Test 1-INDIRECT parasympathomimetics:

Question 1

Pharmacologically significant INDIRECT acting parasympathomimetics:

Answer 1

This group of drugs (and toxins) all work by impairing the function of acetylcholinesterase, thus they are termed acetylcholinesterase inhibitors, anticholinesterases, or cholinesterase inhibitors.

Question 2

Pharmacologically significant INDIRECT acting parasympathomimetics bind (reversibly or irreversibly) to

Answer 2

They bind (reversibly or irreversibly) to the enzyme’s active surface and make it impossible for acetylcholine to bind and be broken down. This results in a build-up of acetylcholine in the synapse. Even though the ‘reversible’ agents do not stay bound to the enzyme, they do remain bound to it FAR longer than the endogenous ligand (acetylcholine) would, and so effectively inactivate the enzyme.

Question 3

REVERSIBLE INDIRECT ACTING PARASYMPATHOMIMETICS:

Answer 3

Neostigmine, Pyridostigmine, Edrophonium, Carbamate Insecticides

Question 4

Neostigmine

Answer 4

Neostigmine (Prostigmin®, Stiglyn®)
- Approved in cattle, horses, pigs and sheep and usually dosed by injection
- It has been used or investigated for; rumen atony, stimulating intestinal motility in horses, and
reversal of competitive neuromuscular blockers. It is occasionally used to treat myasthenia gravis and is intermediate acting (shorter than pyridostigmine, longer than edrophonium - QID dosing typically required).

Question 5

Pyridostigmine

Answer 5

Pyridostigmine (Mestinon®)
- Same MoA as neostigmine but longer duration. More commonly used to treat myasthenia gravis
in small animals (dosed orally BID-TID)

Question 6

Edrophonium

Answer 6

Edrophonium (Tensilon®)
- A very short-acting (minutes) anticholinesterase. It is often used in the diagnosis of myasthenia
gravis and to differentiate between myasthenic crisis (caused by not enough ACh/receptor
interactions) and cholinergic crisis (way too many ACh/receptor interactions).
- Any time you aren’t sure if an anticholinesterase is needed there is a risk that it is not, which translates to a higher risk of adverse effects. When an edrophonium response test is done you
should have a crash cart with atropine on hand and an IV catheter in place.

Question 7

Carbamate Insecticides (Toxin):

Answer 7

Carbamate Insecticides (Toxin):
- Carbamate insecticides typically cause muscarinic signs (DUMBBELS) then nicotinic excitement (muscle tremors, CNS excitement) and eventually nicotinic blockade. They are less selective for motor end plate nicotinic receptors than the drugs listed above, and more likely to cross the blood-brain barrier leading to CNS excitement and potentially seizures.

Question 8

Irreversible indirect acting parasympathomimetics:

Answer 8

Organophosphate insecticides (Toxin) ,

Question 9

Organophosphate insecticides (Toxin)

Answer 9

The clinical signs of OP toxicity are the same as carbamate toxicity. The difference is that OPs are slower to metabolize and bond irreversibly. They have a specific antidote (2-PAM/pralidoxime) which will bind to the OP and ‘pull’ it off the acetylcholinesterase (AChE), thus freeing it up to act again – this will only work if the bond has not undergone ‘aging’, after which point that molecule of AChE is lost. Both Carbamates and OPs can be treated with atropine.


Question 10

Irreversible indirect acting parasympathomimetics:

Answer 10

This group acts exactly the same as the previous one, binding to acetylcholinesterase and making it unable to break down acetylcholine. The only difference is that these are considered ‘irreversible’ because the chemical bond holding them in the enzyme’s active area is very strong, though it can be broken. These agents can undergo ‘aging’ where the bond becomes even stronger, and once that happens then it truly is irreversible.