Flashcards in Cholingeric Pharmacology (Walworth) Deck (12):
Differentiate the major types of cholinoceptors.
Nicotinic ACh receptors - ligand gated ion channel
- Nm: muscle type, endplate receptor
- Nn: neuronal type, ganglion receptor
Muscarinic ACh receptors - metabotropic receptor
- M1: CNS neurons, sympathetic postganglionic neurons (2ndary messenger: inc. IP3, inc. DAG, inc. intracellular Ca2+)
- M2: myocardium, smooth muscle (dissociated beta gamma subunits directly open potassium channels)
- M3: Exocrine glands, smooth muscle (2ndary messenger)
- M4: preferentially expressed in CNS (opens K+ channels)
- M5: predominant mAchR in neurons in VTA and substantia nigra (2ndary messenger)
Explain the difference between ligand-gated and metabotropic ion channels.
Ligand-gated - binding of ligand to receptor opens channel
Metabotropic - receptor itself is not the channel (ligand bound receptor couple with G proteins -> either mediate channel opening by association w/ G protein subunit or through the production of second messengers
List therapeutically useful cholinoceptor stimulants.
1. Succinylcholine (nicotinic agonist)
- less readily hydrolyzed than ACh
- prolongs channel openings -> MUSCLE RELAXATION
3. Varenicline (Smoking cessation)
2. Bethanechol (post-operative ileus - malfunction of intestinal mobility) -> stimulant
3. Pilocarpine (Sjogren's syndrome - dry eyes, dry mouth) -> inc aqueous outflow
List therapeutically useful cholinoceptor antagonists.
1. Ganglion blockers
2. Neuromuscular blockers
1. Atropine (pharmacology of the eye)
2. Scopolamine (pharmacology of the eye)
3. Tropicamide (pharmacology of the eye)
4. Benztropine (parkinson's)
5. ipratropium (COPD)
6. tolterodine (incontinence)
Draw a schematic of the ANS and note the locations of the major types of autonomic receptors.
Refer to notes*
Recognize therapeutically useful drugs that target cholinoceptors.
Bethanechol: muscarinic agonist for post-op ileus (CONSTIPATION)
Pilocarpine: muscarinic agonist for sjogren's syndrome (DRY MOUTH, DRY EYES)
Tropicamide: muscarinic antagonist producing mydriasis for eye exam (pupil dilation)
Ipratropium: muscarinic antagonist for COPD
Tolterodine: muscarinic antagonist for urge incontinence (URINARY RETENTION)
Describe the steps in synthesis, storage, release and termination of action of acetylcholine.
The opening of voltage mediated gates allow influx of calcium -> triggers fusion of vesicles (ACh) w/ plasma membrane
Exocytosis of vesicle contents delivers ACh to synaptic cleft
ACh binds to post synaptic cell to elicit a response
Action is terminated by Acetylcholinesterase which removes the acetyl group from the molecule and allows choline to be taken up once again by presynaptic cell
Distinguish between direct-acting cholinomimetics and indirect-acting agents.
Direct-acting cholinomimetics: mimic action of acetylcholinesterase (enzyme that catalyzes breakdown of ACh); DECREASE ACh levels
Indirect: elevate the levels of ACh by blocking the breakdown of the endogenous ACh; INCREASE ACh levels
Targets of pharmacological intervention:
hemicholiniums and vesamicols
Hemicholiniums - block uptake of choline into presynaptic cell
Vesamicols - prevent ACh entry into vesicles in presynaptic cell
botulinum toxin - blocks exocytosis of ACh -> induce muscle paralysis... used in treatment of spasms and dystonia
Describe the action of cholinesterase inhibitors
Short-acting reversible inhibitors of acetylcholinesterase:
- Binds weakly and reversibly to anionic domain of AChE (limiting access to ACh)
Intermediate-acting reversible carbamate inhibitors of acetylcholinesterase:
- duration of action determined by stability of enzyme-inhibitor complex, not by plasma half life
- goal is for endogenous ACh, when released into synaptic terminal, to persist and not be degraded so that it can bind to more receptors
Long-acting covalent, not readily reversible inhibitors of acetylcholinesterase:
-Chemical warfare agents
*acute intoxication b/c half life is so long
List therapeutic uses for cholinesterase inhibitors
Neostigmine/Pyridostigmine/ambenonium = MG
**physostigmine DOES cross BBB so used topically on the eye