Cholingeric Pharmacology (Walworth) Flashcards
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.
Nicotinic:
- Succinylcholine (nicotinic agonist)
- less readily hydrolyzed than ACh
- prolongs channel openings -> MUSCLE RELAXATION - Nicotine
- Varenicline (Smoking cessation)
Muscarinic:
- Muscarine
- Bethanechol (post-operative ileus - malfunction of intestinal mobility) -> stimulant
- Pilocarpine (Sjogren’s syndrome - dry eyes, dry mouth) -> inc aqueous outflow
List therapeutically useful cholinoceptor antagonists.
Nicotinic:
- Ganglion blockers
- Neuromuscular blockers
Muscarinic:
- Atropine (pharmacology of the eye)
- Scopolamine (pharmacology of the eye)
- Tropicamide (pharmacology of the eye)
- Benztropine (parkinson’s)
- ipratropium (COPD)
- 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
botulinum toxin
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:
EDROPHONIUM
- Binds weakly and reversibly to anionic domain of AChE (limiting access to ACh)
Intermediate-acting reversible carbamate inhibitors of acetylcholinesterase:
NEOSTIGMINE
- 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:
- Organophsophate insecticides
- Chemical warfare agents
- acute intoxication b/c half life is so long
List therapeutic uses for cholinesterase inhibitors
Neostigmine/Pyridostigmine/ambenonium = MG
Demecarium/physostigmine: glaucoma
**physostigmine DOES cross BBB so used topically on the eye
Recognize major signs and symptoms of cholinergic excess
Muscarinic:
- CNS stimulation
- Miosis
- Reflex tachycardia
- Bronchoconstriction
- Excessive GI and GU smooth muscle activity
- Increased secretly activity (sweat, airway, GI, and lacrimal glands)
- Vasodilation
Nicotinic:
- CNS stimulation (convulsions) followed by depression
- NM end plate depolarization (fasciculations, then paralysis)
