I’d Like to Buy the World an Acetyl-Cola Cholinomimetics

Autonomic Pharmacology 1. Parasymp Parasympathetics athetics 2. Sympath Sympathetics etics 1.1 – “I’d Like tto o Buy the W World orld an Acetyl Acetyl--Cola”: Ch Cholinomimetics olinomimetics • acetylcholine (ACh) is the primary signal molecule of parasympathetic nervous system (PNS). Cholinomimetic agents mimic effects of ACh by acting as ACh-receptor agonists or directly modifying ACh (Acetyl-cola mime = ACh mimetic). None of the cholinomimetics are especially specific, so when using clinically, monitor for negative effects. • There are two types of ACh receptors: o Nicotinic receptors (nAChR) (smoker) are ion channels (smoker has his eye on tv channel in storefront). Found in ANS ganglia (electric transformers connected wire-to-wire, like ganglia), NMJ endplate (outlet plate), & adrenal glands (beanie hat) ▪ ANS nerve typically synapse onto a ganglion before reaching target organs. The adrenal glands are an exception to this. o Muscarinic receptors (mAChR) (motorcycle parking spots) are found generally in autonomic effector tissues (heart, SM, some tissues, but not ANS ganglia). All are GPCRs (QIQ market for M1-M2-M3 inducers). In general, Muscarinic agents increase glandular secretion & smooth muscle activity. ▪ M1: Gq → IP3-DAG cascade (3 dogs) →↑intracellular Ca (dog has bone). Found in CNS & enteric nervous system (brain helmet) ▪ M2: Gi → ↓ intracellular cAMP (a rolled-up tent & packs with ↓↓arrows). Found in cardiac atria, SA & AV nodes (jacket with nodal jewels) →↓atrial contraction, ↓sinoatrial HR, ↓AV conduction velocity. Note that cardiac ventricles are controlled primarily by SNS, not PNS (cardiac jacket doesn’t show ventricles) ▪ M3: Gq → IP3-DAG cascade (3 dogs). Found in glands, including bladder & eye, & smooth muscles (SM) (glandular sponge & muscle-like paint job of 3rd biker). In healthy vasculature, IV M3 agonists stimulate NO release → ↑cGMP release →→ vasodilation; with atherosclerosis NO interacts directly with mAChR → vasoconstriction. Cholinomimet Cholinomimetic ic drugs • Bethanechol (Beth the construction worker). Primarily muscarinic. Indications: o Used in neurogenic ileus, non-obstructive GI dysmotility, & congenital megacolon (cement coming from colon spout), d/t stimulation of GI secretion & motor activity ▪ contraindicated in obstructive processes (“DO Not Obstruct” sign). o Used to treat urinary retention from non-obstructive urinary retention, e.g. post-operatively or spinal injury (bladdershaped hose) • Pilocarpine (pile of carp). Primarily muscarinic. Indications: o Used to treat dry mouth, e.g. from Sjogren’s, nerve damage, prescription adverse effects d/t ↑salivary excretion (seawater around carp looks like drool) o Glaucoma. Stimulation of mAChR reduces IOP by contraction of ciliary body → relaxation of zonula fibers → outflow of aqueous humor (SM crane with zonula-like net fibers). Ciliary contraction also results in lens accommodation (round glass floats on top of net) o Activations sphincter pupillary muscle → pupillary constriction → miosis (dock worker with hoodie cinched all the way up – looks like miotic eyeball). Used in acute closed angle glaucoma • Carbachol (person on upper story with drawn hoodie). Nicotinic & muscarinic activity (dude is standing above smoker & looking at cyclists) o Pupillary constriction, used in acute angle closure glaucoma • Methacholine o Contracts bronchiolar SM. Used in pharmacological asthma challenge (marathon challenge = methacholine challenge). Will exacerbate existing obstructive pulmonary processes, such as asthma & COPD (wheezing runner in back) • Varenicline. Nicotinic partial agonists. (1-800-VERY-CLEAN smoking cessation) o Used for smoking cessation • Common adverse effects o COPD, asthma exacerbation o Peptic ulcer exacerbation