak of toxin-induced OPIDN

Ginger Jake Paralysis due to TOCP (triorthocresylphosphate). 1930s, Prohibition-era ginger extract contaminated with pesticide.

Atropine exerts its antidote effects on which aspect of OP poisoning? (which receptors does it antagonize)

Muscarinic. Does not treat the nicotinic (muscular effects)

Main organ system that organochlorines exert their toxicity

Neuro = seizures

What is OPIDN?

OP Induced Delayed Neuropathy. Ginger Jake paralysis (TOCP)

Describe the biochemical mechanism of inhibition of AChE by organophosphates (be specific).

OP binds to hydroxyl group on the serine residue within the AChE active site

How long before RBC-AChE vs Butyrl-AChE regenerate after an OP exposure?

RBC-AChE: 66 days Butyrl-AChE: 2 days