Anticholinesterase

Question 1

What are the 3 classes of anticholinesterase and examples of each?

Answer 1

organophosphate insect icide- malathion, chlorpyrifos
carbamate insecticide - carbaryl, carbofuran
nicotinoid insecticide - imidocloprid

Question 2

Why did these compounds replace organochlorines?

Answer 2

still high mammalian toxicity BUT

readily degraded in alkali or water and have short half life so no residues

Question 3

What are these insecticides used for in pets and livestock in addition to their agricultural application?

Answer 3

warbles, fleas and other insects

Question 4

What are sources of poisonings in animals and birds?

Answer 4

consumption of treated grain, mistaken use as feed additive, excessive application, sprayed forage, malicious poisoning

Question 5

What is the absorption and distribution?

Answer 5

all routes including dermal and resp

rapid distribution to all tissues
no accumulation in fat

Question 6

What is the metabolism and excretion?

Answer 6

some require metabolic activation (melathion)
hydrolysis reduces toxicity
rapid metabolism

rapid excretion of metabolites in a few days

Question 7

What is the MOA?

Answer 7

organophosphates and carbamate inhibit acetylcholinesterase and other cholinesterase enzymes
= no acetylcholine breakdown at synapse or NMJ
= parasym and sym affected

Question 8

what enzymes are affected?

Answer 8

pseudo (plasma) cholinesterase - human and not measured

true (RBC) cholinesterase

• specific to acetylcholine
• excessive NT activity in cholinergic and NM nicotinic sites
• muscarinic much more sensitive
• nicotinic only bind to nicotinic and are less toxic

Question 9

What is detrimental about organophosphate poisoning?

Answer 9

inhibits acetylcholine –> choline and acetic acid (irreversibly)
- after 1-2 days phosphorylated enzyme is stable and irreversible

Question 10

What is unique about carbamate poisoning?

Answer 10

hydrolysis of acetylcholine inhibited same way but reversible and can be reactivated

Question 11

Why is nicotinoid compounds less toxic? e.g. imidacloprid

Answer 11

no inhibition of cholinesterase is observed

- extremely high doses needed to manifest nicotinic signs (muscle tremors, twitching)

Question 12

How fast do you see clinical signs in organophosphates and carbamates?

Answer 12

5min to 1-2h

no chronic ALL ACUTE

Question 13

What are the muscarinic effects? are they life threatening?

Answer 13

life threatening

GIT - diarrhea, vomiting, salivation
Resp - dyspnea (bronchocontriction)
CV - decrease HR (cyanosis)
Eye - myosis (constriction)

Question 14

What are the nicotonic effects?

Answer 14

muscle twitching and tremors

limb rigidity

Question 15

What are the CNS effects?

Answer 15

depression and convulsions

Question 16

What is delayed neurotoxcity? which class does it occur with? whats an example?

Answer 16

sydrome developing after 10d to 3m

ONLY with organophosphates

e.g. TOCP (no anticholinesterase activity) - found in lubricants and moonshine

Question 17

What are the clinical manifestations of delayed neurotoxicity?

Answer 17

begin in distal limb
sensory and motor
irreversible damage
- muscle weakness (hindlimb)
- knuckling (cattle)
- ataxia to flaccid paralysis
- cats unable to retract claws

all other organ systems normal
cholinesterase activity normal

Question 18

Whats the cause of delayed neurotoxicity?

Answer 18

mechanism not sure

toxic phosphate triester

Question 19

What is the typical post mortem finding for delayed neurotoxicity?

Answer 19

axonal degen
peripheral neutropathy
degen of myelin sheath

Question 20

What are DDx for delayed neurotoxicity?

Answer 20

organophosphate
TOCP
2, 4 - D
mushrooms
some plants
methyl mercury
organic arsenic
salt (pigs)
chronic Se (pigs)

Question 21

What is the Dx of delayed neurotoxicity?

Answer 21

histo of SC
chem analysis of tissue
cholinesterase will be normal
a history of exposure for several weeks

Question 22

What is the PM findings for acute poisoning?

Answer 22

typically negative (few lesions)

mild petechial hemorrhage and congestion on viscera
slight pulmonary edema (dyspnea and bronchocontriction)
if seed grain (undigested grain)

Question 23

What is the Dx for acute poisoning?

Answer 23

History (sudden death)
clinical signs (muscarinic, nicotinic)
PM (negative)
chem (tissue levels difficult to detect)
cholinesterase activity

Question 24

What kind of blood must be taken to measure cholinesterase activity?

Answer 24

heparinized blood taken when showing clinical signs

Question 25

What is michels change in pH? what does it work for?

Answer 25

measures drop in pH (acetic acid production)

works for organophosphates only (false negative with carbamates)

Question 26

What is titrimetric pH stat? what does it work for?

Answer 26

no dilution is involved no reaction of enzymes,
pH = 75% of normal = poisoning
pH 40-50% normal = death

carbamates and organophosphates

Question 27

What tissue can you test in dead animals?

Answer 27

brain cholinesterase

Question 28

What factors can influence interpretation?

Answer 28

aging, enzyme denaturation, spontaneous reactivation (carbamates)

Question 29

What immediate treatment can be done for acute poisoning?

Answer 29

atropine = blocks muscarinic receptors symptoms disappear within minutes

2-PAM

Question 30

what is 2-PAM and how does it work?

Answer 30

will reactivate the enzyme if organophosphate exposure has occurred.

contraindicated in carbamates and will further decline activity

Question 31

How can 2-PAM be used to differentiate between organophosphate and carbamate?

Answer 31

take a sample and add 2-PAM and measure cholinesterae activity

if improved = organo
if declined more = carbamate

Question 32

What are some other treatment options?

Answer 32

wash
AC - even on dermal (enterohepatic circ)
anticonvulsants
diphenhydramine (H1 blocker) - reverses nicotinic affects (debatable)

Question 33

What is the withdrawal time after poisoning?

Answer 33

45d