Neostigmine: parasympathomimetic acetylcholinesterase inhibitor

• causes Ach levels to increase in both nicotinic and muscarinic receptors
• when reversing muscle relaxants you only want to affect the nicotinic receptors (especially severe bradycardia)
• use of glycopyrrolate or atropine can block the muscarinic effects

1. Beta blockers (Timolol): decrease intraocular fluid levels

2. Cholinergics (Pilocarpine): produces miosis --> increased drainage

3. Alpha agonists (Apraclonidine): decrease intraocular fluid and increase fluid drainage

4. Carbonic Anhydrase inhibitors (acetazolamide): decreases production of intraocular fluid

Mechanism of action: parasympathetic cholinergic agonist with a large affinity for muscarinic receptors.

1. structurally similar to acetylcholine but not metabolized by acetylcholinesterase

2. duration of action is about 1 hour

Indications: stimulates muscarinic receptors located on smooth muscle in the GI/urinary tracts.

1. Urologically: increases muscle tone in the detrusor urinae muscle and peristalsis in the uretra --> expulsion of urine

2. GI: increases GI peristalsis

1. What are organophosphate compounds?

2. When are these agents used and how would you treat the toxic side effects of these agents?

Organophosphates: degradeable compounds that contain carbon-phosphorous bonds. Diverse group of chemicals used in both industrial and domestic settings.

Toxic side effects: block Ach metabolism by blocking AchE causing Ach levels to be dangerously high --> death

Treatment: (if AchE has aged, treatment is less effective)

1. Atropine: muscarinic effects

2. Mechanical ventilation: nicotinic effects

3. 2-PAM/pralidoxime: reactivate AchE enzyme

What would happen if an individual received:

1. a small dose of Ach?
2. a large dose of Ach?

Small dose of Ach: (mimic vagal stimulation)

1. decrease HR/SV

2. decreases BP by activating M3 receptors on smooth muscle of blood vessels

3. increase GI/intestinal secretions/motility

4. pupil constriction

5. urgency to urinate

Large doses of Ach: (effects are deadly unless reversed)

1. cardiac failure

2. asystole

3. muscle paralysis

1. How do neostigmine, pyridostigmine, edrophonium and physostigmine work?

2. What might be the indications for each of these medications?

These are all indirect-acting cholinergic agonists that inhibit AchE

Neostigmine: antidote to neuromuscular blocking agents. Used in the treatment of Myasthenia Gravis

Pyridostigmine: Used to treat Myasthenia Gravis but with longer duration of action than neostigmine (CAN ONLY BE TAKEN ORALLY)

Edrophonium: similar action as neostigmine but with a rapid onset and short duration of action. Used to treat Myasthenia Gravis --> rapid increase in muscle strength

Physostigmine: substrate for AchE, forming a carbamoylated intermediate with enzyme --> inactivating it. Used for bladder/intestinal motility. Can be used topically to cause miosis. Used to treat OD of anticholinergic agents (atropine, phenothiazine, TCAs)

Atropine (cholinergic antagonist): block all cholinergic action through the inhibition of muscarinic receptors --> dilation of pupil --> increased IOP

Glycopyrrolate (cholinergic antagonist)

Scopolamine (cholinergic antagonist)

Succinylcholine (depolarizing NMB)

Ketamine: may increase IOP

Question 4.1 from book:

A patient with an acute attack of glaucoma is treated with pilocarpine. The primary reason for it's effectiveness in this condition is its:

ABILITY TO LOWER INTRAOCULAR PRESSURE

Pilocarpine causes papillary constriction to lower IOP. It binds mainly to muscarinic receptors and can enter the brain

Question 4.2 from book:

A soldier's unit has come under attack with a nerve gas agent. The symptoms exhibited are skeletal muscle paralysis, profuse bronchial secretions, miosis, bradycardia and convulsions. The alarm indicated exposure to an organophosphate. What is the correct treatment?

ADMINISTER ATROPINE AND 2-PAM (PRALIDOXIME)

Organophosphates exert their effects by irreversibly binding to AchE --> causing a cholinergic crisis.

• Administration of atropine will block the muscarinic site but not reactivate the enzyme
• 2-PAM must be administered as soon as possible to reactive the enzyme before aging occurs

Question 4.3 from book:

A patient being diagnosed for Myasthenia Gravis would be expected to have improved neuromuscular function after being treated with:

EDROPHONIUM

Edrophonium is a short-acting inhibitor of AchE used to diagnose Myasthenia Gravis. It is a quaternary compound that does not enter the CNS.

• Doneprezil, isoflurophate, neostigmine are also AchEs but with longer actions

Question 4.4 from book:

The drug of choice for treating decreased salivation accompanying head and neck irritation is:

PILOCARPINE

Applied topically to the cornea to produce a rapid miosis and contraction of the ciliary muscle. Pilocarpine is one of the most potent stimulators of secretions (secretagogue) such as sweat, tears, and saliva.