The Cholinergic System Flashcards
List 3 ways in which you can enhance or mimic acetylcholine.
- Nicotinic receptor agonist
- Muscarinic receptor agonist
- Acetylcholinesterase inhibition
List 5 ways in which you can block or inhibit acetycholine.
- Nicotinic receptor antagonist
- Muscarinic receptor antagonist
- Inhibit choline uptake (hemicholinium)
- Inhibit vesicular storage (vesamicol)
- Inhibit acetylcholine relase (botulinum toxin)
What receptors exist at the target organ in the parasympathetic nervous system?
Muscarinic receptors
What receptors exist at the ganglia and skeletal muscle in the parasympathetic nervous system?
Nicotinic receptors
How does acetylcholine form?
Cholineacetyltransferase combines choline and acetyl CoA
Describe what happens in the parasympathetic nervous system once acetylcholine is formed.
- Acetylcholine is packaged into vesicles inside the presynaptic side of the neuron
- Once in the vesicle, impulse travels down a neuron and calcium flows in from the outside
- Vesicles fuse with exterior membrane and open to release acetylcholine into the synaptic space
- Acetylcholine acts on muscarinic receptors, target organs, or nicotinic receptors in the ganglia/skeletal muscle
What does acetylcholinesterase produce?
Choline and acetate
What can acetylcholinesterase-produced choline be used for?
Recycled for another biosynthesis event
What receptor type exists on the presynaptic terminal in the parasympathetic nervous system?
Muscarinic receptors (typical for GPCRs)
What role do muscarinic receptors on the presynaptic terminal play in the parasympathetic nervous system?
Serves as a feedback receptor (autoreceptor) to sense how much acetylcholine is in the synapse; if there is excess, it signals to shut off further release
How do M1, M3, and M5 signal?
Via intracellular Ca+ increase and PKC activity
Where are M1 receptors found?
- CNS
- Sympathetic postganglionic cells
- Presynaptic sites
Where are M3 receptors found?
- Smooth muscle
- Lungs
- Eyes
- Effector cell membranes
How do M2 and M4 signal?
Via cAMP decrease and reduced cAMP-dependent PK activity
Where are M2 receptors found?
- Myocardium
- Smooth muscle
- Presynaptic sites
- (K+ channel-linked = slow heart rate)
Where are M4 receptors found?
Central nervous system
What type of site does acetylcholine usually bind to?
Orthosteric sites
What type of site do muscarinic antagonists usally bind to?
Orthosteric sites; competes with acetylcholine (simple, competitive, and reversible)
What analogy can be used when describing binding to allosteric sites?
Dimmer switch; doesn’t shut down activity completely
List the 7 clinical uses of anticholinergics.
- Ocular exams
- Incontinence
- Irritable bowel syndrome
- Pre-operative anti-secretory
- COPD
- Motion sickness
- Parkinson’s
How are anticholinergics used to stimulate mydriasis (pupil dilation)?
Inhibit acetylcholine action on M3 in the pupillary constrictor muscle
How are anticholinergics used to induce cycloplegia (loss of function/regulation of lens thickness)?
Inhibit acetylcholine action on M3 in ciliary muscle
How are anticholinergics used to relax the bladder in order to treat incontinence?
- Via M3 antagonist, which mediates bladder contraction
What receptor indirectly inhibits bladder relaxation?
M2
How are anticholinergics used to treat irritable bowel syndrome?
- Anti-spasmodic agents: induce GI tract intestinal paralysis
- Reduce secretions (useful for ulcers)
How are anticholinergics used in pre-operative anti-secretory settings?
Used with inhalant anesthetics to reduce secretion accumulation
How are anticholinergics used to treat COPD?
- Reduce secretions
- Cause bronchial dilation (used in combination with β-adrenergic agonists)
How are anticholinergics used to treat Parkinson’s disease?
As an adjunct to L-DOPA
What do phenyltropanes consist of?
Phenyl ring + alkyl chain + tropane
Atropine
- Prototype phenyltropane
- Natural anticholinergic
- Antimuscarinic agent
What structural characteristics of anticholinergics helps them travel well and cross the membrane easier?
- Uncharged = lipophilic = crosses easier
- Tertiary amines: uncharged and travel well
Are charged molecules usually used locally or systemically?
Locally; charged molecules cannot travel
Describe the general mechansim of antimuscarinics.
Competitive and irreversible inhibition of muscarinic receptor activation by preventing acetylcholine binding
What two general structural classes do most antimuscarinics typically fall into?
- Tertiary amines (used in ocular and CNS)
- Quaternary amines (used in GI tract and peripheral applications)
Describe the selectivity of antimuscarinic, long-lasting tertiary amines.
M1/M2/M3 non-selective
What are antimuscarinic, long-lasting tertiary amines used to treat?
GI/urinary conditions, motion sickness (scopolamine), adjunct for Parkinson’s
Describe scopolamine’s relationship to the central nervous system.
- Scopolamine has higher CNS penetration
- Low doses = drowsiness
- High doses = hallucinations
What antimuscarinic, long-lasting tertiary amine is naturally occurring?
Jimsonweed: historically used as a hallucinogen; side effects include confusion, dilated pupils, and tachycardia
List two examples of antimuscarinic, long-lasting tertiary amines.
Atropine and scopolamine
List two examples of antimuscarinic, short-acting tertiary amines.
Homatropine and tropicamide
How are antimuscarinic, short-acting tertiary amines used?
In optical applications due to short duration of action (mydriasis and cycloplegia)
Compare homatropine and tropicamide.
Homatropine is less toxic, but tropicamide has a shorter duration of action
Explain the sedative activity of benztropine.
- Tertiary amine used to treat Parkinson’s
- Used as an adjunct therapy with L-DOPA to achieve better balance between dopaminergic and cholinergic neurotransmission
Describe how glycopyrrolate and propantheline bromide are used for GI disorders.
- Quaternary amines
- Used to treat GI spasms and peptic ulcers
- Charged N makes crossing the gut difficult
Explain how ipratropium is used to treat COPD.
- Quaternary amine
- M3 agonist: blocks acetylcholine-mediated constriction and opens the airways
- Less effective as a monotherapy, but enhances the effect of β-adrenergic agonists in COPD
Anticholinergic toxicity is largely ____________.
Dose-dependent
What is the mneumonic device used to describe a toxic dose of atropine?
- Red as a beef (flushed, scarlet skin)
- Dry as a bone (dry mouth and skin, thirst)
- Blind as a bat (blurred vision, obliterated irises)
- Hot as a firestone (hot skin)
- Mad as a hatter (hallucinations and delirium)
Describe nicontic receptors.
- Pentameric, ligand-gated ion channel
- Acetylcholine binds and allows Na+ to flow in and depolarize the neuron
- Located in parasympathetic and sympathetic postganglions (not a good target).
If you can block nicotinic receptors, you can ____________.
Paralyze skeletal muscle
How is skeletal muscle contraction triggered?
- Motor neurons in skeletal muscle come out of the spine
- Signal travels down the neuron and Ca+ enters
- Acetylcholine is released from vesicles into the motor endplate
- Nicotinic receptors are activated
- Na+ flows in and depolarizes the muscle, and triggers contraction
List 4 clinical uses for nicotinic receptor antagonists.
- Muscle relaxation during surgery
- Tracheal intubation (to relax pharyngeal and laryngeal muscles)
- Control of ventilation (reduces chest wall resistance)
- Treatment of convulsions (sometimes used to alleviate peripheral component of convulsions associated with status epilepticus or local anesthetic toxicity; no CNS effect since these drugs don’t penetrate the blood-brain barrier)
How do depolarizing competitive drugs work on nicotinic receptors?
- They bind the nicotinic receptor and keep it in an open state, resulting in a constant influx of Na+ and persistent depolarization
- Takes a long time to repolarize, and the receptor is unresponsive to new impulses at this time (think of a toilet flushing)
How do nondepolarizing competitive drugs act on nicotinic receptors?
They bind nicotinic receptors and keep them in a closed state, with no Na+ influx (act as competitive inhibitors by blocking acetylcholine access)
What is the only depolarizing competitive nicotinic receptor blocker?
Succinylcholine
Phase I
Depolarization phase
Phase II
Desensitization phase
List the 5 nondepolarizing neuromuscular nicotine receptor blockers.
- d-turbcurarine
- Pancuronium
- Atracurium
- Rocuronium
- Mivacurium
d-turbocurarine
- Used as an anesthesia adjunct to provide muscle relaxation during surgery
- Curare substituent: a Native American arrow poison
- Not orally active; given parenterally (usually IV)
- 30-60 minute duration of action
- Overdose managed by maintaining respiration, or reversed by acetylcholinesterase inhibitors (i.e. neostigmine)
Pancuronium
6x more potent than d-turbocurarine
Atracurium, rocuronium, and micacurium
- Used in surgery
- Rapid-acting neuromuscular blockers (1-2 minutes)
- High degree of flexibility in molecules
List the 4 direct-acting cholinergic receptor agonist esters.
- Acetylcholine
- Carbachol
- Methacholine
- Bethanechol
List the 3 direct-acting receptor agonist alkaloids and synthetic analogs.
- (+)-muscarine
- Pilocarpine
- Nicotine
Acetylcholine (+) + aspartic acid (-)
Ion pairing
Acetylcholine + aromatic amino acids
Pi-cation interaction
When does acetylcholine prefer the trans position?
Binding (especially in nicotinic receptors)
When does acetylcholine prefer the cis confomation?
in solution
Why is (+)-muscarine more potent than (-)-muscarine?
Because it has the same down hydrogen as muscarine
How does varenicline tartrate help with smoking cessation?
Partial agonist; blocks nicotine from binding and is well-tolerated
What are some side effects of varenicline tartrate?
- GI (nausea, constipation, gas, vomiting)
- Altered dreams
How many basic nitrogens does nicotine have?
2
Acetylcholine
- Receptor: M,N
- Cholinesterase sensitivity
- Intraocular use for miosis during surgery
Carbachol
- Receptor: M,N
- No cholinesterase sensitivity
- Intraocular use for miosis during surgery, glaucoma
Pilocarpine
- Receptor: M
- No cholinesterase sensitivity
- Glaucoma
Bethanechol
- Receptor: M
- No cholinesterase sensitivity
- Urinary retention, post-operative ileus
Varenicline
- Receptor: N
- No cholinesterase sensitivity
- Smoking cessation
