Cholingeric Pharmacology (Walworth) Flashcards Preview

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Flashcards in Cholingeric Pharmacology (Walworth) Deck (12):
1

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)

2

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

3

List therapeutically useful cholinoceptor stimulants.

Nicotinic:
1. Succinylcholine (nicotinic agonist)
- less readily hydrolyzed than ACh
- prolongs channel openings -> MUSCLE RELAXATION

2. Nicotine
3. Varenicline (Smoking cessation)

Muscarinic:
1. Muscarine
2. Bethanechol (post-operative ileus - malfunction of intestinal mobility) -> stimulant
3. Pilocarpine (Sjogren's syndrome - dry eyes, dry mouth) -> inc aqueous outflow

4

List therapeutically useful cholinoceptor antagonists.

Nicotinic:
1. Ganglion blockers
2. Neuromuscular blockers

Muscarinic:
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)

5

Draw a schematic of the ANS and note the locations of the major types of autonomic receptors.

Refer to notes*

6

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)

7

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

8

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

9

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

10

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

11

List therapeutic uses for cholinesterase inhibitors

Neostigmine/Pyridostigmine/ambenonium = MG

Demecarium/physostigmine: glaucoma

**physostigmine DOES cross BBB so used topically on the eye

12

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)