Where are Anti-cholinesterases found throughout the body?
Synapses in motor end plates in the basal lamina
RBC anchored with GPI-linkages into membrane
Brain - attached to integral peptides that have collagen-like targets anchor them
Cholinesterase Function and Mechanism?
Serine Hydrolase that uses water to Hydrolyze ester bonds through an acylation-deacylation mechanism
Compare and Contrast Aceylcholinesterase vs Butyrylcholinesterase
The 2 mostly differ in Muscarinic Agonist responses and ability to be recovered from inhibition by organophsophates:
-AchE only has selective activity for Acetyl-beta-methylcholine, Can be recovered by Pralidoxime, is found in the CNS, PNS, Muscle and RBC and is Vital!!!
-BuChE has selective activity for Benzoylcholine and Succinylcholine, can NOT be recovered by Pralidoxime, is found in blood, plasma, liver, muscle, brain, but is NOT vital
What are the Reversible Inhibitors of AchE?
Quarternary Amines = Edrophonium (non-covalently blocks peripheral site on enzyme; used for MG diagnosis)
Carbamates = covalent bond formed at serine hydroxyl but cleaved for reversal within minutes = Physostigmine, Neostigmine, Pyridostigmine, Ambenonium
What are the IRREVERSIBLE Inhibitors of AchE?
Organophosphates form covalent bonds with enzyme and need to make new enzymes to replace them or displace with Oxime
What are the Charged AchE inhibitors?
Edrophonium - therefore doesn't cross BBB (used for MG dx) Neostigmine!!!!
How can you potentially reverse effects of Oranophosphates?
Reversible with Oximes like Pralidoxime or Obidoxime also midly inhibit AchE
What are the common insecticides that have AchE inhibitors?
Malathion Diazanon Carbaryl
What are the Chemical Warfare Agents with AchE inhibitors?
Soman Sarin Vx
What are the therapeutic uses of Anticholinesterases?
1) Paralytic Ileus or Atony of urinary bladder
2) Glaucoma - narrow angle glaucoma
3) MG - Myasthenia Gravis or Lambert Eaton
4) Recovery of NM Blockade after surgery with Antimuscarinic Drugs
5) Poisoning treatment
How are these drugs helpful in Glaucoma?
Narrow Angle Glaucoma - shallow anterior chamber bc iris bows forward and blocks access to trabecular meshwork/canal of Schlemm and so Aqueous humor builds up intraocular pressure
Treat with AchE like Physostigmine (+Pilocarpine) to contract the ciliary muscles and pull the iris back to allow drainage of aqueous humor
How are these drugs used in poisoning situations?
Atropine Poisoning - Treat with Physostigmine bc both cross BBB to counteract it Curare Poisoning - treat with Neostigmine (both do NOT cross BBB)
Contraindications for Anticholinesterases?
Same as Muscarinic Agonists Bronchial Asthma, Peptic Ulcers, Coronary Insufficiency, Arrhythmia and hyperthyroidism
Why are Nerve Agents so toxic and what is "aging"?
Nerve agents like Tabun, Sarin, Vx bind AchE IRREVERSIBLY and "age" very rapidly and they are very hydrophobic and so can penetrate skin
Aging means that the enzyme can no longer react with oxime (like 2Pam = Pyrolodoxime) to reverse phosphorylation from OP