Exam 4 - Lecture 40, Medicinal Chemistry of Muscaranic Antagonist & Neuromuscular Blockers

SLUDGEM Salivation, Lacrimation, urination, defecation, GI secretion/mortality, Emesis, Miosis or muscle spasm

Antispasmodics, anticholinergics, antimuscarinic, cholinergic blockers or parasympatholytics Side effects: Dry mouth, blurred vision, difficulty in urination

1st muscarinic antagonist, pKa 9.8 2 main uses: bradycardia an preoperative agent to reduce secretion before surgery Contraindicated in glaucoma used to decrease muscarinic cholinergic action in case of poisoning by organophosphate nerve agents and insecticides racemic mixture

greater ability to cross BBB than atropine, has an epoxide in ring allowing that only (-) form present pKa ~ 7.6

cannot enter BBB

can enter BBB

have quaternary ammonium functional group, not well absorbed from the GI tract. Primarily used in the treatment of ulcers, and other conditions in which a reduction in gastric secretion and reduced motility of the GI tract is desired

lipophilic agents derived from amino alcohols and ethers possessing 3 amine. readily cross the BBB and proven particularly beneficial in treatment of Parkinson’s disease

radio labeled QNB instrumental in development of muscarinic receptor labeling technique as well as discovery of subtypes of receptors used as incapacitating agent by military Physostigmine, which increases the conc of ACh in synapses and in neuromuscular junctions is antidote

exhibit high M1 subtype selectivity and reduce gastric acid secretion with fewer side effects than atropine and other less selective agents

selective for cardiac m2 receptors

skeletal neuromuscular blocking agents ganglionic blocking agents

1st block muscle which produce rapid movements, include muscle of face/eyes/neck muscle of limbs/chest/abdomen are affected next with diaphragm being affected last primary use as adjunct in general anesthesia

hypotension bronchospasm histamine-release membrane depolarization leading to muscle fasciculations (twitching) and cardiac disturbances

act by depolarizing the plasma membrane of skeletal muscle fiber, persistent depolarization makes the muscle fiber resistant to further stimulation by ACh

majority of clinically relevant blocks Act by blocking the binding of ACh to its receptors

anionic-binding sites, both of which had to be occupied for neuromuscular blocking effect

then metabolite is inactive. if one is chopped but one remains then it’ll still remain active

spontaneous but by reversing ester you prevents it from occurring

Metocurine 4 fold more potent

Mivacurium Chloride = shortest acting (double bond O different sides) Atracurium besylate = intermediate acting (Double bond O, ester same side) Doxacurium Chloride = longest acting