Exam 1 Cholinergic Agents Flashcards
What are cholinergic agents?
parasympathetic mechanisms involving acetylcholine and their receptors (cholinergic receptors) and the neurotransmitter is acetylcholine (ACh)
What are the parasympathomimetic actions (agonists)?
- direct agonist → activates cholinoceptors
2. indirect agonist → stimulate acetylcholine release and inhibit acetylcholinesterase (AChE)
What are the parasympatholytic actions (antagonists)?
can be direct or indirect → many drugs exhibit anticholinergic side effects
What are the structural features of acetylcholine?
has an acetyl moiety and a choline group that is a quaternary amine so it has an intrinsic positive charge
What receptors does muscarine bind to?
it selectively binds to muscarinic receptors
What receptors does nicotine bind to?
it selectively binds to nicotinic receptors
What is the tissue distribution, responses, and mechanisms of Nm receptors (nicotinic muscular)?
tissue → skeletal muscle
response → motor end plate depolarization, contraction
mechanism → ligand gated opening of Na+/K+
What is the tissue distribution, response, and mechanism of Nn receptors (nicotinic neuronal)?
tissue → postganglionic & adrenal medulla
response → depolarization & catecholamine secretion
mechanism → ligand gated opening of Na+/K+
What is the tissue distribution, responses, and mechanisms of M1 receptors?
tissue distribution → postganglionic
response → depolarization
mechanism → Gq increase in PLC, IP3, DAG, Ca2+
What is the tissue distribution, responses, and mechanisms of M2 receptors?
tissue distribution → heart
response → inhibition
mechanism → Gi inhibition of adenylyl cyclase (cAMP), activation of K+ channels
What is the tissue distribution, responses, and mechanisms of M3 receptors?
tissue distribution → smooth muscles & exocrine glands & endothelium
response → contraction & secretion & relaxation
mechanism → Gq increase in PLC, IP3, DAG, Ca2+ && release of NO and increase in GC
What is the tissue distribution, responses, and mechanisms of M4 receptors?
tissue distribution → CNS
response → hyperpolarization
mechanism → Gi inhibition of adenylyl cyclase
What is the tissue distribution, responses, and mechanisms of M5 receptors?
tissue → CNS
response → depolarization
mechanism → Gq increase in PLC, IP3, DAG, Ca2+
What is the mnemonic to remember the mechanisms of M1, M2, and M3 receptors?
qiq (Kick) in which M1 is Gq, M2 is Gi, and M3 is Gq
What are some muscarinic agonist effects?
- heart → M2 activation leads to decrease in heart rate, conduction, and force (bradycardia)
- exocrine glands → M3 increase in secretion (lachrymal, tracheobronchial, salivary, digestive, sweat glands)
- smooth muscles → M3 increase in contraction (while M2 inhibits relaxation)
- sphincters → M3 relaxation
What are some CNS effects of muscarinic agonists?
- not all muscarinic agonists are able to access the CNS (because of the net charge)
- CNS effects mainly mediated by M1 receptors
- produces tremor, hypothermia, increased locomotor activity, improved cognition
What is the mechanism of acetylcholine neurotransmission?
- choline is transported into the presynaptic nerve terminal by a Na+ dependent choline transporter (CHT) → the transporter can be inhibited by hemicholinium (no current clinical use)
- acetylcholine is synthesized from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT)
- acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle associated transporter (VAT) → can be inhibited by vesamicol (no current clinical use)
- release of the transmitter occurs when an action potential opens voltage sensitive Ca2+ channels and increases the intracellular calcium → the fusion of vesicles with the surface membrane results in the release of acetylcholine → this step can be clocked by botulinum toxin (botox)
- acetylcholine binds to cholinoceptors on the postsynaptic cell
- acetylcholine’s action is terminated by metabolism by the enzyme acetylcholinesterase (AChE)
- autoreceptors and receptors on the presynaptic nerve ending modulate transmitter release
What are the two classifications of cholinergic agonists?
- direct acting (muscarinic receptor agonists)
2. indirect acting (potentiating ACh) → aka AChE inhibitors
What are examples of direct acting cholinergic agonists?
- choline esters → ACh, methacholine, carbachol, bethanechol
- alkaloids (natural products) → muscarine, pilocarpine
What are examples of indirect acting cholinergic agonists?
reversible → edrophonium, physostigmine, neostigmine
irreversible → organophosphates
What are the symptoms of fast mushroom poisoning?
PSNS → bradycardia, nausea, cramps, vomiting, diarrhea, bronchoconstriction, salivation, visual disturbances
SNS → sweating, hypotension (via uninnervated muscarinic receptors in blood vessel endothelium cells mediating vasodilation via NO)
How is the structure of methacholine different than acetylcholine?
methacholine has an additional methyl group on the beta carbon (introduces chirality!) → selectively reduces binding with nicotinic receptor and reduces hydrolysis by acetylcholinesterase → mimics (+) muscarine so it increases binding with muscarinic receptor
How is the structure of carbachol different than acetylcholine?
carbachol has no acetyl moiety since it is replaced by a carbamate group → makes the molecule less susceptible to esterases